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An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies

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An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies

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AN INDUSTRY SURVEY OF IMPLEMENTATION STRATEGIES FOR CLINICAL
SUPPLY CHAIN MANAGEMENT OF CELL AND GENE THERAPIES

by

Lequina Myles

A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE

May 2021

Copyright 2021 Lequina Myles

ii

Dedication

To my grandmother, the first person to teach me the value and importance of education, I
completed this dissertation in honor of you. To my family and friends, this is for us. To the “jack
of all passions,” visionaries, thrill-seekers, and life-long learners. To those who make the
impossible, possible. To the past, present, and future generations. To the underdogs, those with
massive hurdles, and feel that things are out of reach, I dedicate this research to you. Chase your
dreams and nightmares, stay ambitious, humble, focused, disciplined, and be fearless!

iii

Acknowledgements
I would first like to acknowledge my dissertation committee members: Dr. Terry David
Church, Dr. Francis Richmond, Dr. Nancy Pire-Smerkanich, and Dr. Greys Sosic. Thank you all
for believing in my research and taking the time to share your expertise and experiences with me.
You have all made me a much better researcher and writer, and I am humbled to have work with
you.
To my dissertation chair, Dr. Church, thank you for being you and pushing the envelope.
Thank you for the challenge and pushing me to deliver my best possible work. Thank you for
your open-mindedness and also for allowing me to think outside of the box, even in the moments
when the vision seemed unclear. I also appreciate your encouragement and continuous support
throughout this process.
To Dr. Richmond, words cannot express all of the wisdom I have obtained from working
with you. Every time I thought I was on the right path with this research (and got excited), you
quickly redirected me with a lot of red ink (lol). Thank you for your critique and also bringing
out the best in me as a writer and a researcher. Thank you for your patience, guidance, as well as
your passion for teaching and mentoring.
Dr. Smerkanich, I learned so much from all of your classes, thank you sharing your
experiences, industry stories, and lessons learned. Dr. Eunjoo Pacifici, thank you for sharing
your knowledge and cultural experiences with me. I will never forget all of our travels with the
cohort. Dr. Susan Bain, thank you for all the advice and guidance over the last couple of years.
Thank you to the Regulatory and Quality Sciences and USC Faculty and Staff for all the help
and support throughout my time as a student. Especially Kristen, Toni, and Debbie, you made
this a much easier process for me.

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I would like to give special thanks to those who participated in my focus group. I also
want to thank the participants that shared and responded to my survey, shared insights, and
provided advice. Thank you to my colleagues (industry, academic and professional), especially
those who have become friends. I truly value our new friendships, and your support was
invaluable through this process. I want to give special thanks to the DRSc 2018 Cohort. I am
truly grateful to be apart of the "cool kids." I have learned something from each of you. I
appreciate all of the moments (laughs and disagreements). Everyone has their strengths, and we
genuinely complement and represent one another. Thank you for sharing this journey with me.
Last but not least, my family and friends. We finally did it! Thank you for being patient
with me and always supporting my decisions even when you may not have understood the
journey. Thank you for being my biggest cheerleaders, a voice of reason, reading my research,
listening to me vent and talk about school (sorry, lol), a pulse check when I veered off the path,
and motivation when I became discouraged. To my late grandmother, who instilled the
importance of education, and no excuses, you can rest now. I know I took a few unexpected and
expected detours, but I have my doctorate, and I delivered on my promise. Thank you for raising
me to never give up and be resilient. It is because of you, I am the woman I am today. I will
continue the strive big, carry the torch, and finish what you started.
This dissertation and research journey has been nothing like any other academic and
personal development experience. There are so many people that I have come in contact with and
could thank along the way. I am appreciative to those who continuously supported me and rooted
for me during this journey, even if it was just "How is the program going?”, "Are you finished
yet?” followed by a "You are still in school?" I am finished with this milestone, and this is indeed
a celebration that I am happy to share with you all.

v

TABLE OF CONTENTS
Dedication ....................................................................................................................................... ii
Acknowledgements ........................................................................................................................ iii
List of Tables ............................................................................................................................... viii
List of Figures ..................................................................................................................................x
Abstract .......................................................................................................................................... xi
Chapter 1. Overview ........................................................................................................................1
1.1 Introduction ................................................................................................................. 1
1.2 Statement of the Problem ............................................................................................ 4
1.3 Purpose of the Study ................................................................................................... 6
1.4 Importance of the Study .............................................................................................. 7
1.5 Delimitations, Limitations, Assumptions .................................................................... 8
1.5.1 Delimitations ................................................................................................. 8
1.5.2 Limitations ..................................................................................................... 9
1.5.3 Assumptions .................................................................................................. 9
1.6 Organization of Dissertation ..................................................................................... 10
1.7 Definitions and Acronyms ........................................................................................ 11
Chapter 2. Literature Review .........................................................................................................18
2.1 Background to the Literature Review ....................................................................... 18
2.2 Introduction ............................................................................................................... 21
2.3 History of Biologics and Biologics Regulation in the US ........................................ 34
2.3.1 Evolution of Cell and Gene Therapies ......................................................... 36
2.3.1.1 Mechanism of Action and Regulatory Classification of CGTs ...... 37
2.3.2 Challenges and Special Considerations for Cell and Gene Therapies ......... 39
2.3.2.1 Expedited Pathways and their Implications for Clinical
Development ................................................................................... 41
2.3.2.2 Chemical Manufacturing and Controls (CMC) .............................. 44
2.4 Evolution of Clinical Supply Chain Management .................................................... 49
2.4.1 Challenges with Supply Chain Management for CGTs ............................... 58
2.4.1.1 Cold Chain Management ................................................................ 58
2.4.1.2 Vendor Management ...................................................................... 62
2.4.1.3 Globalization of Clinical Trials ...................................................... 65
2.4.2 Regulatory Landscape for Clinical Trial Distribution of Advanced
Therapies ..................................................................................................... 67
2.4.2.1 External Regulatory Considerations ............................................... 70
2.4.2.2 Internal Regulatory Considerations ................................................ 77
2.5 Current Trends and Industry Views on Clinical Trial Distribution .......................... 82

vi

2.5.1 Industry Perspectives on Supply Chain Management of CGTs .................. 89
2.6 Research Approaches and Framework ...................................................................... 93
2.6.1 Implementation Framework......................................................................... 94
Chapter 3. Methodology ................................................................................................................97
3.1 Introduction ............................................................................................................... 97
3.2 Identification of Study Respondents ......................................................................... 97
3.3 Survey Development and Focus Group .................................................................... 98
3.4 Survey Deployment................................................................................................. 102
3.5 Survey Analysis ...................................................................................................... 103
Chapter 4. Results ........................................................................................................................106
4.1 Survey Participation ................................................................................................ 106
4.2 Demographic Profile of Respondents ..................................................................... 106
4.3 Exploration .............................................................................................................. 114
4.4 Installation ............................................................................................................... 125
4.5 Initial Implementation ............................................................................................. 133
4.6 Full Implementation ................................................................................................ 138
4.7 Sustainability ........................................................................................................... 148
4.8 Analysis of Text-based Responses .......................................................................... 156
4.8.1 Stakeholder Engagement ........................................................................... 157
4.8.2 Resources ................................................................................................... 159
4.8.3 Planning and Forecasting ........................................................................... 160
4.8.4 Material Management ................................................................................ 161
4.8.5 Supplier Management ................................................................................ 161
4.8.6 Data and Documentation ........................................................................... 162
4.8.7 Global and Regulatory Considerations ...................................................... 163
Chapter 5. Discussion ..................................................................................................................165
5.1 Introduction ............................................................................................................. 165
5.2 Methodological Considerations .............................................................................. 165
5.2.1 Delimitations ............................................................................................. 165
5.2.2 Limitations ................................................................................................. 168
5.2.3 Consideration of the Results ...................................................................... 170
5.2.4 Exploration ................................................................................................ 171
5.2.5 Installation ................................................................................................. 173
5.2.6 Initial Implementation ............................................................................... 176
5.2.7 Full Implementation .................................................................................. 180
5.2.7.1 Expertise in CGTs and Clinical Supply Chain Management ........ 181
5.2.7.2 Limited Funding and Resources ................................................... 182
5.2.7.3 Logistics and Transportation Management ................................... 183
5.2.7.4 Regulations ................................................................................... 184

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5.2.7.5 Global Considerations and Constraints in SCM ........................... 186
5.2.7.6 Stakeholder Engagement and Expectations .................................. 187
5.2.7.7 Vendor and Material Management ............................................... 188
5.2.8 Sustainability ............................................................................................. 189
5.2.8.1 Managing Supply Chain “outside” the GXP Ecosystem ............. 191
5.3 Conclusion and Recommendations ......................................................................... 192
5.4 Future Research....................................................................................................... 195
References ....................................................................................................................................197
Appendix A. Definitions and Acronyms .....................................................................................253
Appendix B. Survey Questions ....................................................................................................266
Appendix C. Survey Data Set ......................................................................................................292
Appendix D. Cross Tabulations ...................................................................................................334

viii

List of Tables
Table 1 List of Key Terms and Acronyms.........................................................................11
Table 2 Select Key Term Searches from Citation Search Engines ....................................19
Table 3 Comparison of Monoclonal Antibodies to Autologous Cell Therapies ...............40
Table 4 Regulatory Oversight and Considerations for Clinical Trial Distribution ............68
Table 5 Survey Categories Informed by Implementation Framework ..............................99
Table 6 Focus Group Participants ....................................................................................100
Table 7 Groupings to Cross-tabulate Responses against Company Size .........................108
Table 8 Cross-Tabulation: Industry versus Size of the Company ...................................109
Table 9 Exploration Assessment of Clinical Supply Chain .............................................117
Table 10 Preparedness for Exploration of Supply Chain versus Size of Company.........119
Table 11 Outsourcing Percentage versus Company Size ................................................122
Table 12 Outsourcing of Supply Chain Activities versus Company Size .......................123
Table 13 Open Responses - Supplier Qualification and Onboarding ..............................129
Table 14 Factors Considered when Selecting Suppliers - Part A ....................................130
Table 15 Factors Considered when Selecting Suppliers - Part B ....................................132
Table 16 Supply Chain Concerns when Outsourcing ......................................................133
Table 17 Regulatory Implementation Challenges ............................................................138
Table 18 Retrospective Review of Implementation of Supply Chain Management .......140
Table 19 Views on Medical Product and Supply Chain Regulations ..............................142
Table 20 Supporting Views on GDP Implementation .....................................................143
Table 21 Opposing Views on GDP Implementation .......................................................143
Table 22 Views on Medical Product and Supply Chain Standards .................................144
Table 23 Scale-up Preparation from Clinical to Commercial Phases ..............................151
Table 24 Commercial Upscaling versus Company Size ..................................................152
Table 25 COVID -19 Preparedness - Positive Feedback .................................................153
Table 26 COVID-19 Preparedness - Negative Feedback ................................................154
Table 27 COVID-19 Preparedness versus Company Size ...............................................155
Table 28 Lessons Learned from COVID-19 ....................................................................156
Table 29 Lessons Learned: Stakeholder Engagement .....................................................158
Table 30 Lessons Learned: Resources .............................................................................159
Table 31 Lessons Learned: Planning ...............................................................................160
Table 32 Lessons Learned: Material Management ..........................................................161
Table 33 Lessons Learned: Feedback on Supplier Management .....................................162
Table 34 Lessons Learned: Data and Documentation .....................................................163
Table 35 Lessons Learned: Global Considerations .........................................................164
Table 36 Full Definitions and Acronyms.........................................................................253
Table 37 Years of Experience with CGTs versus Company Role ...................................334

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Table 38 Cross-Tabulation Grouping for Company Size ................................................334
Table 39 Industry Designation versus Size of the Company ...........................................335
Table 40 Preparedness for Exploration of Supply Chain versus Size of Company.........336
Table 41 Supply Chain Challenges versus Company Size - Part A ................................337
Table 42 Supply Chain Challenges versus Company Size - Part B .................................338
Table 43 Outsourcing Percentage versus Company Size ................................................339
Table 44 Outsourcing of Supply Chain Activities versus Company Size .......................340
Table 45 COVID-19 Preparedness versus Company Size ...............................................340
Table 46 Commercial Upscaling versus Company Size ..................................................341
Table 47 Ease of Automation versus Company Size .......................................................341
Table 48 Strategic Partnerships versus Company Size ....................................................342
Table 49 Implementation of Industry Standard versus Company Size............................342
Table 50 Physical Infrastructures versus Company Size .................................................343
Table 51 Implementation of IT / Blockchain versus Company Size ...............................343
Table 52 Vendor Management Programs by Company Size ...........................................344
Table 53 Logistics by Design (LbD) versus Company Size ............................................344
Table 54 Distribution Models versus Company Size – Part A ........................................345
Table 55 Distribution Models versus Company Size – Part B ........................................346
Table 56 Regulatory Views on GDP: Industry Stakeholders ..........................................347
Table 57 GDP Enforcement Viewpoints by Department ................................................347
Table 58 Regulatory Competencies by Industry – Part A ...............................................348
Table 59 Regulatory Competencies by Industry – Part B................................................349

x

List of Figures
Figure 1 Global Clinical Trial Landscape for Cell and Gene Therapies ...........................23
Figure 2 Disease Indications for Cell and Gene Therapies................................................25
Figure 3 Clinical and Commercial Supply Chain Models - Part A ...................................29
Figure 4 Clinical and Commercial Supply Chain Models - Part B....................................30
Figure 5 Dendreon’s Provenge Manufacturing Cycle .......................................................32
Figure 6 Traditional vs Breakthrough Clinical Pathway ...................................................43
Figure 7 Autologous CAR-T Manufacturing Process Flow ..............................................48
Figure 8 Evolution of Clinical Supply Chain ....................................................................51
Figure 9 Pharmaceutical Drug Distribution Pathway ........................................................52
Figure 10 High Level Clinical Trial Distribution Process Flow ........................................53
Figure 11 Autologous CGT Manufacturing Supply Chain Pathways ...............................55
Figure 12 Clinical Trial Distribution Cycle and CAR-T Manufacturing Cycle ................56
Figure 13 External Regulatory Considerations for Clinical Trial Distribution .................69
Figure 14 Internal Regulatory Considerations for Clinical Trial Distribution ..................78
Figure 15 Fixsen’s Implementation Model ........................................................................95
Figure 16 Distribution of Respondents Amongst Companies of Different Types..........107
Figure 17 Distribution of Respondents in Companies of Different Sizes .......................108
Figure 18 Primary Job Function of Respondents .............................................................110
Figure 19 Number of Years of Experience with Cell and Gene Therapies .....................111
Figure 20 Roles and Responsibilities of Respondents .....................................................112
Figure 21 Medical Product Modalities ............................................................................113
Figure 22 Geographies in which Supply Chains Operate ................................................114
Figure 23 Views on Supply Chain and Distribution Planning .........................................116
Figure 24 Outsourcing Activities .....................................................................................120
Figure 25 Percentage of Outsourcing Supply Chain and Distribution ............................121
Figure 26 Alternative Distribution Models ......................................................................125
Figure 27 Onboarding of Supply Chain Vendors ............................................................126
Figure 28 Supplier Quality Techniques ...........................................................................127
Figure 29 Familiarity with Medical Product and Transportation Regulations ................135
Figure 30 Operational Supply Chain Challenges.............................................................137
Figure 31 Knowledge Gap for CGTs and Transportation ...............................................146
Figure 32 Views on Vendor Management Partnerships ..................................................147
Figure 33 Implementation Views from Industry Stakeholders ........................................149

xi

Abstract
Cell and Gene Therapies (CGTs) are technologically sophisticated approaches
that use fragile living organisms, which present challenges for transport and distribution.
These challenges are heightened during the early stages of clinical development. The
present survey-based research examines industry views and impediments associated with
clinical supply chain management. An implementation framework was used to scope and
structure the survey. Participants included 75 mid-level to senior-level professionals in
biopharmaceutical companies and supporting industries such as contract research
organizations and third-party supply chain vendors. Results suggested a number of
challenges, ranging from regulatory dissonance and insufficient regulatory guidance
across different geographic regions to problems stemming from limited resources, vendor
management, high costs, and logistical complexities in the supply chain. Less than half
had business continuity plans in place. Challenges were more pronounced amongst
smaller and mid-size organizations. Initiatives to address these impediments appear to be
directed at improving industry partnerships and creating global standards for CGT
transportation. However, gaps still exist in regulatory knowledge and guidance related to
the special needs of CGTs. Most participants more commonly supported the adoption and
enforcement of Good Distribution Practices (GDPs) in the US (81%). Results suggest
that regulatory harmonization and logistical method development would be important
areas of focus to assure agile systems and robust processes from the loading dock to the
patient.

1

Chapter 1. Overview
1.1 Introduction
Fifty years ago, cures for chronic illnesses such as cancer, Crohn’s disease, or
sickle cell anemia were unimaginable and only attainable through the artful fiction of a
Hollywood film. Today, however, a cure is a reality for many patients through the
development of precision medicine and advanced technologies such as cell and gene
therapies. Between 1989 and 2019, approximately 4,000 cell and gene trials were
conducted worldwide, leading to the approval of more than 20 approvals globally (Hanna
et al., 2016; Hanna et al., 2017; Gerlovin and Diesel, 2018; Shahryari et al., 2019; ARM,
2019; ARM, 2020a; ARM, 2020b; ARM, 2020c). Based on an assessment of the current
industry pipeline and clinical success rates, the Food and Drug Administration (FDA)
predicts that marketing approvals for cell and gene therapies will increase by up to 900
percent by 2025, over the seven commercialized cell and gene-based therapy products
now available in the United States (US)
1
. At this rate, the agency expects to approve 10 to
20 cell and gene therapies annually (Wechsler, 2016; ARM, 2019; ARM, 2020a; ARM,
2020b; ARM, 2020c; Cross, 2019; FDA, 2019f; FDA, 2020d; FDA, 2021; Sagonowsky,
2021).
The FDA defines cell and gene therapies (CGTs) as follows:

Cellular therapy products include cellular immunotherapies, cancer vaccines,
and other types of both autologous and allogeneic cells for specific
therapeutic indications, including hematopoietic stem cells and adult and
consideration embryonic stem cells (FDA, 2019i, para 2).

Human gene therapy seeks to modify or manipulate the expression of a gene
or to alter the biological properties of living cells for therapeutic use (FDA,
2019i, para 2).

1
US FDA cell and gene therapy approvals as of 05-Feb-2021

2

They fall under the category of precision medicine, which is defined as:

…an emerging approach for disease treatment and prevention that takes into
account individual variability in genes, environment, and lifestyle for each
person. This approach will allow doctors and researchers to predict more
accurately which treatment and prevention strategies for a particular disease
will work in which groups of people. It is in contrast to a one-size-fits-all
approach, in which disease treatment and prevention strategies are developed
for the average person, with less consideration for the differences between
individuals (NIH, 2019, para 1).
As the biopharmaceutical industry shifts from shelf-stable synthetic drugs to more
fragile CGTs, the process, management, and execution of transporting medicines to the
patient become more challenging. Clinical trial distribution (CTD), the end-to-end
clinical supply chain of investigational medicinal products (IMPs), is the term used to
describe the movement of CGTs to patients needing access to innovative therapies
globally (FDA, 2018d; ICH, 2015). CTD entails: (1) the physical transport of all
materials (IMPs, biological samples, and clinical supplies such as kits); and (2) the
transfer of data and documentation during the clinical trial. Although this transfer of
material and information along the supply chain is often perceived to be straightforward,
adjustments are needed in manufacturing and distribution to facilitate the entry of CGTs
into the clinical trial landscape. Biologics such as CGTs are created from human cells or
proteins, which are unstable when taken from their natural environment and cannot be
easily characterized or predicted. As a result, CGTs can become immunogenic and
degradable, so they must be carefully protected from uncontrolled transport, storage, and
handling conditions. CGTs also have demanding time and temperature constraints, which
can influence their safety, efficacy, and effectiveness. Thus, supply chain management
(SCM) has become an integral part of the clinical trial process by ensuring that
medications are provided to the patient in a safe, effective, and unadulterated condition.

3

Supply chain management for clinical trials is a relatively new area of focus for
most pharmaceutical manufacturers and regulators. Historically, it was treated as an
afterthought and often planned during the post-market management of the product's
lifecycle (EMA, 2018c; PMDA, 2019; Health Canada, 2019). However, the logistical
management of CGTs is particularly important not only because the products themselves
are unstable, but also because they are being introduced into a clinical trial environment
where trials are extraordinarily complex, unpredictable, and increasingly multinational.
Personnel responsible for the clinical supply chain often must deal with the challenges
posed by long distances, harsh environmental conditions, and burdensome regulations to
meet the specific needs of different countries or regions (EMA, 2018c; PMDA, 2019;
Health Canada, 2019). These constraints often increase resource demands and the costs of
product development. Moreover, these limitations introduce risks and hurdles that were
not considered in past years.
Currently, the distribution of CGTs can face regulatory impediments. Although
many regulations, such as Good Clinical Practices (GCPs) and Good Manufacturing
Practices (GMPs), are in place with respect to the conduct of clinical trials, much
ambiguity surrounds the best ways to distribute and transport test articles because rules
governing these activities are dissonant globally. In the early 1990s, Good Distribution
Practices (GDPs) were established to safeguard the medicinal supply chain from
counterfeits, adulterated drugs, and diverted products that could mislead and harm
consumers. These guidelines describe the minimum requirements that distributors must
meet to ensure the quality and integrity of medicines throughout the supply chain. The
objectives of GDPs are to protect patient safety and ensure medical products are stored,

4

transported, and handled within the product specifications (92/25/EEC; European
Commission, 1992).
Regulators enforce requirements for GDPs in many constituencies, such as the
European Union and many individual countries, such as China and Brazil, in which
medical products are frequently marketed (EMA, 2018c; ANVISA, 2019; NMPA, 2020).
Compliance with GDPs is currently not required in the US. However, the supply chain is
regulated through many regulatory agencies, including the Food and Drug Administration
(FDA), the Department of Transportation (DOT), and US Customs and Border Protection
(CBP). Thus, the overlapping requirements become GDP-like, and can be challenging for
products that may be infectious, pathogenic, and pose a threat to public health.
Requirements are particularly problematic for new drug and device technologies, such as
chimeric antigen receptor T cell (CAR-T) therapies, that are derived from the live cells of
patients. These types of products have short lifespans and demand efficient supply chain
management to ensure that they are developed and manufactured successfully. Their
transport and distribution leave significantly less room for error than would be normally
seen when working with shelf-stable and well-characterized drugs.
1.2 Statement of the Problem
The Food Drug and Cosmetic Act (FD&CA) of 1938 has been amended multiple
times to establish quality standards for food, drugs, medical devices, and cosmetics
manufactured and sold in the US. With respect to medical product manufacturing, Good
Manufacturing Practices (GMPs) are the minimally established requirements for the
industry. However, GMP requirements generally stop at the sponsors' loading dock.
Historically, there has been little equivalent regulatory guidance to assure that

5

manufacturers maintain product integrity, safety, and efficacy along the supply chain.
Nevertheless, regulators, clinicians, manufacturers, and distributors have a responsibility
to protect medicinal products from threats in the supply chain that compromise patient
safety and public health. This is, in part, accomplished by ensuring that standards are
developed, and laws and regulations are followed to prevent product failures such as
contamination, deterioration, and counterfeiting (Kramer et al., 2012).
Although regulations, established practices, and guidelines exist to direct
practitioners in clinical supply chain management, much of the information contained in
those materials relates to finished pharmaceutical products. These commercialized
products undergo a rigorous approval process to ensure safety and efficacy. In contrast,
much less attention has been paid to investigational medicinal products whose safety and
efficacy profiles are typically less well-characterized (USP, 2016; FDA, 2018d; ICH,
2015). Uncertainty and risks increase further for fragile advanced therapies such as
CGTs. We know that CGTs must adhere to strict requirements for temperature controls,
storage conditions, and shipping timelines to be safe and effective. However, we do not
know whether the current practices that underlie these operations are considered effective
and sustainable long-term. This gap in clinical SCM has been identified previously by the
pharmaceutical industry (Carrico, 2016; ASHP, 2017). In 2016, United States
Pharmacopeia (USP), a non-profit that set standards for healthcare products in the US,
proposed a new chapter, Storage and Transportation of Investigational Drug Products
(IDPs), as an addition to the USP 1079, Good Storage and Distribution Practices for
Drug Products, to focus on considerations for investigational drug products (ECA
Academy, 2016; USP, 2016b; Johnson, 2016; Carrico, 2016; USP, 2020).

6

As the interests of the logistics, biopharmaceutical, and healthcare industries start
to converge at the point of clinical trial distribution, the best practices and regulations for
safety and efficacy of IMPs have become blurred. Best practices are currently
underdeveloped, inconsistent, and still evolving for CGTs (Bell, 2018; Elverum and
Whitman, 2019; Lambert and Lehmicke, 2020). Moreover, the current US regulations for
clinical trial management and distribution, more specifically, Good Clinical Practices, E6
(R2) and Good Manufacturing Practices, 21 CFR 211, Subpart H, Holding and
Distribution, do not provide regulatory guidance on alternative distribution models such
as direct-to-patient (DTP) (FDA, 2018d; Sadler-Williams et al., 2019; FDA, 2020a; FDA,
2020b). We know that the ways that clinical trial products are distributed are affected by
changing practices and regulations. What we do not know is how biopharmaceutical
companies are managing their distribution of CGTs from an operational and regulatory
standpoint. We also do not know what challenges have obstructed the implementation of
their clinical supply chain strategies and if the current practices to this point have proven
themselves to be feasible and sustainable long-term for CGTs.
1.3 Purpose of the Study
The research described here aims to: (1) evaluate the current and best practices for
clinical supply management of CGTs throughout the product lifecycle; (2) identify
challenges that hinder the execution of clinical supply chain management; and (3)
evaluate the adequacy of the regulatory systems related to the clinical trial distribution of
CGTs from the perspective of industry stakeholders. A novel survey was developed and
distributed to mid-level and senior-level career practitioners in the biopharmaceutical and
life science supply chain industry who are best able to identify current and best practices

7

to achieve a robust supply chain model for CGTs. The survey was validated through a
focus group with industry experts who have experiences with drug development,
manufacturing, and clinical trial management of biologics such as CGTs. The survey was
disseminated using an electronic distribution and analysis tool, Qualtrics (Qualtrics.com).
1.4 Importance of the Study
The novelty and complexity of cell and gene therapies pose challenges from a
regulatory perspective. Currently, regulations and guidance documents are retrospective;
they are built on emerging science and the experience of early medical products. Thus,
the industry is only beginning to recognize the unique requirements associated with
CGTs. The management of these treatments often involves learning through trial and
error as products evolve through the clinical trial phases. Understanding current and best
practices gleaned from the industry as it gains experience in this newly emerging field
can provide an essential baseline for defining the risks and planning the regulatory
oversight needed to keep these products safe in the future.
This study provides insight into logistical considerations for domestic,
international, and multi-regional trials. By comparing the current practices with the
information obtained from the industry sector, policymakers will have more systematic
insight regarding the current CGT distribution environment. These results may improve
gap analyses to determine which, if any, barriers need to be addressed to provide an
effective system to move products from the laboratory or manufacturing floor to the
patient, a route that has been labeled as the “science to services gap” (Hershenberg,
2012). Additionally, the study could provide insight into clinical trial hurdles for
organizations that must allocate appropriate resources needed for commercial scale-up.

8

This research may serve as a foundation for future research into clinical supply chain
management, regulatory strategy, and medical product development.
1.5 Delimitations, Limitations, Assumptions
1.5.1 Delimitations
This research was delimited to sponsors, manufacturers, distributors, and
biopharmaceutical partners including contract research organizations (CRO), contract
manufacturing organizations (CMO) or specialty service providers such as clinical supply
chain organizations (CSCOs) in the medical product industry. It was delimited further to
respondents who have mid-level to senior-level experience with biologics such as CGTs,
related to the distribution, manufacturing, and commercial development of test products
either domestically, within the US, or internationally. The target respondents had
expertise spanning quality, regulatory, supply chain, and manufacturing sectors. Not
explored in this study were experiences with small-molecule drugs and well-
characterized biologics approved for clinical trials or market registration by the Center
for Drug Evaluation and Research (CDER) by way of a New Drug Application (NDA).
For the purpose of this research, the evaluation of current transportation and medical
product regulations was delimited to federal regulations in the US.
This research is delimited in time, space, and scope. The captured data represents
a snapshot of the policies, practices, and beliefs related to CGTs utilized in clinical trial
development in a timeframe within the last ten years (2010 - 2020). Because this study is
not designed to predict distributional activities associated with the clinical study of CGTs
prospectively, it is not able to predict trends related to some therapies that may arise in

9

future unless the decision is made later to reevaluate the same group of responding
organizations using a similar survey to this.
1.5.2 Limitations
There were limitations associated with this study related to the sample size of the
respondents and the scope of the research. Experts experienced in both clinical trials and
test-article distribution are relatively rare. The pool of respondents was smaller when
considering those with expertise in the fields of cell and gene therapies and precision
medicine. As a result, identifying respondents available to complete the survey was a
challenge, and resulted in a small survey sample. Additionally, busy professionals can be
reluctant to spend a long time completing a survey. Therefore, the survey was restricted
in length to 35 questions to prevent survey fatigue. However, this restriction limited the
depth of the survey content. Even with a relatively short survey, the response rate
appeared relatively low. This was attributed in part to the fact that busy respondents are
often unwilling to spend time to complete the survey. Some respondents may also have
concerns about the proprietary nature of their activities and may be hesitant to answer
survey questions related to their organizational knowledge and experiences. Moreover,
the validity of the survey could be affected if respondents have only limited areas of
knowledge related to the subject of this research, and thus cannot answer the questions
adequately.
1.5.3 Assumptions
A central assumption of this dissertation is that the literature reviewed is adequate
to support analyses and discussions related to the findings of the research. It is also

10

assumed that respondents were knowledgeable and would answer survey questions
truthfully and provide their honest opinions, experience, and expertise.
1.6 Organization of Dissertation
This dissertation consists of five chapters:
Chapter 1 introduces the current challenges related to clinical trial management
and distribution of the cell and gene therapies, as well as provides the rationale for the
study presented herein.
Chapter 2 discusses the literature review findings. This section includes a history
of cell and gene therapies, clinical supply chain management, and introduces the research
framework used in this study.
Chapter 3 defines the study research methods, including the development of the
survey, focus group, target respondent populations, and data collection.
Chapter 4 presents the results of the study, specifically the survey outcomes.
Chapter 5 provides an analysis and discussion of the research results, including,
but not limited to, conclusions, recommendations, and a proposed implementation plan.
Appendices to this dissertation include full table of definitions and acronyms
(Appendix A. Definitions and Acronyms), survey (Appendix B. Survey Questions),
tabulation of results from the survey (Appendix C. Survey Data Set), and cross-tabulation
results (Appendix D. Cross Tabulations).

11

1.7 Definitions and Acronyms
Table 1 List of Key Terms and Acronyms
Key Terms/Acronyms Definition
3PL Third-Party Logistics
Ancillary Materials Ancillary materials (AM) are components used during the
manufacturing process of cell therapy products. However,
these materials are not intended to be part of the final
products. These products can include, but are not limited
to reagents, infusion bags, tubing, delivery-devices,
equipment, and instructions for use (USP, 2008). AMs
are most often shipped with cell and gene therapies.
ATMP Advanced Therapies Medicinal Products (ATMPs) are
medicines for human use that are based on genes, tissues,
or cells. Gene therapy, somatic-cell therapy, and tissue-
engineered, as well as some medical devices (which are
combined ATMPs), fall under the ATMP category within
the European Medicines Agency (EMA, 2019).
Blockchain A distributed digital ledger that is managed by a peer-to-
peer network of computers, rather than a single entity.
Data is added to the network in a time-stamped and
immutable fashion. Each data point is recorded as a
"block" of information. Blocks are secured based on
cryptographic principles and guidelines. After validation
through a consensus of the peer-to-peer network, each
block is cryptographically linked to the previous one
(creating a chain). As new blocks are added, older blocks
cannot be modified without consensus, which makes the
system tamper-resistant (Benchoufi and Ravaud, 2017;
Clauson et al., 2018; Reiff, 2020).
Blinding A method in clinical trial design in which one or more
parties in the trial (the site, sponsor, or the patient) is
unaware of the treatment assignments for the study. In a
single-blinded study, usually, the patients are unaware of
the treatment assignments. In a double-blinded study,
both the patients and the investigators are unaware of the
treatment assignments. In a double-blinded study, at
times, the monitors are unaware of the assignments.
Blinded studies are conducted to prevent the
unintentional biases that can compromise study data
when treatment assignments are known (ICH, 2015;
FDA, 2018d).

12

Key Terms/Acronyms Definition
CAR-T Therapy CAR-T cell stands for chimeric antigen receptor T cell
therapy. CAR-T is a method used to modify a patient's
immune cells (T cells). In CAR-T, the T cells are
modified to add a receptor on their surface of the cell,
which can recognize structures (antigens) on the surface
of malignant cells. Once the receptor binds to a tumor
antigen, the T cell is stimulated to attack and kill the
cancerous cells (Gilead, 2017; Celgene, 2019; Novartis,
2019c; Yescarta, 2019).
CCM Cold Chain Management (CCM) is the system used for
distributing and storing medical products within an
acceptable range until it reaches the user. CCM can
include various temperature ranges and is typically used
for biologics and other temperature-sensitive medical
products.
CFR Code of Federal Regulations
Cell and Gene Therapy Cell and Gene therapies are medical interventions in
which both cell and gene therapies are utilized in
combination to treat various genetic diseases.

Cell Therapy Cell therapy is the transfer of live cells into a patient to
cure or treat a disease. The cells used in cell therapy may
originate from the patient (autologous cells) or a qualified
donor (allogeneic cells). Cell therapies can be defined as
the infusion or transplantation of whole cells into a
patient for the treatment of a disease (ASGCT, 2019b).
CGTs (or GCTs) Cell and Gene Therapies
Clinical Trial(s) A clinical study involves research using human
volunteers. The trial intends to add to medical
knowledge. The clinical trial participants receive specific
interventions according to the research plan or protocol
created by the investigators (ICH, 2015; FDA, 2018d).
CMC Chemistry, Manufacturing, and Controls
CMO Contract Manufacturing Organization
CMS Continuous Monitoring Systems (CMS). Technologies
and devices that can track shipment information such as
temperature, location, vibrations, light, and shock.

13

Key Terms/Acronyms Definition
COC Chain of custody (COC) is the permanent capture of data
related to all parties that handled the product. COC
includes what actions were performed, and the
location/date/time of the actions from the start of
tissue/cell collection through product administration
(Hagen, 2019).
COI Chain of identity (COI) is the permanent and transparent
association of a donor’s unique identifiers to their tissue
or cells (raw material), and the resulting drug product.
This record is maintained through the entire process from
processing the patient’s order through manufacturing of
the product. It also includes the administration of the
treatment and post-treatment monitoring. An autologous
donor’s patient number should be linked to their unique
donation number and manufacturing batch number as part
of the COI (Hagen, 2019).
Consignee The entity that is supposed to receive goods or products
from the courier. In the case of clinical trials, a clinical
site or the patient may be the consignee, as they will
receive the medical product.
Courier A courier is an entity (a person or organization) that
delivers medical products from one entity to another
entity.
CRO Contract Research Organization (CRO) is a company
that is contracted by a sponsor to perform preclinical
alternatively, clinical pharmaceutical research.
CSCO Clinical Supply Chain Organization (CSCO), are
specialized third-party logistics organizations that provide
distribution and supply chain management to the
healthcare and biopharmaceutical industry.
CTD Clinical Trial Distribution (CTD) is the logistics or
distribution of clinical trial material and products. CTD
entails the physical transport or transfer of all materials
(such as raw materials, biological samples, reagents),
equipment (such as kits, packaging, and dry ice), and
documentation (including data) required to get the
investigational medicinal product (IMPs) to the patient.
CTD may also be referred to as clinical supply chain
management.

Direct-from-Patient (DFP
or DfP)
Direct-from-Patient. With the DFP model, medical
products, biological samples, or clinical supplies are
retrieved from the patient.

14

Key Terms/Acronyms Definition
Direct-to-Patient (DTP or
DtP)
Direct-to-Patient. With the DTP model, medical products,
biological samples, or clinical supplies are delivered to
the patient.
FDA Food and Drug Administration
FD&CA Food Drug and Cosmetic Act. The Food Drug and
Cosmetic Act is a set of laws passed in 1938, giving the
Food and Drug Administration to regulatory oversight for
the safety of food, drugs, medical devices, and cosmetics.
This law replaced the Pure Food and Drug Act of 1906.
FDASIA The Food and Drug Administration Safety and Innovation
Act
Gene Therapy Gene therapy is the introduction, alteration, or removal of
a patient's genetic code to treat or cure a disease. The
transferred genetic material can modify how a single
protein or group of proteins is produced by the cell
(ASGCT, 2019b).
GCP Good Clinical Practices. Good Clinical Practices (GCP)
are an international ethical and scientific standards for
conducting biomedical and behavioral research involving
human participants (ICH, 2015).
GDocP Good Documentation Practices
GDP Good Distribution Practices
GDPR General Data Protection Regulation
GMP Good Manufacturing Practices. The “c” in cGXPs
denotes current practices. cGMP denotes current Good
Manufacturing Practices.

GTP Good Tissue Practices
HazMat A Hazardous Materials (also may be referred to
dangerous goods) is any item or agent (biological,
chemical, physical, or radiological), which has the
potential to cause harm to animals, humans, or the
environment. These materials can pose a risk either as a
standalone product or through interaction with other
external factors such as temperature changes or
atmospheric pressure (UPS, 2019).

15

Key Terms/Acronyms Definition
HCT/Ps Human cells, tissues, and cellular and tissue-based
products
IATA International Air Transport Association
ICH ICH is the International Conference on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for Human Use. ICH objectives are to
bring together the regulatory authorities of Europe, Japan,
and the United States to harmonize the technical
guidelines and requirements for product registration. The
goal is to reduce the need to duplicate clinical testing
during the development of new medicines.
Immunogenicity The ability of a molecule or substance to induce an
immune response in a human or animal.
IMP Investigational Medicinal Product. Per ICH GCP
guidelines, an IMP is a pharmaceutical form of an active
ingredient or placebo being tested or used as a reference
in a clinical trial. This definition includes a product with a
marketing authorization when used or assembled
(formulated or packaged) in a way different from the
approved form if used for an unapproved indication, or
when used to obtain additional scientific information on
an approved use. Investigational Medicinal Product may
also be referred to as investigational product (IP), or
investigational drug product (IDP) (ICH, 2015).
Logistics Logistics is a component of supply chain management.
Logistics includes planning, implementing, and
controlling processes and procedures for the efficient and
effective transportation and storage of goods. The
physical exchange of goods can include products,
services, and related information from the point of origin
to the point of consumption to meet the customers’
requirements. Logistics is often referred to as distribution
(CSCMP, 2019).
Outsourcing The practice by which an organization contracts out
aspects of drug development such as research, laboratory
testing, clinical trials, or manufacturing to another firm
outside of the manufacturer entity. Outsourcing may be
referred to as a contract organization.
Patient An individual seeking medical care. Patients that
participate in a clinical trial may also be referred to a
subject.

16

Key Terms/Acronyms Definition
Precision Medicine Precision medicine (commonly referred to as
personalized medicine) is an emerging approach to
disease treatment and prevention. Precision medicine
accounts for genetic variation, environment, and lifestyle
for each person. This approach will allow doctors and
researchers to predict accurate treatment and prevention
strategies for particular diseases and how they will work
in a subpopulation versus using treatment options that are
based on the average patient. There was a concern that
the word "personalized" could be misinterpreted to imply
that treatments and preventions are being developed
uniquely for each individual; in precision medicine, the
focus is on identifying which approaches will be effective
for which patients based on genetic, environmental, and
lifestyle factors. The National Research Council (NRC),
therefore, preferred the term "precision medicine" to
"personalized medicine." However, the lay public often
uses the two terms interchangeably. Note: this term will
be used throughout the remainder of the dissertation
unless there is a direct quote that uses the term
"personalized medicine" (NIH, 2019c; NIH, 2019d).
Protocol The protocol provides the framework and standard
process for clinical study execution. The protocol
includes the study's objectives, design, and methods. It
may include relevant scientific background, rationale, and
statistical information related to the clinical study. An
Institutional Review Board and regulators must approve
the study protocol and protocol amendments prior to trial
initiation (ICH, 2015).
QMS Quality Management System
RMAT Regenerative Medicine Advanced Therapy. A
regenerative medicine advanced therapy is defined as a
cell therapy, therapeutic tissue engineering product,
human cell, and tissue product or any combination
product that is intended to treat, modify, reverse, or cure a
serious or life-threatening disease or condition. The
product must provide preliminary clinical evidence
indicates that the drug has the potential to address unmet
medical needs (FDA, 2019ac).

17

Key Terms/Acronyms Definition
SCM Supply Chain Management. SCM includes the design,
planning, execution, control, and monitoring of supply-
chain activities. Logistics and distribution, movement of
products, is a component of SCM. For medical products,
SCM entails the transport or transfer of all materials
(such as raw materials, biological samples, reagents) and
equipment (such as kits, packaging, dry ice), and
information required to get the product to the patient.
There are multiple stakeholders involved in SCM of
clinical trials, including researchers, sponsors,
manufacturers, site coordinators, clinicians, and
distributors (Rees, 2011; CSCMP, 2019).
Shipper The entity or person that packages and sends products to
an end-user (consignee). In the context of clinical supply
chain, a shipper may send a medical product to a clinical
site or patient. The shipper can be the sponsor,
manufacturer, or the entity authorized to provide the
goods to be transported.
Shipper (packaging
materials)
Shipper boxes, kits, or containers used to maintain
temperature conditions and protect medical products and
biological samples for environmental conditions such as
light, vibration, and physical impact while in transit. A
shipper may include insulating material to maintain
temperature requirements (such as ambient, refrigerated,
frozen, or cryogenic) and packaging supplies such as
biohazard bags.
Site The site is usually a hospital or a health care institution
that has adequate resources (equipment, infrastructure,
and staff) and the ability to recruit qualified patients to
meet the requirements of the clinical trial protocol. The
site is the location where patients come to obtain clinical
trial treatment and monitoring throughout the lifecycle of
the clinical study.
Sponsor An organization or person who initiates a clinical trial
study. The sponsor has authority and control over the
study and usually provides funding for the study (ICH,
2015).
TAT Turnaround Time. The TAT is the amount of time
required for the medical products to be transported from
one location to the next.
Temperature Excursion An excursion event (a change in temperature) in which
the medical product is exposed to temperatures outside
the ranges established in the clinical protocol and stability
data (WHO, 2015).

18

Chapter 2. Literature Review
2.1 Background to the Literature Review
The goal of the literature review was to evaluate the currently available literature
and anecdotal information about biologics and, more specifically, cell and gene therapies.
The focus of the literature review was on clinical trial management and distribution of
therapeutic products along the supply chain to patients.
Scholarly works were evaluated through journals and books using United States
National Library of Medicine (NLM) database, PubMed.Gov, Google Scholar
(scholar.google.com), and the Wiley Online Library (onlinelibrary.wiley.com) by
conducting searches using the keywords: cell and gene therapy, clinical trials, supply
chain management, clinical trial distribution, biologics, and drug development. The yield
of this search is shown in Table 2. In total, 6,984,231 (Wiley); 5,358,778 (PubMed); and
33,934,600 (Google Scholar) citations were found. By narrowing the search terms to
“Cell and Gene Therapy, Clinical Trials, Logistics,” the search yielded over 15,000
citations from Google Scholar, Wiley Online Library, and PubMed.

19

Table 2 Select Key Term Searches from Citation Search Engines
Data shows selected search phrases used in citation search engines, Wiley Online Library
(https://onlinelibrary.wiley.com/), PubMed (http://www.pubmed.gov), and Google Scholar
(http://scholar.google.com). The data within this table were collected on April 22, 2020.

Key Terms Wiley Online PubMed Google Scholar
Cell and Gene Therapy 407,788 756,682 3,270,000
Clinical Trials 1,157,925 750,403 3,020,000
Supply Chain Management 125,176 41,216 3,270,000
Biologics 1,614,605 740,939 289,000
Clinical Trial Distribution 350,859 159,746 3,100,000
Good Distribution Practices 730,090 92,695 4,190,000
Cell and Gene Therapy Clinical
Trials
152,261 246,438 3,030,000
Cell and Gene Therapy Clinical
Trials, Good Distribution Practices
28,503 4,447 87,700
Clinical Trial Logistics 85,288 70,087 121,000
Supply Chain Management, Clinical
Trials
22,702 10,157 208,000
Supply Chain Management, Clinical
Trials, Cell and Gene
13,033 6,648 81,300
Supply Chain Management Good
Distribution Practices
54,684 4,749 2,170,000
Biologics, Cell, and Gene 482,512 483,441 180,000
Biologics, Supply Chain, Distribution 71,818 21,843 29,300
Drug Development 1,106,235 1,206,383 4,190,000
Drug Development, Clinical Trials 368,258 343,191 2,740,000
Drug Development, Cell and Gene
Therapy
196,385 385,499 3,930,000
Cell and Gene Therapy, Clinical
Trials, Logistics
16,109 34,214 28,300
Totals 6,984,231 5,358,778 33,934,600

20

Publications and documents with the perspectives of industry and regulators
related to supply chain management; manufacturing; quality; clinical trial distribution;
and clinical trial management of CGTs were reviewed in detail. This set of documents
included journal articles, books, and referenced documents. Industry surveys, industry
blogs, and trade magazines, as well as conference proceedings, were searched using
google (www.google.com) and referenced to specific groups and sites that would be most
likely to yield information related to current trends in both the medical product and
transportation industries. Due to the broad scope of supply chain management, the
documents for the literature review were narrowed to focus on the management of the life
science supply chain and, more specifically, on biologics and CGTs. Materials were
selected based on their relevance to the current regulatory, quality, and operational
landscape of CGTs and the scope of the research question. Therefore, clinical supply
chain management and distribution of investigational CGTs were the primary focal point
of the literature review.
Clinical trial distribution (CTD) and supply chain management (SCM) is a novel
field of study for cell and gene therapies. Therefore, FDA's viewpoint on the topic is
currently captured in slides, abstracts from presentations, and remarks within the current
guidance documents rather than journal articles. Food and Drug Administration (FDA),
National Institutes of Health (NIH), and European Medicines Agency (EMA) websites
provided some additional content related to projects that they are undertaking to oversee
clinical trial distribution and improve supply chain management. The review included
conference agendas, educational catalogs, abstracts, and general articles with specific
information on cell and gene therapies, clinical trials, and distribution. However,

21

publications that were written in languages other than English and could not be translated
into English were excluded. A final sorting yielded over 1000 documents, articles,
presentations, and papers determined to be most relevant and about 550 were utilized in
this dissertation. In addition, two textbooks, Supply Chain Management in the Drug
Industry: Delivering Patient Value for Pharmaceuticals and Biologics (Rees, 2011) and
An Overview of FDA Regulated Products (Bain and Pacifici, 2018) were found to be
valuable. The material described above forms the basis of the literature review presented
below.
2.2 Introduction
The evolution of medicine and advanced therapies has revolutionized the
biotechnology industry. In contrast to traditional drug development, which often takes a
“one-size-fits-all” approach, therapies focused on precision medicine allow clinicians and
researchers to tailor different treatment options toward specific patients or patient
subpopulations. These treatments are often formulated based on the patient's lifestyle and
attributes, such as genetic profile and metabolic characteristics (NIH, 2019c; NIH,
2019d). Representing, perhaps, the most impactful and disruptive products in both
precision medicine and the biopharmaceutical industry are advanced therapies such as
cell and gene therapies (CGTs). In August 2017, the FDA approved Novartis’
KYMRIAH®, an oncology treatment for adults diagnosed with certain types of non-
Hodgkin lymphoma, as the first chimeric antigen receptor T cell (CAR-T) therapy (FDA,
2018e; Penn Medicine, 2017; Novartis, 2019d). Later that year, the FDA approved Kite
Pharma’s
2
YESCARTA®, the first CAR-T therapy for adult patients with relapsed or

2
A subsidiary of Gilead Sciences

22

refractory large B cell lymphoma. These products are recognized as industry game-
changers that progress cancer therapies from standard treatments to cures (Webster,
2019).
CGT development has delivered products that have modernized treatments of
certain diseases. Amongst patients treated with Kymriah, 83% (52 of 63) attained
remission between 26 and 31 days post-infusion (Novartis, 2019d; Maude et al., 2018).
Likewise, of patients given Yescarta, 72% (73 of 101) responded after a single infusion
with 51% (52 of 101) achieving complete remission (Gilead, 2017; Yescarta, 2017; FDA,
2017b; FDA, 2017c). These success outcomes have not been lost in the industry, as they
have prompted the development of new therapies for other types of indications. In May
2019, the FDA approved Novartis Gene Therapies (Formerly AveXis
3
) drug
ZOLGENSMA®, an adeno-associated virus vector-based gene therapy. Zolgensma is the
first gene therapy approved to treat spinal muscular atrophy (SMA), a rare genetic disease
in children under the age of two, caused by a mutation in the survival motor neuron 1
(SMN1) gene. An improvement of 90% (19 out of 21) was seen among patients treated
with Zolgensma, giving 21 infants the ability to survive without respiratory assistance for
16 hours or more per day. Additionally, 48% of those infants were able to sit up without
additional support (FDA, 2019t; Novartis, 2019a; Novartis, 2019b; Novartis, 2019d).
The projected growth of CGTs in the US is expected to increase and provide
treatments for patient populations that do not have alternative options. By 2030, market
approvals for CGTs are expected to provide 40-60 curative treatments to over 350,000
patients (50,000 patients per year), generating more than $200 billion (USD) a year (MIT,

3
A subsidiary of Novartis International AG

23

2018; Quinn et. al, 2019; Wechsler, 2019a; Wechsler, 2019b; Hargreaves; 2019; BIS
Research, 2019). Currently 50% (~500 companies) of biopharmaceutical organizations
are headquartered in the US (ARM, 2020a; ARM, 2020b). Although there are 19
approved CGTs in the US
4
—seven of which are approved cell-based or gene-based
therapies— the pipeline for CGTs continues to grow. Companies such as Bristol-Myers
Squibb, Atara Biotherapeutics, and Bluebird Bio, to name a few, have applied for new
investigational new drug (IND) and Biologics License Applications (BLA) for
indications ranging from hematology to central nervous system (ARM, 2020a;
ARM,2020b). At the end of 2019, there were over 1,000 IND applications globally in the
pipeline (Figure 1) (ARM, 2020a; ARM, 2020b).
Figure 1 Global Clinical Trial Landscape for Cell and Gene Therapies
This figure gives a detail overview of global clinical trials for cell and gene therapies at the end of 2019.
Graph was created by the author based on statistics captured from source (ARM, 2020a; ARM, 2020b).

4
Number of US FDA approvals as of 05-Feb-2021

24

In July 2020, Kite Pharma reached another milestone, with the approval of
TECARTUS
TM
, the first and only CAR-T treatment for adult patients with relapsed or
refractory mantle cell lymphoma, a rare type of non-Hodgkin lymphoma (Gilead, 2020;
FDA, 2020r). This approval made Kite Pharma, the first manufacturer in the US to have
two commercialized CGTs (Gilead, 2017; Gilead, 2020). Most recently, in February
2021, Juno Therapeutics Inc.
5
obtained approval for CAR-T therapy, BREYANZI®, a
treatment for patients with relapsed and refractory diffuse large B-cell lymphoma
(DLBCL), the most common type of non-Hodgkin lymphoma (FDA, 2021; Sagonowsky,
2021). Breyanzi is the first therapy to be FDA approved with regenerative medicine
advanced therapy (RMAT) designation. Moreover, it is the third FDA approved gene
therapy for non-Hodgkin lymphoma, which has 77,000 new cases in the US each year
(FDA, 2021). Although more than 60% of the indications for CGTs are for oncology,
there are over 30 medical indications in the pipeline (Figure 2) (ARM, 2020a; PhRMA,
2020).

5
A subsidiary of Bristol Myers Squibb

25

Figure 2 Disease Indications for Cell and Gene Therapies
This figure provides a breakdown of the medical indication and phases for CGTs in the pipeline in the year
2020. Figure was recreated and modified by the author from source (Pharmaceutical Research and
Manufacturers of America (PhRMA), 2020).

Although the industry has seen significant milestones with the development of
first-in-class products, obtaining market approvals has been slow in the US due to
challenges with clinical efficacy data and Chemistry, Manufacturing and Controls (CMC)
(CBER, 2019b; BMS, 2020; BioMarin, 2020). In August 2020, the FDA rejected
BioMarin Pharmaceutical Inc.’s Biologics License Application (BLA) for Valoctocogene
Roxaparvovec (ValRox), a gene therapy for severe Hemophilia A, a bleeding disorder.
Although, BioMarin had completed a phase 1/2 and phase 3 trial was in progress, the
agency concluded that the differences between Phase 1/2 and the Phase 3 study limited its
ability to rely on the Phase 1/2 study to support approval (BioMarin, 2020). The agency
also recommended two years of additional data from the ongoing study (Phase 3) to
provide substantial evidence of the clinical endpoints (annualized bleeding rate (ABR)),

26

thus pushing the possibility of approval into the year 2021 (Humer, 2020; BioMarin,
2020). With respect to CMC data, in May 2020, Bristol Myers Squibb (BMS) and
Bluebird Bio received a failure to file from the FDA for their Biologics License
Application (BLA) for idecabtagene vicleucel (ide-cel; bb2121) for patients relapsed and
refractory multiple myeloma. The agency requested more details related to the CMC
module of their submission (BMS, 2020). CMC data also stalled Novartis’ approval for
Zolgensma, in Europe and Japan however, the company was eventually able to obtain
conditional approval in March 2020 and May 2020 in Japan and Europe respectively
(Blankenship, 2019b; Pagliarulo, 2019; Novartis, 2020a; Novartis, 2020b; Novartis,
2020c; Jensen, 2020).
Failure to obtain regulatory approval and support commercial scale-up could be a
significant setback for CGT manufacturers. Clinical trials are a critical late-stage
requirement for drug commercialization. Success in clinical trials is vital to ensuring that
any biopharmaceutical product can be manufactured, distributed, and, in some cases,
reimbursed by insurance payers (Novartis, 2019a). However, the development path for
these life-changing therapies has been very costly, lengthy, and taxing for manufacturers
because clinical trials are incredibly complex and require a multi-million-dollar
investment. For cell and gene therapies, the costs are significantly higher than the costs
that are associated with small-molecule drugs because manufacturing takes place in small
batches, often developed for a single patient (Colasante et al., 2018; Gerlovin and Diesel,
2018). Consequently, the costs to develop an investigational CGT product for a clinical
trial have been estimated to be around $250,000 (USD) per patient, with ranges
forecasted between $100,000 (USD) and $300,000 (USD) per patient (Huss, 2016;

27

Sertkaya et al., 2016; Aspril, 2018; Elverum and Whitman, 2019; Maziarz, 2019). Hence,
any challenges that damage the logistics or supply chain management of these costly and
hard-to-handle investigational products could compromise the success of product
commercialization and waste invested resources.
From a regulatory perspective, precision medicines using cell-based or complex
biological products defy a singular definition and drug development approach. Subclasses
of the general category of biologics, cell therapy, and gene therapies are often described
using interchangeable terms or in ways that denote a unified set of features. However,
fundamental differences exist. Cell therapy is the transfer of intact live cells into a
patient. These cells may originate from that same patient—autologous cells—or from a
donor—allogeneic cells. The donor for allogeneic cells is typically a related or unrelated
provider who is matched with the patient (Weinberg; 2013; ASGCT, 2019a: ASGCT,
2019b). In contrast to cell therapy, gene therapy is a technique that alters genes to treat or
cure disease. Gene therapies work by: (1) replacing a disease-causing gene with a healthy
copy of the gene; (2) inactivating a disease-causing gene that is not functioning correctly;
or (3) introducing a new or modified gene into the body to help treat disease (ASGCT,
2019a; ASGCT, 2019b; NIH, 2019). Products such as Kymriah and Yescarta are cell-
based gene therapies that are modified outside of the body, whereas Zolgensma obtains
its gene-modifying effect through a transmission agent introduced into the body directly
(Kymriah, 2019a; Kymriah, 2019b; Yescarta, 2019; Novartis, 2019c). These technologies
share features and have become much harder to define as targeted disease treatments
evolve within precision medicine.

28

Because CGTs are complex and variable, regulations often present hurdles for
manufacturers. From a regulatory standpoint, most of the guidelines for supply chain
management for investigational medicinal products (IMPs) are based on the ICH E6
(R2), Good Clinical Practices guidance document, or applicable GMP regulations. Within
the US, current practices and standards used in the supply chain management of IMPs
have been primarily based on Good Distribution Practices (GDP) guidelines detailed by
the World Health Organization (WHO, 2010a) and in the United States Pharmacopeia
(USP, 2016a; USP, 2016b; USP, 2011). Still, there is no established nor enforced
regulatory framework for GDPs for IMPs in the US. Moreover, there are no established
distribution frameworks for CGTs that relate directly to supply chain management.
The introduction of immunotherapies and precision medication has forced the
biopharmaceutical industry to address complex manufacturing and supply chain
challenges that were nonexistent 20 years ago with traditional drugs and biologics such as
monoclonal antibodies (Lamb et. al, 2017; Lamb, 2017; Rees, 2018a; Rees, 2018b). In
comparison to more traditional drug distribution models, cell and gene therapy supply
chain is much more complex since the patient is at the beginning and end of the supply
chain for each batch (Srivastava, 2020a; Srivastava, 2020b; Rees 2011) (Figure 3 and
Figure 4).

29

Figure 3 Clinical and Commercial Supply Chain Models - Part A
This figure shows a high-level overview (1) clinical supply chain of traditional pharmaceutical drugs and
(2) commercial drug supply chain. This was recreated by the author based on the supply chain management
streams from literature review (Rees, 2011; Rees, 2018a; Rees, 2018b; Srivastava, 2020a; Srivastava,
2020b).

30

Figure 4 Clinical and Commercial Supply Chain Models - Part B
This figure shows high-level overview of clinical and commercial cell and gene therapies such as CAR-T
therapies. The figure shows autologous CGTs versus allogeneic CGTs. This was created by the author
based on the supply chain management streams from literature review (Rees 2011; Rees, 2018a; Rees,
2018b Srivastava, 2020a; Srivastava, 2020b).

Dendreon Pharmaceuticals’ Provenge® (sipuleucel-T), an intravenous cell-based
treatment for advanced prostate cancer (approved by the FDA in 2010), is a real-life case

31

study of the manufacturing and supply chain hurdles associated with the CGTs. Provenge
is the first product of its kind –personalized, specific to one patient, and autologous, made
from the patients’ own cells. To manufacture the therapy, the first step is a cell collection
from the patient, a process called apheresis. Once the white blood cells (T cells) are
isolated, they are shipped to a manufacturing facility to produce the treatment. Once the
product is produced, it is shipped to the clinic for infusion to the patient (Basta, 2012;
Krader 2020: Provenge, 2020).
In my 30 years in the pharma industry, I’ve never seen a process like this—we
think it’s unique, with unique challenges. But to date, we’ve had 100%
success in receiving and delivering the therapy to patients (quote from Robert
Poulton, Basta, 2012)

Since Provenge is made with live cells, the treatment requires a turnaround time
of three days (72 hours) for the total lifecycle of the product, from the cell collection to
the final infusion (Palmer, 2014; Krader, 2020). There is only an 18-hour window from
the apheresis center to the manufacturing site where the cells are processed and the
therapy is manufactured. This 18-hour window is also required to the get the treatment
back to the patient for the infusion (Basta, 2012). For the complete treatment cycle, the
drug requires six patient visits (three infusion cycles at 2-week intervals) over the course
of 30 days. Each step requires specialty packaging to maintain temperature ranges: (1)
refrigerated (2-8°C) for the live cells shipped from the apheresis centers to the
manufacturing plant and (2) room temperature (20–25°C) for the final infusion (Kantoff,
2010; Basta, 2012; CBER, 2019b; Provenge, 2020). As a result, the manufacturing
process entails a rigid manufacturing and distribution model (Figure 5).

32

Figure 5 Dendreon’s Provenge Manufacturing Cycle
This figure provides an overview of the manufacturing process for Provenge. This figure was created by the
author based the literature (Basta, 2012; CBER, 2019b, Provenge, 2020).

To improve manufacturing efficiencies and reduce waste, Dendreon invested in
automation ($125 million USD per year), and over $200 million USD in infrastructure.
Manufacturing facilities— located in California and Georgia— had to be operable and
strategically built near cell collection facilities (~120 centers) to meet the tight turnaround
times to prevent product spoilage (Basta, 2012; Palmer, 2014; Krader 2020). Although
Dendreon was successful in delivering the treatment to its patient, the company had
unexpectedly high overhead costs associated with manufacturing the CGT. The
challenges to meet sales and reimbursement targets for the drug ($93,000 USD),
eventually led the company to file bankruptcy and sale off some of its assets in 2014
(Palmer, 2014; Marisol, 2017; Macdonald, 2020). Although Provenge revolutionized
prostate cancer treatment, being at the forefront of precision medicine, meant that
Dendreon had no framework for the complex manufacturing and supply chain processes

33

required to maintain safety and efficacy of its cell therapy (Marisol, 2017). Although,
there were many lessons learned from Dendreon, 10 years later, supply chain
management continues to be a hurdle for time-sensitive and temperature-sensitive CGT
products like Yescarta, which has a much more complex manufacturing process steps.
To mitigate some of the supply chain complexities and to reduce the time and
costs expended on the manufacturing process, some CGT manufacturers have opted to
develop allogeneic CGT products. Unlike autologous therapies, allogeneic CGT products
are created from healthy donor cells, meaning that the manufacturing process is not
dependent on the patient’s cell for raw materials. Therefore, multiple batches of the
therapy can be created from a master cell bank and provide treatments to multiple
patients. Cells can be isolated, expanded, and manufactured in bulk and stored until they
are ready for use. Atara Biotherapeutics, a biopharmaceutical company focused on
allogeneic T-cell immunotherapies, currently has two Phase 3 trials and one Phase I trial
in progress for cancer and multiple sclerosis respectively (Atara Biotherapeutics, 2020a;
Atara Biotherapeutics, 2020b; Atara Biotherapeutics, 2020c). The company aspires to
have multiple “off the shelf” therapies that could be shipped directly to the patient within
the 3 days. Although allogenic CGT products can be advantageous, challenges still exist.
Two major challenges are: (1) proof of efficacy in comparison to autologous
counterparts, and (2) safety concerns related to Graft versus host disease (GvHD), a
condition that occurs when donor stem cells attack the recipient (Brindley and Mason,
2012; Malik et al., 2015). Currently, there are no allogeneic CGTs approved in the US.
Although the hope of these products has been to reduce costs and time, from a supply
chain standpoint, these therapies will also have time sensitivity, and require special

34

handling, such as cold chain management, which is discussed later in this dissertation
(Reed, 2019b).
With the novel development of CGTs, comes the recognition that these products
carry new or exaggerated risks. CGTs are highly fragile products whose vitality must be
preserved as materials move from the manufacturer to a patient thousands of miles away.
As a result, the clinical trial distribution of CGTs has become central to the development
and commercialization of these innovative products. Failure to preserve optimal
conditions and quality of these medical products as they pass along the supply chain
could result in therapeutic failures. These failures could pose considerable risks to
patients who are terminally ill and rely on these treatments.
2.3 History of Biologics and Biologics Regulation in the US
Biologics are amongst the earliest of pharmacological treatments. In 1736,
Edward Jenner discovered that cowpox, a skin infection caused by a virus transmitted
from animals, could prevent smallpox, a highly infectious and contagious disease. Jenner
used the cowpox virus as an inoculant to induce immunity to smallpox. This method of
treatment became the foundation for many vaccines used today as a preventative
treatment (Lakhani, 1992; Riedel, 2005).
Nonetheless, these vital treatments brought challenges that made vaccines among
the first types of medical products to be regulated in the US. Those early regulations
came in response to a tragedy in the early 1900s, when multiple children died after
receiving a contaminated diphtheria vaccine derived from the serum of a horse infected
with tetanus (Junod, 2002). In response to the tragedy, Congress passed the Biologics
Control Act in 1902 to give the government control over the processes used to

35

manufacture biological products (Acts of the Seventh Congress of the United States,
1902; Junod 2002; NIH, 1940). Its goal was expressed as below:
Any virus, therapeutic serum, toxin, antitoxin, or analogous product
applicable to the prevention and cure of diseases of man, unless (a) such
virus, serum, toxin, antitoxin, or product has been propagated and prepared
at an establishment holding an unsuspended and unrevoked license, issued by
the Secretary of the Treasury as hereinafter authorized, to propagate and
prepare such virus, serum, toxin, antitoxin, or product for sale in the District
of Columbia, or for sending, bringing, or carrying from place to place
aforesaid; nor (b) unless each package of such virus, serum, toxin, antitoxin,
or product is plainly marked with the proper name of the article contained
therein, the name, address, and license number of the manufacturer, and the
date beyond which the contents cannot be expected beyond a reasonable
doubt to yield their specific results (Acts of the Seventh Congress of the
United States, Fifty-Seventh Congress, Session I, Chapter 1378, 1902, pg.
728)
The contamination failures exposed the lack of control over product quality
typical of most enterprises in the early part of the twentieth century. Soon thereafter, in
1906, Congress passed the broader Pure Food and Drugs Act, which outlawed any foods
and drugs that were mixed with inferior or impure ingredients (adulterated) or that
admitted false or misleading claims on the product packaging (misbranded) (NIH, 1906,
NIH, 1940: Junod, 2002). In 1987, the FDA Center of Biologics Evaluation and Research
(CBER) and the Center for Drug Evaluation and Research (CDER) became separate
branches. Today, the FD&CA and the Public Health Service Act of 1944 are the principal
laws that govern biologics. CBER's oversight is authorized by section 351, which
mandates licensure of biological products that travel by interstate commerce in the United
States, and section 361, which allows the Surgeon General to enforce regulations to
control the interstate spread of infectious disease. This broad authority has been delegated
to the FDA through a Memorandum of Understanding (MOU) (FDA, 2019d; FDA,
2019g). A detailed evaluation of these laws is outside of the scope of this dissertation, but

36

the regulations are well-reviewed in An Overview of FDA Regulated Products (Bain and
Pacifici, 2018).
2.3.1 Evolution of Cell and Gene Therapies
For much of the 20
th
century, commercial production of biologics centered on
three general classes of products— vaccines, hormonal therapies, and antibiotics—
mostly produced by direct extraction from living organisms such as mammalian tissues or
bacterial cultures such as Escherichia coli or yeast. The art, science, and technology of
direct gene manipulation to produce changes in disease by acting directly on targeted
tissues occurred in the latter part of the 20
th
century.
In the late 1980s, Rosenberg of the National Cancer Institute (NCI) became well
known in gene therapy research for success with “adoptive immunotherapy,” a cancer
treatment that involved utilizing the patient’s tumor-infiltrating lymphocytes (TIL),
which are cells to fight cancer (Rosenberg at el, 1990; Henig, 1991; NIH, 1995).
Rosenberg (Rosenberg et al., 1990; Rosenberg et al., 1992) tested the safety and
effectiveness of the gene therapy process in cancer patients by growing TIL cells from
patients with malignant melanoma, a form of skin cancer. The TIL cells were engineered
with a virus that introduced a DNA marker into the cells. The “marked TIL cells” enabled
researchers to analyze cancer treatment methods. Building upon Rosenberg's research,
other scientists such as Anderson and Blaese (Henig,1991; Anderson, 1992; Culver et al.,
1991; Oldfield et al., 1993; Kaneko et al., 1995) attempted to add genetically engineered
viruses into marked TIL cells and re-infuse them into patients to target specific cells in
the body (Rosenberg at el., 1990; Henig, 1991; NIH, 1995; NHGRI, 1995; McCain,
2005). These developments heralded what would become an important part of the

37

“biotechnology” industry. They ushered in several advanced therapies, many of which
are still utilized today (Wirth, Parker and Ylä-Herttuala, 2013; Wirth and Ylä-Herttuala,
2014).
2.3.1.1 Mechanism of Action and Regulatory Classification of CGTs
In CGTs, genes are introduced using a number of mechanisms: (1) physical
delivery methods such as electroporation or ultrasound; (2) viral methods that use viral
vectors of various types to breach the cell wall; (3) non-viral methods that use synthetic
carriers such as liposomes or nanoparticles; and (4) bacterial or yeast carriers
(Nayerossadat, Maedeh and Ali, 2012). Of these methods, viral vectors such lentivirus
and retrovirus (including the human immunodeficiency virus [HIV]), vaccinia virus, and
adeno-associated virus (AAV) are used most (Wirth, Parker and Ylä-Herttuala, 2013;
Wirth and Ylä-Herttuala, 2014; Amer, 2014; Lundstrom, 2018).
Both ex vivo and in vivo CGT methods can be used to change the genetic state of
cells. In ex vivo methods, such as CAR-T therapies, cells are removed, modified outside
of the body by exposure to a virus carrying the desired gene(s), and then reinfused into
the body. In vivo therapy is a form of gene therapy in which a needed gene is transferred
to cells by direct infusion or application inside the patient’s body. In December 2017, the
FDA approved LUXTURNA®, manufactured by Spark Therapeutics, the first approved
gene therapy in the US administered directly into the subretinal layers of the eye.
Luxturna is used to treat mutations in the gene RPE65 that cause congenital retinal
dystrophies such as Leber’s congenital amaurosis (LCA) and retinitis pigmentosa (RP).
As a result of these conditions, diminished enzyme activity in the retina eventually causes
blindness. Luxturna uses an adeno-associated virus, modified using recombinant DNA

38

techniques, to provide a healthy RPE65 gene to the retinal cells by direct injection into
the eye (Spark Therapeutics, 2017).
Over the last 20 years, potential indications, and targeted disease populations for
CGTs have become too diverse for a single set of regulatory requirements to address.
Some types of CGTs carry risks not shared by other biological products. The unique
behaviors and challenges associated with CGTs have become apparent to regulators. To
recognize these differences, CBER added the Office of Cellular, Tissue and Gene
Therapies (OCTGT), renamed the Office of Tissues and Advanced Therapies (OTAT) in
October 2016, to oversee stem cell products as well as other biological products including
gene therapies, tumor vaccines, and immunotherapies. The agency acknowledges that
public health risks could vary from one type of therapy to another. This paradox led the
agency to differentiate cells and tissues from other products and utilize a risk-based
approach during the review process (FDA, 2011; Kooijman et al., 2013; FDA, 1997;
Manganello, 2018; Cauchon at el., 2019; FDA, 2019a).
A.) Products under section 361 (lower risk) tissues such as bone, ligaments, tendons, skin,
pericardium, corneas, and semen. Lower-risk tissues are regulated under section 361 of
the Public Health Act (PHA); they are therefore often given the designation of “361
HCT/Ps”. Typically, 361 HCT/Ps do not require premarket review and approval but must
adhere to requirement outlined in, “Tissue Rules” (21 CFR 1271), issued in 2005, that
formed the basis for regulation of all human cells, tissues, cellular and tissue-based
products (HCT/Ps) (Church, 2018; FDA, 2011; FDA 2019a).

B.) Products under 351 and 361 (higher risk) products such as cultured cartilage cells, gene
therapy products, and human cells involving the transfer of genetic material for
therapeutic purposes. Higher risk products have much more regulatory oversight,
including requirements in an additional section of the Act, section 351. Thus, they are
often designated as “351 HCT/Ps”. Typically, 351 HCT/Ps, such as CGTs, are required
to undergo premarket review and approval. These 351 HCT/Ps must comply with a
number of other regulations, including not only the Good Tissue Regulations in 21 CFR
part 1271, discussed above, but 21 CFR 600, 200, 312, 812, and other parts depending
upon their method of manufacturing (Church, 2018; FDA, 2011; FDA, 2019a).

39

Other countries approach CGTs differently. In Europe, for example, cell and gene
therapies are classified as Advanced Therapy Medicinal Products (ATMPs), and the
oversight of these products is the responsibility of a single regulatory body, the European
Medicines Agency (EMA). ATMPs are divided into three subclasses: (1) gene therapy
medicines, which insert recombinant genes into the body; (2) somatic-cell therapies based
on cells or tissues that have been manipulated to change their biological characteristics;
and (3) tissue-engineered medicines containing cells or tissues that have been modified to
repair, regenerate, or replace human tissue (EMA, 2018e). These products are approved
through a risk-based approach and go through a more rigorous review process than
standard drugs, as detailed elsewhere on the European Medicines Agency website
(Kooijman et al., 2013; EMA, 2018b; EMA, 2018e; EMA, 2019).
2.3.2 Challenges and Special Considerations for Cell and Gene Therapies
Cell and gene therapies have introduced multiple unique challenges that have not
been seen with drug and biologic predecessors (Lamb et al., 2017; Lamb, 2017;
Godshalk, 2020) (Table 3). These challenges have placed time and cost constraints on the
development process and the ability to forecast the manufacturing and clinical planning
needed to attain commercialization. In the next section, this dissertation will explore two,
often underestimated, areas of regulatory management for CGTs that affect later stage
clinical trials: expedited regulatory pathways and rules for Chemistry, Manufacturing,
and Controls (CMC).

40

Table 3 Comparison of Monoclonal Antibodies to Autologous Cell Therapies
This table provides a comparison of monoclonal antibodies to autologous cell therapies. This table was
recreated and modified by the author based on literature review and table created by source (Lamb et al.,
2017; Lamb, 2017).

Monoclonal Antibodies Autologous Cell Therapies
Decision-to-treat process is simplified if
the product and pricing is approved by
payers.
Decision-to-treat will require case-by-case
assessment due to high product and medical
costs to payers.
Starting materials are well-categorized.
Products tend to have a longer shelf-life.
Starting material has high variability due to
the variance of each patient. Materials also
have short shelf-life. .
Single or limited GMP-compliant
sources for active pharmaceutical
ingredient (API).
Multiple sources of starting material
(apheresis centers); each patient utilizes its
own cells. Therefore, there is potential for
inconsistent processes.
Single lot is created to supply thousands
of patients. Bulk or make-to-stock is
possible.
Single lot is specific to one (1) patient;
Therefore, therapy is manufactured in real-
time. Bulk lots are not possible.
Product is not personalized to a single
patient. Treatment may be used for an
average patient within the targeted
indication.
Needle-to-needle (vein-to-vein) traceability is
required. Patient must receive therapy
manufactured from own cells. Product cannot
be used for another patient.
Long and large patient population
(thousands of patients) for clinical trials.
1. Long-term safety and efficacy data is
required.
2. More time is available to build global
experience and plan commercial supply
chains.
Short and small patient populations for
clinical trials (typically less than 100
patients). 1.
Limited data means long-term safety studies
may be required.
2. Less time to plan and develop commercial
supply chain.
Simpler reimbursement models based on
historical commercialization experience.
Reimbursement models potentially more
complex and based on patient outcomes.
Short-term post-market follow-up if
treatment is successful.
Long-term post-market follow-up (~15
years), even if treatment is successful or
curative.
Can be scaled up without scaling out. Scale-up only achieved by scaling out.
Scaling-out increases supply chain
complexity.
Mature, established, and standardized
high-volume transportation lanes from
manufacturing site to distributor using
large integrator couriers.
Less established transportation lanes using
specialized, high cost white glove couriers
with fewer standardized processes.
Critical quality attributes can be clearly
defined.
Process inputs (e.g., handling, environmental
conditions) are not clearly defined and need
to be tightly controlled.

41

2.3.2.1 Expedited Pathways and their Implications for Clinical Development
Especially for gene and cell therapies, measuring all the necessary critical
quality attributes (CQAs) of any product to assure complete safety and
efficacy is impossible. Although a number of CQAs can be identified to define
some aspects of a product’s safety and efficacy, many of the product’s
important attributes are and will always remain essentially unknown or
unmeasurable. The industry typically regards CQAs as those product
attributes that can be measured to establish and document product quality,
with little thought given to controlling unknown product attributes (Witcher,
2020, para 3).
Ultimately, the true measure of product quality is established during clinical
trials by the product’s impact on people (Witcher, 2020, para 4).
It has been the aim of the FDA for several years to expedite the market entry of
innovative medical products that can save lives or manage disabling conditions.
Expedited pathways for CGTs have improved the quality of life for patients by
significantly decreasing regulatory approval hurdles (FDA, 2018b; Beaster and Shields,
2018; FDA, 2019q; FDA, 2019ac). The most recent of its programs to carry out this
objective has been the “Breakthrough Therapy” program. The Food and Drug
Administration Safety and Innovation Act (FDASIA) and foundational provisions of the
FD&CA (21 USC 902 and 21 USC 506(a) respectively) authorized this program. It
encourages a manufacturer of a CGT product to apply for breakthrough therapy
designation if it meets specific criteria:
Breakthrough therapy designation is intended to expedite the development and
review of drugs for serious or life-threatening conditions. The criteria for
breakthrough therapy designation require preliminary clinical evidence that
demonstrates the drug may have substantial improvement on at least one
clinically significant endpoint over available therapy (FDA, 2018b, para 2)

Clinically significant endpoints refer to endpoints that measure an effect on irreversible
morbidity or mortality (IMM) (FDA, 2014; FDA, 2018b; FDA, 2019q; FDA, 2019ac).

42

Designation as a breakthrough therapy benefits the company in many ways, not the least
of which is the prioritization of advice and review by the FDA. The agency approves or
denies the application for breakthrough designation within 60 days of reviewing
submitted scientific and preclinical data plus preliminary clinical evidence. This new
program complements other programs, including fast track and priority review programs
that are intended to accelerate access to much-needed treatments (see the FDA website
for more detailed review). In 2019, the FDA granted the application of Fast
Track, Breakthrough Therapy, and Priority Review designations for Novartis’ Zolgensma
(FDA, 2018b; FDA, 2019w; Novartis, 2019a; Novartis, 2019b).
Additionally, a CGT may be designated as a Regenerative Medicine Advanced
Therapy (RMAT) if primary clinical evidence indicates that the CGT product has the
potential to address unmet medical needs for a serious or life-threatening disease or
condition. These products include engineered tissue products, human cell, and tissue
products, or cell therapies that "are intended to treat, modify, reverse, or cure a serious or
life-threatening disease" (FDA, paragraph 3, 2019ac). This new pathway, described in
Section 3033 of the 21st Century Cures Act, is similar to that of the Breakthrough
Pathway with an intent to provide developers with much greater support in the
consultation and review process to reduce the size and costs of the clinical program
(FDA, 2018c; FDA, 2019b; FDA, 2019q; FDA, 2019ac) (Figure 6).

43

Figure 6 Traditional vs Breakthrough Clinical Pathway
This figure provides a comparison between traditional clinical programs that typically require a three-phase
set clinical studies versus more condensed cell and gene therapy clinical programs such as breakthrough
designation. This figure was created by the author based on the literature review (Kloda and Somerville,
2015; Oliva, 2020).

However, this acceleration puts pressure on the clinical trial to provide convincing data of
potential efficacy as well as safety earlier in the clinical program than would be typical
for traditional drugs. It thus makes every sample and every patient in the trial
indispensable. To meet milestones for designation under breakthrough and RMAT
pathways, the company must provide a significant package of evidence. It includes: (1)
the ability to make the product consistently and according to quality practices; (2)
sufficient evidence of safety in preclinical models, typically including primate studies;
and (3) clinical results from a sufficient number of patients to assure safety and
effectiveness (Richmond and Yu, 2019; Richmond, 2019).

44

The reduced requirement for clinical evidence is one of the most important ways
in which breakthrough and RMAT development differs from that of most other
investigational new drug programs. The well-established three-phase set of clinical trials
that may enroll thousands of patients in a typical drug development program can be
collapsed into a single pivotal study prior to approval if the registrant promises to expand
the datasets by conducting post-approval studies, called Phase 4 studies (FDA, 2018d;
FDA, 2019c). In the case of Kymriah, the pivotal study required for FDA approval was
conducted in only 68 patients (Maude et al., 2014; Novartis, 2019d; Kymriah, 2019b). In
contrast, the clinical program for an anticlotting agent, Xarelto ®, which was approved
by the FDA in October 2018, entailed a Phase 3 study with 27,395 patients from 33
countries (Johnson & Johnson, 2018).
With such small patient samples in typical CGT trials, it is not unusual, and more
desirable, to complete the clinical testing phase in a shorter timeframe. This acceleration
puts a strain on the other activities customarily conducted during the clinical period, such
as the scale-up and validation of manufacturing methods, implementation of effective
quality systems, and development of a robust distribution strategy. Failures of these
aspects can compromise the ability to treat clinical trial participants safely and
effectively, thus preventing regulatory approval.
2.3.2.2 Chemical Manufacturing and Controls (CMC)
In contrast to most drugs that are chemically synthesized, and their structure
is known, most biologics are complex mixtures that are not easily identified or
characterized. Biological products, including those manufactured by
biotechnology, tend to be heat sensitive and susceptible to microbial
contamination. Therefore, it is necessary to use aseptic principles from initial
manufacturing steps, which is also in contrast to most conventional drugs
(CBER, 2019a, para 2)

45

The susceptibility to contamination and the relative instability of CGT products
compared to conventional small-molecule drugs is of great concern to drug developers. It
would be difficult enough if the result were to be simply a loss of therapeutic function.
However, changes in the configuration of proteins and other components can make the
products even more immunogenic than they already may be (Heidaran, 2019). Proving
that products will not be immunogenic before clinical trials begin can be an impossible
task, given the differences that exist between the immune systems of animals and man. In
addition, immune reactions express differently from person to person. At the clinical trial
stage, knowledge about these aspects of product behavior is rudimentary. Thus,
considerable challenges must be anticipated when trying to keep the product in its
manufactured form. Additionally, the accelerated production speed required to meet the
needs of the clinical trials puts added pressure on assuring every test article delivered will
retain its original manufacturing specifications.
Manufacturing is feeling the impact of increased protocol complexity in terms
of risk mitigation (i.e., in the way studies are being designed), as phases are
combined or changes in midstream based on interim results (Shanley, 2018a,
p. 60)

The CMC of cell and gene therapies require strict controls across their lifecycle,
from assuring the quality of the cell source and raw materials, through aseptic
manufacturing processes, to packaging and shipping validation (FDA, 2003a; FDA,
2003b; FDA, 2019ae; FDA, 2019m; FDA, 2020e; Godshalk, 2020). Controls must be
implemented to prevent transmission of infection from the donor or introduction of
infectious agents during cell processing to the recipient of the product. Key goals
articulated by FDA are to: (1) prevent the use of contaminated samples that have the

46

potential to transmit infectious disease; (2) avert improper handling or processing that
might contaminate or damage tissues; and (3) ensure that clinical safety and effectiveness
of the cell and gene therapies (FDA, 2019m). The FDA has issued multiple guidance
documents including, but not limited to: Chemistry, Manufacturing, and Control (CMC)
Information for Human Gene Therapy Investigational New Drug Applications (INDs) and
Current Good Manufacturing Practice for Phase 1 Investigational Drugs (FDA, 2003b;
FDA, 2008; FDA, 2020e; FDA, 2020h).
The complexities involved with producing a cell therapy create added challenges.
Unlike conventional drugs in which the drug’s chemical characteristics, potency, and
impurities can be evaluated, biologics are challenging to characterize. For CGTs, Critical
Quality Attributes (CQA), physical, chemical, biological properties that should be within
an established range, and Critical Process Parameter (CPP), a process parameter whose
variability can affect the critical quality attributes, are often impossible to establish and
control due to variance in the starting material, cell collection, infusion and shipment
distribution processes (Witcher, 2020). FDA then must place more reliance on its
manufacturing process when approving a biologic drug, to ensure that the end product is
consistent between batches. Manufacturing must be flexible enough to accommodate
unspecified numbers of production batches in parallel within a short time so that the short
shelf lives of the cells are not compromised (Meacle et al., 2016; Shanley, 2018a;
Challener, 2017; Schubert, 2018; Buytaert-Hoefen, 2019).
The patients are the beginning and end of the supply chain. Logistically, this
is a very big challenge (Yarbough, 2018, para 6)

47

The manufacturing process is particularly difficult for products such as CGTs
that must be manufactured specifically for a single patient and therefore yields a batch lot
of one product. Every one of those batches will differ according to inherent differences in
the starting materials themselves, which are the patient's own cells (Clarke and Smith,
2019). As a result, a single manufacturing site will be producing several unique and
staggered batches for multiple patients continuously (Wang and Riviere, 2016; Stanton,
2017a; Shanley, 2018a). For such products, a particularly close relationship exists
between manufacturing and clinical logistics because the starting materials must be
obtained from the patient, then transferred to the manufacturing site, reengineered, and
then returned to the clinical site.
An illustration of the rigorous SCM process can be shown through the
manufacturing of CAR-T therapy, Kymriah, a genetically modified autologous T cell
immunotherapy in which each dose is a customized treatment created using an individual
patient's own T cells (Figure 7). The treatment begins with leukapheresis, a process that
separates white blood cells from the blood. In the case of CAR-T therapies, T cells are
collected through an IV catheter from mononuclear cells (PBMCs) circulating in the
patient’s peripheral blood. The T cells are isolated and sent to a manufacturing facility to
be reprogrammed by using a lentivirus (deactivated HIV) to add CD19-detecting
receptors into the T cells. These newly engineered CAR-T cells can now differentiate
cancerous B-cells bearing the CD19 marker from healthy cells without the receptor. Prior
to an infusion of the engineered T cells, the patient receives chemotherapy to prepare the
body to receive the reprogrammed Kymriah CAR-T cells. The reprogrammed cells are
transported from the manufacturing facility to the clinical site so that they can be infused

48

intravenously into the patient (Brooks, 2017; Cauchon at el., 2019; Novartis, 2019c;
Kymriah, 2019a; FDA, 2019ae). The average turnaround time "vein to vein," from
leukapheresis to the delivery of the CAR-T therapy to the treatment center for infusion,
can range from 17-22 days (O’Donnell, 2015; Keshavan, 2016; Brooks, 2017; Stanton,
2017a; Bell, 2018; Yarbough, 2018). These turnaround times are critical for patients who
are terminally ill and their disease progression can outpace the manufacturing process
steps.
Figure 7 Autologous CAR-T Manufacturing Process Flow

This figure illustrates the standard apheresis process flow within the autologous CAR-T manufacturing
process. The author created this figure based on information obtained from the literature review (Stanton,
2017a; Celgene, 2019; Novartis, 2019c; Yescarta, 2019; Kymriah, 2019a).

With all the moving parts of clinical trials for CGTs, the industry is continuously
playing catch up to meet development, manufacturing, and clinical demands
simultaneously. Consequently, supply chain management (SCM) has become integral to
the development of an effective manufacturing process. The product and process

49

development and the clinical data generation for CGTs must be achieved in parallel with
the establishment of a robust supply chain (Stanton, 2017a; Kili et al., 2019). SCM
should be incorporated into the commercial manufacturing strategy. Regulators may
require sponsors to provide evidence that their distribution processes do not affect
product integrity in their regulatory applications (Kili et al., 2019: Lambert et al., 2020).
Therefore, sponsors should understand the impacts of their SCM processes, and evaluate
all aspects of the supply chain management such as clinical research locations, courier
capabilities, and patient appointment times prior to clinical trial execution (Elverum and
Whitman, 2019; Kili et al., 2019).
2.4 Evolution of Clinical Supply Chain Management
The distribution of medical products has come a long way since package delivery
began in 1852. One of the largest courier companies in the world today, the United Parcel
Service (UPS), was founded in Seattle in 1907 by two teenage boys who made deliveries
by foot and bicycle (RTD Logistics, 2019). In 1953, UPS began air service, offering two-
day deliveries to major cities on the East and West coasts by flying packages in the cargo
holds of regularly scheduled airlines. In 1971, Federal Express (FedEx) was founded, and
by 1973, the company used 14 aircraft planes to deliver to 25 US cities from Rochester,
New York, to Miami, Florida. By 1984, FedEx was delivering shipments on an
international scale through parts of Europe and Asia (FedEx, 2019). In 1988, UPS hit an
industry milestone when the company received authorization from the FAA (Federal
Aviation Administration) to operate its own aircraft, thus officially becoming an airline,
UPS Airlines (UPS, 2019d).

50

The straightforward singular relationship between delivery service and customers
underwent further rapid evolution in the 1980s with the introduction of transportation
brokerages and warehouse management. This transition shifted the focus from just
transportation and logistics to logistics and distribution with the addition of planning,
collaboration, execution, performance, and inventory management (NC State University,
2017; emphasis added). The result began a new science called supply chain management
(SCM), a term developed in 1982 by supply chain expert, Keith Oliver (Kransdoroff,
1982; Oliver and Webber, 1982; Cooper et al., 1997; Heckmann et al., 2003; Oliver and
Laseter, 2003; Stock, 2009; Stock et al., 2010).
Oliver envisioned SCM as a process of planning, implementing, and controlling
the operations of the supply chain to satisfy customer requirements efficiently. This
process included all movement, including storage of raw materials, work-in-process
inventory, and finished goods, from origin to destination (Dulababu et al., 2018).
Although the definition has evolved in the last 20 years, SCM is viewed as having two
significant process flows: (1) material flow, including the movement and storage of
goods and materials; and (2) information flow, monitoring communication and
documentation between supply chain partners to control the flow of goods and materials
(NC State University, 2017).
Supply chain management is an integrating function with primary
responsibility for linking major business functions and business processes
within and across companies into a cohesive and high-performing business
model. It includes all of the logistics management activities noted above, as
well as manufacturing operations, and it drives coordination of processes and
activities with and across marketing, sales, product design, finance, and
information technology (CSCMP, 2019, p. 187).

51

The distribution of goods has become a sophisticated enterprise in which
customers and manufacturers have come to expect secure and rapid turnaround times
(TATs) to and from diverse countries. Customized deliveries, subscription-based
deliveries, and even deliveries directly to the trunk of a car or the interior of a home are
no longer considered unusual (Amazon, 2019). The expectations of customers in the
medical products industry are no different from those of Amazon customers waiting for
groceries or books. The biopharmaceutical industry needs require "on-demand" shipping,
rapid turnaround times, and customized services (Figure 8) (Li, 2014; Dal Porto, 2019).
Figure 8 Evolution of Clinical Supply Chain
This figure shows the evolution of clinical supply chain management. This figure was created by the author
based on culmination of events identified in the literature review.

In the context of medical products, SCM covers the design, management, and
improvement of all supply chain activities involved in the movement the product. SCM
includes transportation of raw materials, ancillary supplies (such as reagents, diagnostic
kits, and drug-delivery equipment), IMPs, clinical supplies, and information through

52

progressive stages to become tangible products for the patient (Rees, 2011; USP, 2006;
Ally and Hendriks, 2020). Looking at the supply chains of traditional pharmaceutical
drug distribution, the simplest form of distribution would be a medical product going
from the manufacturer to the patient, typically at pharmacy or clinic. However, most
often once a drug leaves a manufacturer’s custody, the product enters a complex system
of handoffs and distribution chains to get to the patient (Figure 9) (USP, 2006).
Figure 9 Pharmaceutical Drug Distribution Pathway
This figure provides a high-level overview of distribution pathways for finished pharmaceutical drug
products. The figure was copied from source (Unites States Pharmacopeia, 2006, USP, 1079).

For clinical test articles and material, the complete management of the supply
chain for a clinical trial is essential to assure the delivery of quality products along
multiple distribution pathways to and from the patient, manufacturing site, and clinical
site (Rees, 2011). Based on the literature (Rees, 2011; O’Donnell, 2015; Page, 2016;
Sandoz, 2017), a single medical product averages around twenty touchpoints between

53

seven different service providers (Figure 10). Each touchpoint increases the potential for
error and entails multiple transactions, which may include, but are not limited to:
• The transfer of information, including clinical data, patient information, and
shipment documentation.
• The transfer of medical products, including diagnostic material and human
specimens.
• The transfer of ancillary supplies, including packaging material, temperature
monitors, and tracking devices.

Figure 10 High Level Clinical Trial Distribution Process Flow
This figure provides a high-level overview of clinical trial distribution process flow and the types of
material transported along the supply chain. Material such as IMPs, documentation, clinical data, and
packaging can move along the supply chain. The author created this figure based on culmination of the
literature review.

These activities can be illustrated by considering how a manufacturer might
transport their materials to and from a clinical site. At the time of delivery to the site,
medical product is received by site personnel who then distribute drugs appropriately to
the patients. In return, analytical samples (i.e., blood, cells, or tissue specimens) and
expired IMPs may be retrieved from the site. The analytical samples would be sent to a
central lab for further processing, while the expired IMPs would be transported to an

54

approved destruction depot (Rees, 2011). All unused, expired, or damaged test materials
will be returned, which allows the manufacturer or an authorized designee to reconcile
the medication and dispose them per the regulations (ICH E6 (R2), Good Clinical
Practices, 2018). Sponsors, therefore, need to coordinate reverse logistics and incorporate
a two-way distribution process that accounts for material sent to and from the patient
(Rees, 2011).
For CGTs, the number of touchpoints greatly increase due to the manufacturing
and distribution process steps required to manufacture and administer the therapy to the
patient. For autologous CAR-T therapies, there are often three logistics pathways: (1)
tumor cell collection, (2) apheresis and (3) therapy return to the patient (Figure 11 and
Figure 12). The flow of material from the patient to the patient is often referred to a
closed-loop (Jebara, 2015; O’Donnell, 2015).

55

Figure 11 Autologous CGT Manufacturing Supply Chain Pathways
This figure demonstrates the three major cell-therapy manufacturing process steps: (1) tumor cell
collection, (2) apheresis and (3) therapy return to the patient. The diagram provides a more granular
overview of the supply chain touchpoints involved in the manufacturing process of autologous cell and
gene therapies. Graphic re-created by the author and modified based on figure created by O’Donnell, 2015.
Modifications and additions were made to the figure based on the literature review (Rees, 2011; O’Donnell,
2015; Celgene, 2019; Novartis, 2019c; Yescarta, 2019).

56

Figure 12 Clinical Trial Distribution Cycle and CAR-T Manufacturing Cycle
The figure illustrates an example of the process steps in a standard clinical trial distribution (CTD) cycle.
The outer ring represents the clinical trial distribution (CTD) cycle, which can occur multiple times over
the course of the CAR-T manufacturing process. Note that the CAR-T cycle described is based on an
autologous CGT; the cycle may vary depending on the type of therapy. The author created this figure based
on information obtained from the literature review (Rees, 2011; O’Donnell, 2015; Celgene, 2019; Novartis,
2019c; Yescarta, 2019).

Specialized logistics and supply chain management are especially vital in clinical
trial distribution (CTD) due to the complexities of trial protocols and special handling
requirements of CGTs (Rossetti, Handfield, and Dooley, 2010; Rees, 2011). The
complexities of clinical trials coupled with the requirement to distribute those products to
global sites have driven companies to outsource many of these aspects to third-party

57

logistics (3PL) and Clinical Supply Chain Organizations (CSCOs) such as Marken LLP
6
,
World Couriers
7
, QuickSTAT Inc.
8
Cryoport, and Thermo Fisher Scientific, to name a
few. Currently there over 85 specialty logistics services for fragile products like vaccines
and cell and gene therapies. These companies have expertise in distributing clinical trial
supplies, cold chain management including packaging and labeling, and trade compliance
(import and export regulations) (Rees, 2011; AmerisourceBergen, 2012; Reportlinker,
2018; Quick International Courier, 2018; Young, 2019; Cryoport, 2020). To support the
demand of the specialized logistical requirements for CGTs products, clinical trial
logistics organizations have invested in infrastructures (facilities and equipment),
improved tracking technologies, and human resources (Basta, 2019b).
The need for seamless end-to-end supply have led to multiple partnerships,
alliances, and agreements between the biopharmaceutical companies and logistics
services providers (Kurmann Partners, 2018; Srivastava, 2020a; Srivastava, 2020b;
Blankenship, 2020c). In some cases, pharmaceutical companies have acquired or added
specialty logistics business units to manage the total supply chain (from manufacturing to
the patient) in-house (AmerisourceBergen, 2012; UPS, 2016; GE Healthcare, 2019). As
precision medicines bring specific patients into the supply chain more directly, additional
pressure is placed on the supply chain to create logistics platforms that can connect
therapies directly to patients at both clinical and commercial scales, often through a
Logistics by design (LbD) approach. LbD is a risk-based framework used to create a
logistics strategy for clinical and commercial development. Through this process, supply

6
Subsidiary of United Parcel Services
7
Subsidiary of AmerisourceBergen Corporation
8
Subsidiary of Kuehne + Nagel International AG

58

chain management is customized based on the sponsor, manufacturer, and protocol
requirements in tandem with the needs of the patient (Ellison et al., 2018; Ellison, 2018).
2.4.1 Challenges with Supply Chain Management for CGTs
Precision medicines require end-to-end traceability and a chain of identity from
the manufacturing floor to the patient (Sawicki, 2018). The chain of custody (COC), the
data that captures shipment attributes (i.e., physical handovers, location, collection and
delivery times) while in transit, and chain of identity (COI), the patients' data (donor
unique identifiers) linked to the raw material (donor cells), must be maintained
throughout supply chain lifecycle (21 CFR 1271.265(d), Current Good Tissue Practices;
Keshavan, 2016; Lamb at el., 2017; Sawicki, 2018b; Hagen, 2019; Seymour, 2019;
Cytiva, 2019; Cytiva, 2020). This can be difficult because the number and nature of the
stakeholders can vary. Cell and gene therapies depend on flawless execution of SCM;
however, this execution is often easier said than done. Any shortage of IMPs or delays
that compromise the medical product could result in the failure to collect adequate data
and thus create significant setbacks in the commercialization timeline (Meacle et al.,
2016; Dearment, 2019; Kirsh, 2018). One estimate places the monetary loss delays at
about $1 million dollars (USD) per day (Shanley, 2018a).
2.4.1.1 Cold Chain Management
What grocery store would sell unrefrigerated meat or outdated cartons of
milk? Yet, across the globe, billions of dollars worth of pharmaceutical
products are stored and shipped at improper temperatures, or they’re delayed
so they reach their destinations past their shelf lives. Such incidents make
some drugs not only ineffective, but harmful and possibly even life-
threatening to the people who count on them for everything from preventing
the flu to fighting cancer (Sykes, 2018, p.154).

59

A challenge when working with live cells such as those often used in CGTs is the
need to maintain the products under temperature-controlled conditions. However,
maintaining product temperature conditions to ensure stability is not always an easy feat.
The operations involved in storing and transporting medical product at recommended
temperatures between two points are collectively considered as part of Cold Chain
Management (CCM) (Harrington, 2016; Harrington, 2018; Meacle et al., 2016; Bennett,
2018; Bennett, 2019; WHO, 2019). CCM includes, but is not limited to, monitoring
temperature data, producing contemporaneous documentation, package, and labeling, and
ensuring that all equipment used to maintain product integrity is calibrated and qualified
for use.
The temperatures at which medical products must be held can vary depending on
the specifications of the product. Some products can be shipped at ambient or controlled
room temperature (20°C to 25°C); others must be refrigerated (2°C to 8°C); frozen
(-15°C to -20°C); or ultra-low to deep-frozen (-60°C to as low as −200°C) (Meacle et al.,
2016; Sykes, 2018; Tavokoli, 2019). Various stages of the production process can have
different requirements. Most gene therapy products must be kept at cryogenic
temperatures, below -60°C to -150°C, to maintain the cell count and potency needed to
be safe and effective. For example, Yescarta has a target dose of 2 × 10
6
CAR-positive
viable T cells per kilogram (kg) of body weight, with a maximum of 2 × 10
8
CAR-
positive viable T cells in a 68 mL infusion bag (Tavakoli, 2019; FDA, 2017; Yescarta,
2017). Below this limit, the treatment cannot be provided to the patient. Similarly, if the
T cell count initially obtained from the patient is treated in a way that deviates from the
established protocol, the CAR-T therapy cannot be manufactured (Clarke and Smith,

60

2019; Yarbough, 2018). Therefore, medical products must be shipped in validated
packaging to withstand global transportation conditions, such as unpredictable weather
and transit times (21 CFR 1271.265(d), Current Good Tissue Practices, FDA, 2019a).
The appropriate selection of shipping packages is a top priority for manufacturers
and cold chain suppliers. Advanced packaging such as Liquid Nitrogen (LN2) dry vapor
shippers (cryogenic containers), dry ice shippers (shipping kits used for dry ice) and
thermal isolated packaging, such as Crēdo Cube™, that maintain temperature
specifications for an average of 72 hours, are a standard in the industry (Pelican
BioThermal, 2019; Sykes, 2018). Dry ice shippers can hold frozen biological samples at
-80°C, whereas LN2 dry vapor shippers can maintain a lower temperature of -190°C, for
an average of 10 days. For critical applications, packaging approaches must be tested and
then specified as one of the product requirements before trials begin (Meacle et al., 2016;
Sykes, 2018).
A crucial component of cold chain management is the associated documentation
and labeling. For temperature-controlled freight, documentation must include
temperature-control requirements, such as instructions regarding the physical orientation
of the shipper on the labels. Physical orientation is crucial for LN2 dry shippers because
inappropriate orientation may hasten evaporation. In July 2012, International Air
Transportation Association (IATA) mandated, an IATA Time and Temperature Sensitive
Label to specify the shipment's external-temperature range on the label (Schaefer, 2014;
Sorany, 2014; IATA, 2010; IATA, 2013; IATA, 2019a; IATA, 2019b; IATA, 2019c).
These labels are typically used as visual indicators for proper storage at airports, on
airplanes, and at the clinical site.

61

Documenting the appropriate storage conditions is fundamental at all points in the
product's transit and storage. All temperature data must be monitored, collected, and
downloaded to verify that temperature stability had been maintained during transit
(WHO, 2010; WHO, 2011; WHO, 2015; WHO, 2016). Inaccurate and missing
temperature data, and temperature excursions – exposure to temperatures outside of the
prescribed range of the clinical protocol and package insert— can delay patient treatment,
increase drug development costs, and compromise the clinical trial (WHO, 2011; Kumar
and Jha, 2017; Harrington, 2018; Dearment, 2019; Young, 2019). The pharmaceutical
industry loses roughly $35 billion annually due to temperature excursions, making
distribution one of the most fragile links in many manufacturers' product development
(Montgomery, 2015; Sykes, 2018; McHarg, 2019a; McHarg, 2019b). With the increase in
biologics and advanced therapies, Cold Chain Management has become a requirement for
the biopharmaceutical industry. Currently, 95% of all approved biologics are cold chain
dependent, whereas critical tissue and blood samples must be shipped in controlled
temperature conditions (Reportlinker, 2018). Currently, the US and Europe hold
approximately 80% of the market share of temperature-sensitive medical products
(Reportlinker, 2018). Based on the current regulatory pipeline for advanced therapies, it
is predicted that 30 of the 50 top global biopharma products will require CCM by 2022
(McHarg, 2019a; McHarg, 2019b; Pelican BioThermal, 2019; Pharmaceutical
Commerce, 2017; Pharmaceutical Commerce, 2018; Pharmaceutical Commerce, 2020).

62

Established ways of gathering, transferring, and storing data and materials
for traditional biopharmaceuticals will not work in the evolving supply chain
for autologous and allogeneic therapies. For one thing, manufacturing and
transport involve many more diverse stakeholders and patient groups than
traditional programs, while, for autologous therapies, there is a need to
closely coordinate raw material extraction and final product production, and
transport to and from collection centers and from manufacturing to clinic
(Shanley, 2020a, p.48).

2.4.1.2 Vendor Management
The relationship between biopharmaceutical companies and supply chain vendors
has evolved over the last 20 years. In the past, biotechnology and pharmaceutical
companies would handle the distribution for their commercial products and raw materials
by using in-house personnel. However, fragile biologic drugs such as CGTs that require
controlled-conditions, specialized packaging, and containment, have changed the
dynamics of how the two industries work together (Young, 2019). Limited resources,
and costs have driven sponsors and manufacturers to outsource most activities related to
clinical trials, manufacturing, and distribution (Rossetti, Handfield, and Dooley, 2010;
Rees, 2011; UPS, 2014; UPS, 2015: Mattuschka and Santa-Maria, 2015; Harrison et al.,
2017; Harrison et al., 2019; Heidaran, 2019). However, vendor management can be
difficult to control due to the increased number of stakeholders involved in CGTs
products (Shaffer, 2020). CGTs rely on strict coordination with hospital personnel,
clinical sites, manufacturing facilities and couriers, to name a few (Garde, 2017; Stanton,
2018b; Elverum and Whitman, 2019: Labant, 2020). In the case of Yescarta, Kite Pharma
estimated that the production of one batch of product for one patient required over 150
vendors (inclusive of scientists, doctors and nurses, manufacturing and clinical sites, and

63

couriers) over the course of 30-day manufacturing process (Garde, 2017; Hodge, 2019:
Stanton, 2019b).
Due to safety risks associated with CGTs, all vendors have to be qualified along
the supply chain. The risks of cytokine release syndrome (CRS), an immune response to
the activation and proliferation of CAR-T cells, and neurologic toxicities, associated with
CGTs, requires that all hospitals and associated clinics that dispense CGTs be certified to
assure safe administration of the product (FDA, 2017; Gilead, 2017; Hodge, 2019; FDA,
2021l). Moreover, treatment centers must be accredited by the Foundation for the
Accreditation of Cellular Therapy (FACT)
9
, a non-profit that establishes standards and
accreditation for medical and laboratory practice in cellular therapies (Elverum and
Whitman, 2019; FACT, 2020). Although this accreditation does not have FDA oversight,
CGTs products like Kymriah and Yescarta are approved under a Risk Evaluation and
Mitigation Strategy (REMS), an FDA mandated drug safety program required for
products with serious safety concern. REMS requires that vendors and suppliers be
certified, qualified, and approved (FDA, 2017b; FDA, 2017c; Yescarta, 2019; Basta,
2019a). As part of that certification, all staff involved in the prescribing, dispensing, or
administering of products like Yescarta are required to be trained to recognize and
manage severe adverse events such as CRS and nervous system toxicities (FDA, 2017b;
FDA, 2017c). Kite Pharma and Novartis have certified over 80 apheresis centers for cell
collection and over 90 centers in the US and Europe respectively to administer their
CAR-T drug. This certification is to ensure standardization along the supply chain (Kite

9
Co-founded by the International Society for Cell and Gene Therapy (ISCT) and the American Society for
Transplantation and Cellular Therapy (ASTCT)

64

Pharma, 2017; Stanton 2018; Stanton, 2019a; Stanton, 2019b; Blankenship, 2020c; Kite
Pharma, 2020).
Although outsourcing can lift some of the burdens that CTD will impose, the use
of vendors can have its own risks and challenges (Pagliarulo, 2017; Shanley, 2018b;
Shanley, 2018c). High costs for transportation and warehousing can offset the financial
and operational gains of outsourcing (UPS, 2014; UPS, 2015). With the increase in direct
and indirect transactions, vendor oversight can become cumbersome and an almost
impossible task. Foreseen and unforeseen challenges, such as clinical site packaging and
storage capabilities, operating hours and preferences for shipment deliveries are aspects
of considerations may delay or prevent treatment to a patient. Other stakeholders such as
airline personnel can also disrupt the supply chain if CGT product are not stored at the
appropriate temperature ranges, or not loaded on the plane (Jafferi, 2019; Ellison, 2019).
Besides training, communication and process gaps, systems integration between suppliers
can also pose a challenge for sponsors and manufacturers due to variance in software and
standard operating procedures (Lennard and Matlis, 2011; Mitchell et al., 2019; Elverum
and Whitman, 2019).
Vendor and supplier qualification is a regulatory requirement not just in the US,
but also in other geographies such as Europe, Canada, and Asia. Sponsors are responsible
for ensuring that vendors are trained, capable of executing tasks according to the clinical
protocol and based on the product specification and follow all applicable regulations to
reduce protocol deviations and remain compliant. However, this training can be relatively
focused. The literature revealed that only 25% of pharmaceutical companies share their
intellectual property, such as best practices and proprietary information, with their

65

vendors (Lennard and Matlis, 2011). Most sponsors rely on their vendor management
qualification programs such as on-site and paper-based audits to ensure their suppliers are
compliant with applicable regulations. However, these assessments are periodic—usually
every two years— and only provide a snapshot of a facility at the time of the audit. These
intervals make it difficult for sponsors to detect deficiencies proactively. Additionally,
after performing an audit, companies often do not receive new data from their suppliers
or contract providers (Lennard and Matlis, 2011). Although most biopharmaceutical
companies have dedicated personnel to qualify and manage vendors, the size of the
resources can range depending on the size of the organization. Moreover, visibility
becomes limited when vendors are located off-site, in other states, or even more so in
other countries that do not have the technological, operational, and regulatory capabilities
as more developed regions.
2.4.1.3 Globalization of Clinical Trials
With more than 900 regenerative medicine companies and more than 1,000
clinical trials underway worldwide in 2018, the industry is growing at an
exponential pace. Creating robust supply chains that can efficiently scale up
and connect the right therapies to the right patient is key to enabling the
commercialization of cell and gene therapies (GE Healthcare, 2019, para 5).

Between 2011 and 2015, the number of countries conducting Phase III trials at
global trial sites increased by 63 percent (Shanley, 2018a). As of July 13, 2019, ~60% of
clinical trials registered in the United States were being conducted internationally
(ClinicalTrials.gov, 2019a; ClinicalTrials.gov, 2019b; ClinicalTrials.gov, 2019c).
Multinational trials have many advantages for biopharmaceutical manufacturers. Foreign
trials can provide expanded access to treatment naïve patients or patients with rare
conditions, decrease costs, and generate foreign clinical data required for product

66

approvals in other countries (Federal Register, 1998; FDA, 2006; FDA, 2012; Herbert et
al., 2016). However, they can be more difficult to manage because they must make
additional provisions related, for example, to the diverse cultures and languages, country-
specific import and export requirements, time zone differences, airline schedules, and
temperature and humidity variances that can affect distribution logistics.
Regional regulations and policies also present barriers for manufacturers because
these are typically nonstandard and often undergoing change. For example, all
consignments to China must adhere to National Medical Products Administration
(NMPA) regulations, Good Supply Practices for Pharmaceutical Products; shipments to
Brazil must adhere to Good Practices of Medicament Manufacturing during storage and
transportation under the oversight of the Agência Nacisonal de Vigilância Sanitária
(ANVISA); shipments in Canada must adhere to Guidelines for Temperature Control of
Drug Products under Health Canada. At the same time, however, all medical products in
the supply chain must also adhere to the applicable global regulations, policies, and
standards (Health Canada, 2019; ANVISA, 2019; NMPA, 2019; IATA, 2019a).
Because customs and regulatory requirements vary depending upon the country,
import/export and clinical trial license requirements, as applicable, must be considered by
sponsors. The sponsor must ensure that an appropriate level of support and infrastructure
must be in place to transport and manage its clinical supplies, especially in regions where
the physical infrastructures at the sites can lack adequate services, such as electricity or
temperature-controlled equipment, to protect the product (Herbert, 2016; Fleming, 2018;
WHO, 2019).

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2.4.2 Regulatory Landscape for Clinical Trial Distribution of Advanced Therapies
Given the complexities of CGT distribution, it is not surprising that numerous
laws, regulations, and treaties exist across regulatory agencies domestically and globally.
In the US, several governing entities participate in the oversight of CGT distribution.
These include, amongst others: (1) the Food and Drug Administration (FDA); (2) the
Department of Transportation (DOT); (3) the Federal Aviation Administration (FAA); (4)
the Center for Disease Control and Prevention (CDC); (5) the United States Department
of Agriculture (USDA); (6) the US Customs and Border Protection (CBP); and (7)
Environmental Protection Agency (EPA). Each agency serves a different purpose and but
shares a common goal to protect public health and consumer safety, as shown in Table 4.
If a shipment is being transported globally, the International Air Transportation
Association (IATA) and other regulatory agencies related to the target countries have
rules and policies determined by shipment type that also need to be considered. These
regulations have become stricter as threats such as the importation of unapproved medical
products, and substandard drugs have become a societal problem (FDA, 2018f; FDA,
2018g; FDA, 2019n).

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Table 4 Regulatory Oversight and Considerations for Clinical Trial Distribution
This table provides a high-level overview of some of the agencies and associations that provide oversight
of transportation and distribution of products within and outside of the United States. This oversight also
has a direct impact on the clinical supply chain as these agencies have special provisions for medical
products that may spread communicable diseases and introduce threats to the supply chain. This table was
created by the author.
Agency Scope of Oversight
CBP US Customs and Border Protection (CBP), the largest federal law enforcement
agency of the United States Department of Homeland Security, is responsible for
controlling and monitoring at ports of entry, including screening all imported cargo
that enters the United States. Currently, there are more than 300 land, air, and
seaports (CBP, 2020).
CDC Center for Disease Control and Prevention (CDC) is a subset of Department of
Health and Human Services. The agency is responsible for the safety and security
threats to the public, both in the US and abroad. The CDC Import Permit Program
(IPP) regulates the importation of dangerous biological materials. It ensures that
importation is monitored and that facilities receiving permits have appropriate
biosafety measures in place (CDC, 2020).
DOT The U.S. Department of Transportation (DOT), established by Congress in1966,
ensures the safety and efficiency of the transportation system in the world (DOT,
2020a).
EPA The United States Environmental Protection Agency (EPA) is an independent
agency of the United States federal government. EPA regulates and enforces
environmental protection laws, such as the Clean Air Act, which protects the air and
water supply (EPA, 2020b).
FAA Federal Aviation Administration (FAA) is a subdivision of the DOT, Department of
Transportation. The mission of the agency is to ensure the safety and efficiency of
the aeronautics and commercial space system. This agency enforces flight
regulations (FAA, 2020).
FDA The Food and Drug Administration (FDA) is responsible for ensuring the safety,
efficacy, and security of products such as human and veterinary drugs, biological
products, and medical devices. The scope of FDA’s regulatory authority is very
extensive and may involve collaboration with other agencies depending on the
product (FDA, 2018).
FWS The United States Fish and Wildlife Service (FWS) is an agency within the US
Department of the Interior. The US Fish and Wildlife Service has been designated
to carry out the provisions of Convention on International Trade in Endangered
Species of Wild Fauna and Flora (CITES) through the Division of Management
Authority and the Division of Scientific Authority. Sponsors and manufacturers
may require a CITES permit if transporting biological material of an endangered
species (FWS, 2020).
IATA The International Air Transport Association (IATA) is the trade association for the
world's airlines, representing some 290 airlines (82% of total air traffic) in over 117
countries. The association serves and supports the aviation industry by developing
global standards and regulations, such as temperature control and labeling
requirements (IATA, 2019a).
USDA The United States Department of Agriculture (USDA) division Animal and Plant
Health Inspection Service (APHIS) regulates the importation, interstate movement,
or environmental release of certain genetically engineered (GE) organisms, and
must authorize all regulated introductions of GE organisms under either its
permitting or notification procedures (USDA, 2020).

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In the next section, regulations that are in place to for the distribution of cell and
gene therapies are discussed in two blocks: (1) external regulations and standards
governing the preparation, transportation, and distribution of medical products beyond
the loading dock (Figure 13); and (2) regulatory considerations such as Good Clinical
Practices (GCPs), specific to the conduct of the clinical trial. Both groups of rules and
practices must be foundational to a robust supply chain strategy.
Figure 13 External Regulatory Considerations for Clinical Trial Distribution
This figure illustrates the external regulatory landscape of clinical trial distribution. Outside of the clinical
trial itself, there are additional regulations for the supply chain management of medical products. This
regulatory oversight comes from a variety of agencies. The standards and regulations are more inherent to
supply chain management and clinical trial distribution. The author created this figure based on an
assessment of the literature.

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2.4.2.1 External Regulatory Considerations
Many external considerations may affect the supply chain management of clinical
trials. The external environment is very dynamic and can shift from one day to the next,
especially in an economic crisis or a national public health emergency such as the
COVID-19 pandemic (FDA,2020c; FDA, 2020k, ASPR, 2020). This pandemic led to
global government shutdowns, and impeded, and in some cases, halted clinical trials and
medical product development globally, leaving the biopharmaceutical industry in a
reactive state. These external factors are often unforeseen and beyond the control of the
sponsor or manufacturer. However, per FDA regulations, manufacturers and sponsors
have an obligation to ensure products maintain stability during transit. Manufacturers
therefore must consider these impediments in order to ensure that medical products reach
their intended destination in a safe and effective condition. Failure to consider challenges
associated with political vulnerability, transport regulations such as import and export
laws, and potential diversions along the supply chain is a gamble. Each country has its
import and export regulations to which compliance is critical. Manufacturers must adhere
to these new and potentially different regulations to execute and transport IMPs for their
clinical trial. Haphazard planning can lead to consequential delays that could damage
CGT products, make it impossible to follow the dosing regimens in the trial protocol, and
thus affect the validity of the trial (Kirsh, 2018). In this next section, the study will
explore some of the common regulatory considerations that often affect the successful
execution of clinical trial management and distribution.

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2.4.2.1.1 Exported Goods
The FDA Export Reform and Enhancement Act of 1996 outlines the laws
required for investigational medicinal products and medical products, such as human
biological products, exported from the United States to other countries. Sponsors
exporting products from the US may be asked by foreign governments or consignees to
supply certification validating that the medical product has met the regulatory or
marketing requirements for the country of import (FDA, 2019h; FDA, 2019z; FDA,
2020h). Under the Export Reform and Enhancement Act of 1996, the FDA is given the
authority to issue export certificates for food, drugs, animal drugs, and devices within 20
days of receipt of the request. The FDA is also able to issue export certificates for
unapproved drugs that meet the requirements of sections 801(e) (1) or 802 of the
FD&CA. Depending on the country, a Certificate of Pharmaceutical Product (CPG
7150.01) may be required to export human drug products (including biological drugs)
from the US (FDA, 2000, FDA, 2004; FDA, 2019h; FDA, 2020h). The certificate
provides an official attestation that the product being exported is: (1) freely marketed in
the US; (2) complies with US laws and regulations; (3) complies with the importing
country's requirements; (4) meets international standards; and (5) do not contain specific
contaminant (FDA, 2019h; FDA, 2020h). This certificate must accompany the product
while in transit, or the shipment can be rejected upon arrival into the country.
2.4.2.1.2 Imported Goods
FDA-regulated products entering the United States must meet the same laws and
regulations as domestic goods, so they are subject to inspection. The FDA may refuse
entry if it identifies any violations of the Federal Food, Drug, and Cosmetic Act (see

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FD&CA, sections 536 and 801). Refused products must be destroyed or exported from
the United States within 90 days; the sponsor is responsible for ensuring the medical
product is returned and destroyed per the applicable laws (FDA, 2019p FDA, 2019y;
FDA, 2019z; FDA, 2020i).
US Customs and Border Protection (CBP) has a significant role in managing the
import process. CBP is the largest federal law enforcement agency within the Department
of Homeland Security. It monitors and controls all ports of entry. Imported cargo may
require additional import permits from agencies such as Department of Transportation
(DOT), Centers for Disease Control and Prevention (CDC), Department of Agriculture
(USDA), Environmental Protection Agency (EPA), and US Fish and Wildlife Services
(FWS) depending on the medical product type. Import permits are needed for diagnostic
specimens, infectious substances, microbial toxins, and select agents such as hosts and
vectors of human disease. Import material must be packaged and labeled according to
instructions given in 42 CFR 72, 49 CFR 171–178, and IATA Dangerous Good
Regulations (DGR). The materials must also be handled as outlined in the CDC and NIH
guidance documents (CDC, 2020; CBP, 2020). If a shipment does not have all the
required permits and entry documents, it can be held in customs, a delay that poses a risk
to time-sensitive and temperature-sensitive biologics.
2.4.2.1.3 Management of Restricted and Hazardous Materials
Human cells, tissues, and cellular and tissue-based products (HCT/Ps), such as
complex biologics and CGTs that may transmit communicable diseases, have transport
restrictions and declaration requirements. Key to the domestic transport of biologics and
pharmaceutical products are the regulations issued by the Department of Transportation

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(DOT) and the Federal Aviation Administration (FAA). International Air Transportation
Association (IATA) regulations and standards also must be followed when medical
products are sent internationally (Schaefer, 2014; Sorany, 2014; IATA, 2010; IATA,
2013; IATA, 2019a; IATA, 2019b). Under hazardous materials regulations, whether
domestic or international, shipments of biological materials can be divided into four
groups: (1) non-regulated biological material; (2) exempt human or animal specimens;
(3) biological substances in Category B (UN3373), defined as an infectious substance in a
form generally incapable of causing permanent disability or life-threatening disease; and
(4) biological substances in Category A, which are infectious substances assigned to
UN2814, infectious substance, affecting humans or UN2900, infectious substance,
affecting animals (49 CFR Part 173, Subpart E, 2020).
Hazardous materials sent using commercial transportation must follow hazardous
materials (HazMat) regulations, 49 Code of Federal Regulations (CFR) Parts 171-179, to
ensure public safety and occupational safety for those who prepare or transport hazardous
materials. Enforced by the DOT, they provide details on the documentation, preparation,
labeling, and transport of hazardous material. For example, solid carbon dioxide (dry ice)
is commonly used to control the temperature of biological material during transport. Dry
ice (UN1845) is classified by DOT and IATA as a miscellaneous hazard, class 9, and has
strict labeling, weight allowances, and handling requirements because it can explode,
cause suffocation, or burn the skin upon contact (49 CFR 173.217). In the US,
transported materials must also comply with regulations in 40 CFR Parts 239-282
promulgated by the EPA to control hazardous waste from the inception to disposal.
Regulations enforced by agencies such as DOT, EPA, as well as applicable federal, state,

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and local regulations apply to any entity that offers, accepts, or carries hazardous
materials to, from, within, and across the United States (Smith, 2018; FDA, 2020d; FAA,
2019; DOT, 2020b, EPA, 2020a). Those who violate these regulations can be fined up to
$32,500 per violation. Since 1998, the agency has collected a yearly average of $6.5
million for violations of the hazardous materials regulations (FAA, 2019).
2.4.2.1.4 Political Vulnerability
Laws and regulations are often slow to change, but political environments are
much more dynamic. Their changes can have a significant effect on SCM. Imposed
border restrictions may prevent the transfer of goods, whereas inflation and increased
taxes and fees can lead to unexpected shipping costs. In January 2020, for example, the
separation of the United Kingdom (UK) from the EU— BREXIT— was ratified, a
change that will complicate the investigational drug distribution process to the UK. When
the UK leaves the European Union, it could enact new import and export regulations
(BBC, 2019a; BBC, 2019b; Love, 2019; Mueller, 2020; Almac, 2019; O'Connor, 2019).
However, much uncertainty exists regarding these regulations and permit requirements.
New rules hold the potential to disrupt the supply chain strategy and generate process
gaps that were not previously a concern. These inconsistencies would leave sponsors very
reactive and may hinder patient access to medical products.
2.4.2.1.5 Control of Counterfeit and Adulterated Products
A significant challenge for supply chain security globally has been the use of
transport and distribution channels for counterfeit or substandard drugs. In developing
countries, 1 in 10 medical products are adulterated or falsified (Irish, 2010; WHO, 2010b;
Clauson et al., 2018; Breman, 2019; Chavez-Dreyfuss, 2020). Up to $200 billion (USD)

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worth of counterfeit drugs are traded annually, with more than 50% of the drugs in third
world countries made up of counterfeits or substandard products (WHO, 2010b; Clauson
et al., 2018; Breman, 2019; Chavez-Dreyfuss, 2020). Thus, it is not surprising that many
countries have enacted laws to control their entry into the supply chain. As part of the
effort, in the US, Congress passed the two acts: (1) the Food and Drug Administration
Safety and Innovation Act (FDASIA), more specifically, Title VII of FDASIA, Drug
Supply Chain Provisions, in 2012 and (2) the Drug Quality and Security Act (DQSA) in
2013 (FDA, 2018g; FDA, 2018k).
Title VII of FDASIA, Drug Supply Chain Provisions, increased FDA’s oversight
of imported drug products such as active pharmaceutical ingredients (APIs), raw
materials, and finished pharmaceuticals globally (FDA, 2018f; FDA, 2018g; FDA,
2018h). Currently, 40% of finished drugs and 80% of active ingredients are manufactured
outside of the US, which leaves the current pharmaceutical supply chain vulnerable to
theft, adulteration, and counterfeiting (FDA, 2018f; FDA, 2019u). The law amended
section 304(g) of the FD&C Act (21 U.S.C. 334(g)) and provided the FDA the authority
to administratively detain and even destroy suspected adulterated or misbranded drugs. It
allowed the agency to: (1) perform data collection, and analyses for early detection of
public health threats; (2) utilize a risk-based approach when auditing domestic and
foreign drug facilities such as contract development and manufacturing organizations
(CDMO); (3) partner with foreign regulatory authorities; and (4) ensure safety and
quality throughout the supply chain by preventing the entry of substandard products
(FDA, 2018g; FDA, 2018h).

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Similar to FDASIA, the 2013 Drug Supply Chain Security Act (DSCSA), and
specifically Title II of Drug Quality and Security Act (DQSA), gave the FDA more
authority to oversee outsourced activities such as those to third-party logistics suppliers.
The act amended the Food Drug and Cosmetic Act by adding sections 581 and 582 to
establish mechanisms for tracking and verifying the authenticity of finished
pharmaceutical products (Wertheimer et al., 2003; FDA, 2018f; FDA, 2019n). The
amended regulations established national licensure standards and required that wholesale
distributors and third-party logistics providers report licensure and other information to
the FDA annually (FDA, 2018k). New rules regarding the tracking and logistical
management of pharmaceutical products were developed for parties that participate in
drug distribution. They require manufacturers to: (1) provide product identification with a
unique product identifier on specific prescription drug packages to ensure traceability; (2)
establish systems and processes to verify the product identifier; (3) investigate any
unapproved drug promptly and notifying the FDA and other stakeholders of that illicit
drug; and (4) ensure third-party logistics providers have the appropriate state or federal
licenses and that the information is provided to the FDA (FDA, 2018k; FDA, 2019n).
The FDA has recognized that the regulations are burdensome and can face
technological hurdles that may hinder its implementation. The FDA and major
biopharmaceutical companies have invested resources in blockchain technologies to
improve supply chain efficiencies (Schöner et al., 2017; Benchoufi and Ravaud, 2017;
Brettlier, 2019; FDA, 2019g; MediLedger, 2019; Wood, 2019). Blockchain represents a
form of distributed ledger technology (DLT) that allows transactional records or proof of
ownership to be transferred from one entity to another entity. These transactions and the

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associated details are recorded in multiple places simultaneously to preserve data
integrity. Data cannot be changed without validation; information is stored with unique
identifiers that safeguard the data and provides real-time information (Clauson et al.,
2018; Barley, 2019; Challener, 2019; FDA, 2019o; Reiff, 2020). In 2019, the agency also
collaborated with MediLedger, a San Francisco digital solutions organization, to
implement a pilot program utilizing blockchain technology. The goal of the pilot was to
assist manufacturers with testing and implementing tracing systems to comply with the
2023 deadline. The pilot took place for six months (February 2019 – August 2019) and
included more than 20 members from the biopharmaceutical, clinical research, and
wholesale distribution industries (Brettlier, 2019; MediLedger, 2019; FDA, 2019o; FDA,
2020i; Wood, 2019). The MediLedger working group released the outcomes of the pilot
in February 2020 to share lessons learned with the industry (FDA, 2019o; Sample et al.,
2020; Ledger Insights, 2020). In addition, the agency has provided a 10-year plan, which
is set to be implemented fully by 2023, to assist manufacturers with compliance of the
new law. Further, the FDA has established a Division of Supply Chain Integrity to
monitor, control, and safeguard the global drug supply chain (FDA, 2019l). The mission
of the division is to increase transparency and accountability, develop effective
enforcement methods, and promote proactive industry vigilance and voluntary
compliance with regulations and best practices (FDA, 2018; FDA, 2019l).
2.4.2.2 Internal Regulatory Considerations
Regardless of transport specifics, multiple FDA regulations exist with respect to
clinical trials generally and the management of IMPs more specifically. Two major

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standards that are perhaps most relevant are Good Clinical Practices and Good
Distribution Practices, which have considerations for CTD (Figure 14).
Figure 14 Internal Regulatory Considerations for Clinical Trial Distribution
This figure illustrates the internal regulatory landscape of clinical trial distribution. More internal to clinical
trial conduct are: Good Clinical Practices (GCP), Good Distribution Practices (GDP), and Good
Manufacturing Practices (GMP). GCP focuses on clinical trial conduct; however, this standard also aligns
with GMP regulations with respect to how investigational medicinal products (IMPs) are manufactured.
GDP act as an extension of GMP by providing additional specifications regarding storage and distribution.
Outside of the clinical trial itself, there are overarching regulations for the supply chain management of
medical products. The author created this figure based on an assessment of the literature.

2.4.2.2.1 Good Clinical Practices (GCP)
Good Clinical Practices (GCPs) guidelines, initiated by the International Council
for Harmonization (ICH) and World Health Organization in 1996, are accepted as the
industry standard for research conduct by most regulatory agencies globally. GCPs set
the ethical and quality standards for designing, conducting, recording, and reporting
clinical trials that involve the participation of human subjects (ICH, 2015; FDA, 2018d).

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In 2016, ICH E6, Good Clinical Practices, was amended to account for technological
advances and modernized clinical trial designs. The amendment incorporated risk-based
quality management and improved standards for data collection and analyses (ICH, 2015;
FDA, 2018d). In 2018, the FDA accepted E6 GCPs as the standard for US trials.
Amongst its many elements are requirements that the sponsor identifies the acceptable
storage conditions to assure product stability, if appropriate, for IMPs (Khan et al., 2018).
The sponsor must communicate product specifications and protocol requirements to
clinical sites and all vendors to ensure the timely delivery of test products. It must also
maintain records that document the shipment, receipt, disposition, return, and destruction
of IMPs, according to Good Documentation Practices (GDocP) (ICH, 2015; ASQ, 2017;
FDA, 2018d).
Requirements for test article management also extend to the trial site. Personnel
have record-keeping responsibilities to identify when and how they receive the product,
administer treatment to patients, and dispose of or return unused materials to the sponsor.
In addition to written records, computerized systems must have adequate controls to
prevent unauthorized access, data breach, or manipulation of distribution per 21 CFR Part
11 (FDA, 2003a; FDA, 2019j). Thus, validated data protection must be in place for all
computerized systems to safeguard sensitive patient information and adhere to applicable
privacy laws such as Health Insurance Portability and Accountability Act of 1996
(HIPAA) and General Data Protection Regulation (GDPR) (FDA, 2018d; FDA, 2018i;
Regulation (EU) 2016/679, European Commission, 2016; GDPR.eu, 2017; GDPR.eu,
2018).

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Data privacy requirements in the EU are stricter than HIPAA requirements in the
US. The EU Directive, General Data Protection Regulation (GDPR), enacted in May
2018, controls information flow through the supply chain. GDPR requires manufacturers
and distributors to obtain patient consent prior to using their data. Sponsors must
maintain data anonymity, safeguard the transfer of data across borders, provide a data
breach notification, and in some cases, appoint a data protection officer to monitor and
control GDPR compliance (Regulation (EU) 2016/679, European Commission, 2016;
GDPR.eu, 2017; GDPR.eu, 2018). Inspired by GDPR, local, regional, and state data
protection laws have been enacted in parts of the US.
2.4.2.2.2 Good Distribution Practices (GDP)
The term ‘distribute’ or ‘distribution’ means the sale, purchase, trade,
delivery, handling, storage, or receipt of a product, and does not include the
dispensing of a product pursuant to a prescription executed in accordance
with section 503(b)(1) or the dispensing of a product approved under section
512(b) (FDA, 2014, Drug Supply Chain Security, Section 581, p.5 ).

Good Distribution Practices (GDPs) extend requirements implied by GMP
regulations (21 CFR 211) with respect to supply chain management. GMPs focuses
primarily on the intermediary activities that are bookended by upstream and downstream
supply. Whereas GDPs provide more guidance on the transportation and logistics of
medical products, including responsibilities to maintain the integrity of these products
along the supply chain.
GDP is that part of quality assurance which ensures that the quality of
medicinal products is maintained throughout all stages of the supply chain
from the site of the manufacturer to the pharmacy or person authorized or
entitled to supply medicinal products to the public (European Commission,
2013, 2013/3/C 343/01, pg. 13, para 1).

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In 1992, the European Commission (EC) mandated distribution requirements in
Article 10 of Council Directive 92/25/EEC, Wholesale Distribution of Medicinal
Products for Human Use, to guide the implementation of controls at the wholesale level
(92/25/EEC, European Commission, 1992). The established GDP guidelines were
modified in 2013 to incorporate Directive 2011/62/EU, Securing the Supply Chain from
Falsified Medicinal Products (2001/83/EC; 2011/62/EU; 2013/C 343/01). Driven by
concerns of counterfeit medical products and an unsecured supply chain, the directives
provided a framework to maintain the quality and integrity of medicinal products
throughout the supply chain. GDP compliance requires medical products to be stored
under appropriate conditions to control temperature and cross-contamination, for
example. GDP also ensures that products follow a first-in-first-out (FIFO) method to
minimize the possibility of shipping expired medication and requires shipments to be
tracked and traced so that products can be recalled if needed (European Commission,
2013a; European Commission, 2013b; WHO, 2010a; European Commission, 2015;
WHO, 2016 EMA, 2018c; EMA, 2019).
GDP guidelines and associated directives detail elements much like those in the
more general GMPs. Third-party distributors and manufacturers that comply with GDP
should: (1) incorporate and maintain Quality Management Systems (QMS); (2) have
trained personnel and adequate resources; (3) maintain premises and equipment controls
such as pest control and validated systems; (4) follow Good Documentation Practices
(GDocP); (5) have supplier and vendor management oversight; (6) perform internal
audits; (7) establish complaints, returns, suspected falsified medicinal products and

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recalls processes; and, (8) maintain vehicle and transportation controls (ASHP, 2017;
Herbert, 2016; EMA, 2018c; WHO, 2019).
The World Health Organization (WHO) and the United States Pharmacopeia
(USP) have also developed guidelines for Good Distribution Practices of medicinal
products for human use (Carrico, 2016; USP, 2016a; USP, 2016b; USP, 2011; WHO,
2010a). To date, the FDA has not adopted or mandated compliance with any of these
GDP regulations. Nevertheless, GDP regulations are mandated by nearly forty other
constituencies, such as the Singaporean Health Sciences Authority (HAS) and the Indian
Central Drugs Standard Control Organization (CDSCO) (HSA, 2018; CDCSO, 2018;
Sadler-Williams et al., 2019). Moreover, GDPs are routinely the foundation for best
practices for the life science supply chain industry. With the increase of medical product
shipments, GDP standards are also becoming implemented by the airline industry to
protect the integrity of clinical trial shipments (Mattuschka and Santa-Maria, 2015;
Herbert, 2016; World Flight Services, 2019; Swiss WorldCargo, 2019).
Biopharmaceutical sponsors are especially sensitive to the importance of effective
distribution practices. When they outsource such functions, they expect that their
distribution vendors will have a quality system in place that is consistent with GDP
regulations (Marisol, 2019; Khan et al., 2018).
2.5 Current Trends and Industry Views on Clinical Trial Distribution
An important trend in the last decade has been to encourage patient-centric
approaches, such as precision medicine and customized clinical trials. This trend has
shifted the clinical trial paradigm to require a convergence between supply chain,
biopharmaceutical, and healthcare sectors as they develop decentralized, virtual or hybrid

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approaches (Heckman-Stoddard, 2014; Lamb et al., 2017; Paraxel; 2019; Mayo Clinic,
2019; Personalized Medicine Coalition, 2019). Virtual and patient-centered trials are
predicted to fuel the growth of direct-to-patient (DTP) models within supply chain
management (Syed, 2016; Sweeney, 2016; Science 37, 2019; Harrison et al., 2017;
Harrison et al., 2018; Sweeney, 2019; Wechsler, 2019c). Companies like Genentech and
Novartis have partnered with Science 37, a mobile technology and clinical research
organization focused on decentralized trials, to provide “sightless trials” for indications
such as oncology and neurology (Novartis, 2018b; Science 37, 2019). DTP models are
becoming more important for CGTs due to the increase post-market long-term follow-up
requirements (up to 15 years) required by the FDA and other regulatory bodies (FDA,
2020l). This follow-up requires sponsors to continue scheduled patient visits and
assessments post-trial. Additionally, sponsors have begun to explore the DTP options for
patient in allogeneic CGT trials, which require multiple site visits as opposed to their
autologous counterparts (Reed, 2019).
Unlike traditional drug SCM models, where shipments are transported to a depot
in bulk or to a clinical site for redistribution, DTP is a service in which test articles and
supporting supplies are delivered directly to the patients’ location of choice, usually the
home. Using the same services, patients can return biological samples or unused medical
products to the manufacturer or central lab. DTP is often key to the success of CGT trials
that, for example, include late-stage cancer patients who are too ill to travel to a clinical
site (Kumar, 2018; Wheeler, 2018; Sweeney, 2016; 2019). Some Clinical Supply Chain
Organizations (CSCOs) have established global nursing networks to provide home trial
support; through this service, health care professionals are dispatched directly to the

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patients’ homes or locations of choice to administer IMPs to the patient. Their services,
including, for example, intravenous infusions, biologic sampling, and clinical
assessments, mimic the options available traditionally from brick-and-mortar clinical
sites and thus help to streamline the supply chain processes (Syed, 2016; Wylie, 2016,
Sweeney, 2016, Marken, 2019; World Courier, 2019, Symphony Clinical Research,
2020a; Symphony Clinical Research, 2020b).
As new options in transport become more common, novel solutions will
undoubtedly be added. Already such systems have been implemented in a few operations.
For example, UPS collaborated with drone startup, Matternet, to deliver medical supplies
to WakeMed, a hospital in Raleigh, North Carolina. In October 2019, UPS became the
FAA’s first approved drone airline, UPS Flight Forward Inc. This approval established a
major milestone in the supply chain industry (Vyas, 2016; Hawkins, 2019; UPS, 2019b;
UPS, 2019c; UPS, 2019e; Baertlein and Erman, 2019). Although drone deliveries are still
in the infancy and development stage for CGTs, companies such as Zipline, a medical
drone delivery service, have already begun piloting the transport of blood products and
apheresis material to improve supply chain efficiencies in countries such as Africa, India
and the Philippines (Amukele, 2017)). The company has targeted to begin transport in the
US by the end of 2020 (Baker, 2018; Peters, 2018; Zipline, 2020). Anemocyte, an Italy
based biotech company focused on CGTs, has collaborated with RPS Aerospace to
develop remotely piloted drone system to transport final cell and gene therapy products
securely from manufacturing sites to clinical centers (Bennett, 2019; Anemocyte, 2020).
The current prototype can transport CGT material such as apheresis material and biopsy
specimens. The drone also has GPS tracking capabilities, anti-tampering technology,

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temperature control, and continuous real-time monitoring during flight (Bennett, 2019).
Although current applications are for research and development purposes only, the
reduction of costs, times, and supply chain visibility makes this an attractive option for
sponsors. In some cases, drone delivery has cut flight time from 4 hours to 15 minutes
(WHO, 2019). This improvement would be significant for CGTs, which require
extremely strict timelines (Bennett, 2019).
The addition of drone transport provides an option for on-demand and same-
day delivery which may increase medical delivery efficiency, lower costs and
improve the patient experience with potentially life-saving benefits (UPS,
2019, para 2)

Creative approaches to the physical movement of a shipment are just one piece of
the supply chain puzzle. It extends to the use of digital controls and real-time data
collection coupled with "smart" packaging, which can provide real-time temperature and
location data (Uy et al., 2015; Aliakbarian, 2019; Cryoport, 2019; Forcinio, 2019;
Marken, 2019; TransCelerate BioPharma, 2019; Smart Containers, 2020). Also,
Interactive Response Technologies (IRT) have been introduced to facilitate product
transit documentation and manage data security for clinical trials. These technologies
systematize the documentation of drug accountability and automate restocking of
inventory, including not only the IMPs but also source materials and clinical supplies at
the clinical sites (Knepper et al., 2016; Papert et al., 2016; Janssen Research &
Development, 2017; Wohl, 2018; Montoya, 2019). IT companies such as TrakCel and
Vineti, have developed cloud-based data infrastructures that provide integrated
workflows across the entire supply chain including but not limited to hospital sites,
distributors, manufacturers, and contract organizations. The platform captures real-time

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shipment tracking information, laboratory results, manufacturing milestones, and clinical
data that can be reported to doctors to schedule patient slots or to payers for
reimbursement purposes (Basta, 2019; Novartis, 2019a; Vineti, 2020; TrakCel, 2020).
Confidentiality, traceability, and product security are driving the supply chain
industry from manual and paper-based processes to digital and cloud-based platforms
(Estellat et al., 2008; Li, 2014). In 2017, Pfizer and Biogen established the Clinical
Supply Blockchain Working Group (CSBWG), a consortium of sponsors, CMOs, CROs,
academic sites, and couriers to work toward common goals within SCM. The group has
initiated pilot projects focused on digital inventory, data management, and shipment
traceability (LedgerDomain, 2019). Although many of the projects such as KitChain, a
digital inventory and event tracking system, are still in at early stages, they are poised for
testing in an actual GXP environment (Fassbender, 2018; Sklodosky et al., 2019;
KitChain, 2020). The ultimate objective is to develop an interoperable, transparent, and
auditable platform aligned with the Drug Supply Chain Security Act and FDA’s
initiatives to improve traceability of IMPs from the manufacturer to the patient (Barley,
2019; FDA, 2019k; Godfrey, 2019). Technologies such as blockchain would prove
advantageous for CGTs that require a strict labelling, chain of identity and chain of
custody along the supply chain. Additionally, these technologies improve visibility and
the data integrity of transport requirements needed to safely administer the product to the
appropriate patient at the right time and within the right specifications. More importantly,
these technologies enhance partnerships with vendors, clinicians, and patients (Clarke
and Smith, 2019; Clauson et al., 2018; Barley, 2019).

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The advent of precision medicine is challenging the entire medical research
ecosystem to develop more efficient approaches to testing and developing
diagnostics, and therapeutics, to harness the full potential of science to
reduce the suffering, death, and disability caused by complex human illnesses.
The agency is committed to developing a regulatory framework for precision
medicine that generates robust evidence of product safety and efficacy as
efficiently as possible, including frameworks that are more carefully suited to
the kinds of precision technologies that underpin new treatments (FDA,
2019ad, para 2).
While advancements in technologies have improved the productivity in the
clinical supply chain, the long-term sustainability, feasibility, and regulatory landscape
for such novel methods are still immature. FDA and other regulators encourage such
innovation, but they too are trying to characterize the barriers, threats, and opportunities
associated with virtual trials and technologies of CGT products (Kramer et al., 2012;
Charles et al., 2019). Currently, the expertise in the use of innovative technologies such
as blockchain technologies and alternative clinical distribution models are
underdeveloped in many disciplines at the forefront of precision medicine. The current
regulatory landscape does not account for these adaptions in clinical trials; this is left to
the decision of the sponsor. The agency recognizes this gap and has invested resources
and built partnerships to provide guidance to the public sector and meet the demands of
the industry (Lucchini, 2018; Reh and Standing, 2018; Sadler-Williams et al., 2019;
FDA, 2019u; Cross, 2019).
The FDA have collaborated with working groups such as Standards Coordinating
Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery
(SCB), a non-profit organization that works with industry stakeholders to develop
standards for regenerative medicines like CGTs, to identify processes and standards for
regenerative medicines and advanced therapies (SCB, 2020a; SCB, 2020b). In support of
the 21st Century Cures Act, SCB has over 20 projects in the pipeline to develop standards

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to address gaps associated with time-sensitive and temperature-sensitive products like
CGTs. Projects related to supply chain include: (1) chain of custody (COC) and chain of
identity (COI); (2) labeling of apheresis material; (3) establishing international standards
for ancillary materials in cell therapy; and (4) cryopreservation of cells (SCB, 2020a;
SCB, 2020b). In June 2020, the group worked with International Organization for
Standardization (ISO) to develop ISO 21973:2020, Biotechnology — General
requirements for transportation of cells for therapeutic use, which specifies general
requirements and consideration for the transportation of cells for therapeutic use (ISO,
2020). To address the gaps in supply chain guidance for medical products, the United
States Pharmacopeia (USP) has also amended, updated and expanded their supply chain
standards and guidelines to include additional guidance related to: (1) risk mitigation
strategies; (2) transportation of IMP material; (3) supplier qualification; (4) facilities and
equipment qualification for shipping material; (5) temperature excursion, (6) information
systems distribution studies; and (7) transportation qualification (USP, 2020; Hunt,
2020).
In addition, FDA is collaborating with the Asia-Pacific Economic Cooperation
(APEC), an inter-governmental forum for 21 member economies, including the US,
China, and Japan, to produce a Supply Chain Security Toolkit for Medical Products. The
toolkit for medical products aims to maximize global resources and provide quality
training on best practices. It addresses the entire supply chain lifecycle of medical
products from raw materials to products used by patients (Arcidiacono et al., 2012;
Bernstein, 2018; Brennan, 2017; FDA, 2020i; FDA, 2020j; APEC, 2019). This
multiregional international initiative highlights the growing recognition that supply chain

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management is important for medical products and requires a more globally harmonized
focus. This harmonization can enable more standardized supply chain strategies for CGTs
globally.
2.5.1 Industry Perspectives on Supply Chain Management of CGTs
The top supply chain concerns—regulatory compliance, product security,
managing supply chain costs, and product damage and spoilage—are for the
most part being addressed successfully through collaboration and
partnerships, investment in IT, and/or investment in building in-house
expertise (UPS, 2014, pg.14, para 2).

Supply chain management has become an increasing concern for industries
developing advanced biopharmaceutical therapies and relying on globalized drug
development programs. Based on previous research by the consulting firm Axendia,
Improving Visibility of the Pharma Supply Chain: Best Practices and Technologies,
many supply chain impediments exist. These can impede primary aims of industry: (1) to
grow commercial pipelines at an accelerated rate; (2) to reduce development costs; and
(3) to expand market access (Axendia, 2010; Lennard and Matlis, 2011). The survey
revealed that half of the surveys’ healthcare and pharmaceutical executives classified
SCM as a potential high risk to their product’s safety, efficacy, and effectiveness. Many
(61%) were concerned about product loss and spoilage. In addition, many expressed
concerns about the impact of product counterfeits (44%), limited traceability and
inaccessible real-time data (43%), product adulteration due to diversion during transit
(35%), and limited control of the supply chain as high risks to their businesses (Axendia,
2010; Lennard and Matlis, 2011).
The Axendia survey was conducted ten years ago, but its results remain relevant
with current industry views. Supply chain “visibility” –the ability to track products along

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the supply chain once the shipment leaves the manufacturers’ facility— continues to be
challenging for biopharmaceutical executives. Executives desire "on-demand" visibility
so that they can access data and product information in real-time (World Courier, 2019;
Pagliarulo and Lopez, 2018). Technologies such as GPS and continuous monitoring
systems (CMS) are beginning to provide some types of shipment data, such as product
location and temperature, but most logistics tracking still relies on manual processes and
human factors such as the interaction with airline personnel (Badurina et al., 2011; Papert
et al., 2016). Further, in 2011, Lennard and Matlis reported that only 3% of healthcare
organizations had access to their suppliers’ data in real-time. Although (66%) of the
respondents had access to their supplier's data, much of the information required manual
entry and integration, which made it difficult to capture accurate records. More than half
of respondents were unable to track critical supply chain information such as transaction
history, chain of custody, record of ownership, and environmental storage conditions
such as temperature data (Axendia, 2010; Lennard and Matlis, 2011). It is not clear
whether this lack of transparency, identified a decade ago, still exists. However, those
data are consistent with the current challenges and trends identified in the literature,
previously discussed in sections 2.4.1 and 2.5. Furthermore, a more recent industry
assessment, Pharma 2020: Supplying the future- Which path will you take?, conducted by
PricewaterhouseCoopers in 2019, revealed that most pharmaceutical companies do not
have real-time access to supply chain data from their critical suppliers, distributors, and
in some cases, remote sites (PWC, 2019). Moreover, a study by Gartner, Future of Supply
Chain: Reshaping the Profession, conducted in 2019, revealed that 75% of respondents
ranked data integrity and accessibility as one of the top three hurdles for implementing a

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digitalized supply chain (Manenti et al., 2019). To mitigate this hurdle, regulators and the
biopharmaceutical industry are heavily motivated to implement integrated technologies
such as blockchain to improve real-time data collection and information sharing between
stakeholders (Janssen Research & Development, 2017, N-Side, 2019; Clauson et al.,
2018; Barley, 2019; Challener, 2019). However, there has been a lag in implementation;
currently, only 20% of biopharmaceutical companies appear to have implemented these
technologies (Reh and Standing, 2018; FDA, 2020j).
In 2019, World Courier provided data from a survey on product logistics with
inputs from 481 medical product manufacturers. More than 60 percent of the participants
ranked logistical management of CGTs to be extremely difficult, rating the average
difficulty with a score of 8 out of 10 (World Courier, 2019). Moreover, 60 percent of the
respondents identified that cold chain management was the biggest challenge for CGTs
(World Courier, 2019). A survey conducted in 2019 by Pelican BioThermal also
demonstrated that temperature excursions continue to be a concern for manufacturers.
Nearly half (44.6%) of respondents experienced multiple unacceptable temperature
excursions over the course of a year, and 16% stated that temperature excursions were a
monthly occurrence (Pharmaceutical Commerce, 2017; Pelican BioThermal, 2019;
Pharmaceutical Commerce, 2020). In addition, biopharmaceutical manufacturers ranked
customs regulations such as import-export documentation (49%), and risk management
and contingency planning (40%) as impediments for successful CTD execution (World
Courier, 2019). More specifically, with respect to CTD and clinical trials, most
stakeholders were challenged by changing demands and unpredictability despite the

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extensive and proactive planning usually directed at clinical trial and supply chain
management.
The novel requirements of CGTs have also been affected by the way that clinical
trials are approached. Manufacturers recognized that they had knowledge gaps with
respect to clinical trial execution (World Courier, 2019), gaps that had widened as
clinical trial designs became more complex, and the risks associated with innovative
therapies were not well understood (Sonnenberg, 2019; World Courier, 2019).
Regulatory and quality compliance were also seen to be difficult because global
regulations were both complex and dissonant. Most executives (75%) suggested that
difficulties with compliance had two principal sources, unclear regulatory expectations,
and frequent changes in global regulations (UPS, 2014; UPS, 2015). Only 12% of the
executives felt that their organizations were prepared to meet global regulatory and
compliance expectations (UPS, 2014; UPS, 2015). The management of diverse and
variable regulatory expectations was also highlighted in other studies. Although the
United States, European Union, and Japan had relatively stable regulations in place, some
countries are only beginning to establish guidelines for cell and gene therapies (Norton
and Enfeng, 2014; Stanton, 2017). Clinical trial management and distribution pose added
and significant challenges for sponsors that are attempting to execute trials in developing
countries because relevant regulations are new, underdeveloped, or absent altogether.
Globalization has increased the financial, legal, and regulatory complexities of
clinical trial distribution. In 2015, UPS conducted a survey, Pain in the Supply Chain,
with 421 healthcare logistics executives from 16 countries (UPS, 2015). Most
respondents (70%) ranked product security, such as counterfeiting and product spoilage,

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as an exceedingly high risk, particularly in the Asia-Pacific region (UPS, 2014; UPS,
2015; Shenoy, 2016). Additionally, increased risks of data breaches and cybersecurity
concerns across the global supply chain have led the industry to take a more conservative
approach to information sharing and vendor integration. In a recent study conducted in
2019 by Protiviti, Vendor Risk Management Benchmark Study: Running Harder to Stay
in Place, two-thirds of executives across multiple industries, such as manufacturing,
healthcare, and financial services, reported that their organizations experienced had
experienced a significant disruption in their operations consequent to a cyberattack
(Protiviti, 2019). Data protection and data breaches continue to be a particular concern
for sponsors and regulators in clinical trials because of added concerns to protect clinical
data and patient privacy, as discussed earlier.
2.6 Research Approaches and Framework
The literature review presented here describes the current state of regulations and
other instruments meant to structure and harmonize the management of material
movement for CGT clinical trials. It identifies the players and their challenges as
materials and samples follow a path that may originate and end with the patient, who is
sometimes in a geographic location thousands of miles away. What it does not, and
arguably cannot, do is give much insight into the specific views and experiences of a
subsector of that industry concerned with supply chain management for hard-to-handle
clinical trial materials involved in CGT development. The initiatives, surveys and
opinions described above focus mainly on the generic needs of medical product
management, and not on the experiences, practices, and lessons learned from those
engaged in more highly demanding trials of CGTs. It, therefore, seems timely to expand

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this literature by using survey methods more deliberately directed at those performing
CGT trials, to understand better the systems and educational methods that are being
implemented and the challenges faced during the implementation process.
2.6.1 Implementation Framework
Because I am interested in the nature and challenges of implementing supply
chain systems, an appropriate approach to frame the research would seem to come from
the recent models introduced by those in the new field of implementation science. The
underlying foundation for implementation science appears driven to some extent by the
seminal work of Fixsen, co-founder of the National Implementation Research Network
(NIRN), and developer of the widely accepted implementation framework (Fixsen et al.,
2009). According to Fixsen and his colleagues, implementation can be segmented into
four principal stages: (1) exploration and adoption; (2) installation; (3) initial
implementation; and, (4) full implementation. These stages culminate in sustainability,
which typically takes 2-4 years to achieve (Figure 15). The stages of implementation are
consecutive, but it is possible to carry out activities related to more than one stage
simultaneously. These overlaps can exert influence on activities in other stages (Fixsen et
al., 2009).

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Figure 15 Fixsen’s Implementation Model
This figure delineates the four stages of Fixsen’s Implementation Model, including the major benchmarks
undertaken to get a program or practice designed, developed, tested, and implemented. This figure was
recreated by the author with permission (Fixsen et al., 2009).

In exploration and adoption stages, the need for change is defined, and the
foundational elements to begin implementation are put into place. During exploration,
companies must identify their SCM needs and educate themselves about currently
available options. They must characterize their current practices and decide whether a
change is needed. This exploration can provide information that helps to secure
stakeholder buy-in and identify barriers and options to progress to the installation step.
During installation, needed resources and partnerships must be put into place. Key
stakeholders should be identified; roles and responsibilities should be established for
crucial aspects of product validity and stability across the distribution lifecycle. As part of
these activities, the skills necessary to develop the support teams should be assessed and
augmented through hiring, training, and contracting (Fixsen, 2009).
The third stage, initial implementation, is the first use of innovation by
practitioners and designees based on the identified solutions and lessons learned from the
prior two stages. In this stage, changes in the working environment are made, and teams
learn to adjust their approaches and work through the "awkwardness" of a new system

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(Fixsen et al., 2005). In this stage, pilot data is gathered to understand how well the
chosen implementation plan is working and to forecast further implementation progress.
The initial implementation of CTD may include performing a test shipment to certify that
proper systems are in place before shipping the clinical trial product. Because CGT trials
often have unique end users globally, the logistics providers and trial sponsors must
determine how the standard process can be adjusted to accommodate changing
environmental factors, such as weather conditions or clinical factors, such as a patient's
response to treatment. The initial implementation allows the team to evaluate its new
skills and practices and to confront tensions that might initially develop amongst the
stakeholders, for example, between the logistics supplier and the clinical site or patient.
Full implementation is the final stage of implementation in which the industry can
solidify its practices into its core business activities, evaluate what are the current
practices, and identify the best practices that allow for sustainable progress.
In this study, the four stages of Fixsen's Implementation Framework were used to
provide a frame of reference for the survey development. This survey, discussed in the
next section, was conducted to collect industry views on clinical SCM, implementation
strategies, and the influence of impediments and regulations in guiding their supply chain
systems.

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Chapter 3. Methodology
3.1 Introduction
This exploratory study utilized a survey methodology to examine the views of
mid-level to senior-level professionals in the medical product industry who have
expertise in the research, development, manufacturing, commercialization, and
distribution of biologics and CGTs. The objective of the survey was: (1) to detect the best
and current practices in industry for clinical supply chain management of CGTs, and (2)
to evaluate the adequacy of clinical SCM regulations for CGTs from the perspective of
the industry. The survey tool was validated through a focus group of subject matter
experts (SMEs) to ensure optimal data collection and reduce biases that might be
associated with the research. The feedback from the focus group (detailed later in this
chapter) was used to develop the final survey. The survey was disseminated to over 410
individuals in industry that had clinical operations, biopharmaceutical supply chain, and
CGTs.
3.2 Identification of Study Respondents
The objective of this study was to obtain feedback and insights from professionals
who had experience with the clinical trial supply chain management of CGTs. Individuals
working at sponsor companies or provide support to those companies, including contract
organizations (CRO, CMO, CDMO) and specialty supply chain organizations, were
solicited as potential respondents. Those in clinical operations, manufacturing, regulatory
affairs, clinical quality assurance and clinical supply chain management with CGT
experience were encouraged to participate. I targeted mid to senior level employees
familiar with the views of their company and the operational and regulatory landscape of

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the industry. Representatives from regulatory authorities, personnel at study sites and
participants in clinical trials were excluded from the study. Representatives whose
experiences did not include fragile, time-sensitive or temperature-sensitive medical
products were also excluded. Those working with pharmaceutical finished drug products
and medical device companies that did not have combination (i.e., drug-biologic and
biologic-device) modalities were also excluded from the study.
3.3 Survey Development and Focus Group
A novel survey instrument was created based on the framework presented in the
literature review. Questions were developed based on information obtained from the
literature review, discussions with clinical research professionals (specified above), and
consultation with the research dissertation committee from the USC International Center
for Regulatory Science. The survey instrument focused primarily on critical areas based
on Fixsen’s Implementation Framework, which encompasses the following elements: (1)
adoption and exploration; (2) installation; (3) initial implementation; (4) full
implementation; and an overarching element (5) sustainability (Table 5).

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Table 5 Survey Categories Informed by Implementation Framework
This table provides a breakdown of the survey categories based on Fixsen’s Implementation
Framework.

No. Survey Question Categories Number of Questions
1 Demographics 8
2 Exploration (Adoption) 5
3 Installation 6
4 Initial Implementation 3
5 Full Implementation 7
6 Sustainability 6

Prior to survey dissemination, the draft survey was reviewed by a focus group to
evaluate each question individually and provide recommendations to add and delete
questions, clarify verbiage, and to optimize the questions as needed. The focus group was
comprised of nine (9) individuals with different backgrounds in academia, regulatory and
professional organizations, and industry (listed in Table 6). The focus group participants
were selected based on their expertise with clinical operations and supply chain
management of complex biologics and cell and gene therapies. The goal of the focus
group was to review the survey and targeted survey population as well as provide
feedback to the author regarding suggested amendments. This evaluation by experts in
the regulated medical product and logistics industry helped to validate the survey
instrument.

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Table 6 Focus Group Participants
This table provides a list of focus group participants that validated the survey tool. Subject matter
experts (SMEs) came from industry and academia. Titles and industry designation noted at the
time of the focus group.

Name Title Institution/Industry
Frances Richmond,
PhD
Director, D K Kim
International Center for
Regulatory Science, USC
Regulatory Science
Academia
Nancy Smerkanich,
MS, DRSc
Assistant Professor, Dept.
of Regulatory and Quality
Sciences, USC Regulatory
Science
Academia
Terry David Church,
MA, MS, DRSc
Assistant Professor, Dept.
of Regulatory and Quality
Sciences, USC Regulatory
Science
Academia
Susan Bain, MS, DRSc
Assistant Professor, Dept.
of Regulatory and Quality
Sciences, USC Regulatory
Science
Academia
Greys Sosic, MSc, PhD
Professor, Data and
Operations Sciences, USC
Marshall School of
Business, Supply Chain
Academia
Hai Luong, MS
Senior Manager,
Regulatory Strategy, CMC
in Biotechnology Industry
Industry
Anjali Malhotra, MS,
MBA
Director of Quality in
Biotechnology Industry
Industry
James Wabby, MHMS
Executive Director,
Regulatory, Combination
Products in Biotechnology
Industry
Industry
Wendi Lau, MS, DRSc
Vice President, Operational
Improvement & Reporting
Excellence in
Pharmaceutical Industry
Industry

To optimize the feedback from the focus group, ten days before the meeting,
participants were provided with: (1) a proposed draft of the survey in electronic format;
(2) a copy of Chapter 1 of the dissertation; and (3) a meeting agenda. Their pre-meeting

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review of these materials helped to direct the discussion and make the meeting more
efficient. The focus group met on July 30, 2020 via a virtual Zoom meeting. The meeting
lasted approximately 90 minutes. I moderated and led the focus group. My dissertation
supervisor, Dr. Terry David Church, acted as a co-moderator and ensured that the
meeting stayed within the time limit. In addition, the meeting was recorded to allow easy
review of key discussion points. Dr. Church and I also documented notes based on the
discussion and key survey amendments. The focus group began with a brief introduction
of the study and an overview of the survey to establish a standard foundation for the
assessment.
The focus group reviewed each question and provided feedback related to clarity
and scope of each question. Statements and verbiage that were unclear or contradictory
were amended. Feedback regarding the length of the survey and target survey population
was also solicited. Forty-seven (47) questions were reviewed. As a result of these
discussions, I added personnel from contract manufacturing organizations and hospital
GMP facilities with experience in clinical trial management of CGTs to the potential
participant list. I also reduced the survey length from 47 questions to a maximum of 35
questions. Certain questions were changed from matrix or scale-based to rank-order
formats. Lengthy questions that contained multiple statements were also broken into
multiple components. All of these changes produced a final revision of the survey
(Appendix B. Survey Questions).
The final electronic survey was developed using Qualtrics software. Thirty-five
(35) questions (including three (3) skip logic questions) were included in the final survey
(Appendix B. Survey Questions). The survey included a combination of open-ended and

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closed-ended questions such as “yes/no,” “choose one,” “scaled,” “rank-order,” and “true
and false” questions. Free response text boxes were also included to obtain more in-depth
insight and substantial feedback from the respondents, which could not be captured easily
by the standardized choices. The survey was constructed to take no longer than 20-25
minutes. Prior to disseminating the survey, a preliminary copy of the survey was sent to
three individuals in the focus group for a final review. Test surveys were deployed and
tested by Dr. Church and I to ensure that the survey was delivered without functionality
issues and that the results could be captured as planned. Previews to test the survey were
excluded from the survey responses collected from the targeted groups of participants.
3.4 Survey Deployment
The final survey was deployed via Qualtrics between August 25, 2020 and
September 26, 2020. In the target population for this survey were individuals from
regulatory affairs, quality, manufacturing, supply chain, project management, and clinical
research. The sample population was limited to individuals who currently worked or had
previously worked in companies that participate in clinical trials and develop,
manufacture, market, or distribute biologics, cell and gene therapies, or precision
medicines. Additional mid-level to senior-level professionals were recruited based on the
information provided through LinkedIn and referrals. Participants with whom I had direct
contact, who were referred by respondents, or who were identified as potential subject
matter experts were sent a personalized email with the survey link from Qualtrics Mailer.
Each participant who received a direct email was provided a unique survey link from the
system. The email included a short message to introduce the survey and the purpose of
the study. An "opt-out of study" link was also provided for those individuals who did not

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wish to participate in the survey. This accommodation prevented rework or additional
communication efforts with participants who wanted to be excluded. Participants were
also given a sharable link to provide to other colleagues who could be potential
respondents.
The survey was also posted on the social media platform, LinkedIn. LinkedIn
permitted me to share the survey publicly from my LinkedIn profile with individuals with
experience in life science supply chains, regulatory affairs, quality assurance or clinical
operations. An anonymous link was posted on Regulatory Affairs Professionals Society
(RAPS) and Drug Information Association (DIA) advanced therapies and open forums to
attract more respondents who self-elected to the take the survey. Participants were asked
if they could provide contact information for individuals in their extended professional
network who might meet the selection criteria and might be qualified to address the
research topic. Survey participation was anonymous, and no form of compensation was
provided. Respondents who did not complete the survey were sent reminders every 5 to
10 days automatically via Qualtrics until the survey closed. All participants received a
thank you email. The survey was kept open for 5 weeks, until September 26, 2020, at
which time the survey had 82 completed responses. The survey questions and results
were stored electronically and provided in the appendix of the study (Appendix B. Survey
Questions and Appendix C. Survey Data Set).
3.5 Survey Analysis
Results were analyzed using a variety of statistical methods, including descriptive
statistics (mean and standard deviation), graphical representation and cross-tabulation, to
identify trends and correlations in the responses. Because some questions were only

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displayed if certain choices were made in a precedent question, not all respondents
answered all the questions. Only surveys in which the respondent answered more than
half of the questions (62%) were counted as completed. Text-based questions were
analyzed to obtain more specific information concerning the adequacy of the regulations
for cell and gene therapies, supply chain management, and clinical trial management and
distribution. For responses in comment fields, text was analyzed to determine the nature
of the content and regrouped according to those topics. No changes were made to those
comments unless a misspelling was detected.
Questions that were scale-based (Likert-type questions) according to degrees of
preference, importance or agreement were analyzed using a weighting approach. In this
approach, the most positive of the offered choices was assigned a score of 1. For
example, in a 3-scale question, choices of “agree,” “somewhat agree,” and “disagree”
would be assigned a scored as 1, 2, and 3 respectively. The score for each choice was
multiplied by the number of individuals who selected that choice. The resulting scores
were summed and then divided by the total number of respondents who participated in
the question but did not answer “do not know” or “cannot answer”. Thus, a low
calculated score indicated that more respondents agreed than disagreed whereas a higher
score indicated a stronger tendency to disagree. This index assisted in comparing the
“average” preference, agreement, or importance of respondents across questions.
Rank ordered questions in which respondents sorted options by priority were
assigned a rank score. The rank score was calculated by applying a weight to each
response. For example, if there were 5 options (highest priority =rank 1 to lowest
priority= rank 5), the number of responses for that choice was multiplied by a weighted

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score. In this case, an option ranked as the top priority (rank 1) was multiplied by a
factor 5, the number of responses where an option was ranked as second priority (rank 2)
was multiplied by 4, and so on. The sum of the total weighted score [rank 1 (5) + rank 2
(4) + rank 3 (3) + rank 2 (2) + rank 5 (1)] was calculated to get a weighted rank score.
The rank score was then sorted from highest to lowest. The option with the highest rank
score was determined to be the highest priority.
Cross-tabulation analyses were conducted to explore whether differences in
responses were related to certain other characteristics, such as differences in the size of
the company or industry segment with which the respondent was associated. Cross-
tabulations are discussed in Chapter 4. Data sets are included in Appendix D. Cross
Tabulations.

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Chapter 4. Results
4.1 Survey Participation
Links to the survey were sent to 410 participants using individual links developed
through the Qualtrics Mailer. Seventy-eight persons opened the survey, for a response
rate of 19% (78/410), and 54 completed the survey, for a completion rate of 69% (54/78).
Anonymous links to the survey posted on Regulatory Affairs Professional Society
(RAPS) and Drug Information Association (DIA) discussion boards secured the
participation of an additional 29 individuals who accessed the survey and 15 who
completed it. Survey postings on LinkedIn secured the participation of 21 additional
individuals, 6 of whom completed it. By combining all participation methods, 128
individuals accessed a survey link, 105 respondents completed at least one question, and
more than half of those (71%, 75/105) completed the survey. Most drop-offs occurred at
the end of the demographics section (31%, 33/105) (question six [11%; 6/53] and
question eight [51%, 27/53]); see Appendix B. Survey Questions for question numbers).
Forty-one percent (53/128) of the respondents completed less than 25% of the survey,
and all stopped at the demographics section. About 15% (20/128) opened the survey poll
but did not answer any of the questions. Since not all questions were answered by all
participants, the number for respondents for each question will be noted.
4.2 Demographic Profile of Respondents
Most respondents worked for a biotechnology organization (30%, 31/105) or
pharmaceutical company (29%, 30/105). Many of the remaining respondents worked
with medical device companies (10%, 11/105), contract service organizations (CROs,

107

CMOs, CDMOs) (7%, 7/105) or supply chain organizations (third-party logistics and
specialty couriers) (10%, 11/105). A few were from academia (5%, 5/105),
biomanufacturing and cell production facilities (4%, 4/105), consulting services (5%,
5/105); one was employed by an academic cell and gene manufacturing facility (1%,
1/105) (Figure 16).
Figure 16 Distribution of Respondents Amongst Companies of Different Types
My most recent employer or client can best be described as a … (n=105)

Companies employed respondents across a full range of sizes. Slightly less than
half (43%, 45/105) worked at companies with up to 999 employees. About 19% (20/105)
worked in companies with 1,000-4,999 employees, 6% (6/105) with 5,000-9,999
employees, and 30% (32/105) with 10,000 or more employees. Two percent (2/105) did
not know (Figure 17).

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Figure 17 Distribution of Respondents in Companies of Different Sizes
What is the company size of your most recent employer/client in terms of number of
employees? (n=105)

Several cross-tabulations were performed to stratify groups of respondents
according to their roles as well as the size and type of company for which they worked.
For cross-tabulations based on company size, respondents were divided into three groups:
small companies with 1 < 999 employees (45%, 34/75), mid-sized companies with
1000 < 9,999 employees (24%, 18/75), and large companies with greater than or equal to
10,000 employees (31%, 23/75) (Table 7).
Table 7 Groupings to Cross-tabulate Responses against Company Size
Respondents were divided into 3 groups based on company size.

Company Size Number of
Respondents
% Grouping for Cross-
tabulation Analyses
1-999 34 45% Small 34 (45%)
1,000-4,999 14 19%
Mid-Size 18 (24%) 5,000-9,999 4 5%
10,000 + 23 31% Large 23 (31%)
Total 75 100%

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Most respondents worked for large pharmaceutical companies (> 10,000) (61%,
14/23). There were also many that worked for small (<1,000) biotechnology companies
(47%, 16/34) (Table 8). A quarter of the respondents worked for small pharmaceutical
(24%, 8/34) or mid-size companies (1,000 – 9,999) that were either biotechnology (22%,
4/18) or supply chain organizations (22%, 4/18).
Table 8 Cross-Tabulation: Industry versus Size of the Company
This table is to provide a cross-tabulation for respondents based on the industry and the
size of the company. Numbers are in shaded columns, and the bolded values represent the
calculated weighted averages and their standard deviations.

My most
recent
employer
or client
can best be
described
as a…
Organization
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Pharmaceutical
(Drug) Company 8 24% 3 17% 14 61% 25 33%
Medical Device
Company 1 3% 1 6% 3 13% 5 7%
Biotechnology
Company (Cell and
Gene,
Immunotherapies,
Cancer Vaccines) 16 47% 4 22% 4 17% 24 32%
Contract
Organization
(CRO, CMO,
CDMO) 3 9% 2 11% 1 4% 6 8%
Biomanufacturing /
Cell Production
Facility 1 3% 1 6% 0 0% 2 3%
Supply
Chain/Logistics 3 9% 4 22% 0 0% 7 9%
Academia,
Institution, School,
Research Center 0 0% 2 11% 0 0% 2 3%
Other (Please
Specify) 2 6% 1 6% 1 4% 4 5%
Total Count 34

18

23

75

Most respondents worked in regulatory affairs (39%, 41/105), quality
assurance/quality control (21%, 22/105), or supply chain/logistics (19%, 20/105) (Figure
18). Individuals from research and development (5%, 5/105), clinical operations (4%,

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4/105) and manufacturing and operations (5%, 5/105) accounted for most of the rest of
the survey population. Respondents who selected “other” accounted for 8% (8/105)
participants, and self-identified as working in program management (1/105),
commercialization of Advanced Therapy Medicinal Products (ATMPs) (1/105), analysis
and reporting (1/105), innovation scholarship (1/105), drug safety and risk management
(1/105), sterility assurance (1/105), legal (1/105), and regulatory writing (1/105).
Figure 18 Primary Job Function of Respondents
My most recent employer or client can best be described as … (n=105)

Respondents were asked how many years of experience they had with complex
biologics and products like cell and gene therapies (Figure 19). About a third (36%,
38/105) had 15 or more years of experience. About 20% (21/105) had 3 to 5 years of
experience, and 17% (18/105) had less than 3 years of experience. Of the rest, 10% had

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6-9 years (10/105) and 10% had 10 to 14 years (11/105) of experience. Seven percent
(7/105) selected “none”; these respondents were sent to the end of the survey.
Figure 19 Number of Years of Experience with Cell and Gene Therapies
How many years of experience do you have with complex biologics, advanced medicinal
therapies, or cell and gene therapies? n=105

Most commonly, respondents were senior directors or directors (45%, 47/105)
(Figure 20). Fewer were managers or senior managers (14%, 15/105), vice presidents /
presidents / C-suite members (13%, 14/105), consultants (9%, 9/105), or coordinators
(9%, 9/105). Five percent were researchers or scientists (5/105) and two were project
managers, (2%, 2/105). Less than 5 percent (4/105) of respondents selected the category
of “other,” and self-identified as medical writer (1/105), packaging engineer (1/105),
logistics manager (1/105), and statistician (1/105), respectively.

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Figure 20 Roles and Responsibilities of Respondents
My primary role is … (n=105)

Respondents were also asked about the types of biologic treatment modalities
with which they had experience (Figure 21). Most had experiences with cell-based gene
therapies (i.e., CAR-T) (62%, 58/93), and combination products (device-biologics) (53%,
49/93). About 40% had experience with gene-based therapies such as adeno-associated
virus (AAV) (42%, 39/93), CGT components such as viral vectors (42%, 39/93), or
vaccines (cancer vaccines) (42%, 39/93). Fewer had experience with novel proteins
(siRNA) (38%, 35/93) and stem cells (30%, 28/93). Twelve percent (11/93) of
respondents selected “other," which they identified to include fusion proteins (I/O PD-1),
regulatory T cells (Tregs), medical devices, plasma-based products, investigational
medicinal product (IMP), antibodies, and combination devices and radioisotope-based
therapies. Two respondents, 2% (2/93), did not know the biologic product types to select.

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The total number of choices was higher than the number of respondents because many
selected more than one answer.
Figure 21 Medical Product Modalities
What type of medical products do you or your organization have experience with (please
select all that apply): (n=93)

Respondents had varied experiences with the distribution of their clinical trial
materials using domestic and international transport systems (Figure 22). Most
respondents had such experiences in the US (86%, 81/94), Europe (73%, 69/94), Canada
(53%, 50/94), and/or Asia-Pacific (52%, 49/94). Many had distribution experience with
China (34%, 32/94) and Latin America (35%, 33/94), and about a quarter had experience
with Middle East (28%, 26/94), Russia (23%, 22/94), and/or Africa (21%, 20/94). Four
percent participants (4/94) selected "other," one specifying Australia, India, and global.
About 5% (6%, 6/94) did not know, whereas 4% (4/94) selected "none." The participants

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who selected "none" were taken to the end of the survey because they did not have
experiences with the distribution of clinical trial material. The total number of choices
was higher than the number of respondents because many selected more than one answer.
Figure 22 Geographies in which Supply Chains Operate
In terms of the supply chain, which countries have you or your organization transported
clinical trial material (i.e., supplies, raw materials, investigational medicinal products) to
or from... (Please select all that apply) (n=94):

4.3 Exploration
Respondents were asked to evaluate the state of their organization’s SCM
planning processes by responding to a series of statements, captured in Figure 23. Most
respondents (80%, 51/64) indicated that they understood US FDA requirements for the
distribution of IMPs. Of the others, 16% (10/64) somewhat agreed, 2% (1/64) disagreed

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and 3% (2/64) were not sure. Most (75%, 47/63) understood their role as a sponsor in the
distribution of IMPs. Of the others, 19% (12/63) somewhat agreed, 2% (1/63) disagreed
and 5% (3/63) were not sure. Most also were experienced (66%, 42/64) with international
requirements for distribution of IMPs. Of the others, 25% (16/64) somewhat agreed, 2%
(1/64) disagreed and 8% (5/64) were not sure.
More than half (56%, 36/64) agreed that they had a well-defined distribution plan
for the clinical supply of IMPs. Of the others, 33% (21/64) somewhat agreed, 6% (4/64)
disagreed and 5% (3/64) were not sure. Asked then if their organization supports
innovative clinical supply chain initiatives, about half agreed (53%, 34/64), 28% (18/64)
somewhat agreed, 5% (3/64) disagreed and 14% (9/64) were not sure. A similar
distribution of responses was seen when asked two other questions. When asked if the
organization had assessed its organizational readiness, about half (55%, 35/64) agreed,
28% (18/64) somewhat agreed, 13% (8/64) disagreed and 5% (3/64) were not sure. When
asked if sufficient funding was available to meet distribution costs, 55% (35/64) agreed,
30% (19/64) somewhat agreed, 8% (5/64) disagreed and 8% (5/64) were not sure. A
slightly different pattern was seen when asked whether contingency and business
continuity plans were in place for distribution; less than half (44%, 28/64) agreed, 33%
(21/64) somewhat agreed, 16% (10/64) disagreed, and 8% (5/64) were not sure if their
organizations had contingency and business continuity plans were in place for
distribution.
The distributions reported above were reflected in the calculated index of
agreement for the various statements. In a range from 1 (agree) to 3 (disagree),
statements related to the understanding of US FDA regulatory requirements and the role

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of the sponsor in the distribution of investigational medical products (IMPs) had
weighted scores of 1.2; understanding international regulatory requirements had a score
of 1.3; support of innovation had a score of 1.4; those related to the sufficiency of
funding and definition of a distribution plan had a score of 1.5; assessment of
organization readiness had a score of 1.6; and planning for contingencies and continuity
has a score of 1.7 (Table 9).
Figure 23 Views on Supply Chain and Distribution Planning
Please indicate your level of agreement with the following statements regarding your
organization's planning of Clinical Supply Chain Management. (IMP= Investigational
Medicinal Product) (n=64)*

*Understands the role of the sponsor in the distribution of IMPs had an (n=63)

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Table 9 Exploration Assessment of Clinical Supply Chain
Please indicate your level of agreement with the following statements regarding your
organization's planning of Clinical Supply Chain Management. (IMP= Investigational Medicinal
Product) (n=64)*. Numbers are in shaded columns, and the bolded values represent the
calculated weighted averages and their standard deviations.

Question
Agree
Somewhat
Agree Disagree
Not Sure

Total

Mean

SD

1 2 3
Has a well-defined
distribution plan for clinical
supply chain of IMPs 56% 36 33% 21 6% 4 5% 3 64 1.5 1.1
Supports innovative clinical
supply chain initiatives 53% 34 28% 18 5% 3 14% 9 64 1.4 1.0
Assesses the readiness of the
organization for supply chain
management 55% 35 28% 18 13% 8 5% 3 64 1.6 1.4
Has Sufficient funding is
available to meet distribution
costs 55% 35 30% 19 8% 5 8% 5 64 1.5 1.2
Has Contingency and business
continuity plans are in place
for distribution 44% 28 33% 21 16% 10 8% 5 64 1.7 1.7
Understands the role of the
sponsor in the distribution of
IMPs 75% 47 19% 12 2% 1 5% 3 63 1.2 0.5
Understands the US FDA
requirements for distribution
of IMPs 80% 51 16% 10 2% 1 3% 2 64 1.2 0.4
Understands the international
requirements for distribution
of IMPs 66% 42 25% 16 2% 1 8% 5 64 1.3 0.6

For many of the questions in this survey, large and small companies shared
similar views. Areas of divergence were, however, apparent, as shown in the cross-
tabulations below that represent the largest areas of difference (Table 10). These included
differences in certain aspects of readiness for supply chain management. For example,
71% (15/21) of respondents from large size companies indicated that they had well-
defined distribution plans compared to 57% (8/14) for mid-sized and 45% (13/29) for
small-sized organizations. Most large companies (76%, 16/21) also assessed their

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organization's readiness for the supply chain management compared to mid-size (36%,
5/14) and small companies (48%,14/29). The understanding of US FDA and international
distribution requirements were consistent across all the organization. Ninety percent
(18/20) of respondents from large organizations agreed that their organization understood
their role as the sponsor. Fewer respondents from small size (66%, 19/29) and mid-size
(71%, 10/14) organizations had that same confidence. Also, those from large
organizations more frequently viewed the funding for clinical supply chain and
contingency plans as sufficient (71%, 15/21) than lower for mid-size (57%, 8/14) and
smaller companies (41%, 12/29). Those from large companies had contingency plans
(67%, 14/21) compared to mid-size (43%, 6/14) and small organizations (28%, 8/29).

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Table 10 Preparedness for Exploration of Supply Chain versus Size of Company
The table provides a cross-tabulation of the planning phase of exploration compared to the size of
the company. Numbers are in shaded columns, and the bolded values represent total count for
each subcategory.

Questions Agreement 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Has a well-
defined
distribution
plan for clinical
supply chain of
IMPs
Agree 13 45% 8 57% 15 71% 36 56%
Somewhat Agree 14 48% 2 14% 5 24% 21 33%
Disagree 2 7% 2 14% 0 0% 4 6%
Not Sure 0 0% 2 14% 1 5% 3 5%

Total Count 29

14

21

64
Supports
innovative
clinical supply
chain initiatives
Agree 14 48% 7 50% 13 62% 34 53%
Somewhat Agree 9 31% 5 36% 4 19% 18 28%
Disagree 2 7% 1 7% 0 0% 3 5%
Not Sure 4 14% 1 7% 4 19% 9 14%

Total Count 29

14

21

64
Assesses the
readiness of the
organization for
supply chain
management
Agree 14 48% 5 36% 16 76% 35 55%
Somewhat Agree 11 38% 3 21% 4 19% 18 28%
Disagree 3 10% 5 36% 0 0% 8 13%
Not Sure 1 3% 1 7% 1 5% 3 5%

Total Count 29

14

21

64
Has Sufficient
funding is
available to
meet
distribution
costs
Agree 12 41% 8 57% 15 71% 35 55%
Somewhat Agree 11 38% 4 29% 4 19% 19 30%
Disagree 4 14% 1 7% 0 0% 5 8%
Not Sure 2 7% 1 7% 2 10% 5 8%

Total Count 29

14

21

64
Has
Contingency
and business
continuity plans
are in place for
distribution
Agree 8 28% 6 43% 14 67% 28 44%
Somewhat Agree 10 34% 6 43% 5 24% 21 33%
Disagree 8 28% 1 7% 1 5% 10 16%
Not Sure 3 10% 1 7% 1 5% 5 8%

Total Count 29

14

21

64
Understands the
role of the
sponsor in the
distribution of
IMPs
Agree 19 66% 10 71% 18 90% 47 75%
Somewhat Agree 9 31% 2 14% 1 5% 12 19%
Disagree 0 0% 1 7% 0 0% 1 2%
Not Sure 1 3% 1 7% 1 5% 3 5%

Total Count 29

14

20

63
Understands the
US FDA
requirements
for distribution
of IMPs
Agree 24 83% 10 71% 17 81% 51 80%
Somewhat Agree 4 14% 3 21% 3 14% 10 16%
Disagree 1 3% 0 0% 0 0% 1 2%
Not Sure 0 0% 1 7% 1 5% 2 3%

Total Count 29

14

21

64
Understands the
international
requirements
for distribution
of IMPs
Agree 19 66% 9 64% 14 67% 42 66%
Somewhat Agree 7 24% 4 29% 5 24% 16 25%
Disagree 1 3% 0 0% 0 0% 1 2%
Not Sure 2 7% 1 7% 2 10% 5 8%

Total 29

14

21

64

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Respondents were asked about their use of different outsourced options to assist
in clinical trial management and distribution of their medical products (Figure 24). They
appeared to be using a mix of options as suggested by 120 choices made by the 60
individuals answering this question. Many (67%, 40/60) identified that they used in-
house dedicated staff. However, half (30/60) outsourced their clinical trial management
to a contract research organization, 40% (24/60) outsourced distribution, and 30%
(18/60) utilized a contract manufacturing organization to manufacture their investigation
medical products (IMP). Thirteen percent (8/60) were not sure.
Figure 24 Outsourcing Activities
How does your organization currently manage the supply chain of clinical trials of cell
and gene therapies? (Select all that apply) n=60.

However, it would appear that respondents often found it difficult to identify the
relative split between in-house and outsourced operations, as suggested by the relatively
common choice of “not sure” (33%, 17/52). Seventeen percent (9/52) outsourced less

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than 10% of their supply chain, 4% (2/52) outsourced 11-20%, 14% (7/52) outsourced
21-40%, and 17% (9/52) outsourced 41-60% (Figure 25). Fifteen percent (8/52)
outsourced more than 60% of supply chain activities.
Figure 25 Percentage of Outsourcing Supply Chain and Distribution
If you outsource your supply chain management, overall, how much of your clinical
supply chain is outsourced? (n=52)

The results indicated that half of the respondents from all company sizes used in-
house dedicated staff to manage clinical trials of their CGTs [small, (56%, 19/34); mid-
size, (50%, 9/18); large (52%, 12/23)] (Table 11). There was no correlation related to in-
house staff. Respondents from large size (44%, 10/23) and small companies (44%,
15/34) indicated they utilized CROs, whereas mid-size companies only had 28% (5/18).
Fewer respondents from mid-size organizations (22%, 4/18) used specialty couriers for
their distribution, whereas small companies (38%, 13/34) and large (30%, 7/23) were
within 10% of each other. Similarly, far less mid-size organizations (11%, 2/18) utilized

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CMOs compared to large size (30%, 7/23) and small companies (27%, 9/34). The total
number of choices was higher than the number of respondents because many selected
more than one answer.
Table 11 Outsourcing Percentage versus Company Size
This table provides a cross-tabulation of outsourcing activities versus company size.

How does your
organization
currently
manage the
supply chain of
clinical trials of
cell and gene
therapies?
(select all that
apply)
Question
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
In-house
Dedicated Staff 19 56% 9 50% 12 52% 40 53%
Clinical Trial
Management is
Outsourced (i.e.,
CRO) 15 44% 5 28% 10 44% 30 40%
Raw Material or
Investigational
Product
Manufacturing is
Outsourced (i.e.,
CMO) 9 27% 2 11% 7 30% 18 24%
Clinical Trial
Distribution is
Outsourced (i.e.,
3PL Service
Provider) 13 38% 4 22% 7 30% 24 32%
I am not sure 1 3% 3 17% 4 17% 8 11%
Total
Respondents 34 18 23 75
Total Choice
Count 57 23 40 120

When looking into outsourcing the supply chain, it was determined that smaller
organizations outsource a larger percentage of their supply chain activities compared to
larger organizations (Table 12). Small-sized companies outsourced 41-60% of their
supply chain at 31% (8/26) compared to 6% (1/17) large companies. Moreover, there was
a 7% increase in small companies, 19% (5/26), compared to 12% (2/17) for large
companies that outsource more than 61% of their supply chain.

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Table 12 Outsourcing of Supply Chain Activities versus Company Size

What is the company size of your most recent
employer/client in terms of the number of
employees?

% 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 + (large) Total
If you outsource
your supply
chain
management,
overall, how
much of your
clinical supply
chain is
outsourced?
0-10% 6 23% 2 22% 1 6% 9
11-20% 0 0% 0 0% 2 12% 2
21-40% 3 12% 2 22% 2 12% 7
41-60% 8 31% 0 0% 1 6% 9
61%+ 5 19% 1 11% 2 12% 8
Not Sure 4 15% 4 44% 9 53% 17

Total
Count
26 9 17 52

Respondents were asked about their use of alternative distribution models (
Figure 26). Most respondents had used specialty couriers (65%, 40/62). Ten
percent (6/62) considered their use in the future, 2% (1/62) considered but did not use
them, and 5% (3/62) had not considered this approach. About 20% (19%, 12/62) did not
know. Slightly more than half (53%, 33/62) had used integrator services. Thirteen percent
(8/62) considered such services in the future, 5% (3/62) considered but did not use such
services, and 10% (6/62) had not considered this approach. Nineteen percent (12/62) did
not know.
Only 28% (17/61) had used direct-to-patient (DTP) and home health support in
the past. Thirty-three percent (20/61) had considered but did not use DTP, 11% (7/61)
considered but did not use DTP and 10% (6/61) were considering the use of DTP and
home health support in the future. Eighteen percent (11/61) were not sure of this
approach. Use of drones was the least common delivery system. In fact, no respondents

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(0/60) had yet considered and used this model; 67% (40/60) had not considered use and
of the others, 7% (4/60) had considered use in the future and 2% (1/60) had considered
but did not use it. About a quarter (15/60) did not know.
The use of certain technologies was also explored. About half (54%, 33/61)
considered and used smart packaging. Fifteen percent (9/61) considered its use in the
future, 7% (4/61) had considered but did not use it, and 10% (6/61) had not considered it.
About 15% (9/61) did not know. Only one (2%, 1/60) had considered and used IT
technologies such as Blockchain. About a quarter were either considering its use in the
future (27%, 16/60), or had not considered use of this approach (25%, 15/60). About 5%
(3/60) considered but did not use this approach. Forty-two percent (25/60) were not sure
of their organization’s IT initiatives.

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Figure 26 Alternative Distribution Models
What resources have you or your organization considered for managing the distribution
of medical products for your clinical trials? N varied based on the statement.

4.4 Installation
To prepare for the implementation of supply chain elements, respondents were
asked about the onboarding process used to link vendors with sponsors (Figure 27). Most
respondents (79%, 44/56) had shared standard operating procedures with their vendors;
14% (8/56) did not and 7% (4/56) were unsure. Sixty-six percent (38/58) performed test
runs of the transportation routes; 17% (10/58) did not and 17% (10/58) were unsure.
Most provided (60%, 34/57) vendor training on their clinical protocols; 23% (13/57) did
not and 18% (10/57) were unsure. Half (49%, 28/57) established hybrid project teams
with vendors; a quarter did not (25%, 14/57) and the rest were not sure (26%, 15/57).

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Slightly less than half (46%, 26/57) developed joint contingency plans with vendors;
about a quarter did not (28%, 16/57) and another quarter were unsure (26%, 15/57).
Figure 27 Onboarding of Supply Chain Vendors
Thinking of one particular trial, you have engaged in, did your organization utilize any of
the following techniques when onboarding clinical trial supply chain vendors? (n=57*)

*n=56 for Develop and Share Standard Operating Procedures, n=58 for Perform Test Runs of Transportation Routes
Respondents were asked about the activities to qualify their supply chain vendors
(Figure 28). Most respondents (93%, 54/58) conducted quality audits through document
review. None denied that this type of audit was conducted but 7% (4/58) were not sure.
Most respondents (86%, 50/58) established a statement of work. Only one (1/58)
indicated that his/her organization did not establish a statement of work but 12% (7/58)
were not sure. Similarly, most respondents (84%, 49/58) also developed Quality
Technical Agreements (QTAs). Only one (1/58) identified that his/her organization did
not develop a QTA, and 14% (8/58) were not sure. Most respondents (79%, 46/58)

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conducted onsite quality audits. The others were split between having no such audits
(10%, 6/58) or not knowing if they were conducted (10%, 6/58).
Figure 28 Supplier Quality Techniques
To qualify your supply chain vendors, did your organization utilize any of the following
techniques: (n=58)

Respondents were asked if other techniques had been used to qualify their
vendors. Numerous respondents provided an text response to two of the questions
illustrated in Figure 27: (1) what are other activities do you perform to qualify vendors
when outsourcing supply chain activities?, and (2) what other activities do you perform
to prepare vendors when outsourcing supply chain activities? (Table 13).
To qualify their vendors, some respondents performed security and privacy
assessments. Packaging validation, qualification, and storage capabilities were also
mentioned as a part of the qualification process. Others performed mock and test runs to
assess feasibility or conducted business-focused audits, in addition to quality audits, on
their vendors. Multiple respondents identified that their organizations reviewed the

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competencies of the suppliers including verification of training, certifications, and a
quality management system. One respondent mentioned the need to have global
expertise.
For onboarding activities, some respondents held weekly meetings with vendors
and had dedicated subject matter experts (SME) from the vendor to provide expertise and
oversight to supply chain activities for their clinical trials. One mentioned that the
organization had hired a consultant who had a direct line of communication with the CEO
and coordinated the global trial activities. Others discussed how they built partnerships
with their vendors, through agreements and contracts, business continuity plans and
insurance (in case of theft). Some respondents had not started their clinical trials and so
could not provide feedback on supplier qualification, and another respondent did not
understand what a “hybrid” team entailed.

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Table 13 Open Responses - Supplier Qualification and Onboarding
This table provides an overview of text-based responses related to onboarding and
qualifying suppliers.

Supplier Qualification – Open Text
Basically paid for a consultant who was an employee of the vendor. They were not just a PM,
but a highly experienced SME in the clinical supply field. By establishing that direct and
dedicated resource, they were able to coordinate activities across a dozen global sites and get
traction much faster than a standard project manager. They could flag issues not just in the
clinical supply plan (trial focused) but how that strategy would integrate into the
systems/processes at the specific vendor. It also opened the door to direct CEO to CEO
conversations if needed.
On site audits are not just Quality focused, but also business process focused. We assess
insurance risks, business continuity plans, interview project managers and site heads from a
relationship basis. We tried to build the trust and be candid with site staff to understand what
THEY worry about. This let us flag the unknown unknowns. Any audit can flag that a rat trap is
missing from a pest control plan, but building the abstract dialog gives the vendor room to
share items you may not know to worry about (e.g. south african depot staff have panic buttons
on their key chains due to high crime rates, trucks have active GPS tracking for hijacking,
power outages occur at a high frequency due to the economics of wire theft, etc).
Try a dry run/a mock exercise to assess gaps.
Developing robust service contracts are important and not the same as a Statement of Work.
Confirm training, certifications, qualifications, product storage, adequate QMS, privacy and
security

Respondents were asked about the importance of certain regulatory and
operational elements when selecting a supply vendor (Table 14). A large majority of
respondents (90%, 53/59) ranked expertise in cold chain management and temperature-
controlled services as very important. Only 5% (3/59) suggested that it was somewhat
important, 2% (1/59) not important, and 3% (2/59) not sure. Regulatory expertise in
areas such as trade compliance, import and exports were also viewed as very important
by most respondents (83%, 49/59); 14% (8/59) ranked is as somewhat important, and 3%
(2/59) were not sure.

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Similarly, many respondents (78%, 46/59) regarded strong distributional and
storage networks as very important. Seventeen percent (10/59) regarded it as somewhat
important and only one respondent (2%, 1/59) identified it as unimportant. Two
respondents (3%, 2/59) indicated they were not sure. In a range from 1 (very important)
to 3 (not important), each of these statements had weighted scores of 1.1, with the
exception of possession of warehouse and distribution networks that had a score of 1.2
(Table 9).
Table 14 Factors Considered when Selecting Suppliers - Part A
When selecting a clinical supply chain vendor/supplier, in your opinion, rate the
importance of the factors below (n=59). Numbers are in shaded columns, and the bolded
values represent the calculated weighted averages and their standard deviations.

Question
Very Important Somewhat Important Not Important Not Sure Total Mean SD
1 2 3
Regulatory
Expertise -
Trade
Compliance,
Import and
Exports,
Transportation
83% 49 14% 8 0% 0 3% 2 59 1.1 0.3
Expertise in
Cold Chain
Management /
Temperature
Controlled
Services
90% 53 5% 3 2% 1 3% 2 59 1.1 0.2
Possession of
Warehouse
and
Distribution
Networks
(Depots,
Storage
Capabilities,
Airline
Partnerships)
78% 46 17% 10 2% 1 3% 2 59 1.2 0.5

Additional questions were posed regarding capabilities related to the regulatory,
clinical, and quality capabilities of the vendor (Table 15). Most respondents (81%, 48/59)
identified that knowledgeable staff familiar with conducting clinical trials was very

131

important. Of the rest, 12% (7/59) ranked this as somewhat important, and 7% (4/59)
were not sure. Many respondents (80%, 47/59) also identified a quality management
system (QMS) to be very important. Seventeen percent (10/59) identified it as somewhat
important, and only one respondent (2%, 1/59) as unimportant. One respondent (2%,
1/59) was not sure. Many respondents (71%, 42/59) viewed medical product regulatory
expertise as very important. About a quarter (24%, 14/59) viewed it as somewhat
important and only one respondent (2%, 1/59) not important. Two respondents (3%,
2/59) were not sure. Similarly, most (71%, 42/59) viewed alignment with Good
Manufacturing Practices (GMP) as very important; about 20% (12/59) viewed it as
somewhat important and 3% (2/59) as not important. Five percent (3/59) were not sure.
Seventy percent (69%, 41/59) viewed alignment with Good Clinical Practices (GCP) as
very important, about a quarter (24%, 14/59) as somewhat important and 5% (3/59) as
not important. One respondent (2%, 1/59) was not sure. Two-thirds of the respondents
(66%, 39/59) viewed alignment with Good Distribution Practices (GDP) as very
important, a quarter (24%, 14/59) as somewhat important and 3% (2/59) as not important.
Seven percent (4/59) were not sure.
About a third of respondents (68%, 40/59) viewed familiarity with CGT products
as important and a quarter (24%, 14/59) as somewhat important; 8% (5/59) were not sure.
In a range from 1 (very important) to 3 (not important), the question on clinical trial
knowledge has a score of 1.1; having an established quality system had a score of 1.2,
and all of the others were 1.3 (Table 15).

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Table 15 Factors Considered when Selecting Suppliers - Part B
When selecting a clinical supply chain vendor/supplier, in your opinion, rate the
importance of the factors below (n=59). Numbers are in shaded columns, and the bolded
values represent the calculated weighted averages and their standard deviations.

Question
Very Important Somewhat Important Not Important Not Sure Total Mean SD
1 2 3
Knowledgeable
staff familiar
with conducting
clinical trials
81% 48 12% 7 0% 0 7% 4 59 1.1 0.3
Having a
Quality System
and established
quality
standards
80% 47 17% 10 2% 1 2% 1 59 1.2 0.4
Knowledgeable
staff familiar
with products
like cell and
gene therapies
68% 40 24% 14 0% 0 8% 5 59 1.3 0.5
Regulatory
Expertise -
Medical
Product
71% 42 24% 14 2% 1 3% 2 59 1.3 0.6
Aligned with
Good
Manufacturing
Practices (GMP
Certified)
71% 42 20% 12 3% 2 5% 3 59 1.3 0.6
Aligned with
Good Clinical
Practices (GCP
Certified)
69% 41 24% 14 5% 3 2% 1 59 1.3 0.8
Aligned with
Good
Distribution
Practices (GDP
Certified)
66% 39 24% 14 3% 2 7% 4 59 1.3 0.7

Respondents were also asked to rank concerns with certain aspects with
outsourcing their shipping activities from the highest concern (scored at 5) to lowest
concern (scored at 1) (Table 16). Respondents ranked temperature monitoring and
temperature excursions (rank 1; score = 179), meeting turnaround times (rank 2; score =
163), and shipping visibility (rank 3; score = 143) as the top three concerns when
outsourcing shipping activities. Data integrity and data breach (rank 4; score = 120) and
diversion (counterfeiting) (rank 5; score = 70) were ranked as least concerning.

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Table 16 Supply Chain Concerns when Outsourcing
When considering outsourcing your supply chain management activities, please rate your
concerns with the following elements related to transport of the cell and gene therapies
(please rank 1= highest concern to lowest concern) (n=45):

n=45
Supply Chain
Concerns
Rank
1
Rank
2
Rank
3
Rank
4
Rank
5 Total
Rank
Score Rank
Temperature
Monitoring /
Temperature
Excursions 18 12 12 2 1 45 179 1
Meeting
Turnaround
Times (TAT) 15 11 9 7 3 45 163 2
Shipping Visibility
/ Traceability 5 10 19 10 1 45 143 3
Data Integrity /
Data Breach 6 8 3 21 7 45 120 4
Diversion /
Counterfeiting 1 4 2 5 33 45 70 5

The rank score was calculated by applying a weight to each response. For example, if there were 5
options (highest concern =rank 1 to lowest concern= rank 5), the number of responses for that choice
was multiplied by a weighted score. In this case, an option ranked as the highest concern (rank 1) was
multiplied by a factor 5, the number of responses where an option was ranked second (rank 2) was
multiplied by 4, and so on. The sum of the total weighted score [rank 1 (5) + rank 2 (4) + rank 3 (3) +
rank 2 (2) + rank 5 (1)] was calculated to get a weighted rank score. The rank score was then sorted
from highest to lowest. The option with the highest rank score was determined to be most concerning.

4.5 Initial Implementation
Respondents were asked to describe their experience or familiarity with certain
regulations relevant to transportation and management of medical product regulations
(Figure 29). Most commonly, respondents (84%, 54/64) had experience with GMPs; 14%
(9/64) described themselves as familiar, and one respondent (2%, 1/64) as unfamiliar.
Many respondents (80%, 51/64) were also experienced with GCP; 17% (11/64) were
familiar, and 3% (2/64) were unfamiliar. More than half (57%, 36/63) were experienced
GDP. Of the rest, 37% (23/63) were familiar, and 6% (4/63) were unfamiliar with GDP.

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Fewer respondents (41%, 26/63) were experienced with Good Tissue Practices (GTP);
about 40% (38%, 24/63) were familiar, and 21% (13/63) were unfamiliar with GTP.
About half of the respondents (53%, 33/62) were experienced with cold chain
management. Of the others, 31% (19/62) were familiar, and 16% (10/62) were unfamiliar
with cold chain management. Nearly half were either experienced (45%, 28/63) or
familiar (43%, 27/63) with hazardous material regulations whereas 13% (8/63) were
unfamiliar with them. Nearly half (45%, 28/62) were experienced with International Air
Transport Association (IATA) standards; the others were familiar (29%, 18/62), or
unfamiliar (26%, 16/62). Approximately equal thirds were experienced (33%, 20/61),
familiar (38%, 23/61), or unfamiliar (30%, 18/61) with Federal Aviation Administration
(FAA) regulations. Only about a quarter (27%, 17/63) were experienced with the Drug
Supply Chain Security Act (DSCSA), a further third were familiar (34%, 22/63) and the
remaining 38% (24/63) were not familiar with that Act.
Slightly less than half (44%, 28/63) were experienced with domestic (US) import
and export regulations. Thirty-five percent (22/63) were familiar, and 21% (13/63) were
unfamiliar with domestic (US) import and export regulations. Fewer than half were
experienced (41%, 26/63) with international import and export regulations. Thirty-eight
percent (24/63) were familiar, and 21% (13/63) were unfamiliar with international import
and export regulations.

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Figure 29 Familiarity with Medical Product and Transportation Regulations
Please indicate you or your organization's level of familiarity with the following
requirements and best practices associated with supply chain management (n=varies):

Respondents were asked to evaluate operational challenges related to the transport
of cell and gene therapies (Figure 30). Many respondents (42%, 25/59) viewed force
majeure (uncontrollable external factors) as very challenging, a third (32%, 19/59) as
moderately challenging and only one respondent (2%, 1/59) as not at all challenging. A
quarter (24%, 14/59) were not sure. About a third of respondents (33%, 20/60) viewed
human error (i.e., improper storage, shipment misroute) as very challenging, nearly half
(43%, 26/60) as moderately challenging and only 12% (7/60) as not at all challenging. A
further 12% (7/60) were not sure. A similar pattern of response was associated with the
challenge of the unpredictability of transportation management. A third (32%, 19/60)
viewed it as very challenging, more than half (52%, 31/60) as moderately challenging,

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5% (3/60) as not at all challenging and 12% (7/60) were not sure. Similarly, about a third
(32%, 19/60) viewed airline handling as very challenging, but more (43%, 26/60) viewed
it as moderately challenging and 12% (7/60) as not at all challenging. Thirteen percent
(8/60) were not sure.
Vendor management appeared to be less challenging in comparison. Twenty-two
percent (13/60) viewed it as very challenging, about half (52%, 31/60) as moderately
challenging, 13% (8/60) as not at all challenging, and 13% (8/60) were not sure. A
similar pattern of response was associated with cold chain management. Twenty percent
(12/60) identified that establishing cold chain management was very challenging, slightly
less than half (45%, 27/60) that it was moderately challenging, 23% (14/60) not at all
challenging and 12% (7/60) were not sure.
The remaining operational elements were ranked on average as less challenging
than the others. About 15% viewed distributor handling as very challenging (17%,
10/59), half (49%, 29/59) as moderately challenging, 14% (8/59) not at all challenging
and 20% (12/59) were not sure. Access to the patient and clinical sites was rated as very
challenging by only 7% (4/60) of respondents moderately challenging by more than half
(55%, 33/60), not at all challenging by 17% (10/60) and 22% (13/60) were not sure.
Shipment tracking and traceability was very challenging to less than ten percent (7%,
4/60) and moderately challenging to half (50%, 30/60) of respondents. Thirty percent
(18/60) viewed shipment tracking and traceability as not as all challenging and 13%
(8/60) were not sure.

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Figure 30 Operational Supply Chain Challenges
Please indicate how challenging the following factors related to operational
considerations when transporting of cell and gene therapies have been for you or your
organization: (n=60*)

* n=59 for Force Majeure (Uncontrollable External Factors) and Distributor Handling.

Challenges related to regulatory impediments for the distribution of cell and gene
therapies were also explored (Table 17). Respondents were asked to rank regulatory
impediments from most challenging (scored at 5) to least challenging (scored at 1). Based
on the ranked score, import and export regulations (rank 1; score = 187), maintaining
product stability (rank 2; score = 184) adhering to regulations and laws (rank 3; score =
183) were the top three challenges. Maintaining the chain of custody (rank 4; score =
159) and documentation/labeling requirements (rank 5; score = 142) were ranked the
least challenging.

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Table 17 Regulatory Implementation Challenges
Please rank how challenging the following factors related to regulatory considerations for
the distribution of cell and gene therapies have been for you or your organization (Please
rank the 1=most challenging to 5=least challenging) (n=57).

n=57
Regulatory Challenge Rank 1 Rank 2 Rank 3 Rank 4 Rank 5 Total
Rank
Score Rank
Import and Export
Regulations /
Customs 13 18 7 10 9 57 187 1
Maintaining Product
Stability 14 9 16 12 6 57 184 2
Adhering to
Regulations / Laws 13 12 13 12 7 57 183 3
Maintaining the
Chain of Custody /
Shipment Identity 7 13 14 7 16 57 159 4
Documentation /
Labeling
Requirements 10 5 7 16 19 57 142 5

The rank score was calculated by applying a weight to each response. For example, if there were 5 options
(most challenging =rank 1 to least challenging= rank 5), the number of responses for that choice was
multiplied by a weighted score. In this case, an option ranked as the most challenging (rank 1) was
multiplied by a factor 5, the number of responses where an option was ranked second (rank 2) was
multiplied by 4, and so on. The sum of the total weighted score [rank 1 (5) + rank 2 (4) + rank 3 (3) + rank
2 (2) + rank 5 (1)] was calculated to get a weighted rank score. The rank score was then sorted from
highest to lowest. The option with the highest rank score was determined to be number most challenging.

4.6 Full Implementation
As implementation proceeds, hurdles related to ongoing interactions with
vendors, clinical partners and supply chain partners can be identified (Table 18). Six
potential challenges were examined to determine the experiences of the respondents.
Most respondents (60%, 38/63) identified that their organizations had adequate
distributional controls to ensure the safety, efficacy, and quality of the medical product.
However, 29% (18/63) somewhat agreed, 3% (2/63) disagreed and 8% (5/63) were not

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sure. The weighted score for this statement was 1.4. Slightly less than half (41%, 26/63)
agreed that access to the shipment documentation and data was readily available. Of the
others, 32% (20/63) somewhat agreed, 10% (6/63) disagreed, and 17% (11/63) were not
sure. The average weighted score for this statement was 1.6.
About a quarter (24%, 15/63) identified that their supply chain costs were higher
than they expected. Of the rest, 38% (24/63) somewhat agreed and 8% (5/63) disagreed.
Notably, 30% (19/63) were not sure. The average weighted score was 1.8.
About one-fifth (21%, 13/63) agreed that the communication with their clinical
sites was better than they expected. Of the rest, 40% (25/63) somewhat agreed, 21%
(13/63) disagreed, and 19% (12/63) were not sure. The average weighted score for this
statement was 2.0. About one-fifth (21%, 13/63) agreed that the communication with
their vendors was better than they expected; 44% (28/63) somewhat agreed, 17% (11/63)
disagreed, and 17% (11/63) were not sure. The average weighted score was also 2.0.
Far fewer (11%, 7/63) agreed that implementation of the clinical trial logistics
was easier than expected. Thirty percent (19/63) somewhat agreed, nearly half disagreed
(46%, 29/63), and 13% (8/63) were not sure. The distribution of responses was consistent
with the average weighted score of 2.4.

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Table 18 Retrospective Review of Implementation of Supply Chain Management
Thinking back to a recently implemented clinical trial supply chain project, please
indicate your level of agreement with the following statements (n-63). Numbers are in
shaded columns, and the bolded values represent the calculated weighted averages and
their standard deviations.

Question
Agree
Somewhat
Agree Disagree Not Sure Total Mean SD
1 2 3

The implementation of
clinical trial logistics was
easier than expected 11% 7 30% 19 46% 29 13% 8 63 2.4 3.9
The communication with
clinical sites was better than
I anticipated 21% 13 40% 25 21% 13 19% 12 63 2.0 2.5
The communication with
my vendors was better than
I anticipated 21% 13 44% 28 17% 11 17% 11 63 2.0 2.3
The access to my shipment
data and documentation
was readily available 41% 26 32% 20 10% 6 17% 11 63 1.6 1.5
My organization had
adequate process controls
in place ensure the safety,
efficacy, and quality of the
medical product during
distribution 60% 38 29% 18 3% 2 8% 5 63 1.4 0.8
The costs of the supply
chain management for my
clinical trial were higher
than I expected 24% 15 38% 24 8% 5 30% 19 63 1.8 1.8

Respondents were asked to evaluate statements related to the current regulatory
climate governing supply chain management (Table 19). When asked if regulators
should work together to harmonize or standardize distribution and transport laws and
regulations, most respondents (82%, 51/62) strongly agreed, 13% (8/62) somewhat
agreed, and one respondent (2%, 1/62) disagreed. Two respondents were not sure (3%,
2/62). The average weighted score was 1.2. More than half (68%, 42/62) felt that clinical
supply chain management regulations should be flexible, adaptable, and risk based. Of
the rest, 26% (16/62) somewhat agreed, 3% (2/62) disagreed, and two respondents (3%,

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2/62) were not sure. The average weighted score was 1.3. About a third (33%, 20/61)
agreed that current US FDA Good Manufacturing Practices (GMP) regulations were
sufficient for clinical trial distribution; about half (51%, 31/61) somewhat agreed and 8%
(5/61) disagreed. Eight percent (5/61) were not sure. The average weighted score was 1.7.
Twenty-three percent (14/62) agreed that current US FDA Good Clinical
Practices (GCP) were sufficient; about half (48%, 30/62) somewhat agreed, 13% (8/62)
disagreed and 16% (10/62) were not sure. The average weighted score was 1.9. Far fewer
agreed (13%, 8/62) that regulatory guidance was sufficient to support supply chain
management. Forty-eight percent (47%, 29/62) somewhat agreed, 29% (18/62) disagreed
and 11% (7/62) were not sure. The average weighted score for this statement was 2.2.

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Table 19 Views on Medical Product and Supply Chain Regulations
Please indicate your level of agreement with the following statements regarding current
regulations of clinical trial distribution of cell and gene therapies (n=62)*.Numbers are in
shaded columns, and the bolded values represent the calculated weighted averages and
their standard deviations.

Question
Agree
Somewhat
Agree Disagree Not Sure Total Mean SD
1 2 3

Current US FDA GCP regulations
are sufficient for the distribution
of clinical trials. 23% 14 48% 30 13% 8 16% 10 62 1.9 2.1
Current US FDA GMP regulations
are sufficient for the distribution
of clinical trials. 33% 20 51% 31 8% 5 8% 5 61 1.7 1.6
Regulators should work together
to harmonize or standardize
distribution and transport laws
and regulations 82% 51 13% 8 2% 1 3% 2 62 1.2 0.4
Clinical Supply Chain
Management regulations should be
flexible, adaptable and risk-based 68% 42 26% 16 3% 2 3% 2 62 1.3 0.7
There is sufficient regulatory
guidance to support the supply
chain management of Cell and
Gene Therapies 13% 8 47% 29 29% 18 11% 7 62 2.2 3.0
*n=61 for Current US FDA Good Manufacturing Practices (GMP) regulations are sufficient for the distribution of
clinical trials.

Respondents were asked whether GDP guidelines should be adopted and enforced
by the US FDA to transport IMPs. Most (81%, 39/48) agreed, and many expanded on
this view. They observed that the adoption of GDPs would harmonize the US with the
rest of the world, standardize distribution processes, bring awareness to the GDP
regulation, and provide a baseline for the practices of vendors and the industry. Some
respondents also identified that their adoption would improve product traceability and
help to ensure product integrity and quality (Table 20). However, about one-fifth (19%,
9/48) disagreed with the adoption and enforcement of GDPs . Some felt that the current
GMP and GCP regulations were sufficient. A few suggested that more flexible and risk-

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based guidance documents could be developed by the FDA to provide baseline
expectations and to help harmonize the standards for distributing IMPs (Table 21).
Table 20 Supporting Views on GDP Implementation
Response selected: Yes, the US FDA should adapt GDP regulations for IMP distribution,
because ... (please specific why)

Harmonization and Standardization
Global harmonization and ensuring the integrity and quality of IMPs is key.
This will lead to harmonization of distribution practices as well as ensure more people are
aware of GDP regulations.
Yes to establish a baseline and aid in vendor compliance expectations for heavily outsourced
companies. The regulations must include flexibility though due to the real world adaptive
strategies and pivots required for cell therapies specifically. If you need to charter a helicopter
or snowcat to get the product to the patient, the snowmobile may not be audited.
To increase continuity of process between regions in a global clinical trial. I always advocate
for increased harmonization across regional regulatory authorities.
GDPs should be required and implemented to continue "GXP" practices end-to-end through the
total life cycle of the product(s).
Product Accountability
In a nutshell, it makes sense! Safety for product/material equals safety for clinical trials.
Traceability & accountability
Table 21 Opposing Views on GDP Implementation
Response selected: No, the US FDA should not adapt GDP regulations for IMP
distribution, because ... (please specific why)

GMP and GCP are sufficient
Following cGMP should suffice
The requirements are well covered elsewhere in the CFR and additional enforcement is not
required.
GMP and GCP regulations adequately address GDP requirements.
Items of importance are already covered in other US regs.
Require harmonization, for IMP should be guideline, otherwise may be a constraint not based
on risk assessment
FDA should supply guidelines that leave room for Pharma to adapt to fit their procedures
I think they should consider it more in conjunction with industry

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Respondents were asked about their regulatory expectations for supply chain
providers (Table 22). More than half (62%, 39/63) agreed and another quarter (16/63)
somewhat agreed that third-party logistics providers transporting clinical trial material
should establish the same regulatory and quality standards as the medical product
industry. Only eight percent (5/63) disagreed and a further five percent (3/63) were not
sure. The average weighted score for this statement was 1.4.
About half (52%, 33/63) agreed that transportation service providers should be
subject to the same regulatory oversight as the medical product industry. Twenty-nine
percent (18/63) somewhat agreed and 19% (12/63) disagreed. The average weighted
score for this statement was 1.7.
Table 22 Views on Medical Product and Supply Chain Standards
Please indicate your level of agreement with the following statements regarding third-
party distribution companies. Numbers are in shaded columns, and the bolded values
represent the calculated weighted averages and their standard deviations.

Transportation service providers (3PL) that transport clinical trial material should...
(n=63)

Question
Agree
Somewhat
Agree Disagree Not Sure Total Mean SD
1 2 3
Establish the same
regulatory and quality
standards of medical
product regulations as
the medical product
industry 62% 39 25% 16 8% 5 5% 3 63 1.4 1.0
Should have the same
oversight by the FDA
and other regulators as
the medical product
industry 52% 33 29% 18 19% 12 0% 0 63 1.7 1.7

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When asked about areas in which industry had gaps in their knowledge (Figure
31), respondents suggested significant gaps across several areas, A similar distribution of
agreement was seen for knowledge related to CGT regulations governing the products
themselves (41%, 26/63), their transportation (47%, 29/62), and their management (43%,
27/63) more generally. About thirty-five percent somewhat agreed [35 % (22/63) for
CGT medical product regulations; 37 % (23/62) for CGTs transport regulations; and 37%
(23/63) for CGT management]. Between 3 to 15% disagreed [13 % (8/63) for CGT
medical product regulations; 3% (2/62) for CGTs transport regulations; 8% (5/63) for
CGT management]. Knowledge gaps appeared to be viewed as less pronounced for
supply chain management for clinical trials. Thirty percent (19/63) agreed that a
knowledge gap existed, but many more (41%, 26/63) somewhat agreed, 16%, (10/63)
disagreed. In all these areas, between 11-16% were not sure whether gaps existed in the
knowledge related to any one of the offered areas.

146

Figure 31 Knowledge Gap for CGTs and Transportation
Please indicate your level of agreement with the following statements related to cell and
gene therapies and supply chain management.

There is an industry knowledge gap in... (n=63*)

*n=62* Cell and Gene Therapies Transportation Regulations
Respondents were asked whether biotechnology and biopharmaceutical
manufacturers held different views than supply chain vendors (third-party logistics,
specialty couriers) about requirements and regulations (Figure 32). Some respondents
(34%, 21/62) agreed that the two types of organizations view clinical supply chain
requirements differently. Of the rest, 39% (24/62) somewhat agreed, 16 % (10/62)
disagreed, and 11% (7/62) were not sure. Similarly, about 31% (19/61) agreed that the
two industries viewed medical product regulations differently. Of the rest, 36% (22/61)
agreed, 13 % (8/61) disagreed, and 20% (12/61) were not sure. Respondents were then

147

asked about transparency and communication between partners. Far fewer (16%, 10/62)
agreed that communication was transparent. About a third either somewhat agreed (35 %,
22/62) or disagreed (35%, 22/62), and 13% (8/62) were not sure. Similarly, 15% (9/62)
agreed that the information sharing between the partners were transparent. About a third
(34 %, 21/62) somewhat agreed or disagreed (35%, 22/62) and 16% (10/62) were not
sure.
Figure 32 Views on Vendor Management Partnerships
Please indicate your level of agreement with the following statements related to
partnerships between biopharmaceutical and supply chain industry.

Medical product manufacturers (biotech, biopharma) and supply chain vendors (3PL
couriers, specialty couriers) ... (n=62*)

*n=61 view medical product regulations differently

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4.7 Sustainability
To explore sustainability, respondents were asked about the ease with which long-
term supply chain strategies could be supported by certain types of infrastructure or
logistical solutions (Figure 33). Amongst the most difficult approach to implement
appeared to be automation; about a third (37%, 22/59) viewed automation as difficult to
implement. Of the others, 17% (10/59) indicated that automation was somewhat easy
implement and only 5% (3/59) found it easy to implement. Nearly a quarter of
respondents (22%, 13/59) had not implemented automation and a further 19% (11/59)
were not sure. Other suggested approaches were also found to be difficult to implement,
albeit by lower numbers of respondents. “Logistics by design” such as treatment-based
distribution was difficult for about a third (31%, 18/59). However, more than a third
found it to be somewhat easy (36%, 21/59). Three percent (2/59) found it easy to
implement; 10% (6/59) did not implement logistics by design and 20% (12/59) were not
sure. Similarly, a third (31%, 18/59) viewed a robust vendor management program as
difficult to implement, but 37% (22/59) indicated that it was somewhat easy to implement
and 10% (6/59) that it was easy to implement. Seven percent (4/59) had not implemented
vendor management programs and 15% (9/59) were not sure.
Respondents found it less difficult to build physical infrastructure. Twenty-four
percent (14/59) regarded it as difficult, about half (46%, 27/59) as somewhat easy, 7%
(4/59) as easy, and 14% (8/59) did not build physical infrastructure. Ten percent (6/59)
were not sure. A similar distribution of responses was associated with the perceived
difficulty of implementing strategic partnerships. About a quarter (22%, 13/59) indicated
this implementation as difficult, 39% (23/59) as somewhat easy, 7% (4/59) as easy, and

149

8% (5/59) did not implement partnerships programs. Twenty-four percent (14/59) were
not sure. Similarly, fewer difficulties were identified when implementing industry
standards. Seventeen percent (10/59) ranked implementation as difficult, 54% (32/59) as
somewhat easy, 10% (6/59) as easy, and 5% (3/59) did not implement industry standards.
Fourteen percent (8/59) were not sure. The implementation of IT and blockchain systems
had mixed views. Fifteen percent (9/59) identified ranked it as difficult and about a
quarter (28%, 17/59) identified that it was somewhat easy. None characterized the
implementation of IT and blockchain approaches as easy. Thirty-two (19/59) did not
implement this strategy, and 24% (14/59) were not sure of the difficulty.
Figure 33 Implementation Views from Industry Stakeholders
Based on prior experiences, how easy was it to implement the following elements of
clinical supply management? (n=59)

150

Respondents were also asked if they were prepared to scale up from clinical to
commercial phases (Table 23). About half felt that they were ready (46%, 21/46), and
another half that they were not (54%, 25/46). Respondents prepared for the scale-up
attributed their readiness to their experience with commercial products, adequacy of
financial resources, and availability of in-house expertise and subject matter experts.
They also felt that they were aided by access to legacy systems for validation, stability,
and distribution. One respondent also identified that their organizations were scaling out
to larger facilities with multiple temperature rooms. Strategic supplier partnerships were
also identified as important to facilitate scale up into the commercial phase. Respondents
who felt that the company was unprepared attributed this state to inadequate resources or
inexperience with commercialized products. Multiple respondents noted that the supply
chain requirements would not easily scale from clinical to commercial needs, and
limitations existed in supplying the amount of product needed for commercialization.

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Table 23 Scale-up Preparation from Clinical to Commercial Phases
Positive views for upscaling into commercial phases (Part A)
Yes, the organization is well-prepared to upscale because …
We are already implementing practices that we will use in the commercial phase.
We have the financial resources and expertise to upscale.
We are moving into a bigger facility that has multiple temp range rooms.
Large company with experience and resources
We have well established and experienced team in place.
This has been done in the past
Because we have an in house experiences team and we do not rely on questionable experts and
consultants.
We have a full tool box that can be deployed for both clinical and commercial scenarios
Mainly because the organization does have experience with commercialized products, so
leveraging legacy validation, stability and supply chain requirements have become
standardized from clinical to commercialization.
We partner with some of the best consulting firms and supply chain vendors which makes/made
it possible
Robust supplier management partnerships
Opposing views for upscaling into commercial phases (Part B)
No, the organization is not well prepared to upscale because…
Difficulty converting clinical standards to commercial standards
We do not have the capabilities to manufacture the quantities need for commercialization.
We have limited resources to tackle supply chain and would likely have to outsource it to a
third party supplier.
Temp controlled storage is a large constraint / concern for transition to commercial phase.
Scaling up and training must go hand in hand, a well defined program, mentoring and buddy
system is key to successful scale up
Lack internal expertise
Small companies struggle with cash flow and adequate resources.
Very few with commercial experience.
Cost of infrastructure build to account for commercial scale exceeds the available budget for a
smaller company
It is contracted out
Systems and tools are not in place to provide the visibility and risk assessment necessary to
carry out the activity and be consistently successful. Additionally, gaps exist in vendor
management knowledge concerning cell and gene therapies.

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A cross-tabulation was also carried out to determine if small and large companies
had different views with regard to the ease of scaling up from clinical to commercial
phases (Table 24). Many more respondents from large companies (69%, 9/13) than small
(36 %, 8/14) and mid-size (36%, 4/11) companies indicated that they were well prepared
to scale up into the commercial phase.
Table 24 Commercial Upscaling versus Company Size
This table provides a cross-tabulation of upscale from clinical to commercial versus the
size of the company.

What is the company size of
your most recent
employer/client in terms of
number of employees?

Choice
1-999
(small)
1,000 -
9,999
(mid-size)
10,000 +
(large) Total

As you move from clinical into
commercial phases of product
development, from a perspective of
the sustainability of the supply
chain for time-sensitive and
temperature-sensitive medical
products like cell and gene
therapies, do you feel your
organization is well prepared to
upscale?
Yes
8 4 9
21

36% 36% 69%

No
14 7 4
25

64% 64% 31%

Total
Count 22 11 13 46

Respondents were asked if the supply chain strategy was sufficiently robust to
deal with the disruption presented by COVID-19 (Table 25 and Table 26). Many more
respondents felt that their strategies were insufficient (63%, 31/49) than sufficient (37%,
18/49) to deal with the disruption. Unprepared respondents did not have the appropriate
contingency plans, redundancies, or resources in place. In some cases, this retarded
access to their raw materials or to apheresis centers. Closure of clinical sites was
identified, and flight disruptions and export delays threatened the stability of their

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products. Of those who considered their companies as prepared, many were assisted by a
diverse network of suppliers, access to technology, business continuity plans and/or
robust logistics planning. One respondent had worked directly with the US Department of
Health and Human Services (HHS) and US regulators, in order to import their products
faster than ordinary circumstances would allow. One respondent stated the organization
could not plan for COVID-19 but was prepared to react as needed.
Table 25 COVID -19 Preparedness - Positive Feedback
Yes, the supply chain management plans in place were adequate, because ... (please
specific why)

Feedback on COVID-19 Contingency Plans
We had business continuity plans in place.
The critical elements had a diverse logistics network, strong logistics planning function at our
label pack vendors, and strong connections with US regulators (operation warp speed). By
having strong oversight, the technology supporting tracking (GPS) and direct contacts with
heads of HHS, we were able to import faster than normal. We are actually moving pipelines
faster based on COVID urgency rather than encountering delays to the standard timelines.
We're also getting a much bigger focus on risk based strategies and creative solutions to
overcome standard turn around times.
The plans was independent and functional with Covid.
A complete disruption first for medical necessity and now for political reasons can not be
planned for. You can one react to them. Which we have.
We started preparing earlier than most and had key asset and network advantages
we met early and anticipated the supply chain issues, changing our core offerings from
reusable solutions to single use, reducing exposure of COVID-19
They are applicable to any situation.
We haven't seen disruptions in shipping.
Full business continuity planning in play, regardless of COVID-19
COVID-19 did not impact the process itself, just made it more difficult.
we had strong contingency and disaster recovery plans
We had to rely upon the flexibility of our network in order to meet the customer's needs.
Contingency plans/return to BAU always in place

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Table 26 COVID-19 Preparedness - Negative Feedback
No, the supply chain management plans in place were not adequate because....

COVID-19 Preparedness
Not something that we had considered in our planning
we did not have redundancy built into our supply chain management
We have been having issues exporting shipments to countries where WHO is providing the
approval, but not the local authorities.
Use China as a source of clinical trial material
Availability of ancillary supplies
Clinical supply was single sourced overseas. COVID created an inability to receive materials
"just in time".
No due to limited shipping transportation availability, industry had to react to alternate
shipping lanes and modes of transportation to meet validated shipping requirements.
Shipping to clinical sites was stopped when clinics closed. Getting supplies to patients became
difficult.
If apheresis centers come to a stop the supply chain breaks down, shipments are no longer
reliable and short IMP shelf-life is problematic
I don't think anyone sufficiently prepared for interruption with this magnitude.
Absolutely no plan in place for my current clients.
We were not prepared for a pandemic but I will say we adapted quickly.
Companies were not prepared with backup plans in case of transportation delivery delays
and/or trial shut-downs.

When evaluating preparedness for COVID-19, respondents from larger
organizations appeared to have more contingency plans in place for COVID-19 (Table
27). Twenty-nine percent (7/24) from small companies indicated yes compared to mid-
size (46%, 5/11) and large-sized (43%, 6/14) organizations.

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Table 27 COVID-19 Preparedness versus Company Size
This table provides a cross-tabulation of COVID-19 preparation versus company size.

What is the company size of your
most recent employer/client in
terms of number of employees?

Choice
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
A global pandemic (such as
COVID-19) has been identified as
a disruptor in supply chain
management implementation for
clinical trials. Looking back at
your planning activities for your
supply chain strategy, do you feel
that you were adequately
prepared for COVID-19?
Yes
7 5 6
18
29% 46% 43%
No
17 6 8
31
71% 55% 57%
Total Count 24 11 14 49

A range of lessons learned from the COVID-19 challenges included the need for
contingency planning and built-in redundancies, such as secondary suppliers or backup
for raw materials, reagents, and supplies. Respondents recommended more diversity in
supply chain options related to materials, shipping lanes, and service providers (Table
28).

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Table 28 Lessons Learned from COVID-19
Looking back (pre-COVID-19), is there anything you would have done differently for
your supply chain planning?

Lessons Learned
Build redundancy in terms of suppliers as well as vendors for key reagents and materials
We could have been more prepared for example we could have had back up options if the
airlines were not an option.
Yes stocked up on ancillary supplies (IV sets, IV bags)
Invest more in redundant temperature control equipment and test BCP/DRP more frequently.
We could have done an even better job, by executing scenario planning to further anticipate
resource and training needs
Better defined alternate vendors, supply routes, etc. Would have included verbiage in QAG that
mandated we have a stockpile of materials.
Have a plan B and plan C. Use lessons learned from COVID, establish, test and implement
plans NOW rather than react to next situation
Had a stronger backup plan for transportation delivery delays at all steps, pick-up, transport
and delivery.
Insure more lead-time. Importation took more time.
We could not really have planned for COVID. I don't believe plans could have ever been put in
place to effectively react to the complete shutdown of global air travel.
4.8 Analysis of Text-based Responses
Throughout the survey, respondents were asked four additional open-text questions
related to challenges, lessons learned and best practices along the supply chain for CGTs:
• Are there any other challenges there were not previously discussed in the survey
you experienced with your clinical trial's supply chain?
• Thinking back to clinical trials you have managed or collaborated on in the past,
what was one lesson learned from your experience with supply chain
management?

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• When thinking back to how you recently implemented a clinical trial, is there
anything you would have done differently across the supply chain?
• Are there additional factors not mentioned above that you and your organization
consider important for clinical trial distribution and transport of cell and gene
therapies?
Each of these questions elicited over 50 responses that are all presented in
Appendix C. Survey Data Set. In some cases, responses were lengthy and covered
multiple topics. Thus the responses were regrouped into emergent themes:
(1) Stakeholder Engagement, (2) Resources, (3) Planning and Forecasting, (4) Supplier
Management, (5) Data and Documentation, (6) Material Management, and (7) Global and
Regulatory Considerations.
4.8.1 Stakeholder Engagement
Respondents emphasized the importance of stakeholder management and
engagement to assure seamless distribution (Table 29). Many comments focused on
maintaining cross-functional teams and having continuous and transparent
communication with stakeholders such as nurses and distributors along the supply chain.
Coordination between manufacturing, the product release team, and clinical operations to
track shipment materials between clinical sites and detect changes to inventory and
packaging requirements was also mentioned. Some respondents suggested that customs
brokers and/or regulatory agencies should be included in the planning process.
Many respondents mentioned the need to plan early with key stakeholders such as
supply chain partners, vendors and Chemistry Manufacturing and Control (CMC)
personnel (Table 29). Insufficient communication and misaligned expectations were

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identified to cause errors in critical process steps such as labeling and documentation.
Internal tensions were identified when pressures to complete the trial led practitioners to
neglect planning for supply chain management.
Table 29 Lessons Learned: Stakeholder Engagement

Stakeholder Engagement
We would have included the custom brokers and the border/custom agents early in our
planning process to ensure cell therapy products will not have custom clearance delays.
However, the last time I ran a clinical study for a company I was an employee of, I ran into
communication issues between the manufacturing operations group in labeling the product
appropriately and following shipping and import requirements to enable the clinical material to
arrive at the clinical site on-time and stored appropriately. The issue was really the VP of
Operations was hostile towards the Regulatory/Quality/Clinical department and wanted to
undermine this group wherever possible. Most of my other experiences have been relatively
collaborative.
Would have involved the clinical operations group earlier in the discussion of supply chain
logistics, maintained cross functional communications between product release and clinical ops
in terms of packaging changes and transport tracking, verification of material transfer between
sites, etc.
Need to get regulatory feedback on this process from regulatory agencies, what if there is a
regulatory concern Clinical Op didn't foresee.

Quality does not have much say to decisions for a new trial. The sponsor creates and
environment of entrepreneurship motives (get things done at any cost).No plan to critically
access the supply chain for a new trial.
You have to keep the clinic/patient focused and bring it ALL THE WAY back to process
development. They hate it but if they don't have the right target...they're running down a tangent
path for 12-36mo only to find out it doesn't meet end user requirements. Failing to have clinical
supply leads in CMC core meetings is also a risk. We've seen PD/MFG want to use
concentrations, fill volumes, or containers that are incompatible with trial designs. We've seen
specifications that aren't aligned with target dose levels (e.g. min concentration spec is far
higher than the target dose risking unnecessary lot rejection)
Cross Functional Planning, test shipments, written procedures, written risk management and
mitigation plans!

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4.8.2 Resources
Impediments often included insufficient personnel with CGT and supply chain
competencies and inadequate funding (Table 30). To cut costs, underqualified personnel
were seen to be tasked with various roles. Respondents identified that one lesson learned
was the need to determine competencies along the supply chain and ensure training at all
stages in the distribution chain.
Table 30 Lessons Learned: Resources

Resources
Most companies do not want to pay a consultant or CRO to manage logistics and that can be
one of the biggest challenges in a clinical trial.
Most small companies hire very under qualified people to help them save money but that
oftentimes sets them up for failure.
Everyone wants to see the clinical trial be successful so most of the other issues I have run into
are related to lack of funding, people resources, or lack of experience for those who were
tasked with various roles.
Company was small, did not have strong supply chain resources and was unfamiliar with many
of the constraints prior to initiating shipments.
Need for expertise in global import/export requirements by country
It is preferable then to have experienced in-house personnel dedicated to supply chain
management rather than generalist to assume such work.
We needed to assist small research based organization with regulatory, QMS, and compliance
requirements.
Costs - Most clients do not want to pay for the resources they truly need to make their supply
chain effective.
Smaller companies don't usually have a clinical supply role etc. is a last minute though in many
cases for small companies.

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4.8.3 Planning and Forecasting
Respondents emphasized the need to plan early and to include risk-based
contingency plans (Table 31) to assure that sufficient materials, packaging, and product
was stocked with a view to potential risks. The importance of developing a plan and
performing feasibility runs were commonly recommended practices for those activities
that could threaten timelines. Respondents identified the potential for automation and
computer modeling systems to forecast distribution activities.
Table 31 Lessons Learned: Planning

Planning
Start earlier with supply chain and logistics planning, understanding existing capabilities and
matching them to product requirements is key. We need to plan accordingly in terms of
matching a solution that ensures product integrity.
Planning sufficient validation for temperature, duration, and shipping lanes in early clinical
trials while considering expansion of (collection/manufacturing/infusion) sites.
Allow more time for labeling, packaging and/or kitting.
When doing due diligence I've seen executives fail to really quantify the logistics element of
cost-of-goods.
Having automation / ERP is key. Managing without it is a recipe for mistakes
We have gone from government/non-profit trial endorsement to target subject dosing in 4-8
weeks. In that timeframe you have to establish all of that ownership, optimize strategies, pray
you have existing network (i.e. avoid auditing a new depot in Russia or Argentina), get
financials in order to meet SOCS compliance (i.e. no work prior to PO approval), and then find
creative solutions to trim 5 day turn around times to same day turn around times. All of this has
to happen across timezones and languages.
Defining decision deadlines can be one of the biggest keys in a timeline focused startup.
Recognizing that at some point you have to pull the trigger on a plan that can't be reassessed
without timeline impact. This decisiveness must be present to enable aggressiveness on
development timelines.
It is more unpredictable than one can imagine and whenever you think it is all working
optimally, there is a new problem that needs a solution.
Map Map Map!!! All scenarios should be considered and assessed for risk. For CGT, we must
be able to anticipate what is going to happen and when. From that, then we need to make
contingency plans based upon known risk factors.

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4.8.4 Material Management
Some respondents were challenged by the need to obtain customized components,
equipment, and devices such as temperature monitor and tracking devices to support
some CGT products (Table 32). Raw materials, reagents, and excipients used in the
process may not always be available in GMP grade, and compatible product container
closures that hold the CGT material were challenging.
Table 32 Lessons Learned: Material Management

Material Management
We send duplicate CTM to ensure adequate supply in case any doses are compromised during
shipment
We also had situations where semi-custom raw materials fail or have issues. You then have to
trouble shoot with the vendor while not giving away proprietary info that is critical to your
process (cell processing equipment has issues but then the MFG sees your parameters as you
troubleshoot).
Take a hyperstack for instance. There was a shortage due to viral vector production. When the
big 5 players commit to buying 80% of their volume, we have to work on relationship
management to get a steady trickle of units for just-in-time delivery. Playing the ultimatum
hardball card won't work in that instance
Raw materials are not always available in a GMP grade, are proprietary or of an undefined
composition. Therefore the idea of secondary supplier sourcing has to be adapted. We've had
magnetic beads, custom media or medical devices (cell reactors) that need complex contracts,
process bridging or can be snatched by a competitor via exclusivity agreements.
New technology often involve small research-based

4.8.5 Supplier Management
Respondents identified a need for better planning and qualification of suppliers
(Table 33). Business contracts and quality agreements were a “best practice,” and

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respondents recommended the need to clarify roles and responsibilities. Ensuring that the
clinical sites were trained on key areas in the shipping process was also a lesson learned.
Table 33 Lessons Learned: Feedback on Supplier Management

Supplier Management
A better job of qualifying COMs, vendors and transportation companies before the trial
started.
Engage a supply chain SME earlier
Picked fewer CROs with larger patient population
Outsourcing isn't just with 3rd party subcontractors, but can also be done via COMPLEX
alliance partnerships with other companies, subcontractors managed by alliance partners,
non-profit organizations, academia which owns contracts with governmental organizations,
etc. Establishing robust contracts, roles/responsibilities, quality agreements and supply
networks is key. That framework must also be established EXTREMELY fast.
It is very important to do a thorough job of qualifying and educating vendors before you
initiate the trial
There exists a lack of understanding on the part of vendors and how important these
materials are. The human error factor cannot be underestimated when analyzing risk.
I would also want to see more of a priority of these materials with the airlines themselves.
Currently, this is a country by country, airline by airline situation. Because the impact of
failure is so great (patient could potentially die), these types of materials need to be treated
as the most valuable of cargo by the airlines and the airline handlers.
I've seen automation be a total debacle with vendors over promising capabilities.
My perspective is often, how can my organization be flexible and dynamic enough to fit into
the systems of 20 different vendors while at the same time accelerating their systems. The
idea is that trying to make 20 vendors operate within YOUR internal SOPs and arbitrary
risk tolerance will never be the fast path. Don't rock the boat...adapt to their requirements
with minor modification and things will go smoothly and quickly. It also links into
relationship management. The enjoyable companies often miraculously find production
slots.
4.8.6 Data and Documentation
Documentation, labeling, and ensuring chain of identity (COI) and chain of
custody (COC) of trial material was an area of concern (Table 34). Having written
materials in the local language was a lesson highlighted by multiple respondents. Best

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practices included assuring that detailed stability documentation was reviewed by quality
assurance and that a return process for temperature sensing devices was developed. Some
respondents preferred simplifying processes for chain of identity and chain of custody.
Table 34 Lessons Learned: Data and Documentation

Documentation and Labeling
I will make sure the readiness of the label in the local language.
Document everything, don’t assume anything, confirm, pressure test
Would like to ensure that the documentation of the IMP for the retest dates for stability studies
was more detailed and included QA sign off.
Chain of Custody
System changes would have been put in place to allow more visibility to the classification of the
material, the real time status of the material (temperature and location), and real time alerting
of the same.
Monitoring of return devices and tracking of devices.
Knowing what I know now, I would simplify the process in the areas of COC/COI.
A common understanding of chain of custody between various parties, internally and externally
Return policy and procedures, how do you get the unused specimen back so it can be properly
investigated.

4.8.7 Global and Regulatory Considerations
Some responses focused on challenges associated with cultural differences,
language barriers, and time zones as well as logistical challenges such as air shipments
(Table 35). They noted dissonance across standards and regulations, as well as customs
and export delays in countries such as China. The need to have a qualified person (QP)
release CGT products and the uncertainties of Brexit were concerning. Respondents
suggested that clearer and more transparent regulations and policies would be valuable,

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and that more interaction and feedback from international authorities would help mitigate
some of the supply chain challenges.
Table 35 Lessons Learned: Global Considerations

Global Considerations
I will make sure the readiness of the label in the local language.
More upfront planning for QP release for some markets outside the EU
We would have included the custom brokers and the border/custom agents early in our
planning process to ensure cell therapy products will not have custom clearance delays.
Following shipping and import requirements to enable the clinical material to arrive at the
clinical site on-time and stored appropriately.
My experience with a radioisotope containing product in that we did not have choices re:
shipper to Europe. The air carriers could refuse for any reason, despite the therapeutic need
and short useable product half life
BREXIT
Lack of standardization of handling clinical trial materials.
New chapter in SC management is being written with CGT, with limited standardization.
Additionally, we need to have a standardized database of International Customs regulations
for the entire globe based upon HTS Code classification. This would allow visibility to the
customs requirements of each country in advance of shipping and would greatly reduce the risk
of delay due to lack of the proper documentation and or labeling.
More defined regulations and transparency from the health authorities in China would have
been helpful.

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Chapter 5. Discussion
5.1 Introduction
Precision Medicines such as CGTs will continue to transform the
biopharmaceutical enterprise, however they present new challenges. Much has been
written about the challenges associated with manufacturing and variability in starting
materials. Discussed less frequently are the additional hurdles associated with getting
those often-fragile treatments to the patient, the subject of research presented here.
Results present a more systematic picture of the views of experts dealing with CGT
supply chains than can be gained from the often-anecdotal literature presented in chapter
2. The interpretation of this new research will, however, depend on understanding some
of the delimitations and limitations that will affect the conclusions that can be drawn.
5.2 Methodological Considerations
5.2.1 Delimitations
CGTs are unique products whose unusually time-sensitive and temperature-
sensitive features increase the demands on their management. This research is delimited
to only one aspect of this management: transporting the products from the loading dock
of the manufacturer to the loading dock of the hospital or to the patient's front door.
Thus, it does not deal with preserving the products prior to their release from the
manufacturer or after they arrive at the hospital, clinical site, or patient. These additional
topics are addressed to some extent by regulatory guidance documents and industry
standards for upstream supply chain processes (USP; 2000; Potts, 2017; FDA, 2019ad;
FDA, 2019w) and through previous research related to clinical supply management at the

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clinical site or hospital (Bell et al., 2001; Brown et al., 2004; Redrup et al., 2016). It was
further confined to clinical trials. These are interesting because the delivery systems
typically put into place for the movement of test articles are not as well-defined as those
for commercial products. The challenges are particularly large for CGTs whose product
stability, safety, and efficacy profiles may still be underdeveloped.
As outlined in chapter 2, most of the issues when moving CGTs across countries
or continents are concerned with the implementation of effective logistics. The use of an
implementation framework (Fixsen et al., 2009) to structure the survey proved to be a
valuable way to assure that various aspects of system development, from exploring
options to the final implementation of standards and systems, were studied more
systematically. In the past, implementation frameworks have been used in medicine,
psychology, and education to evaluate evidence-based approaches and applications as
they transition from research and policy to practice (Fixsen et al., 2013; Horner et al.,
2017). In this study, the framework helped to set the boundaries on the study.
Because the study focused on the CGTs, which are a relatively novel technology,
the survey sample was chosen to reflect the views and experiences of a rare and diverse
group of individuals familiar with various aspects of CGT logistics. Identifying a
suitable sample of respondents to represent a population of interest is key to assure the
validity and generalizability of a survey (Rea and Parker, 2014; Devroe and Wauters,
2019). Because moving a CGT between sites can involve several players, it seemed
necessary to include individuals representing sponsors, manufacturers, distributors, and
biopharmaceutical partners such as contract research organizations (CROs) and clinical
supply chain organizations (CSCOs). A wide cross-section was thought to be needed

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because some of these individuals are responsible for only certain aspects of CGT
distribution and management, so they might not answer all of the questions. However, by
including a diverse group, it was possible to achieve the desired objective of reaching an
appropriate sample dominated by respondents in diverse management roles and employed
either in the biopharmaceutical industries or in companies relevant to the logistics of
CGT supply chain management. It was apparent that this objective was achieved from the
profiles of the respondents, most of whom had senior positions in companies with a broad
geographic reach and experience with CGTs as well as similarly complex biologics such
as vaccines. In these roles, participants would be best placed to identify the challenges
with the clinical management of cell and gene therapies. As part of their professional
responsibilities, they would also have to be well-versed in the current US GMP and GCP
regulations and standards. Thus, they were well-positioned to provide insight into the
gaps and adequacy of the regulations for CGTs.
A survey directed at a diverse grouping of experts could easily become undirected
if it also tried to address too wide a set of logistical considerations. Rules and regulations
governing clinical trials, medical product importation, and supply chain requirements
differ across countries. Even within the US, regulations can vary from state to state. To
focus the analysis, the decision was made to delimit the survey to the federal regulatory
framework for CGT transportation in the United States. This focus seemed to make the
most sense as a starting point because US clinical trials of CGTs comprise the largest
share of such activities globally (ARM, 2019; ARM, 2020a; ARM, 2020b). Also, the US
requirements are amongst the most rigorous in the world. Thus, US regulatory systems
often provide a benchmark and model for the management of CGTs in other regions.

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Last, this research is delimited in time. The captured data represents a snapshot of
the policies and practices related to the movement of CGTs used for clinical trials over
the last ten years (2010 - 2020). This study was not designed to predict the distribution of
such products prospectively, because logistical methods and regulations almost certainly
will change as technologies advance and best practices become hardened into
requirements.
5.2.2 Limitations
A key requirement for the success of this research was the ability to engage a
diverse group of geographically distributed experts. To reach these experts, I considered
a survey approach to be more appropriate than certain other possible options, such as
interviews or focus groups. A well-crafted survey can increase the yield of responses
within a defined time and at reasonable cost, considerations recognized elsewhere as key
to data-gathering (Marshall and Rossman, 2014). An electronic survey was also the best
way to ensure faster turnaround times and more accurate data collection (Sue and Ritter,
2012; Saleh and Bista, 2017). Additionally, an electronic survey administered through a
distribution intermediary such as Qualtrics can increase confidence in anonymity.
Because most of the individuals surveyed here are employed by companies in which
proprietary information needs to be protected, the confidentiality of results can increase
response rates and decrease the likelihood of interviewer bias (Marshall and Rossman,
2014).
Although survey tools have many advantages, inherent disadvantages can also
challenge the validity of the results (Zuidgeest et al., 2011). Perhaps the biggest concern
in a survey such as this is its ability to assure a significant response rate. Because

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respondents are expected to have substantial experience with the logistics of CGTs, some
potential participants may decide that they are not qualified to complete the survey.
Additionally, most individuals in the targeted population are busy and may only respond
to survey solicitations if they feel that the research is relevant to them and their
participation is not prohibited by an employer (Baruch, 1999). Of some concern was the
need to distribute the survey during the COVID-19 pandemic, when the workload for
multiple organizations within the healthcare and biotechnology industries had typically
increased (Rosales-Mendoza et al., 2020). Nevertheless, the 19% response rate seen in
this study was within a range typically considered as reasonable for academic studies,
which can be as low as 6% and as high as the mid-60 percent range (Baruch and Holtom,
2008; Hoonakker and Carayon, 2009; Fan and Yan, 2010; Saleh and Bista, 2017).
Response rates for electronic surveys have also been identified to be lower than surveys
distributed through conventional mailing methods (Baruch and Holton, 2008; Nulty,
2008). Several factors may affect the response rates of electronic surveys, so surveys
with even a 10% response rate have been viewed as viable (Nair et al., 2008; CHEQ,
2008).
Although email communication is fast to arrive at a recipient, messages can be
held without action for long periods or discarded immediately. Further, some companies
have effective filters to remove email communications that do not appear to be related
directly to the company's business. Because individuals in the pharmaceutical and
biotechnology sectors change jobs quite frequently, email addresses may fail to connect.
Research has also shown that most individuals have more than one email address;
alternate email addresses may not be checked as often or may be inactive for extended

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periods (Fan and Yan, 2010; Silva and Durante, 2014; Saleh and Bista, 2017). Even after
the survey is opened, respondents can be capricious in their decision to participate.
Several factors were considered as the survey tool was constructed. These
included the types and numbers of questions and the use of multiple reminders, predicted
by methodological literature to increase the response rate (Sue and Ritter, 2015; Saleh
and Bista, 2017). The response rate is also impossible to compute accurately when some
participants are recruited through open access links such as those posted on message
boards (Baruch and Holton, 2008; Nair et al., 2008). In some studies, monetary
recompense is used to encourage participation (Baruch and Holtom, 2008). However, the
types of individuals solicited here are typically well-recompensed, so the value of a
monetary incentive may be less important than the offer to share the survey results after
analysis.
5.2.3 Consideration of the Results
Attention to the pharmaceutical supply chain is not new. Organizations such as
WHO, PDA, ISO, and USP have all performed extensive research as they developed
standards to ensure that medical products would reach patients safely and effectively. As
discussed in section 2.4.2.1.5, managing the supply chain has also been a focus of
regulatory agencies globally to prevent misbranded and adulterated medical products
broadly. Recently, more specific research has been directed at the supply chain of CGTs
(Jebara, 2015; O’ Donnell, 2015; Lamb et al., 2017; Rees, 2017; Rees, 2018; Ellison et
al., 2019; Stanton; 2019; Elverum and Whitman, 2019). However, this work dealt
primarily with the more mature supply chain issues associated with commercialized
products. Although impediments to clinical product supply can be imputed from previous

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research, those data do not provide specific insight into the more unique challenges
associated with the distribution of clinical trial materials from the perspective of the
industry stakeholders. Additionally, they are narrow with regard to US regulations related
to investigational medicinal products and CGT supply chain implementation strategies.
The objectives of this research were to: (1) evaluate the current and best practices
for clinical supply management of CGTs throughout the product lifecycle; (2) identify
challenges that hinder the execution of clinical supply chain management for CGTs at
different stages; and (3) evaluate the adequacy of regulatory systems related to the
clinical supply chain of CGTs from the perspective of industry stakeholders. To this end,
Fixsen's Implementation Framework was used to provide a frame of reference for the
survey development. Thus, the following discussion is arranged in five phases—
exploration, installation, initial implementation, full implementation, and sustainability—
corresponding to what Fixsen and Blase (2010) regarded as key steps in project
maturation. To my knowledge, this is the only study to evaluate the implementation of
clinical supply chain management for CGTs using a systematic implementation approach.
5.2.4 Exploration
The goal of exploration is to determine operational readiness and feasibility of
various options for clinical product distribution. During this phase, sponsors of clinical
trials must identify the resources, costs, and transportation requirements for their CGTs
and associated components to meet protocol requirements and product specifications. It
is also a time to define the roles and requirements for the various players in the
distribution chain. It seemed clear that most respondents thought that their organizations
understood the FDA regulatory requirements and the sponsor's role in distributing IMPs.

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If their assessments are valid, they seem to contradict the finding of Jones (2020) that
sponsors often act as though they are exempted from responsibilities if they delegate their
responsibilities through outsourcing. As one potential explanation, it may be that
respondents interpreted this question as asking if the organization understood the
sponsor's role with specific reference to the FDA requirements that the products
themselves must meet clinical safety and efficacy endpoints. Their answers might have
been different if the question had asked more directly about the responsibilities when
outsourcing clinical trial and supply chain management. Perhaps informative was the
finding that many companies, especially smaller companies, chose to answer “somewhat
agree” rather than agree to many questions regarding operational readiness. It could also
be that some respondents may not even know the full extent of responsibilities related to
the supply chain and so would have trouble to see the gaps with respect to their
outsourcing activities. This problem may account at least in part for the observation that
a significant number of respondents did not have established vendor management
programs or provide training for their vendors (discussed also in 5.2.5).
Given the difficulties of distributing a fragile CGT test product, it might not be
surprising to find that most of the supply chain solutions adopted by the companies
represented here were relatively conservative. Most were found to focus on specialty
couriers, smart packaging, and transportation integrators such as the conventional
delivery systems, UPS, FedEx, and DHL. Although much has recently been written about
the advantages of novel methods, such as direct-to-patient deliveries or the use of drones
(Kumar, 2018; Wheeler, 2018; Sweeney, 2019; Baertlein and Erman, 2019; Bennett,
2019; Anemocyte, 2019; Anemocyte, 2020), these options were seldom considered, even

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though most respondents, especially those from large companies, suggested that their
companies support innovative clinical supply chain initiatives. It would be interesting to
investigate in future research whether more innovative methods are adopted at a later
stage, perhaps after commercialization, or whether conservative methods continue to
dominate the approaches to CGT distribution.
Although technological and alternative distribution models such as
direct-to-patient delivery had been used or considered by many of the respondents, data
suggests that sponsors may not be open to experiments at this time with uncertainties
associated with next-generation technologies like drones and blockchain. These results
may reflect the fact that the biopharmaceutical industry is typically risk-averse. For
example, research conducted by Lau (2020) indicated that 100% of its industry
participants preferred traditional trial structures under the direct oversight of healthcare
providers rather than hybrid or decentralized protocols for products requiring specialized
handling, including CGT products (Lau, 2020). Some of this hesitation may relate to
concerns about whether regulators would accept innovative models for CGTs. To this
point, no approvals for CGTs have been based on virtual or hybrid clinical trial models,
where alternative or novel transportation methods may be more relevant. Thus, sponsors
are more likely to play it safe until alternative distribution models are accepted more
readily.
5.2.5 Installation
The installation stage is critical to secure and develop the resources needed to
establish an effective supply chain system. At this stage, clinical protocol specifications
should be disseminated to all stakeholder groups, including sites, manufacturers, couriers,

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and vendors. Patients and doctors should be involved in the planning process and aware
of the protocol requirements (Garde, 2017; Elverum and Whitman, 2019; Labant, 2020).
It is at this stage that decisions are also being made about potential supply chain partners.
The results of this survey are instructive in this regard. They suggest that the most
important attributes for those vendors center around expertise in cold chain management,
import/export capabilities, and experience with the conduct of clinical trials.
Additionally, most respondents viewed the capabilities related to quality – an
established quality system, warehouse and distribution networks, GCP and GDP
certification, and GMP alignment— as particularly important. Some of these
requirements appear to be heightened because of the added complexities of CGTs, so it is
perhaps not surprising that many respondents had training programs for their outsourcing
partners. Interactions appeared to be focused on logistical capabilities; fewer developed
hybrid teams or joint contingency plans whereas some did not provide protocol training.
This finding is interesting because GCP regulations require that all parties involved in a
clinical trial be qualified by education, training, and experience (ICH, 2015; FDA,
2018d). Moreover, sponsors must ensure that they have written procedures for storage
and handling of their IMPs, and that all parties are aware of the product specifications
(ICH, 2015; FDA, 2018d). Without training on the clinical protocol, which provides the
details of shipping and receipt requirements, it might be difficult for vendors to
appreciate the expectations of the sponsor (Malikova, 2018).
Since US regulations require that manufacturers qualify their suppliers (21 CFR
312.3; 21 CFR 211; FDA, 2018i), it was no surprise to find that most clinical trial
sponsors perform onsite or paper-based audits and develop quality technical agreements

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(QTAs) with their vendors. Audits are the current gold standard for qualification;
however, they are not without limitations. As the literature points out, they can only
provide sponsors with a snapshot of the conditions at the time of the audit (Lennard and
Matlis, 2011). Further, COVID-19 has reduced the opportunities for regulatory
inspections by regulatory agencies (FDA, 2020f), and this may contribute to a climate of
false confidence or even permissiveness amongst the providers. Data from this study
support previous assertions (Wright, 2013) that some vendors overstate their capabilities
during an audit; this misleading information could leave sponsors open to compliance
challenges.
Although most of the organizations surveyed here performed onsite audits, some
relied on document reviews. Such an approach is less likely to yield a comprehensive
picture of the vendors’ capabilities and shortcomings but may be the only solution that
seems viable to companies with limited resources for vendor qualification. Notable was
the finding that smaller companies most often reported that they lacked robust vendor
management programs and found vendor management to be particularly challenging.
To ensure that audits are as effective as possible, Jones suggests that sponsors
perform a more extensive audit that examines the quality systems and capabilities of the
vendors as well as areas that are often overlooked, such as business practices and cultural
fit (Jones, 2020). These recommendations resonate with the comments of one respondent:
On site audits are not just Quality focused, but also business process focused.
We assess insurance risks, business continuity plans, interview project
managers and site heads from a relationship basis. … building the abstract
dialog gives the vendor room to share items you may not know to worry about
(e.g. south african depot staff have panic buttons on their key chains due to
high crime rates, trucks have active GPS tracking for hijacking, power
outages occur at a high frequency due to the economics of wire theft, etc).
Respondent 01.

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Other comments in this research reinforce the importance of best practices suggested
elsewhere, that contracts, statements of work, and applicable regulatory documents
should clearly define the scope of work, expectations, and defined roles and
responsibilities (Malikova, 2018; Jones, 2020).
5.2.6 Initial Implementation
During initial implementation, the implementing team learns to exercise new
skills and practices before fully integrating the chosen supply chain solutions into
ongoing practice (Fixsen et al., 2009). In this highly dynamic phase, different approaches
may be attempted to improve outcomes with respect to target benchmarks. Not
surprisingly, many external factors, such as airline handling issues, human error, and
unpredictability within various parts of the supply chain, provide teachable moments,
many of which were captured in the comments. All these results are aligned with areas
identified as challenges in the literature (Badurina et al., 2011; Papert et al., 2016; Jafferi,
2019; Ellison, 2019). More interesting, perhaps, was the level of challenge assigned to
“force majeure,” an impediment discussed quite rarely in the relevant literature. Because
this survey was disseminated during the COVID-19 pandemic, respondents appeared to
be more sensitive to the effect that serious crises can have on such activities as
transportation, site delivery and storage. Their experiences resonate with comments of
Dendreon Pharmaceutical’s Former Chief Operations Officer, Christina Yi :
However, the cost for us to transport patients’ cells from the patients to our
plans can go up to 20-fold higher than what they would typically run to
because of the fact that the commercial airlines aren’t operating as normal.
We are now paying for charter flights for one patient’s cells to get to and
from the plants. Christina Yi, Former COO, Dendreon Pharmaceuticals
(Hargreaves, 2020).

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Supply chains were also disrupted during COVID-19 when approximately 1050
clinical trials were placed on hold (as of December 1, 2020) (Cancer Research Institute,
2020; National Cancer Institute, 2020). Although the industry found ways to adapt their
clinical supply chains, the pandemic clearly strained their implementation strategies.
Some sponsors had to adjust their protocols to continue treatment and routine visits by
directing materials to remote sites and home-health alternatives. The data revealed that
most small organizations did not have contingency plans in place during COVID-19; only
a quarter of the small organizations felt adequately prepared for the pandemic. The
challenges associated with pandemic conditions are consistent with the literature (Unger
et al., 2019; Loche et al., 2020; Upadhaya et al., 2020; Wosik et al., 2020; Babato et al.,
2020; Xue et al., 2020; Hargreaves, 2020; Mooraj et al., 2020).
Respondents also made clear the importance of human and company relationships
as part of supply chain logistics. Transparent communication and information sharing are
critical to limit the mistrust that can be caused by errors in the supply chain. Present
results corroborate previous findings that open communication between suppliers and
sponsors can be difficult to ensure (Lennard and Matlis, 2011). The gap widens as the
numbers of vendors and clinical sites increase. However, continuous information sharing
would appear to be especially important for CGTs, which require strict management of
chain of identity (COI) and chain of custody (COC) requirements (Sawicki, 2018a;
Sawicki, 2018b; Hagen, 2019; Mooraj et al., 2020; Shanley, 2020b).
It is important to integrate data management, chain of compliance, and chain
of custody, by tracking every single unit operation, every activity, every piece
of equipment, and every operator back to every batch, and connecting that
data to the external supply chain. -Joerg Ahlgrimm, President and Chief
operating officer at The Discovery Labs (Shanley, 2020b).

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Results here further suggest that the interactions between vendors and sponsors
can best be characterized as a business-client relationship rather than a true partnership.
In this relationship, the sponsor or manufacturer may be reluctant to share proprietary or
other confidential information about the progress of a clinical trial because of potential
legal, financial, and business implications. An excerpt from one of the respondents is
illustrative:
Raw materials are not always available in a GMP grade, are proprietary or
of an undefined composition. Therefore the idea of secondary supplier
sourcing has to be adapted. We've had magnetic beads, custom media or
medical devices (cell reactors) that need complex contracts, process bridging
or can be snatched by a competitor via exclusivity agreements.
Respondent 02.

Sponsors depend on the exclusivity of their intellectual property (IP) and critical
components to recoup the development costs and provide a return on investment (Raidt,
2014; Biotechnology Innovation Organization, 2019; Congressional Research Service,
2019). Should a vendor disclose confidential information to a competitor, the extremely
high costs and time spent on a lawsuit could impede or halt commercialization efforts
(Keown, 2020; Sagonowsky, 2020; PWC, 2020; CPhI North America, 2019).
What are the areas seen as most critical for quality outcomes as companies begin
to implement their clinical supply-chain activities? Survey results suggest that turnaround
times (TAT), temperature management and shipment visibility are key concerns, while
diversion and counterfeiting rank lower. This ranking does not seem to align with the
concerns of legislators and regulators to combat counterfeiting and diversion through
laws such as the Drug Supply Chain Security Act (DSCSA) and their activities such as
collaborating with working groups such as Standards Coordinating Body for Gene, Cell,
and Regenerative Medicines and Cell-Based Drug Discovery (SCB) to develop supply

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chain standards for CGTs (SCB, 2020a; SCB,2020b; SBC, 2020c). Nonetheless, the
reduced attention to diversion and counterfeiting may not be surprising when considering
the nature of the product. Typically, counterfeiting and diversion are most important for
marketed products of high value such as Fentanyl (DEA, 2020). However, CGT clinical
products are unlikely targets because their value is still unclear at the time of clinical
trials. These products would also be difficult to divert in any large quantity because
clinical test materials are typically shipped in small amounts and under rigorous cold-
chain provisions and tracking. However, those risks may increase once the product is
marketed. At that point, some of these products become valuable and vulnerable to
counterfeiting and diversion. It seems important to recognize that the changing profile of
the product should force a reconsideration of the supply chain for these therapies as they
graduate out of clinical trial status.
Assuring data integrity and maintaining adequate shipping documentation and
temperature data has been a challenge for the management of CGTs, which relies on
accurate, traceable, and contemporaneous documentation to administer medication to the
patient (Reed, 2018; Sykes, 2018; Manenti et al., 2019). Therefore, it is surprising that
data integrity, fundamental for clinical trial validity, was also ranked as a relatively low
factor of concern when outsourcing supply chain activities. This finding is interesting
because it might suggest that clinical trial practitioners do not see the supply chain as an
integral part of the clinical trial that requires management. Alternatively, it may be of
lesser concern because the tracking requirements for these products are rigorous and the
shipment documentation is readily available. The literature has also suggested that many
CGT sponsors have opted for cloud-based orchestra platforms that can monitor and track

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the full manufacturing, supply chain, as well as the clinical aspects of their trials (Lamb
et al., 2017; Reed, 2018; TrakCel, 2020; Vineti, 2020). Nonetheless, problems with
documentation and data management were mentioned as one source of “lessons learned”
by multiple survey respondents. We might expect that the risk posed to data integrity will
vary greatly depending on the sophistication of systems in place for data collection and
tracking.
5.2.7 Full Implementation
At the stage of full implementation, the organization adopts a standardized suite
of practices to assure the sustainable delivery of clinical and perhaps eventually marketed
product. At this stage, most respondents suggested that their organizations had adequate
process controls to ensure the safety and quality of the medical product during
distribution, yet they had many unexpected challenges. The costs of the supply chain
management associated with their trial were often found to be higher than expected, and
communication challenges continued to be seen. Logistical issues with documentation,
chain of custody, supplier and inventory management, and regulatory confusions
continued to create roadblocks. To facilitate discussion, most challenges identified
during the implementation phase were associated with one or more themes: (1) CGT and
SCM Expertise, (2) Resources, (3) Regulations, (4) Global Considerations, (5) Logistics
and Transportation Management, (6) Stakeholder Engagement, and (7) Vendor and
Material Management.

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5.2.7.1 Expertise in CGTs and Clinical Supply Chain Management
Based on the survey, there are multiple knowledge gaps, not just with respect to
the CGT products themselves but also with supply chain regulations (Ruffin, 2018). In
our sample, many decision-makers at the manager level or higher had less than 5 years of
experience with CGTs. This finding is consistent with the literature, and not surprising
since the first commercial product in the US was approved only about 10 years ago
(FDA, 2010; Lynch, 2019; Labant, 2020; Provenge, 2020). Results here show that some
organizations rely on consultants, presumably because qualified people can be difficult to
hire. Moreover, smaller organizations have neither the ability nor the experience to scale
up as quickly as product development requires. It also underlines the need for a cottage
industry of educational programs. As identified by senior executives in clinical research
and development organizations,
Trials require specific medical expertise, institutional infrastructure,
sophisticated management resources to handle potential adverse effects, and
the resources to retrieve and store the cells to manage the investigational
products. Due to the current state of the technology, only a limited number of
sites have all the capabilities in place…[there is]… a need for increased
training, upskilling, and certification of a broader group of investigators and
sites. Creative approaches to manage the required long-term follow up,
including decentralized trials, will be used more frequently (Labant, 2020).

To meet these needs are growing numbers for training and educational programs to close
the talent gap needed for the more demanding management of CGT products (NIJT,
2018; International Society of Cell and Gene Therapy, 2019; CHOP Research Institute;
2020).
Although the adoption of more stable protocols has been considered here as a sign
of “full implementation,” one might question whether full implementation is ever really

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achieved when managing CGT supply chains for clinical trials. In the models suggested
by Fixsen, “full implementation” describes better a situation in which a new process or
system is fine-tuned and then inserted into an ongoing set of activities without too much
change in later stages. However, the clinical trials to support commercial CGT product
may never settle down to what might be considered steady state. The development path
is typically accelerated so that extremely sick patients without other therapeutic options
can gain access to the novel treatments as soon as possible, using programs such as the
RMAT and Breakthrough programs described in chapter 2. Thus, strategic plans face
changeable shorter-term tactical modification at every stage, less typical of the turnkey
systems for synthetic drug products, and this would appear to require that industry
stakeholders, including regulators and key opinion leaders, demonstrate a level of breadth
and flexibility beyond that typically seen in traditional large pharmaceutical companies
(Labant, 2020: Hagen, 2019).
5.2.7.2 Limited Funding and Resources
Everyone wants to see the clinical trial be successful so most of the other
issues I have run into are related to lack of funding, people resources, or lack
of experience for those who were tasked with various roles. Respondent 03.
Company was small, did not have strong supply chain resources and was
unfamiliar with many of the constraints prior to initiating shipments.
Respondent 04.
Resources can present a large barrier for some companies as they enter clinical
trials, which is a stage when costs escalate hugely (Colasante et al., 2018; Gerlovin and
Diesel, 2018; Heidaran, 2019). Several respondents, predominately from small and
medium-sized companies, appeared to doubt whether their companies had the funding
and human resources to sustain effective distribution. Historically, CGTs have been

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developed by smaller research and academic organizations with limited resources
(AuWerter et al., 2020). These smaller companies often cannot afford to develop their
products to the stage of commercialization, where sunk costs are estimated to average
around 2.6 billion USD (Sullivan, 2019; CPhI North America, 2019, p. 56). Supply chain
costs make up approximately 25% of those costs, escalating at a rate of nine percent each
year (Ebel at al., 2013; Grande, 2020). These costs are beyond reach of small companies
without access to private investments, partnership with a large pharmaceutical company,
or the opportunity for an initial public offering (IPO) (Gu, 2017; CPhI North America,
2019, p. 56). The successful CGT products now on the market serve as useful case
studies. For example, Gilead’s purchase of Kite Pharma and Novartis’ purchase of
AveXis occurred late in the clinical phases of investigation (Novartis, 2018c; Miller,
2018; Rockford and Roland, 2017). In such a situation, decisions about supply chain
solutions early in the clinical trial period may have come from relatively inexperienced
companies at a time when the supply chain was not a primary focus. These decisions may
then flavor the supply chain planning that occurs when the regulatory filing is submitted
and continued post-approval (Rees, 2020).
5.2.7.3 Logistics and Transportation Management
Start earlier with supply chain and logistics planning, understanding existing
capabilities and matching them to product requirements is key. We need to
plan accordingly in terms of matching a solution that ensures product
integrity. Respondent 05.
Many respondents did not seem confident that they had a well-defined
distribution plan for the clinical supply chain of IMPs. They note the challenges of
meeting temperature requirements and turnaround times well into the stage of full
implementation. In some cases, respondents suggest that site personnel remained

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unfamiliar with supply chain processes and medical product regulations that govern IMP
returns, packaging, and storage, for example. They often identified challenges with
traceability and cold chain management, concerns reflected in trade discussions that also
emphasize such problems (Pharmaceutical Commerce, 2018; Pelican BioThermal, 2020;
World Courier, 2019). US FDA inspections also show that logistics remain a difficult
aspect of trials, as evidenced by deficiencies noted in 483 findings and warning letters
related to inadequate storage, labeling, reconciliation of IMPs, and shipment
documentation. All of these issues have led to regulatory actions (FDA, 2017a; FDA,
2018j; FDA, 2018m; FDA, 2019ab; FDA, 2020o, FDA, 2020s). The lack of proper data
and documentation can also affect the quality of the clinical test articles, and thus damage
or halt the clinical trial and even compromise product approval (Reed, 2018a; Reed,
2018b).

5.2.7.4 Regulations
Standardization of anything to do with IMP would be beneficial to the
outcomes of the life cycle of these types of shipments. Respondent 06.
To increase continuity of process between regions in a global clinical trial. I
always advocate for increased harmonization across regional regulatory
authorities. Respondent 07.
Because clinical trials increasingly have a global footprint, CGT companies must
deal with the dissonance that exists between the regulations and standards of different
economies. Several aspects of this dissonance could be discussed, but perhaps that most
relevant to the challenges of supply chain management is the differing reliance on GDPs.
The US is one of the few developed countries that does not mandate the management of
logistics through the GDP standard (Carrico, 2016; EMA, 2018b; ANVISA, 2019;

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NMPA, 2020). Nevertheless, most respondents favored the adoption of GDPs and many
organizations have adopted GDP standards for their supply chain management in order to
harmonize with the rest of the world. A small proportion of respondents felt that the
current GMP and GCP regulations were sufficient and that GDP rules on top of those
requirements were not needed. However, even these respondents often supported the
adoption of universal harmonized standards to distribute CGTs and IMPs. These views
are probably one of the drivers for work by regulatory and industry stakeholders to
establish transportation standards for fragile products like CGTs (USP, 2020; SCB, 2020;
Hunt, 2020).
In the absence of a formal requirement for GDPs, present results suggest that
companies would profit from additional regulatory guidance. Inconsistencies in
regulations across clinical sites in different countries make it difficult to standardize
supply chain processes. Based on previous research (Wiggins and Schneider, 2012;
Sheehan, 2020), harmonized standards can reduce product development hurdles, improve
collaboration within the industry, and allow sharing of information and work across
industry stakeholders. It is therefore not surprising that multiple working groups have
developed and published standards for the supply chain management and distribution of
CGTs. Nevertheless, the adoption of these standards and how they fit into the established
processes require further research.
One area in which standards and regulations will need to evolve relates to the use
of technologically advanced methods of product delivery. Currently, the regulations do
not address the use of drones and alternative distribution models. However, COVID-19
has potentially improved and accelerated the acceptance of the DTP and home health

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models (Spinner, 2020; Xue et al., 2020). Thus, consideration and use of DTP and home
health models may have increased slightly in comparison to the research by Lau, which
was conducted before the COVID pandemic (Lau, 2020). Data in this study suggest that
sponsors appear open to innovative supply chain initiatives and many plan to explore the
use of DTP models in the future. ICH has recognized the need to incorporate
nontraditional models, such as decentralized trials, that may rely on the use of
nontraditional distribution methods. As a result, ICH is updating GCP standards (ICH
E(6) R3) to incorporate these considerations (ICH, 2019; EMA, 2020).
5.2.7.5 Global Considerations and Constraints in SCM
Inconsistencies across clinical sites and regulations in a regional location
can limit the standardization of supply chain processes. For example,
sponsors fail to consider the qualified person (QP) release required in the EU
for cell-based therapies. This process could mean a product must be shipped
to different geography to be released, adding additional transit times, process
steps, and the potential for delays. Respondent 08.
Globalization will be inevitable as clinical trials try to assure access to patients
who can be rare and difficult to recruit (FDA, 2012; Herbert et al., 2016). It can also be
motivated by the remarkably high per-patient cost of conducting a trial in the US
(Rossetti, Handfield, and Dooley, 2010; Mattuschka and Santa-Maria, 2015; Harrison et
al., 2017; Harrison et al., 2018; Harrison et al., 2019; Heidaran, 2019). However, the
global expansion puts strain on logistics and distribution for many reasons— cultural and
socio-economic factors, processes, systems, and regulatory requirements (Lynch, 2019;
Geiger, 2019). The results here make it clear that CGT studies are particularly vulnerable
to these challenges and that adequate planning for global distribution remains a challenge
for sponsors. This problem cannot be solved by reducing the global footprint without
compromising the development time and cost of a CGT clinical program. Thus, it will be

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important for those experienced in the types of challenges inherent in global distribution
recognize the educational role that they will need to play to educate the program
managers and senior leadership.
5.2.7.6 Stakeholder Engagement and Expectations
Would have involved the clinical operations group earlier in the discussion of
supply chain logistics, maintained cross functional communications between
product release and clinical ops in terms of packaging changes and transport
tracking, verification of material transfer between sites, etc. Respondent 09.
The importance of communication and engagement is a recurring theme in this
study. It reinforces a growing literature that identifies barriers posed by insufficient
stakeholder engagement (Ebel at el., 2013). Decision-making in silos can result in
misalignment, delays, and process failures (Shaffer, 2020). These problems are
magnified if senior leaders underestimate the requirements and timelines for supply chain
activities (Rees, 2011; Rees, 2018a; Rees, 2018b; Rees, 2020). The misalignment and
communication gaps increased for organizations that had a larger number of stakeholders
(i.e., internal business units, contractors, vendors, couriers, and collection centers) and
global manufacturing and clinical sites (Shaffer, 2020).
It is critical that in the earliest stages, companies consider their long-term
development strategy, including clinical, regulatory, and reimbursement
strategies. Marketing approval is no longer the only hurdle, and companies
need to select a partner with expertise in areas that are critical to their
success so they can get it right the first time and mitigate any unnecessary
risk of delays or failure. -James Anthony, Senior Vice President, Global
Head, Paraxel Biotech (Labant, 2020).
Open and honest communication will be required to ensure that all stakeholders
understand the clinical trial and approval milestones and develop the trust needed to close
the communication gaps (Shaffer, 2020). As discussed above, it would be a best practice

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to include stakeholders early, prior to executing the trial, and be mindful of long-term
development strategies beyond the clinical phases (Ellison et al., 2019; Labant, 2020).

5.2.7.7 Vendor and Material Management
Take a hyperstack for instance. There was a shortage due to viral vector
production. When the big 5 players commit to buying 80% of their volume, we
have to work on relationship management to get a steady trickle of units for
just-in-time delivery. Playing the ultimatum hardball card won't work in that
instance. Respondent 10.
No amount of relationship building or regulatory revision will be effective if the
vendors and suppliers cannot meet needs. Comments from the respondents suggest that
the supply chain for CGTs can become a bottleneck for clinical development because few
qualified suppliers can handle the requirements of personalized and customized therapies
that cannot survive disruptions in their distribution. To ensure better control, expanded
partnerships or centers of excellence have attempted to align processes from start to
finish and sponsors are opting for fewer suppliers (Kurmann Partners, 2018; Srivastava,
2020; Blankenship, 2020b; Blankenship, 2020c). In this study, most organizations had a
core in-house team to manage the supply issues, but then used a variable amount of
outsourcing. The trend appears therefore to be shifting away from primary reliance on
outsourcing partners. Others have noted that sponsors brought much of their supply
chain in-house, driving the outsourcing companies toward alliances, mergers and
acquisitions (Rockoff and Roland, 2017; Miller, 2018; Kurmann Partners, 2018; CPhI
North America, 2019, p. 90; Shakil, 2019; Spark Therapeutics, 2019). To this end, the
CGT industry has been experimenting with collaborative rather than transactional
partnerships with stakeholders such as regulators and vendors (Bennett 2018; Herbert et

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al., 2016; Mattuschka, 2016; GE Healthcare, 2019). Feedback from one of the
respondents supports this assessment:
Outsourcing isn't just with 3rd party subcontractors, but can also be done via
COMPLEX alliance partnerships with other companies, subcontractors
managed by alliance partners, non-profit organizations, academia which
owns contracts with governmental organizations, etc. Establishing robust
contracts, roles/responsibilities, quality agreements and supply networks is
key. That framework must also be established EXTREMELY fast.
Respondent 11.

Contract service providers such as contract research organizations (CROs) have also
adjusted their business models to accommodate this shift. For example, contract
development and manufacturing organizations (CDMOs) and contract research
organizations (CROs) offer all-in-one development and commercialization programs. At
the end of 2018, the top five CMDOs and CROs controlled 15% and 70% of the market
share, respectively (Kurmann Partners, 2018; CPhI North America, 2019, p. 90). These
partnerships are even more vital to CGTs, which will require seamless execution across
the supply chain (Kurmann Partners, 2018).
5.2.8 Sustainability
Because the science behind CGTs is relatively new, the field of regenerative
medicine faces challenges that are common to many emerging industries –
including fragmentation of knowledge, insufficient communication and
coordination, and unpredictable innovation. It can take decades for new in-
dustries to establish standards that address these issues and accelerate
innovation (Hagen, 2019).
Previous descriptions of Fixsen’s Implementation Framework suggest that
sustainability may be achieved within 2 to 4 years; however, for CGTs, this phase may be
difficult to assess or impossible to attain due to the short and accelerated nature of the
clinical trials and the diverse features that experimental products may have. Scalability

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into the commercial phases will determine the longevity of the CGTs in the
biopharmaceutical industry. For autologous therapies, for example, much of the supply
chain strategy in the clinical phase may be preserved into commercial phases, since even
after commercialization, each batch is associated with a single patient. However, for
allogeneic therapies, the supply chain considerations may be more like those for other
complex biologics, where efficiencies can be captured with larger shipments (Reed,
2019a; Reed, 2019b; Rees, 2018a; Rees, 2020; Ellison et al., 2020; Labant, 2020). As
expected, smaller organizations were far less prepared than larger organizations with
more resources, better legacy systems and extensive in-house expertise (AuWerter et al.,
2020; Labant, 2020).
Logistics by design (LbD), tailoring the supply chain to the patient, was
highlighted in the literature as an area of opportunity for CGTs to improve sustainability
(Ellison et al, 2019; Geiger, 2019). However, views were mixed regarding its feasibility.
Respondents from smaller and mid-size companies appeared to have more difficulties
with such implementation. Moreover, some smaller organizations did not implement this
strategy although it is not clear whether LbD was implemented by their contractors
downstream.
Building strategic partnerships and physical infrastructures were identified the
literature as essential for CGT manufacturers and sponsors to expand into the commercial
phases. Many companies with approved CGTs, such as Novartis and Kite Pharma,
increased their global footprint by establishing local partnerships, building new
manufacturing and production facilities, and establishing CGT network providers in their
region of interest (Leu, 2018; Kurmann Partners, 2018; Blankenship, 2019a,

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Blankenship, 2020a; Blankenship, 2020b; Blankenship, 2020c; Kite Pharma, 2020;
Novartis, 2020). However, building physical infrastructures and establishing strategic
partnerships was identified to be more difficult for smaller and mid-size organizations.
The costs (over 100 million USD) and time (about two years) required to build out these
global infrastructures may be unrealistic for start-ups with limited investment capital
(Blankenship, 2019a; Blankenship, 2020a; Blankenship, 2020c).
5.2.8.1 Managing Supply Chain “outside” the GXP Ecosystem
There exists a lack of understanding on the part of vendors and how
important these materials are. The human error factor cannot be
underestimated when analyzing risk. I would also want to see more of a
priority of these materials with the airlines themselves. Currently, this is a
country by country, airline by airline situation. Because the impact of failure
is so great (patient could potentially die), these types of materials need to be
treated as the most valuable of cargo by the airlines and the airline handlers.
Respondent 12.
It is very important to do a thorough job of qualifying and educating vendors
before you initiate the trial. Respondent 13.
One of the challenges with reaching a sustainable supply chain is that some
players, such as airlines and handlers, are accustomed to working under a different set of
laws, regulations, and standards. This inconsistency can make it difficult for sponsors to
obtain sustainability. Respondents expressed concerns about the limited information
related to CGTs that might educate transportation and health facility industries that might
not even know the meaning of the acronym, GMP (Frontline Medical Communications,
2020). Currently, those organizations are not required to adhere to GMPs for their other
products. It may therefore prove difficult to hold them accountable or responsible
(Mitchell et al., 2019; Elverum and Whitman, 2019).

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My perspective is often, how can my organization be flexible and dynamic
enough to fit into the systems of 20 different vendors while at the same time
accelerating their systems. The idea is that trying to make 20 vendors operate
within YOUR internal SOPs and arbitrary risk tolerance will never be the fast
path. Don't rock the boat...adapt to their requirements with minor
modification and things will go smoothly and quickly. It also links into
relationship management. The enjoyable companies often miraculously find
production slots. Respondent 14.
Better train the clinical sites to return shipment documentation especially the
temperature monitor. Respondent 15.

The data suggests that training of site personnel and even parts of the airline
industry would be valuable. The need to handle time-sensitive and temperature-sensitive
medical products have led some hospitals and airlines to adopt systems compliant with
GMP and GDP to ensure that medical products maintain their integrity, and that those
handling the products can do their jobs without errors (Alici and Blomberg, 2010; DHL,
2019; World Flight Services, 2019; Swiss WorldCargo, 2019; Boldt, 2020; Bersenev and
Fesnak, 2020).
5.3 Conclusion and Recommendations
The usefulness of CGTs depends not only on the effectiveness of the therapeutic
product but also on its availability. Clinical trials using such products thus need a clear
roadmap for transport and delivery that can assure availability without product
degradation or loss. The importance of supply chain management has gained higher
visibility, not only because some of the new CGT products are so fragile but also because
the COVID-19 pandemic has exposed some of the system’s vulnerabilities. These new
stresses give an opportunity to recognize the risks and improve the resilience of the
supply chain.

193

Organizations must have robust systems for CGT products and supplies from
cradle to grave. This includes but is not limited to developing transportation and vendor
management partnerships that ensure a consistent supply chain for CGTs. Although many
companies have begun to strengthen their systems, the special needs for CGT products
will prove difficult to manage for organizations lacking resources, expertise, or
infrastructure. At a minimum, a supply chain and distribution management plan should
include considerations of (1) costs, (2) quality and regulatory compliance, (3) resource
management, (4) stakeholder and communication management, and (5) business
continuity plans. This supply chain and distribution plan should be developed in the
earliest stage of clinical trial development in collaboration with key stakeholders to
ensure alignment with the capabilities of the clinical sites and the protocol restrictions.
Supply chain management must be evaluated on a case-by-case basis as the industry
moves toward tailored therapies built on variable human factors, disease progression,
genetics, environment, and mobility. Agile workstreams will therefore be needed to
capture gaps, identify and mitigate risks, and share lessons learned. Such activities take
resources, but the investment is small compared to the possibilities of product spoilage,
lost time and costs, and impact on the clinical trial and patient.
As CGTs become more common, their changing needs will impact regulatory
systems and standards. Customization and standardization are at the opposite ends of the
spectrum. The industry must decide on the balance that might best protect the products
and the metrics that might benchmark the desired performance. Current regulations and
standards are tailored to the needs of more conventional products for which GDPs may be
less important than for CGTs. They do not specifically address DTP and home health

194

models to any great degree. Thus, sponsors are left to rely on judgement when
integrating supply chain considerations into their quality management systems and their
vendor management and qualification programs. Results suggest that more guidance
from regulators and standards-setting bodies would be welcomed.
All the results here suggest that the supply chain remains undervalued and
underestimated in the drug development process. Education and engagement in supply
chain considerations cannot be limited to the implementation team but must include
planners and decision-makers responsible for CGT development and commercialization.
Failure to maintain the medical product's stability has not only financial but also safety
and quality implications.
Results of this study lead me to suggest the following recommendations. First, the
US FDA should adopt Good Distribution Practices and develop distribution guidance
documents related to CGTs. The regulations and applicable guidance documents will
ensure that sponsors, manufacturers, and industry stakeholders have a consistent
framework for CGTs. Policymakers should also consider expanding the regulatory
oversight and management for CGTs beyond the scope of sponsors and manufacturers to
other industry stakeholders that handle and distribute CGTs. There is room to educate and
train industry stakeholders that operate within and outside the GXP ecosystem. Second,
CGT sponsors should develop a robust supply chain management plan and ensure that
key stakeholders are trained on this plan. The industry must engage vendors and suppliers
throughout this process to assure effective communication and collaboration.

195

5.4 Future Research
Research here expands our understanding practices and views from the supply
chain “trenches”. It can serve as an input for discussions of current policies and
regulations in the US. It does not however give more than tangential insight into global
regulations and regulatory dissonance. Research is still needed to explore how regulatory
systems elsewhere affect supply chain strategies in geographies such as Latin America
and Asia. In under-resourced regions such as Africa, constrained finances and weak
governmental infrastructures may further handicap the development and enforcement of
regulations. Such research will be critical to support harmonization efforts. It would be
interesting to see how a study like this would compare to a similar survey conducted in
other regions, as a foundation for consensus on the necessary regulations.
Alternative distribution models, direct-to-patient, home healthcare, and
technologies such as drones are not incorporated in the current regulations. Although they
are briefly discussed in this study, it is not clear if the FDA or other constituencies have
accepted these models. It is also not clear whether such methods are even suitable to
deliver products for CGT clinical trials. If they do have promise, it would be useful to
explore whether such methods are scalable in the post approval period where scale-up is
needed.
Additionally, there is opportunity to explore the feasibility of these requirements
in other industries that operate outside of the purview of the FDA, such as the hospitals
and the airline industry. It would be interesting to see whether and how these facilities
and providers adapt to the GMP, GCP, and GDP requirements. Although early adopters
of GDPs exist in the airline and freight industry (Mattuschka and Santa-Maria, 2015;

196

Herbert, 2016; World Flight Services, 2019; Swiss WorldCargo, 2019), more work is
needed to understand how these key players can be helped to adopt and enforce these
requirements for medical products.

197

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Appendix A. Definitions and Acronyms
Table 36 Full Definitions and Acronyms
Key Terms/Acronyms Definition
3PL Third-Party Logistics
Ancillary Materials Ancillary materials (AM) are components used during the
manufacturing process of cell therapy products. However,
these materials are not intended to be part of the final
products. These products can include, but are not limited
to reagents, infusion bags, tubing, delivery-devices,
equipment, and instructions for use (USP, 2008). AMs
are most often shipped with cell and gene therapies.
APEC Asia-Pacific Economic Cooperation (APEC) is an inter-
governmental forum consisting of 21 Pacific Rim
economies with the goal of promoting commerce and
business harmonization among the member states (APEC,
2019).
API Active Pharmaceutical Ingredient
ATMP Advanced Therapies Medicinal Products (ATMPs) are
medicines for human use that are based on genes, tissues,
or cells. Gene therapy, somatic-cell therapy, and tissue-
engineered, as well as some medical devices (which are
combined ATMPs), fall under the ATMP category within
the European Medicines Agency (EMA, 2019).
B Cells A B lymphocytes cell is a type of leukocyte, white blood
cell that is located in the bone marrow. B cells circulate
in the blood and help fight bacteria and viruses by
making proteins called antibodies. These antibodies are
pathogen-specific and are able to lock onto the surface of
an invading cell and mark it for destruction by other
immune cells (CTCA, 2017).
Blockchain A distributed digital ledger that is managed by a peer-to-
peer network of computers, rather than a single entity.
Data is added to the network in a time-stamped and
immutable fashion. Each data point is recorded as a
"block" of information. Blocks are secured based on
cryptographic principles and guidelines. After validation
through a consensus of the peer-to-peer network, each
block is cryptographically linked to the previous one
(creating a chain). As new blocks are added, older blocks
cannot be modified without consensus, which makes the
system tamper-resistant (Benchoufi and Ravaud, 2017;
Clauson et al., 2018; Reiff, 2020).

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Key Terms/Acronyms Definition
Blinding A method in clinical trial design in which one or more
parties in the trial (the site, sponsor, or the patient) is
unaware of the treatment assignments for the study. In a
single-blinded study, usually, the patients are unaware of
the treatment assignments. In a double-blinded study,
both the patients and the investigators are unaware of the
treatment assignments. In a double-blinded study, at
times, the monitors are unaware of the assignments.
Blinded studies are conducted to prevent the
unintentional biases that can compromise study data
when treatment assignments are known (ICH, 2015;
FDA, 2018d).
CAR-T Therapy CAR-T cell stands for chimeric antigen receptor T cell
therapy. CAR-T is a method used to modify a patient's
immune cells (T cells). In CAR-T, the T cells are
modified to add a receptor on their surface of the cell,
which can recognize structures (antigens) on the surface
of malignant cells. Once the receptor binds to a tumor
antigen, the T cell is stimulated to attack and kill the
cancerous cells (Gilead, 2017; Celgene, 2019; Novartis,
2019c; Yescarta, 2019).
CBER Center for Biologics Evaluation and Research
CBP US Customs and Border Protection
CCM Cold Chain Management (CCM) is the system used for
distributing and storing medical products within an
acceptable range until it reaches the user. CCM can
include various temperature ranges and is typically used
for biologics and other temperature-sensitive medical
products.
CDC Center for Disease Control and Prevention
CDER Center for Drug Evaluation and Research
CDMO Contract Development and Manufacturing Organization
CFR Code of Federal Regulations
Cell and Gene Therapy Cell and Gene therapies are medical interventions in
which both cell and gene therapies are utilized in
combination to treat various genetic diseases.

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Key Terms/Acronyms Definition
Cell Therapy Cell therapy is the transfer of live cells into a patient to
cure or treat a disease. The cells used in cell therapy may
originate from the patient (autologous cells) or a qualified
donor (allogeneic cells). Cell therapies can be defined as
the infusion or transplantation of whole cells into a
patient for the treatment of a disease (ASGCT, 2019b).
CGTs (or GCTs) Cell and Gene Therapies
CGCT

Cell and Gene Clinical Trials
Clinical Endpoint An indicator (such as blood pressure) measured in human
subjects to assess the safety, efficacy, or another
objective of a clinical trial (ICH, 2015, FDA, 2018d).
Clinical Hold A temporary cessation of a clinical trial mandated by a
regulatory agency such as the FDA. This hold is placed
on the study by the agency if there are concerns with the
safety of a medical product or the study protocol. The
trial may resume when the concerns are addressed with
appropriate corrective and preventative actions (FDA,
2015).
Clinical Trial(s) A clinical study involves research using human
volunteers. The trial intends to add to medical
knowledge. The clinical trial participants receive specific
interventions according to the research plan or protocol
created by the investigators (ICH, 2015; FDA, 2018d).
CMC Chemistry, Manufacturing, and Controls
CMO Contract Manufacturing Organization
CMS Continuous Monitoring Systems (CMS). Technologies
and devices that can track shipment information such as
temperature, location, vibrations, light, and shock.

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Key Terms/Acronyms Definition
COC Chain of custody (COC) is the permanent capture of data
related to the entity that handled a product or material.
COC includes but is not limited to the location, date, and
time of the actions performed along the supply chain
from the start of tissue and cell collection up to product
administration to the patient (Hagen, 2019).
COI Chain of identity (COI) is the permanent and transparent
association of a donor’s unique identifiers to their tissue
or cells (raw material), and the resulting drug product.
This record is maintained through the entire process from
processing the patient’s order through manufacturing of
the product. It also includes the administration of the
treatment and post-treatment monitoring. In the case of
autologous therapies, the donor’s patient number should
be linked to their unique donation number and
manufacturing batch number as part of the COI (Hagen,
2019).
Consignee The entity that is supposed to receive goods or products
from the carrier. In the case of clinical trials, a clinical
site or the patient may be the consignee, as they will
receive the medical product.
Courier A courier is an entity (a person or organization) that
delivers medical products from one entity to another
entity.
CRO Contract Research Organization. A CRO is a company
that is contracted by a sponsor to perform preclinical
alternatively, clinical pharmaceutical research.
CSCO Clinical Supply Chain Organization (CSCO), are
specialized third-party logistics organizations that provide
distribution and supply chain management to the
healthcare and biopharmaceutical industry.
CTD Clinical Trial Distribution (CTD) is the logistics or
distribution of clinical trial material and products. CTD
entails the physical transport or transfer of all materials
(such as raw materials, biological samples, reagents),
equipment (such as kits, packaging, and dry ice), and
documentation (including data) required to get the
investigational medicinal product (IMPs) to the patient.
CTD may also be referred to as clinical supply chain
management.

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Key Terms/Acronyms Definition
Dangerous Goods (DG) A dangerous good (also referred to as hazardous material
or hazmat) is any material or substance that has the
potential to pose a risk to health and safety when
transported. Identifying dangerous goods reduces risks by
ensuring that medical products have proper packaging,
documentation, handling, and storage (UPS, 2019).
DCT Decentralized Clinical Trial. DCT is sometimes known as
virtual or “patient-centric” trials in which the trial is
brought directly to the patient (usually in the home)
instead of having the patient travel to a clinical site
(Science 37, 2019).
DLT Distributed ledger technology (DLT) is a digital system
that records the transaction of assets in which the
transactions and their details are recorded in multiple
places at the same time. Unlike traditional
databases, distributed ledgers do not have central data
storage or administrative authority. A distributed ledger is
decentralized to eliminate the need for a central authority
to validate, process, or authenticate transactions. All files
are timestamped and given a unique cryptographic
signature, and all of the participants on the distributed
ledger can view all of the records in question in real-time
(Belin, 2018).
DOT US Department of Transportation
Direct-from-Patient (DFP
of DfP)
Direct-from-Patient. With the DFP model, medical
products, biological samples, or clinical supplies are
retrieved from the patient.
Direct-to-Patient (DTP or
DtP)
Direct-to-Patient. With the DTP model, medical products,
biological samples, or clinical supplies are delivered to
the patient.
DQSA Drug Quality and Security Act
DSCSA Drug Supply Chain Security Act
EC European Commission
EMA European Medicines Agency
EPA US Environmental Protection Agency
EU European Union
FAA Federal Aviation Administration
FDA Food and Drug Administration
FD&CA Food Drug and Cosmetic Act. The Food Drug and
Cosmetic Act is a set of laws passed in 1938, giving the
Food and Drug Administration to regulatory oversight for
the safety of food, drugs, medical devices, and cosmetics.
This law replaced the Pure Food and Drug Act of 1906.

258

Key Terms/Acronyms Definition
FDASIA The Food and Drug Administration Safety and Innovation
Act
FWS US Fish and Wildlife Services

Gene Therapy Gene therapy is the introduction, alteration, or removal of
a patient's genetic code to treat or cure a disease. The
transferred genetic material can modify how a single
protein or group of proteins is produced by the cell
(ASGCT, 2019b).
GCP Good Clinical Practices (GCP) are an international ethical
and scientific standards for conducting biomedical and
behavioral research involving human participants (ICH,
2015).
GCTs Global Clinical Trials
GDocP Good Documentation Practices
GDP Good Distribution Practices
GDPR General Data Protection Regulation
GMP Good Manufacturing Practices. The “c” in cGXPs
denotes current practices. cGMP denotes current Good
Manufacturing Practices.

GTP Good Tissue Practices
HazMat A Hazardous Materials (also may be referred to
dangerous goods) is any item or agent (biological,
chemical, physical, or radiological), which has the
potential to cause harm to animals, humans, or the
environment. These materials can pose a risk either as a
standalone product or through interaction with other
external factors such as temperature changes or
atmospheric pressure (UPS, 2019).
HCT/Ps Human cells, tissues, and cellular and tissue-based
products

259

Key Terms/Acronyms Definition
Harmonized Tariff
Schedule
Harmonized Tariff Schedule (HTS) is the statute used to
determine tariff classifications for goods imported into
the United States and maintained and published by the
United States International Trade Commission (USITC).
The HTS is based on the international Harmonized
System. Nearly all countries base their tariff schedules on
the Harmonized System, making it easier to conduct
international trade and compare trade data. Harmonized
Tariff Schedule (HTS) Code is a classification, codes are
used to classify and define internationally traded goods.
The Harmonized System, is an international product
nomenclature system used by over 100 countries for
classifying traded goods (USITC, 2020).
IATA International Air Transport Association
ICH ICH is the International Conference on Harmonization of
Technical Requirements for Registration of
Pharmaceuticals for Human Use. ICH objectives are to
bring together the regulatory authorities of Europe, Japan,
and the United States to harmonize the technical
guidelines and requirements for product registration. The
goal is to reduce the need to duplicate clinical testing
during the development of new medicines.
Immunogenicity The ability of a molecule or substance to induce an
immune response in a human or animal.
IMP Investigational Medicinal Product. Per ICH GCP
guidelines, an IMP is a pharmaceutical form of an active
ingredient or placebo being tested or used as a reference
in a clinical trial. This definition includes a product with a
marketing authorization when used or assembled
(formulated or packaged) in a way different from the
approved form if used for an unapproved indication, or
when used to obtain additional scientific information on
an approved use. Investigational Medicinal Product may
also be referred to as investigational product (IP), or
investigational drug product (IDP) (ICH, 2015).

260

Key Terms/Acronyms Definition
IND Investigational New Drug application. An IND is a
process required for an organization to initiate a clinical
trial study and test new medical products on human
subjects. The request must be submitted to the FDA and
approved for permission to test experimental drugs or
medical products in human volunteers. This application
must be filed for each clinical study performed.
Typically, there are three phases in a study (FDA, 2018d;
FDA, 2020p).
Investigator A medical professional, usually a physician or other
health care professional, who oversees the clinical
activities of a trial. These activities may include how an
investigational drug is administered or dispensed to the
patient. A principal investigator is responsible for the
overall execution and oversight of the clinical trial at his
or her site.
Logistics Logistics is a component of supply chain management.
Logistics includes planning, implementing, and
controlling processes and procedures for the efficient and
effective transportation and storage of goods. The
physical exchange of goods can include products,
services, and related information from the point of origin
to the point of consumption to meet the customers’
requirements. Logistics is often referred to as distribution
(CSCMP, 2019).
Logistics by design (LbD) Logistics by design (LbD) is a risk-based framework used
to identify and address gaps within the supply chain to
create a logistics platform that meets the needs of the
patients and manufacturers on a clinical and commercial
scale (Ellison et al., 2018).
Lot release testing Samples from each drug lot (batch) manufactured for
clinical trials or (later) for sale are tested to prove that
the batch meets specifications for content and purity
before it is released for use.
Manufacturer An organization that takes primary ownership and
responsibility for a medical product; the manufacturer is
usually the license holder.
NCI National Cancer Institute
NIH National Institutes of Health

261

Key Terms/Acronyms Definition
NIRN National Implementation Research Network
NLM National Library of Medicine
NMPA National Medical Products Administration
Outsourcing The practice by which an organization contracts out
aspects of drug development such as research, laboratory
testing, clinical trials, or manufacturing to another firm
outside of the manufacturer entity. Outsourcing may be
referred to as a contract organization.
Patient An individual seeking medical care. Patients that
participate in a clinical trial may also be referred to a
subject.
PBMCs Peripheral blood mononuclear cells (PBMCs) are blood
cells that have a round nucleus. These blood cells consist
of lymphocytes such as T cells, B cells, and Nature Killer
cells).
Personalized Medicine Personalized medicine is the tailoring of medical
treatment to the individual characteristics of each patient.
The treatment options are developed based on patients’
genomic data. Based on the genomic characteristics,
biologic pathways, and external factors such as
environment and lifestyle, clinicians can determine a
patient’s disease susceptibility, define preventive
measures, and enable targeted therapies to promote.
Personalized medicine can be individualized medicine,
which is specific to the patient; however, that factor is not
always the case. The term does not literally mean to
create a drug or device to a patient; however, this concept
can be misinterpreted. As such, personalized medicine
has evolved over the years to be “precision medicine,”
which is the preferred nomenclature for stakeholders.
Personalized medicine is often referred to as
individualized or precision medicine (see definition)
(NIH, 2019).

262

Key Terms/Acronyms Definition
Pivotal Study Pivotal studies provide the clinical (efficacy and safety)
data that a regulatory agency can use to decide on the
approval of a medical product. A pivotal study will
generally be well-controlled, randomized, of adequate
size, and whenever possible, double-blinded. Pivotal
studies are typically phase III study. However, in the case
of CGTs, these studies may be phase II (FDA, 2018c;
FDA, 2018d).
POE Port of Entry (POE) is a place where a person or product
may lawfully enter a country.
Precision Medicine Precision medicine (commonly referred to as
personalized medicine) is an emerging approach to
disease treatment and prevention. Precision medicine
accounts for genetic variation, environment, and lifestyle
for each person. This approach will allow doctors and
researchers to predict accurate treatment and prevention
strategies for particular diseases and how they will work
in a subpopulation versus using treatment options that are
based on the average patient. There was a concern that
the word "personalized" could be misinterpreted to imply
that treatments and preventions are being developed
uniquely for each individual; in precision medicine, the
focus is on identifying which approaches will be effective
for which patients based on genetic, environmental, and
lifestyle factors. The National Research Council (NRC),
therefore, preferred the term "precision medicine" to
"personalized medicine." However, the lay public often
uses the two terms interchangeably. Note: this term will
be used throughout the remainder of the dissertation
unless there is a direct quote that uses the term
"personalized medicine" (NIH, 2019c; NIH, 2019d).
Protocol The protocol provides the framework and standard
process for clinical study execution. The protocol
includes the study's objectives, design, and methods. It
may include relevant scientific background, rationale, and
statistical information related to the clinical study. An
Institutional Review Board and regulators must approve
the study protocol and protocol amendments prior to trial
initiation (ICH, 2015).
QMS Quality Management System

263

Key Terms/Acronyms Definition
QR barcode A quick response barcode is a type of matrix barcode (or
two-dimensional barcode) that serves a machine-readable
optical label. In the case of medical products, the label
serves as a unique identifier. The barcode can be scanned
and provide information such as product specifications
and storage conditions.
Regenerative Medicine A branch of translational research in tissue engineering
and molecular biology. Regenerative Medicine deals with
the process of replacing, re-engineering, or regenerating
human cells, tissues, or organs to restore or establish
normal function (PEW, 2019).
RMAT Regenerative Medicine Advanced Therapy. A
regenerative medicine advanced therapy is defined as a
cell therapy, therapeutic tissue engineering product,
human cell, and tissue product or any combination
product that is intended to treat, modify, reverse, or cure a
serious or life-threatening disease or condition. The
product must provide preliminary clinical evidence
indicates that the drug has the potential to address unmet
medical needs (FDA, 2019ac).
SMA Spinal Muscular Atrophy (SMA) is a rare genetic disease
in children under the age of two, caused by a mutation in
the survival motor neuron 1 (SMN1) gene.
SCM Supply Chain Management. SCM includes the design,
planning, execution, control, and monitoring of supply-
chain activities. Logistics and distribution, movement of
products, is a component of SCM. For medical products,
SCM entails the transport or transfer of all materials
(such as raw materials, biological samples, reagents) and
equipment (such as kits, packaging, dry ice), and
information required to get the product to the patient.
There are multiple stakeholders involved in SCM of
clinical trials, including researchers, sponsors,
manufacturers, site coordinators, clinicians, and
distributors (Rees, 2011; CSCMP, 2019).
Shipper The entity or person that packages and sends products to
an end-user (consignee). In the context of clinical supply
chain, a shipper may send a medical product to a clinical
site or patient. The shipper can be the sponsor,
manufacturer, or the entity authorized to provide the
goods to be transported.

264

Key Terms/Acronyms Definition
Shipper (packaging
materials)
Shipper boxes, kits, or containers used to maintain
temperature conditions and protect medical products and
biological samples for environmental conditions such as
light, vibration, and physical impact while in transit. A
shipper may include insulating material to maintain
temperature requirements (such as ambient, refrigerated,
frozen, or cryogenic) and packaging supplies such as
biohazard bags.
Site The site is usually a hospital or a health care institution
that has adequate resources (equipment, infrastructure,
and staff) and the ability to recruit qualified patients to
meet the requirements of the clinical trial protocol. The
site is the location where patients come to obtain clinical
trial treatment and monitoring throughout the lifecycle of
the clinical study.
Sponsor An organization or person who initiates a clinical trial
study. The sponsor has authority and control over the
study and usually provides funding for the study (ICH,
2015).
Study Design The scientific and administrative methods and strategies
used to plan and implement in the clinical study.
t-PA Tissue Plasminogen Activator
T cell(s) A T lymphocyte cell is a type of leukocyte, white blood
cell that is located in the thymus. T cells determine the
specificity of the immune system's response to antigens
(foreign or potentially harmful substances) in the body. T
cells can assist the body with fighting infectious cells or
killing harmful viruses. T cells can be distinguished from
other lymphocytes by the presence of a T cell receptor on
the cell surface (CTCA, 2017).
TAT Turnaround Time. The TAT is the amount of time
required for the medical products to be transported from
one location to the next.
Temperature Excursion An excursion event (a change in temperature) in which
the medical product is exposed to temperatures outside
the ranges established in the clinical protocol and stability
data (WHO, 2015).
TTSPP Time and temperature-sensitive pharmaceutical product
(TTSPP) is any pharmaceutical or medical product that
requires predefined environmental storage conditions or
predefined time limitations. When the product is not
stored or transported within predefined specifications, the
product may degrade and no longer perform as originally
intended (WHO, 2015).

265

Key Terms/Acronyms Definition
Test Article According to the FDA, a test article is a drug, biological
product, electronic product, a medical device for human
use, or any other article subject to regulation under the
FD&C Act or under sections 351 and 354-360F of the
Public Health Service Act.
UK United Kingdom
US United States
USDA United States Department of Agriculture
USP Unites States Pharmacopeia (USP) is a private, nonprofit
organization composed of over 300 delegates
representing state and national associations, including but
not limited to the biopharmaceutical industry, regulatory
agencies. USP set standards for health care products in
the US, collects, and disseminates product use
information to providers and consumers.
USP publishes revised standards for drugs in The United
States Pharmacopeia and The National Formulary every
five years. The standards are recognized as official by the
federal government and are enforceable by the FDA. The
standards include specifications pertaining to quality,
distribution, purity, packaging, and labeling (Institute of
Medicine (US) Council on Health Care Technology,
1988; USP, 2020).

Vector The plasmid, virus, or other vehicles used to carry
recombinant DNA into the cell of
another species.
WHO World Health Organization (WHO) has partnerships with
government agencies and industry stakeholders in 194
member states, across six regions, in over 150 countries.
WHO advocates for universal healthcare, monitors public
health risks, coordinates responses to health emergencies,
and promotes public health and safety. Also, the
organization provides technical and regulatory assistance
to countries by setting international health standards and
guidelines (WHO, 2020).

266

Appendix B. Survey Questions
Clinical Supply Chain Management of Cell and Gene Therapies
Survey Flow
Standard: Introduction (1 Question)
Block: Demographics (7 Questions)
Standard: Implementation Feasibility - Exploration to Installation (12 Questions)
Standard: Installation (3 Questions)
Standard: Initial Implementation to Full Implementation (9 Questions)
Standard: Full Implementation to Sustainability (4 Questions)
Standard: SURVEY IS NOW COMPLETE (1 Question)

Start of Block: Introduction
Q1 Thank you for agreeing to participate. This survey will help us understand the
clinical trial distribution and supply chain management of cell and gene therapies
(CGTs). The following survey is conducted by Lequina Myles, doctoral candidate of the
Regulatory and Quality Sciences program at the University of Southern California,
School of Pharmacy. This research seeks to understand the views on clinical trial
distribution and supply chain management of precision medicines and advanced
medicinal therapies such as cell and gene therapies (i.e., CAR-T, Cancer Vaccines, and
CRISPR).

This survey will ask you about your experience regarding policies and current regulations
in the United States related to the transportation and distribution of clinical trial material.
The survey is anonymous, and your responses will not be associated with you or your
company. Your candid responses are important to the validity of this research. If you do
not want to answer a question, you can skip it. If you would like a copy of the aggregate
results, please supply an email address at the end of this survey, or contact me
separately. For questions, please contact me at lmyles@usc.edu or my dissertation
supervisor, tdchurch@usc.edu.

Note : For the purposes of this survey, the following definitions will be utilized:
- Cellular therapy products are considered to include cellular immunotherapies, cancer
vaccines, and other types of both autologous and allogenic cells regardless of therapeutic
indication.

- Human gene therapies encompass any therapy that seeks to modify or manipulate the
expression of a gene or to alter the biological properties of living cells for therapeutic
use.

End of Block: Introduction

267

Start of Block: Demographics: Tell me about you and your organization

Q2 My most recent employer or client can best be described as a…
o Pharmaceutical (Drug) Company
o Medical Device Company
o Biotechnology Company (Cell and Gene, Immunotherapies, Cancer Vaccines)
o Contract Organization (CRO, CMO, CDMO)
o Biomanufacturing / Cell Production Facility (i.e., Hospital GMP Facility)
o Supply Chain/Logistics (Specialized Packaging, Cold Chain, 3 PL)
o Academia, Institution, School, Research Center
o Other (Please Specify) ________________________________________________

268

Q3 My department or area of expertise is best described as:
o Regulatory Affairs
o Quality Assurance / Quality Control
o Research & Development (R&D) / Clinical Research
o Manufacturing / Operations
o Clinical Operations
o Supply Chain / Logistics
o Other (Please Specify) ________________________________________________

Q4 What is the company size of your most recent employer/client in terms of number of
employees?
o 1-999
o 1,000-4,999
o 5,000-9,999
o 10,000 +
o I don’t know

269

Q5 My primary role is...
o Vice President / President / C-Suite
o Director / Sr. Director
o Sr. Manager / Manager
o Project Manager
o Associate / Specialist / Coordinator
o Researcher / Scientist
o Consultant
o Other (Please Specify) ________________________________________________

Q6 How many years of experience do you have with complex biologics, advanced
medicinal therapies, or cell and gene therapies ?
o Less than 3 years
o 3-5 years
o 6- 9 years
o 10 to 14 years
o 15+ years
o None

Skip To: End of Survey If Q6 = None

270

Q7 Which modalities do you or your organization have experience with (please select all
that apply):
▢ Cell-based Gene Therapies (i.e. CAR-T, T cell Immunotherapies, Allogeneic and
Autologous Immunotherapies)
▢ Gene-Based Therapies (i.e. CRISPR-Cas9, Adeno-associated virus (AAV)
Therapies)
▢ Novel Proteins and Peptides (i.e. nucleotide-based therapies include mRNAs,
small interfering RNAs (siRNAs), antisense oligonucleotides, and aptamers)
▢ Stem Cells (i.e. Hematopoetic Stem cells, Adult and Embryonic Stem Cells)
▢ Vaccines (i.e. Cancer Vaccines)
▢ Combination Products (i.e. Device-Biologics)
▢ Cell and Gene Therapies Components (i.e. Engineered Tissues, Viral Vectors,
Cell Banks, Apheresis Material)
▢ Other (Please Specify) __________________________________________
▢ I don't know

271

Q8 In terms of supply chain, which countries have you or your organization transported
clinical trial material (i.e. supplies, raw materials, investigational medical products) to or
from... (please select all that apply):
▢ United States
▢ Canada
▢ Europe
▢ Asia-Pacific
▢ China
▢ Latin America
▢ Middle East
▢ Africa
▢ Russia
▢ Other (Please Specify): ___________________________________________
▢ I Don't Know (16)
▢ None (19)

Skip To: End of Survey If Q8 = None
End of Block: Demographics: Tell me about you and your organization

Start of Block: Implementation Feasibility

272

Q9 Please indicate your level of agreement with the following statements regarding your
organization's planning of Clinical Supply Chain Management.
(IMP= Investigational Medicinal Product)

My organization...
Agree Somewhat Agree Disagree Not Sure
Has a well-defined
distribution plan for
clinical supply chain
of IMPs
o o o o
Supports innovative
clinical supply chain
initiatives
o o o o
Assesses the
readiness of the
organization for
supply chain
management
o o o o
Has Sufficient
funding is available
to meet distribution
costs
o o o o
Has Contingency and
business continuity
plans are in place for
distribution
o o o o
Understands the role
of the sponsor in the
distribution of IMPs
o o o o
Understands the US
FDA requirements
for distribution of
IMPs
o o o o
Understands the
international
requirements for
distribution of IMPs
o o o o

273

Q10 Thinking back to a recently implemented Clinical Trial Supply Chain project, please
indicate your level of agreement with the following statements:
Agree Somewhat Agree Disagree Not Sure
The implementation
of clinical trial
logistics was easier
than expected
o o o o
The communication
with clinical sites
was better than I
anticipated
o o o o
The communication
with my vendors
was better than I
anticipated
o o o o
The access to my
shipment data and
documentation was
readily available
o o o o
My organization
had adequate
process controls in
place ensure the
safety, efficacy, and
quality of the
medical product
during distribution
o o o o
The costs of the
supply chain
management for my
clinical trial were
higher than I
expected
o o o o

274

Q11 When thinking back to how you recently implemented a clinical trial, is there
anything you would have done differently across the supply chain? If so, please explain
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q12 Please indicate you or your organization's level of familiarity with the following
requirements and best practices associated with supply chain management :
Unfamiliar Familiar Experienced
Drug Supply Chain
Security Act (DSCSA)
o o o
Good Distribution
Practices (GDP)
o o o
Good Manufacturing
Practices (GMP)
o o o
Good Clinical Practices
(GCP)
o o o
Good Tissue Practices
(GTPs)
o o o
International Air
Transport Association
(IATA) Standards
o o o

275

Unfamiliar Familiar Experienced
Federal Aviation
Administration (FAA)
Regulations
o o o
Domestic (US) Import /
Export Regulations
o o o
International Import /
Export Regulations
o o o
Cold Chain
Management Standards
/ Regulations
o o o
Hazardous Material
(Hazmat) / Dangerous
Goods (DG)
Regulations
o o o

276

Q13 Please indicate your level of agreement with the following statements regarding
current regulations of clinical trial distribution of cell and gene therapies:
Agree Somewhat Agree Disagree Not Sure
Current US FDA
Good Clinical
Practices (GCP)
regulations are
sufficient for the
distribution for
clinical trials.
o o o o
Current US FDA
Good
Manufacturing
Practices (GMP)
regulations are
sufficient for the
distribution for
clinical trials.
o o o o
Regulators (i.e. US
FDA, EMA) should
work together to
harmonize or
standardize
distribution and
transport laws and
regulations
o o o o
Clinical Supply
Chain Management
regulations should
be flexible,
adaptable and risk-
based
o o o o
There is sufficient
regulatory guidance
to support the
supply chain
management of
Cell and Gene
Therapies
o o o o

277

Q14 Although Good Distribution Practices are not mandated in the United States (US) by
the FDA, these regulations are mandated by other global regulatory bodies. Do you think
the Good Distribution Practices guidelines should be adapted and enforced by the FDA
for the transportation of investigational medical products (IMP) ?
o Yes, the US FDA should adapt GDP regulations for IMP distribution, because ...(please
specific why) ________________________________________________
o No, the US FDA should not adapt GDP regulations for IMP distribution, because
...(please specific why) ________________________________________________

Q15 Please rank how challenging the following factors related to regulatory
considerations for the distribution of cell and gene therapies have been for you or your
organization (Please rank the 1=most challenging to 5=least challenging):
______ Adhering to Regulations / Laws
______ Import and Export Regulations / Customs
______ Maintaining Product Stability
______ Documentation / Labeling Requirements
______ Maintaining the Chain of Custody / Shipment Identity

278

Q16 Please indicate your level of agreement with the following statements regarding
third party distribution companies.

Transportation service providers (3PL) that transport clinical trial material should...
Agree Somewhat Agree Disagree Not Sure
Establish the same
regulatory and
quality standards
of medical product
regulations as the
medical product
industry
o o o o
Should have the
same oversight by
the FDA and other
regulators as the
medical product
industry
o o o o

279

Q17 Please indicate your level of agreement with the following statements related to cell
and gene therapies and supply chain management.

There is an industry knowledge gap in...
Agree
Somewhat
Agree
Disagree Not Sure
Cell and Gene
Therapies
Management
o o o o
Clinical Trial
Supply Chain
Management
o o o o
Cell and Gene
Therapies
Regulations
o o o o
Cell and
Therapies
Transportation
Regulations
o o o o

280

Q18 Please indicate your level of agreement with the following statements related to
partnerships between biopharmaceutical and supply chain industry.

Medical product manufacturers (biotech, biopharma) and supply chain vendors (3PL
couriers, specialty couriers)...
Agree
Somewhat
Agree
Disagree Not Sure
View medical
product
regulations
differently
o o o o
View clinical
supply chain
requirements
differently
o o o o
Have transparent
information
sharing
o o o o
Have transparent
communication
o o o o

281

Q19 A global pandemic (such as COVID-19) has been identified as a disruptor in supply
chain management implementation for clinical trials. Looking back at your planning
activities for your supply chain strategy, do you feel that you were adequately prepared
for COVID-19?
o Yes, the supply chain management plans in place were adequate, because ...(please
specific why) ________________________________________________
o No, the supply chain management plans in place were not adequate, because ...(please
specific why) ________________________________________________

Q20 Looking back (pre-COVID-19), is there anything you would have done differently
for your supply chain planning?
________________________________________________________________

End of Block: Implementation Feasibility - Exploration

Start of Block: Installation

Q21 How does your organization currently manage the supply chain of clinical trials of
cell and gene therapies? (select all that apply)
▢ In-house Dedicated Staff
▢ Clinical Trial Management is Outsourced (i.e CRO)
▢ Raw Material or Investigational Product Manufacturing is Outsourced (i.e CMO)
▢ Clinical Trial Distribution is Outsourced (i.e 3PL Service Provider)
▢ I am not sure
Skip To: Q23 If Q21 = I am not sure

282

Q22 If you outsource your supply chain management, overall how much of your clinical
supply chain is outsourced?
o 0-10%
o 11-20%
o 21-40%
o 41-60%
o 61%+
o Not Sure

283

Q23 What resources have you or your organization considered for managing the
distribution of medical product for your clinical trials?

Have not
considered
Considered
but did not
use
Considering
use in the
future
Considered
and used in
the past
Do Not
Know
Direct to
Patient /
Home
Supported
Trials
o o o o o
Delivery by
Drones
o o o o o
Integrators
such as UPS,
FedEx, DHL
o o o o o
Specialty
Courier
Services such
as Marken,
World
Courier,
QuickSTAT
o o o o o
"Smart" and
"Intelligent"
packaging
(Shipper
containers that
have built-in
tracking
devices,
temperature
controls
o o o o o
IT
Technologies
such as
Blockchain
o o o o o

End of Block: Installation

284

Start of Block: Initial Implementation and Full Implementation
Q24 Please indicate how challenging the following factors related to operational
considerations when transporting of cell and gene therapies have been for you or your
organization :

Not at all
Challenging
Moderately
Challenging
Very Challenging Not Sure
Unpredictability in
Transportation
Management
o o o o
Obtaining Access
to Clinical Site /
Patient Location
o o o o
Shipment Tracking
/ Visibility
o o o o
Establishing Cold
Chain Management
(Temperature
Control,
Packaging)
o o o o
Human Error (i.e.
Improper Storage,
Shipment
Misroute)
o o o o
Vendor
Management
o o o o
Airline Handling
o o o o

285

Q25 When considering outsourcing your supply chain management activities, please rate
your concerns with the following elements related to transport of the cell and gene
therapies (please rank 1= highest concern to lowest concern):
______ Meeting Turnaround Times (TAT)
______ Temperature Monitoring / Temperature Excursions
______ Shipping Visibility / Traceability
______ Diversion / Counterfeiting
______ Data Integrity / Data Breach

Q26 Besides the elements describe above, are there any additional concerns with
outsourcing supply chain activities?
________________________________________________________________

Not at all
Challenging
Moderately
Challenging
Very Challenging Not Sure
Distributor
Handling
o o o o
Force Majeure
(Uncontrollable
External Factors)
o o o o

286

Q27 Thinking of one particular trial you have engaged in, did your organization utilize
any of the following techniques when onboarding clinical trial supply chain vendors?
Yes No Not Sure
Provide Training on
Clinical Protocols
o o o
Develop and Share
Standard Operating
Procedures
o o o
Perform Test Runs of
Transportation Routes
o o o
Develop a Hybrid
Project Team
o o o
Develop Joint
Contingency Plans
o o o

Q28 Besides the elements describe above, what are other activities do you perform to
prepare vendors when outsourcing supply chain activities?
________________________________________________________________

287

Q29 To qualify your supply chain vendors, did your organization utilize any of the
following techniques :
Yes No Not Sure
Quality Audits - Onsite
o o o
Quality Audits -
Document Review
o o o
Develop Quality
Technical Agreements
o o o
Establish a Statement of
Work
o o o

Q30 Besides the elements describe above, what are other activities do you perform to
qualify vendors when outsourcing supply chain activities?
________________________________________________________________

288

Q31 When selecting a clinical supply chain vendor/supplier, in your opinion, rate the
importance of the factors below :

Not Important
Somewhat
Important
Very Important Not Sure
Knowledgeable
staff familiar with
conducting clinical
trials
o o o o
Knowledgeable
staff familiar with
products like cell
and gene therapies
o o o o
Regulatory
Expertise - Medical
Product (i.e. 21
CFR 211, 210, 600)
o o o o
Regulatory
Expertise - Trade
Compliance, Import
and Exports,
Transportation
o o o o
Expertise in Cold
Chain Management
/ Temperature
Controlled Services
o o o o
Possession of
Warehouse and
Distribution
Networks (Depots,
Storage
Capabilities, Airline
Partnerships)
o o o o
Having a Quality
System and
established quality
standards i.e. ISO
9001
o o o o

289

Q32 Are there additional factors not mentioned above that you and your organization
consider important for clinical trial distribution and transport of cell and gene therapies ?
(please explain)
________________________________________________________________

End of Block: Initial Implementation and Full Implementation

Start of Block: Full Implementation and Sustainability

Not Important Somewhat
Important
Very Important Not Sure
Aligned with Good
Manufacturing
Practices (GMP
Certified)
o o o o
Aligned with Good
Clinical Practices
(GCP Certified)
o o o o
Aligned with Good
Distribution
Practices (GDP
Certified)
o o o o

290

Q33 Based on prior experiences, how easy was it to implement the following elements
clinical supply management?

Easy to
Implement
Somewhat
Easy to
Implement
Difficult to
Implement
Did Not
Implement
Not Sure
Automation
o o o o o
Strategic
Partnerships/Industry
Network Group
o o o o o
Industry Standards
o o o o o
Physical Infrastructures
(Buildings / Equipment)
o o o o o
IT / Blockchain
Infrastructures
o o o o o
Robust Vendor
Management Programs
o o o o o
Logistics by Design
(Treatment-Based
Supply Chain /
Customized Supply
Chain Programs)
o o o o o

291

Q34 As you move from clinical into commercial phases of product development, from a
perspective of the sustainability of the supply chain for time-sensitive and temperature-
sensitive medical products like cell and gene therapies, do you feel your organization is
well-prepared to upscale?
o Yes, the organization is well-prepared to upscale because (please explain) :
________________________________________________
o No, the organization is not well-prepared to upscale because (please explain) :
________________________________________________

Q35 Are there any other challenges there were not previously discussed in the survey that
you experienced with the supply chain of your clinical trial (please specify)?
________________________________________________________________

Q36
Thinking back to clinical trials you have managed or collaborated on in the past, what
was one lesson learned from your experience with supply chain management.
________________________________________________________________

End of Block: Full Implementation and Sustainability

Start of Block: SURVEY IS NOW COMPLETE

292

Appendix C. Survey Data Set
Q2 - My most recent employer or client can best be described as a…

# Answer % Count
1 Pharmaceutical (Drug) Company 28.57% 30
2 Medical Device Company 10.48% 11
4
Biotechnology Company (Cell and Gene, Immunotherapies,
Cancer Vaccines)
29.52% 31
7 Contract Organization (CRO, CMO, CDMO) 6.67% 7
8 Academia, Institution, School, Research Center 4.76% 5
9 Other (Please Specify) 5.71% 6
10
Supply Chain/Logistics (Specialized Packaging, Cold Chain, 3
PL)
10.48% 11
13
Biomanufacturing / Cell Production Facility (i.e., Hospital GMP
Facility)
3.81% 4
Total 100% 105

Other (Please Specify) – Text
Consultant
Consultancy in life science supply-chains
Consultant
Consulting
Academic Cell & Gene Therapy Manufacturing Facility
Consulting Firm

293

Q3 - My department or area of expertise is best described as:

# Answer % Count
5 Regulatory Affairs 39.05% 41
8 Research & Development (R&D) / Clinical Research 4.76% 5
12 Manufacturing / Operations 4.76% 5
13 Supply Chain / Logistics 19.05% 20
16 Other (Please Specify) 7.62% 8
17 Quality Assurance / Quality Control 20.95% 22
18 Clinical Operations 3.81% 4
Total 100% 105

Other (Please Specify) - Text
Innovation scholar
Legal
Sterility Assurance
Drug safety and risk management
Program Management
Commercialization of ATMPs
Analysis and Reporting
Regulatory Writing

294

Q4 - What is the company size of your most recent employer/client in terms of number of
employees?

# Answer % Count
2 1-999 42.86% 45
5 5,000-9,999 5.71% 6
6 10,000 + 30.48% 32
7 I don’t know 1.90% 2
9 1,000-4,999 19.05% 20
Total 100% 105

295

Q5 - My primary role is...

# Answer % Count
1 Vice President / President / C-Suite 13.33% 14
3 Director / Sr.Director 44.76% 47
4 Sr. Manager / Manager 14.29% 15
6 Associate / Specialist / Coordinator 8.57% 9
7 Researcher / Scientist 4.76% 5
9 Consultant 8.57% 9
11 Other (Please Specify) 3.81% 4
12 Project Manager 1.90% 2
Total 100% 105

Other (Please Specify) - Text
Logistics Manager
Medical writer
Packaging Engineering
Statistician

296

Q6 - How many years of experience do you have with complex biologics, advanced
medicinal therapies, or cell and gene therapies ?

# Answer % Count
1 Less than 3 years 17.14% 18
2 3-5 years 20.00% 21
3 6- 9 years 9.52% 10
4 10 to 14 years 10.48% 11
5 15+ years 36.19% 38
8 None 6.67% 7
Total 100% 105

297

Q7 - Which modalities do you or your organization have experience with (please select
all that apply):

# Answer % Count
1
Novel Proteins and Peptides (i.e. nucleotide-based therapies
include mRNAs, small interfering RNAs (siRNAs), antisense
oligonucleotides, and aptamers)
11.67% 35
2 Combination Products (i.e. Device-Biologics) 16.33% 49
3
Cell-based Gene Therapies (i.e. CAR-T, T cell
Immunotherapies, Allogeneic and Autologous
Immunotherapies)
19.33% 58
4 Vaccines (i.e. Cancer Vaccines) 13.00% 39
7 Other (Please Specify) 3.67% 11
8
Gene-Based Therapies (i.e. CRISPR-Cas9, Adeno-associated
virus (AAV) Therapies)
13.00% 39
9
Cell and Gene Therapies Components (i.e. Engineered Tissues,
Viral Vectors, Cell Banks, Apheresis Material)
13.00% 39
10
Stem Cells (i.e. Hematopoetic Stem cells, Adult and Embryonic
Stem Cells)
9.33% 28
13 I don't know 0.67% 2
Total 100% 300

Other (Please Specify) - Text
None
medical devices
Regulatory T Cells (Tregs)
Fusion protein, I/O PD-l
Medical Device
Plasma based products
IMP
Antibodies
Medical Devices
Combination Devices, radioisotope based therapies

298

Q8 - In terms of supply chain, which countries have you or your organization transported
clinical trial material (i.e. supplies, raw materials, investigational medical products) to or
from... (please select all that apply):

# Answer % Count
1 United States 20.45% 81
5 Europe 17.42% 69
6 Asia-Pacific 12.37% 49
7 Latin America 8.33% 33
8 Other (Please Specify): 1.01% 4
10 China 8.08% 32
15 Canada 12.63% 50
16 I Don't Know 1.52% 6
19 None 1.01% 4
20 Middle East 6.57% 26
21 Africa 5.05% 20
22 Russia 5.56% 22
Total 100% 396

Other (Please Specify): - Text
India
Global
Australia

299

Q9 - Please indicate your level of agreement with the following statements regarding
your organization's planning of Clinical Supply Chain Management. (IMP=
Investigational Medicinal Product)

My organization...

# Question Agree
Somewhat
Agree
Disagree Not Sure Total
1
Has a well-
defined
distribution plan
for clinical
supply chain of
IMPs
56.25% 36 32.81% 21 6.25% 4 4.69% 3 64
2
Supports
innovative
clinical supply
chain initiatives
53.13% 34 28.13% 18 4.69% 3 14.06% 9 64
3
Assesses the
readiness of the
organization for
supply chain
management
54.69% 35 28.13% 18 12.50% 8 4.69% 3 64
4
Has Sufficient
funding is
available to meet
distribution costs
54.69% 35 29.69% 19 7.81% 5 7.81% 5 64
5
Has Contingency
and business
continuity plans
are in place for
distribution
43.75% 28 32.81% 21 15.63% 10 7.81% 5 64
6
Understands the
role of the
sponsor in the
distribution of
IMPs
74.60% 47 19.05% 12 1.59% 1 4.76% 3 63
7
Understands the
US FDA
requirements for
distribution of
IMPs
79.69% 51 15.63% 10 1.56% 1 3.13% 2 64
8
Understands the
international
requirements for
distribution of
IMPs
65.63% 42 25.00% 16 1.56% 1 7.81% 5 64

300

Q10 - Thinking back to a recently implemented Clinical Trial Supply Chain project,
please indicate your level of agreement with the following statements:

# Question Agree
Somewhat
Agree
Disagree Not Sure Total
1
The
implementation
of clinical trial
logistics was
easier than
expected
11.11% 7 30.16% 19 46.03% 29 12.70% 8 63
2
The
communication
with clinical
sites was better
than I
anticipated
20.63% 13 39.68% 25 20.63% 13 19.05% 12 63
3
The
communication
with my vendors
was better than I
anticipated
20.63% 13 44.44% 28 17.46% 11 17.46% 11 63
4
The access to
my shipment
data and
documentation
was readily
available
41.27% 26 31.75% 20 9.52% 6 17.46% 11 63
5
My organization
had adequate
process controls
in place ensure
the safety,
efficacy, and
quality of the
medical product
during
distribution
60.32% 38 28.57% 18 3.17% 2 7.94% 5 63
6
The costs of the
supply chain
management for
my clinical trial
were higher than
I expected
23.81% 15 38.10% 24 7.94% 5 30.16% 19 63

301

Q11 - When thinking back to how you recently implemented a clinical trial, is there
anything you would have done differently across the supply chain? If so, please explain

When thinking back to how you recently implemented a clinical trial, is there
anything you would have done differently across the supply chain? If so, please
explain
My company has not yet started planned clinical trials or associated clinical trial
supply chain project.
I will make sure the readiness of the label in the local language.
NA
Did not work much with Clinical Trial Material
A better job of qualifying COMs, vendors and transportation companies before the trial
started.
We would have included the custom brokers and the border/custom agents early in our
planning process to ensure cell therapy products will not have custom clearance delays.
More up front planning for QP release for some markets outside EU
No
Allow more time for labeling, packaging and/or kitting. Smaller companies don't
usually have a clinical supply role and labeling etc. is a last minute though in many
cases for small companies.
Would like to ensure that the documentation of the IMP for the retest dates for stability
studies was more detailed and included QA sign off.
More robust testing of the distribution model.
Engage a supply chain SME earlier
Start earlier with supply chain and logistics planning, understanding existing
capabilities and matching them to product requirements is key. We need to plan
accordingly in terms of matching a solution that ensures product integrity.
Picked fewer CROs with larger patient population
NA
I am a consultant so most of what I do is coordination and strategy. However, the last
time I ran a clinical study for a company I was an employee of, I ran into
communication issues between the manufacturing operations group in labeling the
product appropriately and following shipping and import requirements to enable the
clinical material to arrive at the clinical site on-time and stored appropriately. The
issue was really the VP of Operations was hostile towards the
Regulatory/Quality/Clinical department and wanted to undermine this group wherever
possible. Most of my other experiences have been relatively collaborative. Everyone
wants to see the clinical trial be successful so most of the other issues I have run into
are related to lack of funding, people resources, or lack of experience for those who
were tasked with various roles. Most small companies hire very under qualified people
to help them save money but that oftentimes sets them up for failure.

302

Most companies do not want to pay a consultant or CRO to manage logistics and that
can be one of the biggest challenges in a clinical trial.
Monitoring of return devices and tracking of devices.
Knowing what I know now, I would simplify the process in the areas of COC/COI.
Better logistics provider with better tracking and communication
N/A
identify local couriers
My experience with a radioisotope containing product in that we did not have choices
re: shipper to Europe. The air carriers could refuse for any reason, despite the
therapeutic need and short usuable product half life. Company was small, did not
have strong supply chain resources and was unfamiliar with many of the constraints
prior to initiating shipments. Would have involved the clinical operations group
earlier in the discussion of supply chain logistics, maintained cross functional
communications between product release and clinical ops in terms of packaging
changes and transport tracking, verification of material transfer between sites, etc.
NOTE: Many of the requirements listed below are N/A as they were not in force
during my experiences
N/A
we send duplicate CTM to ensure adequate supply in case any doses are compromised
during shipment
Written a backup plan
Don't do it at all! (Joking) China customs is a big challenge, especially in these days of
international trade tensions
Quality does not have much say to decisions for a new trial. The sponsor creates and
environment of entrepreneurship motives( get things done at any cost).No plan to
critically access the supply chain for a new trial.
Better train the clinical sites to return shipment documentation especially the
temperature monitor.
There were the usual hiccups, but overall the process worked to expectations.
Clarification to above answers: i disagreed with the statements because I expected the
communications to be good and they were. To answer this question, more defined
regulations and transparency from the health authorities in China would have been
helpful.
N/A
System changes would have been put in place to allow more visibility to the
classification of the material, the real time status of the material (temperature and
location), and real time alerting of the same. Additionally, I would want to see tools in
place to measure the level of risk of air travel across the globe. Currently, and I
believe this is probably in place for most companies, there is no automated fashion to
select airlines/flights/times and assess the risk of those choices. Some of the risks may
be offloading, cancellation of flights and timeliness of flights. I would also want to see

303

more of a priority of these materials with the airlines themselves. Currently, this is a
country by country, airline by airline situation. Because the impact of failure is so
great (patient could potentially die), these types of materials need to be treated as the
most valuable of cargo by the airlines and the airline handlers. Additionally, we need
to have a standardized database of International Customs regulations for the entire
globe based upon HTS Code classification. This would allow visibility to the customs
requirements of each country in advance of shipping and would greatly reduce the risk
of delay due to lack of the proper documentation and or labeling.
N/a

304

Q12 - Please indicate you or your organization's level of familiarity with the following
requirements and best practices associated with supply chain management :

# Question Unfamiliar Familiar Experienced Total
1
Drug Supply Chain
Security Act
(DSCSA)
38.10% 24 34.92% 22 26.98% 17 63
2
Good Distribution
Practices (GDP)
6.35% 4 36.51% 23 57.14% 36 63
3
Good Manufacturing
Practices (GMP)
1.56% 1 14.06% 9 84.38% 54 64
4
Good Clinical
Practices (GCP)
3.13% 2 17.19% 11 79.69% 51 64
5
Good Tissue Practices
(GTPs)
20.63% 13 38.10% 24 41.27% 26 63
6
International Air
Transport Association
(IATA) Standards
25.81% 16 29.03% 18 45.16% 28 62
7
Federal Aviation
Administration
(FAA) Regulations
29.51% 18 37.70% 23 32.79% 20 61
8
Domestic (US)
Import / Export
Regulations
20.63% 13 34.92% 22 44.44% 28 63
9
International Import /
Export Regulations
20.63% 13 38.10% 24 41.27% 26 63
10
Cold Chain
Management
Standards /
Regulations
16.13% 10 30.65% 19 53.23% 33 62
11
Hazardous Material
(Hazmat) / Dangerous
Goods (DG)
Regulations
12.70% 8 42.86% 27 44.44% 28 63

305

Q13 - Please indicate your level of agreement with the following statements regarding
current regulations of clinical trial distribution of cell and gene therapies:

# Question Agree
Somewhat
Agree
Disagree Not Sure Total
1
Current US FDA
Good Clinical
Practices (GCP)
regulations are
sufficient for the
distribution for
clinical trials.
22.58% 14 48.39% 30 12.90% 8 16.13% 10 62
2
Current US FDA
Good
Manufacturing
Practices (GMP)
regulations are
sufficient for the
distribution for
clinical trials.
32.79% 20 50.82% 31 8.20% 5 8.20% 5 61
3
Regulators (i.e.
US FDA, EMA)
should work
together to
harmonize or
standardize
distribution and
transport laws
and regulations
82.26% 51 12.90% 8 1.61% 1 3.23% 2 62
4
Clinical Supply
Chain
Management
regulations
should be
flexible,
adaptable and
risk-based
67.74% 42 25.81% 16 3.23% 2 3.23% 2 62
5
There is
sufficient
regulatory
guidance to
support the
supply chain
management of
Cell and Gene
Therapies
12.90% 8 46.77% 29 29.03% 18 11.29% 7 62

306

Q14 - Although Good Distribution Practices are not mandated in the United States (US)
by the FDA, these regulations are mandated by other global regulatory bodies. Do you
think the Good Distribution Practices guidelines should be adapted and enforced by the
FDA for the transportation of investigational medical products (IMP) ?

# Answer % Count
1
Yes, the US FDA should adapt GDP regulations for IMP
distribution, because ...(please specific why)
81.25% 39
2
No, the US FDA should not adapt GDP regulations for IMP
distribution, because ...(please specific why)
18.75% 9
Total 100% 48

Yes, the US FDA should adapt GDP regulations for IMP distribution, because
...(please specific why) - Text
global harmonization and ensuring the integrity and quality of IMPs is key.
Traceability & accountability
Harmonization with other countries
This will lead to harmonization of distribution practices as well as ensure more people
are aware of GDP regulations.
ensure consistency for companies
Yes to establish a baseline and aid in vendor compliance expectations for heavily
outsourced companies. The regulations must include flexibility though due to the real
world adaptive strategies and pivots required for cell therapies specifically. If you need
to charter a helicopter or snowcat to get the product to the patient, the snowmobile may
not be audited.
to harmonize globally1
Standardization of requirements
A guidance would be helpful For minimum regulatory expectations. Currently,
requirements are govern by contract and QAA between sponsors, MAH and
distribution centers.
in a nutshell, it makes sense! Safety for product/material equals safety for clinical
trials.
all biologics should have traceability
I believe in consistency.
In a global economy, harmonization of practices and standards is key.
Without clear regulations companies can skirt the edges of good practice.

307

To increase continuity of process between regions in a global clinical trial. I always
advocate for increased harmonization across regional regulatory authorities.
International Harmonisation
consistent practice
Yes
These should be applied to the manufacturer of the product. 1
Consistency across regions helps ensure overall compliance.
ICH Standards
products are fragile and very expensive
GDPs should be required and implemented to continue "GXP" practices end-to-end
through the total life cycle of the product(s).
Always better to have aglobal consensus in a globl industry with multinational trials
GDP represents a global standard.
To be consistent with other bodies
Standardization of anything to do with IMP would be beneficial to the outcomes of the
life cycle of these types of shipments.
Consistency
To harmonize global regulations

No, the US FDA should not adapt GDP regulations for IMP distribution, because
...(please specific why) - Text
Following cGMP should suffice
The requirements are well covered elsewhere in the CFR and additional enforcement is
not required.
GMP and GCP regulations adequately address GDP requirements.1
Items of importance are already covered in other US regs.
Require harmonization, for IMP should be guideline, otherwise may be a constraint not
based on risk assessment
FDA should supply guidelines that leave room for Pharma to adapt to fit their
procedures
I think they should consider it more in conjunction with industry

308

Q15 - Please rank how challenging the following factors related to regulatory
considerations for the distribution of cell and gene therapies have been for you or your
organization (Please rank the 1=most challenging to 5=least challenging):

# Question 1 2 3 4 5 Total
1
Adhering to
Regulations /
Laws
22.81% 13 21.05% 12 22.81% 13 21.05% 12 12.28% 7 57
2
Import and
Export
Regulations /
Customs
22.81% 13 31.58% 18 12.28% 7 17.54% 10 15.79% 9 57
3
Maintaining
Product
Stability
24.56% 14 15.79% 9 28.07% 16 21.05% 12 10.53% 6 57
4
Documentation
/ Labeling
Requirements
17.54% 10 8.77% 5 12.28% 7 28.07% 16 33.33% 19 57
5
Maintaining
the Chain of
Custody /
Shipment
Identity
12.28% 7 22.81% 13 24.56% 14 12.28% 7 28.07% 16 57

309

Q16 - Please indicate your level of agreement with the following statements regarding
third party distribution companies.

Transportation service providers (3PL) that transport clinical trial material should...

# Question Agree
Somewhat
Agree
Disagree
Not
Sure
Total
1
Establish the
same
regulatory and
quality
standards of
medical
product
regulations as
the medical
product
industry
61.90% 39 25.40% 16 7.94% 5 4.76% 3 63
2
Should have
the same
oversight by
the FDA and
other regulators
as the medical
product
industry
52.38% 33 28.57% 18 19.05% 12 0.00% 0 63

310

Q17 - Please indicate your level of agreement with the following statements related to
cell and gene therapies and supply chain management.

There is an industry knowledge gap in...

# Question Agree
Somewhat
Agree
Disagree
Not
Sure
Total
1
Cell and Gene
Therapies
Management
42.86% 27 36.51% 23 7.94% 5 12.70% 8 63
2
Clinical Trial
Supply Chain
Management
30.16% 19 41.27% 26 15.87% 10 12.70% 8 63
3
Cell and Gene
Therapies
Regulations
41.27% 26 34.92% 22 12.70% 8 11.11% 7 63
4
Cell and
Therapies
Transportation
Regulations
46.77% 29 37.10% 23 3.23% 2 12.90% 8 62

311

Q18 - Please indicate your level of agreement with the following statements related to
partnerships between biopharmaceutical and supply chain industry.

Medical product manufacturers (biotech, biopharma) and supply chain vendors (3PL
couriers, specialty couriers)...

# Question Agree
Somewhat
Agree
Disagree
Not
Sure
Total
1
View medical product
regulations differently
31.15% 19 36.07% 22 13.11% 8 19.67% 12 61
2
View clinical supply
chain requirements
differently
33.87% 21 38.71% 24 16.13% 10 11.29% 7 62
3
Have transparent
information sharing
14.52% 9 33.87% 21 35.48% 22 16.13% 10 62
4
Have transparent
communication
16.13% 10 35.48% 22 35.48% 22 12.90% 8 62

312

Q19 - A global pandemic (such as COVID-19) has been identified as a disruptor in
supply chain management implementation for clinical trials. Looking back at your
planning activities for your supply chain strategy, do you feel that you were adequately
prepared for COVID-19?

# Answer % Count
1
Yes, the supply chain management plans in place were
adequate, because ...(please specific why)
36.73% 18
2
No, the supply chain management plans in place were not
adequate, because ...(please specific why)
63.27% 31
Total 100% 49

Yes, the supply chain management plans in place were adequate, because ...
(please specific why) - Text
We had business continuity plans in place.
The critical elements were having a diverse logistics network, strong logistics planning
function at our label pack vendors and strong connections with US regulators
(operation warp speed). By having strong oversight, technology supporting tracking
(GPS) and direct contacts with heads of HHS, we were able to import faster than
normal. We are actually moving pipelines faster based on COVID urgency rather than
encountering delays to the standard timelines. We're also getting a much bigger focus
on risk based strategies and creative solutions to overcome standard turn around times.
The plans was independent and functional with Covid.
A complete disruption first for medical necessity and now for political reasons can not
be planned for. You can one react to them. Which we have.
We started preparing earlier than most and had key asset and network advantages
we met early and anticipated the supply chain issues, changing our core offerings from
reuusable soltions to single use, reducing exposure of COVID-19
they are applicable to any situation.
We haven’t seen disruptions in shipping.
Full business continuity planning in play, regardless of COVID-19
COVID-19 did not impact the process itself, just made it more difficult.
we had strong contingency and disaster recovery plans
We had to rely upon the flexibility of our network in order to meet the customer's
needs.
Contingency plans/return to BAU always in place

313

No, the supply chain management plans in place were not adequate, because ...
(please specific why) - Text
we are still developing supply chain strategy generally, let alone with a global
pandemic in mind.
Not something that we had considered in our planning
we did not have redundancy built into our supply chain management
We have been having issues exporting shipments to countries where WHO is providing
the approval, but not the local authorities.
use CHina as a source of clinical trial material
n/a
Availability of ancillary supplies
there are delays everywhere, this is unprecedented.
clinical supply was single sourced overseas. Covid created an inability to receive
materials "just in time".
other organization supply chain relies on are also affected by the pandemic
Such a distraction was not commonly thought of
Direct to subject requirements were not always clear
No due to limited shipping transportation availability, industry had to react to alternate
shipping lanes and modes of transportation to meet validated shipping requirements.
Shipping to clinical sites was stopped when clinics closed. Getting supplies to patients
became difficult.
Material Supply Disruptions
no contingent plan/ no backup
we could not get IMP shipments delivered
No
If apheresis centers come to a stop the supply chain breaks down, shipments are no
longer reliable and short IMP shelf-life is problematic
i don't think anyone sufficiently prepared for interruption with this magnitude.
Absolutely no plan in place for my current clients.
We were not prepared for a pandemic but I will say we adapted quickly.
Companies were not prepared with back-up plans in case of transportation delivery
delays and/or trial shut-downs.
Outlook on potential pandemic was not a deliverable

314

Q20 - Looking back (pre-COVID-19), is there anything you would have done differently
for your supply chain planning?

Looking back (pre-COVID-19), is there anything you would have done differently
for your supply chain planning?
N/A
N/A, I was severed at the begining of the Covid-19 shutdow
Build redundancy in terms of suppliers as well as vendors for key reagents and
materials
We could have been more prepared for example we could have had back up options if
the airlines were not an option.
This did not impact me personally
Yes stocked up on ancillary supplies (IV sets, IV bags
I don't think anybody could have prepared for COVID disruption adequately. Perhaps
delaying the trial, but risk falling behind,
Planned emergency product back ups
No
diversify suppliers for redundancy
Higher inventory levels and backup 3pl providers.
Invest more in redundant temperature control equipment and test BCP/DRP more
frequently.
we could have done an even better job, by executing scenario planning to further
anticipate resource and training needs
Plan for such a problem worldwide
Acted more quickly
I think having individual conatct information for those who would ultimately be
handling and storing the clinical materials would be good to have, regardless of
COVID.
broaden our material supply base
outsourced the logistics/ transportation
more contingency planning
Better planning
Better defined alternate vendors, supply routes, etc. Would have included verbiage in
QAG that mandated we have a stockpile of materials.
Have a plan B and plan C. Use lessons learned from COVID, establish, test and
implement plans NOW rather than react to next situation
Had a stronger back-up plan for transportation delivery delays at all steps, pick-up,
transport and delivery.

315

Insure more lead time. Importation took more time.
Things worked very well due to our strong disaster recovery plans
We could not really have planned for COVID. I don't believe plans could have ever
been put in place to effectively react to the complete shut down of global air travel.
N/A
Better planning for pandemics

Q21 - How does your organization currently manage the supply chain of clinical trials of
cell and gene therapies? (select all that apply)

# Answer % Count
1 In-house Dedicated Staff 33.33% 40
2 Clinical Trial Management is Outsourced (i.e CRO) 25.00% 30
3
Clinical Trial Distribution is Outsourced (i.e 3PL Service
Provider)
20.00% 24
6 I am not sure 6.67% 8
7
Raw Material or Investigational Product Manufacturing is
Outsourced (i.e CMO)
15.00% 18
Total 100% 120

316

Q22 - If you outsource your supply chain management, overall how much of your clinical
supply chain is outsourced?

# Answer % Count
1 0-10% 17.31% 9
2 11-20% 3.85% 2
3 21-40% 13.46% 7
4 41-60% 17.31% 9
5 61%+ 15.38% 8
6 Not Sure 32.69% 17
Total 100% 52

317

Q23 - What resources have you or your organization considered for managing the
distribution of medical product for your clinical trials?

# Question
Have not
considered

Considered
but did not
use

Considering
use in the
future

Considered
and used in
the past

Do Not
Know
Total
1
Direct to
Patient /
Home
Supported
Trials
32.79% 20 11.48% 7 9.84% 6 27.87% 17 18.03% 11 61
2
Delivery by
Drones
66.67% 40 1.67% 1 6.67% 4 0.00% 0 25.00% 15 60
3
Integrators
such as UPS,
FedEx, DHL
9.68% 6 4.84% 3 12.90% 8 53.23% 33 19.35% 12 62
4
Specialty
Courier
Services
such as
Marken,
World
Courier,
QuickSTAT
4.84% 3 1.61% 1 9.68% 6 64.52% 40 19.35% 12 62
5
"Smart" and
"Intelligent"
packaging
(Shipper
containers
that have
built-in
tracking
devices,
temperature
controls
9.84% 6 6.56% 4 14.75% 9 54.10% 33 14.75% 9 61
6
IT
Technologies
such as
Blockchain
25.00% 15 5.00% 3 26.67% 16 1.67% 1 41.67% 25 60

318

Q24 - Please indicate how challenging the following factors related to operational
considerations when transporting of cell and gene therapies have been for you or your
organization :

# Question
Not at all
Challenging

Moderately
Challenging

Very
Challenging

Not
Sure
Total
1
Unpredictability in
Transportation
Management
5.00% 3 51.67% 31 31.67% 19 11.67% 7 60
2
Obtaining Access to
Clinical Site / Patient
Location
16.67% 10 55.00% 33 6.67% 4 21.67% 13 60
3
Shipment Tracking /
Visibility
30.00% 18 50.00% 30 6.67% 4 13.33% 8 60
4
Establishing Cold Chain
Management
(Temperature Control,
Packaging)
23.33% 14 45.00% 27 20.00% 12 11.67% 7 60
5
Human Error (i.e.
Improper Storage,
Shipment Misroute)
11.67% 7 43.33% 26 33.33% 20 11.67% 7 60
6 Vendor Management 13.33% 8 51.67% 31 21.67% 13 13.33% 8 60
7 Airline Handling 11.67% 7 43.33% 26 31.67% 19 13.33% 8 60
8 Distributor Handling 13.56% 8 49.15% 29 16.95% 10 20.34% 12 59
9
Force Majeure
(Uncontrollable External
Factors)
1.69% 1 32.20% 19 42.37% 25 23.73% 14 59

319

Q25 - When considering outsourcing your supply chain management activities, please
rate your concerns with the following elements related to transport of the cell and gene
therapies (please rank 1= highest concern to lowest concern):

# Question 1 2 3 4 5 Total
1
Meeting
Turnaround
Times (TAT)
33.33% 15 24.44% 11 20.00% 9 15.56% 7 6.67% 3 45
2
Temperature
Monitoring /
Temperature
Excursions
40.00% 18 26.67% 12 26.67% 12 4.44% 2 2.22% 1 45
3
Shipping
Visibility /
Traceability
11.11% 5 22.22% 10 42.22% 19 22.22% 10 2.22% 1 45
4
Diversion /
Counterfeiting
2.22% 1 8.89% 4 4.44% 2 11.11% 5 73.33% 33 45
5
Data Integrity /
Data Breach
13.33% 6 17.78% 8 6.67% 3 46.67% 21 15.56% 7 45

320

Q26 - Besides the elements describe above, are there any additional concerns with
outsourcing supply chain activities?
Besides the elements describe above, are there any additional concerns with
outsourcing supply chain activities?
None
Overall cost it adds to the clinical trial budget
Customs delays
n/a
Outsourcing isn't just with 3rd party subcontractors, but can also be done via
COMPLEX alliance partnerships with other companies, subcontractors managed by
alliance partners, non-profit organizations, academia which owns contracts with
governmental organizations, etc. Establishing robust contracts, roles/responsibilities,
quality agreements and supply networks is key. That framework must also be
established EXTREMELY fast. We have gone from government/non-profit trial
endorsement to target subject dosing in 4-8 weeks. In that timeframe you have to
establish all of that ownership, optimize strategies, pray you have existing network (i.e.
avoid auditing a new depot in Russia or Argentina), get financials in order to meet
SOCS compliance (i.e. no work prior to PO approval), and then find creative solutions
to trim 5 day turn around times to same day turn around times. All of this has to
happen across timezones and languages. My perspective is often, how can my
organization be flexible and dynamic enough to fit into the systems of 20 different
vendors while at the same time accellerating their systems. The idea is that trying to
make 20 vendors operate within YOUR internal SOPs and arbitrary risk tollerance will
never be the fast path. Don't rock the boat....adapt to their requirements with minor
modification and things will go smoothly and quickly. It also links into relationship
management. The enjoyable companies often miraculously find production slots.
return policy and procedures, how do you get the unused specimen back so it can be
properly investigated.
No
none
no
Costs - Most clients do not want to pay for the resources they truly need to make their
supply chain effective.
Product damage, cost
No
Loss focus on priority to ship on-time, esp. for patients that must lympho deplete and
count on the IMP being there on-time.
When new state regulations are implemented requiring couriers to end.
Customs and importation

321

NO
Lack of standardization of handling clinical trial materials. There exists a lack of
understanding on the part of vendors and how important these materials are. The
human error factor cannot be underestimated when analyzing risk.
Chain of custody is key
Strategic Supplier Selection for outsourcing critical clinical supply chain management
responsibilities.

Q27 - Thinking of one particular trial you have engaged in, did your organization utilize
any of the following techniques when onboarding clinical trial supply chain vendors?

# Question Yes
Not
Sure
No Total
1
Provide Training on Clinical
Protocols
59.65% 34 17.54% 10 22.81% 13 57
2
Develop and Share Standard
Operating Procedures
78.57% 44 7.14% 4 14.29% 8 56
3
Perform Test Runs of
Transportation Routes
65.52% 38 17.24% 10 17.24% 10 58
4
Develop a Hybrid Project
Team
49.12% 28 26.32% 15 24.56% 14 57
5
Develop Joint Contingency
Plans
45.61% 26 26.32% 15 28.07% 16 57

322

Q28 - Besides the elements describe above, what are other activities do you perform to
prepare vendors when outsourcing supply chain activities?

Besides the elements describe above, what are other activities do you perform to
prepare vendors when outsourcing supply chain activities?
My company has not started its planned clinical trials, so it has not engaged in any of
the listed techniques yet.
None
n/a for my role
Basically paid for a consultant who was an employee of the vendor. They were not just
a PM, but a highly experienced SME in the clinical supply field. By establishing that
direct and dedicated resource, they were able to coordinate activities across a dozen
global sites and get traction much faster than a standard project manager. They could
flag issues not just in the clinical supply plan (trial focused) but how that strategy
would integrate into the systems/processes at the specific vendor. It also opened the
door to direct CEO to CEO conversations if needed.
review vendor's competency carefully.
No
Audit of vendor
Packaging validation
Host weekly update meetings/calls to ensure everyone stays on the same page
throughout the project.
Qualification, Privacy and security assessments
provide training on the product
None
i don't know what you mean about hybrid project team. In what way is it a hybrid? by
project? internal/external members? X functional?
N/A

323

Q29 - To qualify your supply chain vendors, did your organization utilize any of the
following techniques :

# Question Yes
Not
Sure
No Total
1 Quality Audits - Onsite 79.31% 46 10.34% 6 10.34% 6 58
2
Quality Audits - Document
Review
93.10% 54 6.90% 4 0.00% 0 58
3
Develop Quality Technical
Agreements
84.48% 49 13.79% 8 1.72% 1 58
4 Establish a Statement of Work 86.21% 50 12.07% 7 1.72% 1 58

324

Q30 - Besides the elements describe above, what are other activities do you perform to
qualify vendors when outsourcing supply chain activities?

Besides the elements describe above, what are other activities do you perform to
qualify vendors when outsourcing supply chain activities?
My company has not started its planned clinical trials, so it has not engaged in any of
the listed techniques yet.
Test runs with a variety of parameters
none
On site audits are not just Quality focused, but also business process focused. We
assess insurance risks, business continuity plans, interview project managers and site
heads from a relationship basis. We tried to build the trust and be candid with site staff
to understand what THEY worry about. This let us flag the unknown unknowns. Any
audit can flag that a rat trap is missing from a pest control plan, but building the
abstract dialog gives the vendor room to share items you may not know to worry about
(e.g. south african depot staff have panic buttons on their key chains due to high crime
rates, trucks have active GPS tracking for hijacking, power outages occur at a high
frequency due to the economics of wire theft, etc).
try a dry run/a mock exercise to assess gaps.
No
none
No
Developing robust service contracts are important and not the same as a Statement of
Work.
Confirm training, certifications, qualifications, product storage, adequate QMS,
privacy and security
some local drug release
A
None
N/A

325

Q31 - When selecting a clinical supply chain vendor/supplier, in your opinion, rate the
importance of the factors below :

# Question
Not
Important

Somewhat
Important

Very
Important

Not
Sure
Total
1
Knowledgeable staff
familiar with conducting
clinical trials
0.00% 0 11.86% 7 81.36% 48 6.78% 4 59
2
Knowledgeable staff
familiar with products like
cell and gene therapies
0.00% 0 23.73% 14 67.80% 40 8.47% 5 59
3
Regulatory Expertise -
Medical Product (i.e. 21
CFR 211, 210, 600)
1.69% 1 23.73% 14 71.19% 42 3.39% 2 59
4
Regulatory Expertise -
Trade Compliance, Import
and Exports, Transportation
0.00% 0 13.56% 8 83.05% 49 3.39% 2 59
5
Expertise in Cold Chain
Management / Temperature
Controlled Services
1.69% 1 5.08% 3 89.83% 53 3.39% 2 59
6
Possession of Warehouse
and Distribution Networks
(Depots, Storage
Capabilities, Airline
Partnerships)
1.69% 1 16.95% 10 77.97% 46 3.39% 2 59
7
Having a Quality System
and established quality
standards i.e. ISO 9001
1.69% 1 16.95% 10 79.66% 47 1.69% 1 59
8
Aligned with Good
Manufacturing Practices
(GMP Certified)
3.39% 2 20.34% 12 71.19% 42 5.08% 3 59
9
Aligned with Good Clinical
Practices (GCP Certified)
5.08% 3 23.73% 14 69.49% 41 1.69% 1 59
10
Aligned with Good
Distribution Practices
(GDP Certified)
3.39% 2 23.73% 14 66.10% 39 6.78% 4 59

326

Q32 - Are there additional factors not mentioned above that you and your organization
consider important for clinical trial distribution and transport of cell and gene therapies ?
(please explain)

Are there additional factors not mentioned above that you and your organization
consider important for clinical trial distribution and transport of cell and gene
therapies ? (please explain)
Personal experience with vendor and reputation is a key factor at my company.
None
Flexible systems in the event we need to do risk based strategies (e.g. ship under
quarantine for further manufacturing).
most vendors over promised and under perform. Mock run are time consuming but
identifies not so competent players.
No
No
global expertise
No
N/A

327

Q33 - Based on prior experiences, how easy was it to implement the following elements
clinical supply management?

# Question
Easy to
Implement

Somewhat
Easy to
Implement

Difficult
to
Implement

Not
Sure

Did Not
Implement
Total
1 Automation 5.08% 3 16.95% 10 37.29% 22 18.64% 11 22.03% 13 59
2
Strategic
Partnerships/Industry
Network Group
6.78% 4 38.98% 23 22.03% 13 23.73% 14 8.47% 5 59
3 Industry Standards 10.17% 6 54.24% 32 16.95% 10 13.56% 8 5.08% 3 59
4
Physical
Infrastructures
(Buildings /
Equipment)
6.78% 4 45.76% 27 23.73% 14 10.17% 6 13.56% 8 59
5
IT / Blockchain
Infrastructures
0.00% 0 28.81% 17 15.25% 9 23.73% 14 32.20% 19 59
6
Robust Vendor
Management
Programs
10.17% 6 37.29% 22 30.51% 18 15.25% 9 6.78% 4 59
7
Logistics by Design
(Treatment-Based
Supply Chain /
Customized Supply
Chain Programs)
3.39% 2 35.59% 21 30.51% 18 20.34% 12 10.17% 6 59

328

Q34 - As you move from clinical into commercial phases of product development, from a
perspective of the sustainability of the supply chain for time-sensitive and temperature-
sensitive medical products like cell and gene therapies, do you feel your organization is
well-prepared to upscale?

# Answer % Count
11
Yes, the organization is well-prepared to upscale because
(please explain) :
45.65% 21
14
No, the organization is not well-prepared to upscale because
(please explain) :
54.35% 25
Total 100% 46

Yes, the organization is well-prepared to upscale because (please explain) : - Text
we are already implementing practices that we will use in the commercial phase.
We have the financial resources and expertise to upscale.
We are moving into a bigger facility that has multiple temp range rooms.
large company with experience and resources
Strong and robust foundation
We have well established and experienced team in place.
This has been done in the past
Because we have an in house experiences team and we do not rely on questionable
experts and consultants.
We have a full tool box that can be deployed for both clinical and commercial
scenarios
Mainly because the organization does have experience with commercialized products,
so leveraging legacy validation, stability and supply chain requirements have become
standardized from clinical to commercialization.
focus on reducing VtV and scale-out planning.
We are in the process of scaling up now for our commercial product.
we have sufficient expertise and processes in place
We partner with some of the best consulting firms and supply chain vendors which
makes/made it possible
Robust supplier management partnerships

329

No, the organization is not well-prepared to upscale because (please explain) : -
Text
Difficulty converting clinical standards to commercial standards
We do not have the capabilities to manufacture the quantities need for
commercialization.
we have limited resources to tackle supply chain and would likely have to out-source it
to a third party supplier.
We do not own products, we are a service provider
could always improve, always
Temp controlled storage is a large constraint / concern for transition to commercial
phase.
scaling up and training must go hand in hand, a well defined program, mentoring and
buddy system is key to successful scale up
Lack internal expertise
small companies struggle with cash flow and adequate resources.
The supply chain process for clinical phase does not scale to commercial phase
normally.
scaling in the commercial setting is different from the clinical setting
more contingency planning needed
No
Very few with commercial experience.
Cost of infrastructure build to account for commercial scale exceeds the available
budget for a smaller company
We are not involved with commercialization.
Not applicable
It is contracted out
Systems and tools are not in place to provide the visibility and risk assessment
necessary to carry out the activity and be consistently successful. Additionally, gaps
exist in vendor management knowledge concerning cell and gene therapies.

330

Q35 - Are there any other challenges there were not previously discussed in the survey
that you experienced with the supply chain of your clinical trial (please specify)?
Are there any other challenges there were not previously discussed in the survey
that you experienced with the supply chain of your clinical trial (please specify)?
N/A
None
no
Raw materials are not always available in a GMP grade, are proprietary or of an
undefined composition. Therefore the idea of secondary supplier sourcing has to be
adapted. We've had magnetic beads, custom media or medical devices (cell reactors)
that need complex contracts, process bridging or can be snatched by a competitor via
exclusivity agreements. Take a hyperstack for instance. There was a shortage due to
viral vector production. When the big 5 players commit to buying 80% of their volume,
we have to work on relationship management to get a steady trickle of units for just-in-
time delivery. Playing the ultimatum hardball card won't work in that instance. We also
had situations where semi-custom raw materials fail or have issues. You then have to
trouble shoot with the vendor while not giving away proprietary info that is critical to
your process (cell processing equipment has issues but then the MFG sees your
parameters as you troubleshoot). You have to ensure your product container closure is
compatible with the customer (nurse, clinic). We implemented a vial that helped
stability but resulted in needle sticks at clinical sites. You found yourself trying to find
a needle guard, instead of focusing on the science. I think that's a big concept. You
have to keep the clinic/patient focused and bring it ALL THE WAY back to process
development. They hate it but if they don't have the right target...they're running down
a tangent path for 12-36mo only to find out it doesn't meet end user requirements.
Failing to have clinical supply leads in CMC core meetings is also a risk. We've seen
PD/MFG want to use concentrations, fill volumes, or containers that are incompatible
with trial designs. We've seen specifications that aren't aligned with target dose levels
(e.g. min concentration spec is far higher than the target dose risking unnecessary lot
rejection). When doing due diligence I've seen executives fail to really quantify the
logistics element of cost-of-goods. Take an allogeneic cell therapy that is HSA
matched. Allo seems cheaper than autologous, but now you have 15 different HLA
type SKUs, LN2 shipping costs, storage costs since HLA matching is just-in-time at
patient screening. Now layer on a trial design where you want weekly dosing for 9
months. Are you going to ask the clinical site to have huge LN2 tanks to hold your
safety stock of drug product? How do you get that to be community care compatible
(doctor's office down the street), etc. I've seen automation be a total debachle with
vendors over promising capabilities. I remember a "semi-automated" vial fill line
device. It still meant a person inserted vials and when they did a demo with our
formulation there was overflow and foaming that culminated with the vendor throwing
their hand into the "light curtain" to trigger an emergency stop of the equipment. This
need for equipment to almost be process/product specific can be tough.
need to get regulatory feedback on this process from regulatory agencies, what if there
is a regulatory concern Clinical Op didn't foresee.

331

No
New technology often involve small research-based
none come to mind
No
Planning sufficient validation for temperature, duration, and shipping lanes in early
clinical trials while considering expansion of (collection/manufacturing/infusion) sites.
no
Many organizations in the supply chain are not traditional vendors, stakeholders
include many clinics and hospital based organizations.
Previously described
BREXIT
No
A common understanding of chain of custody between various parties, internally and
externally
N/A

Q36 - Thinking back to clinical trials you have managed or collaborated on in the past,
what was one lesson learned from your experience with supply chain management.

Thinking back to clinical trials you have managed or collaborated on in the past,
what was one lesson learned from your experience with supply chain
management.
It is preferable then to have experienced in-house personnel dedicated to supply chain
management rather than for a generalist to assume such work.
Do not manage by Bill of Materials, create new BOM per specification
It is very important to do a thorough job of qualifying and educating vendors before
you initiate the trial
It is more unpredictable than one can imagine and whenever you think it is all working
optimally, there is a new problem that needs a solution.
good relationships matter
plan early
Defining decision deadlines can be one of the biggest keys in a timeline focused
startup. Recognizing that at some point you have to pull the trigger on a plan that can't
be reassessed without timeline impact. This decisiveness must be present to enable
aggressiveness on development timelines. I'd like to see more investment in
computational modeling of logistics. It isn't that hard with mathematica + tableau and
you can go from stacked individual risks to a strategy wide uncertainty curve.
Sensitivity analysis should be a HUGE focus for companies. What variables really

332

matter and are impactful. It's really easy for companies to inadvertently bias their risk
assessments on the risks they can already assess. I think it's human nature to put more
focus on things you understand. it's comfortable. It's harder if not impossible to
properly assess the items you don't fully understand, yet you can't always do the
research on all the unknowns. It's a tough balance but the sensitivity analysis can really
help. We modeled a distribution plan for a flu trial where you had to follow peak flu
seasons from country to country, dose within 6 weeks and keep moving vials ahead of
the wave, often without time to actually do depot to depot transfers. Doing predictive
modeling on where patients would be, how many we may lose and how to inventory
balance was key.
trust, but verify.
Ensure audit trail of the travel temperature logs to ensure stability of shipped IMP
We needed to assist small research based organization with regulatory, QMS and
compliance requirements.
nothing is ever as easy as it appears on the initial plan. be willing to accept things not
occurring "as planned"
Trust no one. Plan, and verify.
Let the supply chain SMEs guide on the activities releated to supply chain.
Having automation / ERP is key. managing without it is a recipe for mistakes
The need of internal resources
Start early
Communication is key.
Need for expertise in global import/exportation requirements by country
need to tap into local expertise
Have a couple of back-up plans and stay focus on the patient needs
Cross Functional Planning, test shipments, written procedures, written risk
management and mitigation plans!
New chapter in SC management is being written with CGT, with limited
standardization.
Perform robust audits of the supply chain vendor prior to signing the contract!
supliers respect what you inspect.
Document, document, document
it is important to have a few, trusted partners.
Map Map Map!!! All scenarios should be considered and assessed for risk. For CGT,
we must be able to anticipate what is going to happen and when. From that, then we
need to make contingency plans based upon known risk factors.
Document everything, don’t assume anything, confirm, pressure test

333

Selecting the most compliant and experienced vendor vs. cost

334

Appendix D. Cross Tabulations
Table 37 Years of Experience with CGTs versus Company Role
This table provides a cross-tabulation of the years of experience versus company role.

Years of Experience
Vice
President
/
President
/ C-Suite
Director
/ Sr.
Director
Sr.
Manager
/
Manager
Project
Manager
Associate /
Specialist /
Coordinator
Researcher
/ Scientist Consultant Other Total
Less than 3 years
0 5 2 0 1 0 0 0 8
0% 14% 17% 0% 17% 0% 0% 0% 11%
3-5 years
0 9 3 1 1 1 1 1 17
0% 26% 25% 100% 17% 50% 13% 33% 23%
6- 9 years
2 2 2 0 1 0 0 1 8
25% 6% 17% 0% 17% 0% 0% 33% 11%
10 to 14 years
0 6 1 0 1 0 0 0 8
0% 17% 8% 0% 17% 0% 0% 0% 11%
15+ years
5 8 4 0 2 1 7 0 27
63% 23% 33% 0% 33% 50% 88% 0% 36%
None
1 5 0 0 0 0 0 1 7
13% 14% 0% 0% 0% 0% 0% 33% 9%
Total Count 8 35 12 1 6 2 8 3 75

Table 38 Cross-Tabulation Grouping for Company Size
This table provides cross-tabulation grouping. The grouping was used for calculations
based on company size.

Company Size Number of
Respondents
% Grouping for Cross-
tabulation Analyses
1-999 34 45% Small 34 (45%)
1,000-4,999 14 19%
Mid-Size 18 (24%) 5,000-9,999 4 5%
10,000 + 23 31% Large 23 (31%)
Total 75 100%

335

Table 39 Industry Designation versus Size of the Company
This table is to provide a cross-tabulation for respondents based on the industry and the
size of the company. Numbers are in shaded columns, and the bolded values represent the
calculated weighted averages and their standard deviations.

My most
recent
employer or
client can
best be
described as
a…
Organization
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Pharmaceutical
(Drug) Company 8 24% 3 17% 14 61% 25 33%
Medical Device
Company 1 3% 1 6% 3 13% 5 7%
Biotechnology
Company (Cell
and Gene,
Immunotherapies,
Cancer Vaccines) 16 47% 4 22% 4 17% 24 32%
Contract
Organization
(CRO, CMO,
CDMO) 3 9% 2 11% 1 4% 6 8%
Biomanufacturing
/ Cell Production
Facility (i.e.,
Hospital GMP
Facility) 1 3% 1 6% 0 0% 2 3%
Supply
Chain/Logistics
(Specialized
Packaging, Cold
Chain, 3 PL) 3 9% 4 22% 0 0% 7 9%
Academia,
Institution, School,
Research Center 0 0% 2 11% 0 0% 2 3%
Other (Please
Specify) 2 6% 1 6% 1 4% 4 5%
Total Count 34

18

23

75

336

Table 40 Preparedness for Exploration of Supply Chain versus Size of Company
The table provides a cross-tabulation of the planning phase of exploration compared to
the size of the company. Numbers are in shaded columns, and the bolded values represent
total count for each subcategory.

Questions Agreement 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Has a well-
defined
distribution
plan for clinical
supply chain of
IMPs
Agree 13 45% 8 57% 15 71% 36 56%
Somewhat Agree 14 48% 2 14% 5 24% 21 33%
Disagree 2 7% 2 14% 0 0% 4 6%
Not Sure 0 0% 2 14% 1 5% 3 5%

Total Count 29

14

21

64
Supports
innovative
clinical supply
chain initiatives
Agree 14 48% 7 50% 13 62% 34 53%
Somewhat Agree 9 31% 5 36% 4 19% 18 28%
Disagree 2 7% 1 7% 0 0% 3 5%
Not Sure 4 14% 1 7% 4 19% 9 14%

Total Count 29

14

21

64
Assesses the
readiness of the
organization for
supply chain
management
Agree 14 48% 5 36% 16 76% 35 55%
Somewhat Agree 11 38% 3 21% 4 19% 18 28%
Disagree 3 10% 5 36% 0 0% 8 13%
Not Sure 1 3% 1 7% 1 5% 3 5%

Total Count 29

14

21

64
Has Sufficient
funding is
available to
meet
distribution
costs
Agree 12 41% 8 57% 15 71% 35 55%
Somewhat Agree 11 38% 4 29% 4 19% 19 30%
Disagree 4 14% 1 7% 0 0% 5 8%
Not Sure 2 7% 1 7% 2 10% 5 8%

Total Count 29

14

21

64
Has
Contingency
and business
continuity plans
are in place for
distribution
Agree 8 28% 6 43% 14 67% 28 44%
Somewhat Agree 10 34% 6 43% 5 24% 21 33%
Disagree 8 28% 1 7% 1 5% 10 16%
Not Sure 3 10% 1 7% 1 5% 5 8%

Total Count 29

14

21

64
Understands the
role of the
sponsor in the
distribution of
IMPs
Agree 19 66% 10 71% 18 90% 47 75%
Somewhat Agree 9 31% 2 14% 1 5% 12 19%
Disagree 0 0% 1 7% 0 0% 1 2%
Not Sure 1 3% 1 7% 1 5% 3 5%

Total Count 29

14

20

63
Understands the
US FDA
requirements
for distribution
of IMPs
Agree 24 83% 10 71% 17 81% 51 80%
Somewhat Agree 4 14% 3 21% 3 14% 10 16%
Disagree 1 3% 0 0% 0 0% 1 2%
Not Sure 0 0% 1 7% 1 5% 2 3%

Total Count 29

14

21

64
Understands the
international
requirements
for distribution
of IMPs
Agree 19 66% 9 64% 14 67% 42 66%
Somewhat Agree 7 24% 4 29% 5 24% 16 25%
Disagree 1 3% 0 0% 0 0% 1 2%
Not Sure 2 7% 1 7% 2 10% 5 8%

Total 29

14

21

64

337

Table 41 Supply Chain Challenges versus Company Size - Part A
This table is to provide a cross-tabulation of supply chain challenges versus company
size. Numbers are in shaded columns, and the bolded values represent total count for each
subcategory.

Questions

Agreement
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Unpredictability
in Transportation
Management
Not at all
Challenging 0 0% 1 8% 2 11% 3 5%
Moderately
Challenging 13 46% 7 54% 11 58% 31 52%
Very
Challenging 14 50% 3 23% 2 11% 19 32%
Not Sure 1 4% 2 15% 4 21% 7 12%

Total Count 28

13

19

60
Obtaining Access
to Clinical Site /
Patient Location
Not at all
Challenging 5 18% 1 8% 4 21% 10 17%
Moderately
Challenging 17 61% 7 54% 9 47% 33 55%
Very
Challenging 1 4% 2 15% 1 5% 4 7%
Not Sure 5 18% 3 23% 5 26% 13 22%

Total Count 28

13

19

60
Shipment
Tracking /
Visibility
Not at all
Challenging 6 21% 4 31% 8 42% 18 30%
Moderately
Challenging 18 64% 5 38% 7 37% 30 50%
Very
Challenging 2 7% 2 15% 0 0% 4 7%
Not Sure 2 7% 2 15% 4 21% 8 13%

Total Count 28

13

19

60
Establishing Cold
Chain
Management
(Temperature
Control,
Packaging)
Not at all
Challenging 7 25% 3 23% 4 21% 14 23%
Moderately
Challenging 12 43% 5 38% 10 53% 27 45%
Very
Challenging 8 29% 3 23% 1 5% 12 20%
Not Sure 1 4% 2 15% 4 21% 7 12%

Total Count 28

13

19

60
Human Error
Not at all
Challenging 3 11% 0 0% 4 21% 7 12%
Moderately
Challenging 14 50% 3 23% 9 47% 26 43%
Very
Challenging 10 36% 8 62% 2 11% 20 33%
Not Sure 1 4% 2 15% 4 21% 7 12%

Total Count 28

13

19

60

338

Table 42 Supply Chain Challenges versus Company Size - Part B
This table is to provide a cross-tabulation of supply chain challenges versus company
size. Numbers are in shaded columns, and the bolded values represent total count for each
subcategory.

Questions

Agreement
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Vendor
Management
Not at all
Challenging 3 11% 3 23% 2 11% 8 13%
Moderately
Challenging 18 64% 2 15% 11 58% 31 52%
Very
Challenging 5 18% 6 46% 2 11% 13 22%
Not Sure 2 7% 2 15% 4 21% 8 13%

Total Count 28

13

19

60
Airline Handling
Not at all
Challenging 0 0% 2 15% 5 26% 7 12%
Moderately
Challenging 15 54% 3 23% 8 42% 26 43%
Very
Challenging 11 39% 6 46% 2 11% 19 32%
Not Sure 2 7% 2 15% 4 21% 8 13%

Total Count 28

13

19

60
Distributor
Handling
Not at all
Challenging 2 7% 3 23% 3 17% 8 14%
Moderately
Challenging 15 54% 4 31% 10 56% 29 49%
Very
Challenging 6 21% 4 31% 0 0% 10 17%
Not Sure 5 18% 2 15% 5 28% 12 20%

Total Count 28

13

18

59
Force Majeure
Not at all
Challenging 1 4% 0 0% 0 0% 1 2%
Moderately
Challenging 6 21% 4 31% 9 50% 19 32%
Very
Challenging 16 57% 7 54% 2 11% 25 42%
Not Sure 5 18% 2 15% 7 39% 14 24%

Total Count 28

13

18

59

339

Table 43 Outsourcing Percentage versus Company Size
This table provides a cross-tabulation of outsourcing activities versus company size.

How does your
organization
currently
manage the
supply chain of
clinical trials of
cell and gene
therapies?
(select all that
apply)
Question
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
In-house
Dedicated Staff 19 56% 9 50% 12 52% 40 53%
Clinical Trial
Management is
Outsourced (i.e.,
CRO) 15 44% 5 28% 10 44% 30 40%
Raw Material or
Investigational
Product
Manufacturing is
Outsourced (i.e.,
CMO) 9 27% 2 11% 7 30% 18 24%
Clinical Trial
Distribution is
Outsourced (i.e.,
3PL Service
Provider) 13 38% 4 22% 7 30% 24 32%
I am not sure 1 3% 3 17% 4 17% 8 11%
Total
Respondents 34 18 23 75
Total Choice
Count 57 23 40 120

340

Table 44 Outsourcing of Supply Chain Activities versus Company Size
This table shows a cross-tabulation company size versus the percentage of supply chain
outsourcing.

What is the company size of your most recent
employer/client in terms of the number of
employees?

% 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 + (large) Total
If you outsource
your supply
chain
management,
overall, how
much of your
clinical supply
chain is
outsourced?
0-10% 6 23% 2 22% 1 6% 9
11-20% 0 0% 0 0% 2 12% 2
21-40% 3 12% 2 22% 2 12% 7
41-60% 8 31% 0 0% 1 6% 9
61%+ 5 19% 1 11% 2 12% 8
Not Sure 4 15% 4 44% 9 53% 17

Total
Count
26 9 17 52

Table 45 COVID-19 Preparedness versus Company Size
This table provides a cross-tabulation of COVID-19 preparation versus company size.

What is the company size of your
most recent employer/client in
terms of number of employees?

Choice
1-999
(small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
A global pandemic (such as
COVID-19) has been identified as
a disruptor in supply chain
management implementation for
clinical trials. Looking back at
your planning activities for your
supply chain strategy, do you feel
that you were adequately
prepared for COVID-19?
Yes
7 5 6
18
29% 46% 43%
No
17 6 8
31
71% 55% 57%
Total Count 24 11 14 49

341

Table 46 Commercial Upscaling versus Company Size
This table provides a cross-tabulation of upscale from clinical to commercial versus the
size of the company.

What is the company size of
your most recent
employer/client in terms of
number of employees?

Choice
1-999
(small)
1,000 -
9,999
(mid-size)
10,000 +
(large) Total

As you move from clinical into
commercial phases of product
development, from a perspective of
the sustainability of the supply
chain for time-sensitive and
temperature-sensitive medical
products like cell and gene
therapies, do you feel your
organization is well prepared to
upscale?
Yes
8 4 9
21

36% 36% 69%

No
14 7 4
25

64% 64% 31%

Total
Count 22 11 13 46

Table 47 Ease of Automation versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of automation by company size. Numbers are in shaded columns, and the
bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Question Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Automation
Easy to Implement 0 0% 1 8% 2 11% 3 5%
Somewhat Easy to Implement 5 19% 1 8% 4 21% 10 17%
Difficult to Implement 9 33% 7 54% 6 32% 22 37%
Did Not Implement 10 37% 2 15% 1 5% 13 22%
Not Sure 3 11% 2 15% 6 32% 11 19%

Total Count 27

13

19

59

342

Table 48 Strategic Partnerships versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of strategic partnerships by company size. Numbers are in shaded
columns, and the bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Question Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Strategic
Partnerships/Industry
Network Group
Easy to Implement 3 11% 0 0% 1 5% 4 7%
Somewhat Easy to Implement 8 30% 6 46% 9 47% 23 39%
Difficult to Implement 7 26% 4 31% 2 11% 13 22%
Did Not Implement 5 19% 0 0% 0 0% 5 8%
Not Sure 4 15% 3 23% 7 37% 14 24%

Total Count 27

13

19

59

Table 49 Implementation of Industry Standard versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of industry standards by company size.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Questions Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Industry
Standards
Easy to Implement 2 7% 2 15% 2 11% 6 10%
Somewhat Easy to Implement 15 56% 7 54% 10 53% 32 54%
Difficult to Implement 5 19% 2 15% 3 16% 10 17%
Did Not Implement 2 7% 1 8% 0 0% 3 5%
Not Sure 3 11% 1 8% 4 21% 8 14%

Total Count 27

13

19

59

343

Table 50 Physical Infrastructures versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of physical infrastructures by company size. Numbers are in shaded
columns, and the bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Questions Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Physical
Infrastructures
(Buildings /
Equipment)
Easy to Implement 1 4% 1 8% 2 11% 4 7%
Somewhat Easy to Implement 11 41% 6 46% 10 53% 27 46%
Difficult to Implement 8 30% 4 31% 2 11% 14 24%
Did Not Implement 6 22% 1 8% 1 5% 8 14%
Not Sure 1 4% 1 8% 4 21% 6 10%

Total Count 27

13

19

59

Table 51 Implementation of IT / Blockchain versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of IT and Blockchain Infrastructures by company size. Numbers are in
shaded columns, and the bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Question Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
IT / Blockchain
Infrastructures
Easy to Implement 0 0% 0 0% 0 0% 0 0%
Somewhat Easy to Implement 8 30% 5 38% 4 21% 17 29%
Difficult to Implement 6 22% 0 0% 3 16% 9 15%
Did Not Implement 10 37% 5 38% 4 21% 19 32%
Not Sure 3 11% 3 23% 8 42% 14 24%

Total Count 27

13

19

59

344

Table 52 Vendor Management Programs by Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation of robust vendor management programs by company size. Numbers are
in shaded columns, and the bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements clinical
supply management?

Question Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Robust Vendor
Management
Programs
Easy to Implement 2 7% 2 15% 2 11% 6 10%
Somewhat Easy to Implement 12 44% 3 23% 7 37% 22 37%
Difficult to Implement 7 26% 6 46% 5 26% 18 31%
Did Not Implement 4 15% 0 0% 0 0% 4 7%
Not Sure 2 7% 2 15% 5 26% 9 15%

Total Count 27

13

19

59

Table 53 Logistics by Design (LbD) versus Company Size
This table provides a cross-tabulation of industry stakeholder views on the ease of
implementation logistics by design (LbD) by company size. Numbers are in shaded
columns, and the bolded values represent total count for each subcategory.

Based on prior experiences, how easy was it to implement the following elements of
clinical supply management?

Question Selection
1-999
(small)
1,000 -
9,999
(mid-
size)
10,000 +
(large) Total
Logistics by Design
(Treatment-Based
Supply Chain /
Customized Supply
Chain Programs)
Easy to Implement 0 0% 1 8% 1 5% 2 3%
Somewhat Easy to Implement 10 37% 5 38% 6 32% 21 36%
Difficult to Implement 8 30% 5 38% 5 26% 18 31%
Did Not Implement 6 22% 0 0% 0 0% 6 10%
Not Sure 3 11% 2 15% 7 37% 12 20%

Total Count 27

13

19

59

345

Table 54 Distribution Models versus Company Size – Part A
This table provides a cross-tabulation of alternative distribution models and innovation
versus company size. Numbers are in shaded columns, and the bolded values represent
total count for each subcategory.

Questions Considerations 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Direct to Patient /
Home Supported
Trials
Have not
considered 11 39% 4 31% 5 25% 20 33%
Considered but did
not use 2 7% 2 15% 3 15% 7 11%
Considering use in
the future 2 7% 1 8% 3 15% 6 10%
Considered and
used in the past 8 29% 3 23% 6 30% 17 28%
Do Not Know 5 18% 3 23% 3 15% 11 18%

Total Count 28

13

20

61
Delivery by Drones
Have not
considered 23 82% 6 46% 11 58% 40 67%
Considered but did
not use 0 0% 1 8% 0 0% 1 2%
Considering use in
the future 0 0% 2 15% 2 11% 4 7%
Considered and
used in the past 0 0% 0 0% 0 0% 0 0%
Do Not Know 5 18% 4 31% 6 32% 15 25%

Total Count 28

13

19

60
Integrators such as
UPS, FedEx, DHL
Have not
considered 3 11% 3 21% 0 0% 6 10%
Considered but did
not use 3 11% 0 0% 0 0% 3 5%
Considering use in
the future 3 11% 3 21% 2 10% 8 13%
Considered and
used in the past 16 57% 6 43% 11 55% 33 53%
Do Not Know 3 11% 2 14% 7 35% 12 19%

Total Count 28

14

20

62

346

Table 55 Distribution Models versus Company Size – Part B
This table provides a cross-tabulation of alternative distribution models and innovation
versus company size. Numbers are in shaded columns, and the bolded values represent
total count for each subcategory.

Questions Considerations 1-999 (small)
1,000 - 9,999
(mid-size)
10,000 +
(large) Total
Specialty Courier
Services
Have not considered 1 4% 2 14% 0 0% 3 5%
Considered but did
not use 0 0% 1 7% 0 0% 1 2%
Considering use in
the future 4 14% 1 7% 1 5% 6 10%
Considered and
used in the past 20 71% 8 57% 12 60% 40 65%
Do Not Know 3 11% 2 14% 7 35% 12 19%

Total Count 28

14

20

62
"Smart" and
"Intelligent" packaging
Have not considered 3 11% 2 14% 1 5% 6 10%
Considered but did
not use 3 11% 1 7% 0 0% 4 7%
Considering use in
the future 3 11% 3 21% 3 16% 9 15%
Considered and
used in the past 18 64% 6 43% 9 47% 33 54%
Do Not Know 1 4% 2 14% 6 32% 9 15%

Total Count 28

14

19

61
IT Technologies such as
Blockchain
Have not considered 10 36% 2 15% 3 16% 15 25%
Considered but did
not use 1 4% 2 15% 0 0% 3 5%
Considering use in
the future 7 25% 4 31% 5 26% 16 27%
Considered and
used in the past 0 0% 0 0% 1 5% 1 2%
Do Not Know 10 36% 5 38% 10 53% 25 42%

Total Count 28

13

19

60

347

Table 56 Regulatory Views on GDP: Industry Stakeholders
This table provides a cross-tabulation of industry stakeholder views on GDP
requirements by industry. Numbers are in shaded columns, and the bolded values
represent total count for each subcategory.

Although Good Distribution Practices are not mandated in the United States (US) by the FDA,
these regulations are mandated by other global regulatory bodies. Do you think the Good
Distribution Practices guidelines should be adopted and enforced by the FDA for the
transportation of investigational medicinal products (IMP)?

Choice Pharma
Medical
Device Academia Biomanufacturing Biotech
Supply
Chain
Contract
Organization
Total
Yes
12 1 1 2 14 4 4 38
92% 50% 100% 100% 78% 67% 100% 83%
No
1 1 0 0 4 2 0 8
8% 50% 0% 0% 22% 33% 0% 17%
Total Count 13 2 1 2 18 6 4 46

Table 57 GDP Enforcement Viewpoints by Department
This table provides a cross-tabulation of industry stakeholder views on GDP
requirements by department. Numbers are in shaded columns, and the bolded values
represent total count for each subcategory.

Although Good Distribution Practices are not mandated in the United States (US) by the FDA,
these regulations are mandated by other global regulatory bodies. Do you think the Good
Distribution Practices guidelines should be adopted and enforced by the FDA for the
transportation of investigational medicinal products (IMP)?

Choice
Regulatory
Affairs
Quality
Assurance /
Quality
Control
Research &
Development
(R&D) / Clinical
Research
Supply Chain
/ Logistics Total
Yes
13 13 3 7 36
77% 100% 100% 64% 82%
No
4 0 0 4 8
24% 0% 0% 36% 18%
Total
Count 17 13 3 11 44

348

Table 58 Regulatory Competencies by Industry – Part A
This table provides a cross-tabulation across industry stakeholders and competencies with
medical product and transportation regulations for US FDA regulations and GXPs.
Numbers are in shaded columns, and the bolded values represent total count for each
subcategory.

Question Agreement
Pharmaceutical
(Drug)
Company
Biotechnology
Company
Contract
Organization
Supply
Chain/Logistics Total
Drug Supply
Chain Security
Act (DSCSA)
Unfamiliar 4 21% 10 42% 2 50% 3 43% 19 35%
Familiar 8 42% 10 42% 0 0% 1 14% 19 35%
Experienced 7 37% 4 17% 2 50% 3 43% 16 30%

Total Count 19

24

4

7

54
Good
Distribution
Practices
(GDP)
Unfamiliar 1 6% 3 13% 0 0% 0 0% 4 8%
Familiar 6 33% 7 29% 1 25% 2 29% 16 30%
Experienced 11 61% 14 58% 3 75% 5 71% 33 62%

Total Count 18

24

4

7

53
Good
Manufacturing
Practices
(GMP)
Unfamiliar 0 0% 0 0% 0 0% 1 14% 1 2%
Familiar 3 16% 2 8% 1 25% 1 14% 7 13%
Experienced 16 84% 22 92% 3 75% 5 71% 46 85%

Total Count 19

24

4

7

54
Good Clinical
Practices
(GCP)
Unfamiliar 0 0% 0 0% 0 0% 2 29% 2 4%
Familiar 2 11% 4 17% 0 0% 2 29% 8 15%
Experienced 17 89% 20 83% 4 100% 3 43% 44 81%

Total Count 19

24

4

7

54
Good Tissue
Practices
(GTPs)
Unfamiliar 4 21% 3 13% 0 0% 5 71% 12 22%
Familiar 9 47% 7 29% 2 50% 2 29% 20 37%
Experienced 6 32% 14 58% 2 50% 0 0% 22 41%

Total Count 19

24

4

7

54

349

Table 59 Regulatory Competencies by Industry – Part B
This table provides a cross-tabulation across industry stakeholders and competencies with
medical products and transportation regulations. Numbers are in shaded columns, and the
bolded values represent total count for each subcategory.

Question Agreement
Pharmaceutical
(Drug)
Company
Biotechnology
Company
Contract
Organization
Supply
Chain/Logistics Total
(International
Air Transport
Association
(IATA)
Standards
Unfamiliar 4 24% 7 29% 1 25% 1 14% 13 25%
Familiar 5 29% 7 29% 0 0% 2 29% 14 27%
Experienced 8 47% 10 42% 3 75% 4 57% 25 48%

Total Count 17

24

4

7

52
Federal
Aviation
Administration
(FAA)
Regulations
Unfamiliar 4 24% 8 35% 1 25% 1 14% 14 27%
Familiar 7 41% 8 35% 2 50% 2 29% 19 37%
Experienced 6 35% 7 30% 1 25% 4 57% 18 35%

Total Count 17

23

4

7

51
Domestic (US)
Import /
Export
Regulations
Unfamiliar 3 17% 7 29% 1 25% 1 14% 12 23%
Familiar 6 33% 6 25% 2 50% 2 29% 16 30%
Experienced 9 50% 11 46% 1 25% 4 57% 25 47%

Total Count 18

24

4

7

53
International
Import /
Export
Regulations
Unfamiliar 2 11% 7 29% 1 25% 1 14% 11 20%
Familiar 9 50% 8 33% 1 25% 2 29% 20 38%
Experienced 7 39% 9 38% 2 50% 4 57% 22 42%

Total Count 18

24

4

7

53
Cold Chain
Management
Standards /
Regulations
Unfamiliar 2 11% 5 21% 1 25% 0 0% 8 15%
Familiar 5 28% 7 29% 0 0% 2 29% 14 26%
Experienced 11 61% 12 50% 3 75% 5 71% 31 58%

Total Count 18

24

4

7

53
Hazardous
Material
(Hazmat) /
Dangerous
Goods (DG)
Regulations
Unfamiliar 3 17% 4 17% 0 0% 1 14% 8 15%
Familiar 7 39% 8 33% 2 50% 3 43% 20 38%
Experienced 8 44% 12 50% 2 50% 3 43% 25 47%
Total Count 18 24 4 7 53

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Asset Metadata

Creator Myles, Lequina (author)

Core Title An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 03/29/2021

Defense Date 02/23/2021

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag CAR-T therapies,cell and gene therapies,clinical supply chain,clinical trial distribution,clinical trial logistics,direct to patient,Good Distribution Practices,OAI-PMH Harvest,supply chain management

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Church, Terry David (committee chair), Pire-Smerkanich, Nancy (committee member), Richmond, Francis (committee member), Sosic, Greys (committee member)

Creator Email lmyles@usc.edu,lmyles28@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-434450

Unique identifier UC11668238

Identifier etd-MylesLequi-9349.pdf (filename),usctheses-c89-434450 (legacy record id)

Legacy Identifier etd-MylesLequi-9349.pdf

Dmrecord 434450

Document Type Dissertation

Rights Myles, Lequina

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA