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Examining the cord blood industry views on the biologic license application regulatory framework
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Examining the cord blood industry views on the biologic license application regulatory framework
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Content
EXAMINING THE CORD BLOOD INDUSTRY VIEWS ON THE BIOLOGIC LICENSE
APPLICATION REGULATORY FRAMEWORK
by
Katherine St. Martin
A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE
December 2020
Copyright 2020 Katherine St. Martin
ii
Dedication
I dedicate this dissertation to my husband and children, and especially to my incredible
mothers. To my mother, Dr. Sandra Smyser, Ph.D. for her constant support of my endeavors and
encouragement during difficult times. Her leadership example and selfless service to our nation’s
educational system was my primary inspiration for pursuing a doctorate. To my mother in law,
Lynn, for her love and dedication to my young children, including her willingness to care for
them during their infancy and travel to our home each time I attended doctoral trips and
presentations associated with this program.
iii
Acknowledgments
This dissertation is the culminating product of a six-year journey of study and research. I
would like to take this opportunity to thank the faculty and staff members that made this
substantial academic journey possible. First, I would like to thank my advisor Dr. Eunjoo
Pacifici, Ph.D. and acknowledge her crucial guidance, patience, and continual support. Dr.
Pacifici’s tireless dedication encouraged the development of a research lens which improved this
work and my own academic mindset immeasurably. I would also like to thank Dr. Frances
Richmond, Ph.D. for her program leadership and committee guidance; her early support and
enthusiasm gave my research question credence and set me moving in the right direction.
Second, I would like to thank and acknowledge my committee members, including Dr’s. Nancy
Pire-Smerkanich and Terry Church for their probing questions, insightful comments, and
assistance with my dissertation and survey development. Third, I would like to acknowledge
members of my focus group and professional affiliations for providing real-world perspective on
the relevant organizations and prospective respondents. Fourth, I would like to thank the
wonderful regulatory science staff that provided valuable assistance navigating the
administrative aspects of this program throughout the past years. In closing, I would like to
acknowledge that the author’s published prior work including content and original tables are
reproduced in this dissertation with permission from the publisher. The author individually
researched and wrote the chapter entitled: FDA Regulation of Cord Blood Products, as part of
the Elsevier reference module in biomedical sciences (St. Martin, 2019).
iv
Table of Contents
Dedication ........................................................................................................................... ii
Acknowledgments.............................................................................................................. iii
List of Tables ..................................................................................................................... vi
List of Figures ................................................................................................................... vii
Abstract ............................................................................................................................ viii
Chapter 1. Overview ........................................................................................................... 9
1.1 Introduction .................................................................................................... 9
1.2 Statement of the Problem ............................................................................. 15
1.3 Purpose of the Study .................................................................................... 16
1.4 Importance of the Study ............................................................................... 16
1.5 Delimitations, Limitations, Assumptions ..................................................... 17
1.6 Organization of Thesis ................................................................................. 19
1.7 Definitions .................................................................................................... 19
Chapter 2. Literature Review ............................................................................................ 22
2.1 Cord Blood History ...................................................................................... 22
2.1.1 Early History ................................................................................... 23
2.1.2 Modern Use .................................................................................... 25
2.1.3 Current Use of Cord Blood Products .............................................. 28
2.2 Evolution of Biologic Product Regulation ................................................... 31
2.2.1 The Beginnings of Biologics Legislation ....................................... 34
2.2.2 Virus, Blood, and Blood Component Products............................... 36
2.2.3 Regulatory Oversight of Human Cellular and Tissue-Based Products
........................................................................................................ 40
2.3 Current Regulatory Landscape for Cord Blood Banks ................................ 47
2.3.1 Exploring CBB Industry Views ...................................................... 52
2.3.2 Applying Implementation Science ................................................. 54
2.4 Framing the Study of Cord Blood Regulatory Policy .................................. 58
2.5 Summary and Research Direction ................................................................ 62
Chapter 3. Methodology ................................................................................................... 63
3.1 Introduction .................................................................................................. 63
3.2 Survey Development and Finalization ......................................................... 63
3.3 Focus Group Input to Survey Development ................................................. 64
3.4 Survey Deployment and Data Analysis ....................................................... 64
v
Chapter 4. Results ............................................................................................................. 66
4.1 Survey Logistics ........................................................................................... 66
4.2 Profiles and Background of Respondents .................................................... 66
4.3 Experiences with BLA Process .................................................................... 70
4.3.1 Views of Respondents with BLA Experience ................................ 72
4.3.2 Views of Respondents without BLA Experience ........................... 78
4.4 Views on Current FDA Requirements ......................................................... 80
4.4.1 Manufacturing Process Requirements ............................................ 80
4.4.2 Manufacturing Distribution Requirements ..................................... 83
4.4.3 Submission, Reporting, and Inspection Requirements ................... 85
4.5 Views on the BLA Framework .................................................................... 87
4.5.1 The Impact of BLA Requirements ................................................. 87
4.5.2 The Challenges of Pursuing a BLA ................................................ 88
4.6 Barriers to BLA Implementation ................................................................. 91
4.6.1 Views of CBBs ............................................................................... 91
4.6.1.1 Assessment and Preparation Stages of BLA...................... 92
4.6.1.2 Implementation and Sustainment Stages of BLA .............. 96
4.6.2 Views of the Affiliated Organizations ............................................ 99
4.6.2.1 Assessment and Preparation Stages of CGMP ................ 100
4.6.2.2 Implementation and Sustainment Stages of CGMP ........ 104
4.6.3 Most Difficult Activities Across Implementation Stages ............. 109
4.6.4 Views on Requiring BLA Submission ......................................... 109
4.7 Additional Thoughts on the BLA Pathway ................................................ 111
Chapter 5. Discussion ..................................................................................................... 115
5.1 Overview .................................................................................................... 115
5.2 Methodological Considerations ................................................................. 115
5.3 Consideration of Results ............................................................................ 119
5.3.1 Limited Regulatory Incentive for BLAs ....................................... 120
5.3.2 Limited Economic Incentive for BLAs ........................................ 125
5.3.3 Ineffectual Implementation of the Regulatory Framework .......... 127
5.4 Future Directions and Concluding Thoughts ............................................. 129
References ....................................................................................................................... 131
Appendix A: Survey ....................................................................................................... 136
Appendix B: Survey Cross Tabulation ........................................................................... 157
Appendix C: Respondent Identification.......................................................................... 161
vi
List of Tables
Table 1: Licensed Cord Blood Banks (CBBs) ...................................................................13
Table 2: History of HCT/P Final Rules and Location in 21 CFR 1271 .............................41
Table 3: Cord Blood Product Regulation...........................................................................45
Table 4: Research Framework ...........................................................................................61
Table 5: Administrative/Director/Program Manager Titles ...............................................68
Table 6: Helpful BLA Resources .......................................................................................76
Table 7: Additional Resource Suggestions ........................................................................77
Table 8: Ranked Barriers to Pursuing a BLA ....................................................................80
Table 9: Ranked Barriers to Obtaining a BLA ..................................................................91
Table 10: CBB Comments on BLA Assessment & Preparation........................................95
Table 11: CBB Comments on BLA Implementation & Sustainment ................................99
Table 12: Affiliated Comments on CGMP Assessment & Preparation ...........................103
Table 13: Affiliated Comments on CGMP Implementation & Sustainment ...................108
Table 14: Most Difficult Activities Across Implementation Stages ................................109
Table 15: Additional Comments on FDA’s Regulation ..................................................112
vii
List of Figures
Figure 1: Section 361 Cellular Products ............................................................................11
Figure 2: Section 351 Cellular Products ............................................................................14
Figure 3: Timeline of Cord Blood Medical Research ........................................................23
Figure 4: Biologic Product Regulatory Evolution .............................................................33
Figure 5: Implementation Stages .......................................................................................56
Figure 6: Biotechnology Policy Analysis Elements ..........................................................58
Figure 7: Distribution of Respondents by Department ......................................................67
Figure 8: Respondent Experience in Current Role ............................................................69
Figure 9: Distribution of Respondents by Organizational Affiliation ...............................70
Figure 10: Experience Supporting a Licensed CBB ..........................................................71
Figure 11: Experience with the BLA Process ....................................................................72
Figure 12: BLA Application Drivers .................................................................................73
Figure 13: FDA Review Division Viewpoints...................................................................74
Figure 14: Necessity of Additional FDA Guidance ...........................................................77
Figure 15: Current Stage of BLA Planning .......................................................................79
Figure 16: Views on IND Manufacturing Process Requirements .....................................81
Figure 17: Views on BLA Manufacturing Process Requirements .....................................83
Figure 18: Views on IND Manufacturing Distribution Requirements ..............................84
Figure 19: Views on BLA Manufacturing Distribution Requirements .............................85
Figure 20: Views on IND Submission, Reporting, and Inspection Requirements ............86
Figure 21: Views on BLA Submission, Reporting, and Inspection Requirements ...........87
Figure 22: BLA Regulatory Requirement Impacts ............................................................88
Figure 23: CBB Industry Resources to Meet BLA Requirement ......................................89
Figure 24: Level of Difficulty Transitioning CGMP from IND to BLA ...........................90
Figure 25: Difficulty of BLA Assessment Activities ........................................................93
Figure 26: Difficulty of BLA Preparation Activities .........................................................94
Figure 27: Difficulty of Implementing BLA Activities .....................................................97
Figure 28: Difficulty of Sustaining BLA Process Activities .............................................98
Figure 29: Difficulty of Assessing CGMP Compliance Activities ..................................101
Figure 30: Difficulty of Preparing for CGMP Compliance Activities ............................102
Figure 31: Difficulty of Implementing CGMP Compliance Activities ...........................105
Figure 32: Difficulty of Sustaining CGMP Compliance Activities .................................107
Figure 33: CBB Opinion on Requiring BLA Submission ...............................................110
Figure 34: Affiliated Organization Opinion on Requiring BLA Submission ..................111
viii
Abstract
Cord blood was the first product designated under the category of “Human Cells, Tissues, and
Cellular and Tissue-based Products” (HCT/Ps) to be described specifically in FDA guidance
documents that established their regulatory framework and a BLA pathway to market. As a
Section 351 HCT/P, FDA set expectations for dual Current Good Tissue Practice (CGTP) and
Current Good Manufacturing Practice (CGMP) compliance for IND and BLA activities. Further,
the agency issued a final guidance document in 2014 to clarify CMC requirements for BLA.
However, to date only eight Cord Blood Banks (CBBs) have successfully obtained BLAs for
their products, pointing to lingering implementation challenges. This study aimed to investigate
the views of cord blood industry regarding the current regulatory framework and the challenges
faced across stages of implementation for the BLA process. A survey instrument was used to
examine the views of this group across the following areas: financial & economic, operations,
legal & regulatory, and training & education. Data analysis was conducted on completed surveys
from 55 respondents across professionals at CBBs and other affiliated manufacturing
organizations. Results suggest that the most significant challenges were funding the necessary
facility changes and implementing the unfamiliar CGMP compliance necessary for the BLA. The
study also indicates that the ongoing activities associated with sustaining a license are
burdensome for sponsors, contract manufactures, and others involved in the manufacturing
process, from product collection and processing to distribution. The study further suggests that
more work is needed to build the case for product translation and more policy needed to clarify
CGMP application.
9
Chapter 1. Overview
1.1 Introduction
The birth of a child is the beginning of an individual life and the continuation of an
intergenerational ritual. Our parental genetic makeup is blended and passed on, creating a child
that embodies the present culmination of our cellular heritage. In this way, children provide their
families the prospect of “living forever” but the birthing process itself also presents a brief
opportunity to collect stem cells that could be developed into life-saving therapeutic products.
The transplant industry administers cellular products derived from stem cells for a variety of
blood cancer indications, including leukemia, lymphoma, and multiple myeloma. These products
are typically delivered to the patient through an intravenous infusion. The new stem cells graft
into the patient’s bone marrow and multiply, replacing the patient’s offending immune system.
Stem cells can be obtained from a variety of sources including bone marrow, peripheral blood,
and cord blood. Cord blood, for example, collected from the umbilical cord at the time of birth,
contains multipotent stem cells that can develop into different types of blood cells and provide a
continuous source of new cells through their unlimited divisions. Since the 1950s, cord blood has
been collected under the practice of medicine for a myriad of diagnostic and study purposes.
Over the years, the collection procedure has been perfected to be safe for both the mother and
baby. Furthermore, research during the 1970s and 1980s demonstrated that cord blood can be an
alternative source to bone marrow for hematopoietic stem cell transplantation. Based on these
findings, an industry emerged in the 1990s, consisting of private, public, and hybrid Cord Blood
Banks (CBBs), that collect, process, and store cord blood. For almost 15 years, cord blood
transplantation remained under ‘practice of medicine’ and not regulated. Over time, however,
FDA determined that cord blood for administration to an unrelated recipient may pose higher
10
risks than for administration to a closely related recipient and should be appropriately regulated.
Therefore, the FDA announced in 2009 that these high-risk cellular products must be
manufactured either through the Investigational New Drug (IND) process or an approved
Biologic License Application (BLA). The target date for implementing the new requirement was
set as October of 2011. Following this announcement, there was a flurry of activity by the cord
blood industry to transition operations under IND in their work toward anticipated BLA filings.
To date, however, only a few CBBs have in fact obtained BLA approvals for their products.
Thus, it would be helpful to understand the views of the cord blood manufacturing professionals
on the new regulatory framework and identify roadblocks in its implementation.
FDA regulation of cord blood is primarily shaped by the existing legal framework for
biological products. The Public Health Services Act (PHS, 1944) identifies two categories of
cellular products, often called “Section 361 products” that are considered to be lower risk with
relatively few regulatory requirements and “Section 351 products” that are considered to be
higher risk and regulated rigorously as biologic drugs or devices. All Section 361 products,
including cord blood, are for administration to either the original donor (autologous use) or a
first-degree or second-degree relative (allogeneic -related). In both cases, the manufacturing
processes must be restricted to “minimal manipulation” in order for the products to be classified
under Section 361 (Figure 1).
11
Figure 1: Section 361 Cellular Products
For Section 361 products, an attending physician can order the collection of a patient’s
stem cells and infuse them back into the patient or to a first/second degree relative as part of
medical practice. This practice does not require the FDA’s approval but must adhere to standard
of care and rules that are established by the institution. These institutions also provide approval,
resources, and monitoring for physician-run clinical trials and case studies where innovations
and variations of transplant science are tested in order to improve patient outcomes. The results
of these studies may be published in medical journals to disseminate the findings and improve
the medical practice more broadly. The institutions themselves must register their cellular and
tissue-based activities with the FDA under the Current Good Tissue Practice (CGTP) regulations
that require detailed donor testing and proper processing of the product to prevent the spread of
communicable diseases and minimize contamination. Institutions that are registered as cellular
and tissue establishments undergo FDA inspection and oversight according to the CGTP
regulations.
12
Section 351 products, unlike Section 361 products, fall outside of the practice of
medicine and must satisfy the FDA’s regulatory pathway for a new biologic product, including
pre-market evaluation, review, and approval. Accordingly, the sponsor will need to demonstrate
the product’s safety and efficacy profile through phased clinical trials. These trials follow all the
individual institutional standards and policies in addition to the FDA’s oversight under the IND
process. If the clinical results are deemed to meet the FDA’s expectations, the sponsoring
institution could submit the data along with nonclinical and manufacturing information as part of
a BLA. This is an expensive and prolonged process that presents a significant burden for the
sponsor.
Cord blood was the first cellular product to fall under Section 351 product classification.
Thus, FDA announced through a 2009 draft guidance document that all cord blood banks must
meet the regulatory requirements of Section 351 cellular products by October of 2011 (FDA,
2009). Hence, the cord blood banks can only manufacture their Section 351 products either under
an IND or a BLA. To clarify requirements for a cord blood BLA, the draft guidance document
detailed the required content of the Chemistry and Manufacturing Controls (CMC) section. The
recommendations in this guidance represented a significant change to the existing paradigm. One
area that was especially impacted was in the manufacture of product in that the industry must
now meet FDA’s Current Good Manufacturing Practice (CGMP) requirements, which were
originally established for pharmaceutical drugs and now also applies to biologic drugs.
Applying the biologic drug CGMP regulations onto cord blood manufacturing has been a
difficult task for the industry as evidenced by the fact that only 8 of the approximately 25
applicable CBBs have achieved pre-market approvals through the BLA process (FDA, 2019a).
The remaining institutions are likely operating under INDs and their plans for BLA submissions
13
are not clear. Examination of the quality of the BLAs submitted to date have shed some light on
the challenges faced by the industry. Table 1 below lists the licensed CBBs and their approval
timing.
Table 1: Licensed Cord Blood Banks (CBBs)
Cord Blood Bank
Approval
Date
Review
Time
Significant
Delays
New York Blood Center (NYBC) 11/10/2011 10 months
Duke University School of
Medicine
10/4/2012 13 months
Major
Amendment
ClinImmune Labs, University of
Colorado Cord Blood Bank
5/24/2012 12 months
Major
Amendment
LifeSouth Community Blood
Centers, Inc.
6/13/2013 13 months
Major
Amendment
SSM Cardinal Glennon
Children's Medical Center
5/30/2013 19 months
BLA
Resubmission
Bloodworks 1/28/2016 10 months
Cleveland Cord Blood Center 9/1/2016 13 months
Major
Amendment
MD Anderson Cord Blood Bank 6/21/2018 12 months
According to Rafael Cassatas, Deputy Director of Regulatory Affairs at the American
Association of Blood Banks, four of the first five BLAs required major amendments to the CMC
sections for issues related to CGMP compliance that delayed product approvals (Cassata, 2013).
SSM Cardinal Glennon Children’s Medical Center experienced a BLA resubmission which
resulted in a significant delay of 600 calendar days from original submission to approval
(Cassata, 2013). The major CGMP deficiencies were issues related to validation of the product
collection from hospitals, facility and equipment requirements, and sterility testing for lot release
(Cassata, 2013). Moreover, the FDA included additional CGMP requirements for cord blood
products from unrelated donors in its 2014 final guidance document (FDA, 2014). This presented
14
additional hurdles for the industry, especially the public CBBs, which are the primary providers
of cord blood.
As can be seen in Figure 2 below, examples of Section 351 cellular products include both
autologous and allogeneic products. The panel on the left shows an autologous example in which
a patient’s own cells are collected, processed (more than minimally), and infused back into the
patient. This category includes the next generation of cellular products like the Chimeric Antigen
Receptor T-cells (CAR T) immunotherapies. Although the CAR T products have their own
specific FDA guidance documents, they share CGTP and CGMP requirements that are common
with other cellular products for the collection, processing, and banking of the starting material.
The panel on the right shows an allogeneic example in which a donor mother provides a cord
blood product from her infant’s umbilical cord to an unrelated recipient.
Figure 2: Section 351 Cellular Products
The next generation cellular products are typically developed and commercialized by
major biopharmaceutical companies like Novartis and Gilead Sciences that are experienced in
15
CGMP requirements for their other products. The cord blood industry, on the other hand, is
comprised of research hospitals, CBBs, and affiliated non-profit organizations that serve as IND
sponsors and facilitate product distribution. Hence, these organizations may not have the
experience or the resources to comply with all the regulatory requirements associated with BLA
submissions.
1.2 Statement of the Problem
It has been over a decade since FDA codified the requirement for Section 351 cord blood
products to be regulated as biologic products. However, concerns have been raised that the
additional CGMP requirements of the licensure process are discouraging CBBs from pursuing
BLAs, thereby denying patient access to licensed products with the highest quality standards.
The few BLAs that were approved were done so after many delays due to additional requests by
the FDA to address deficiencies. Some, like the Cleveland CBB, faced severe delays prior to
their BLA submission. Cleveland CBB began pre-BLA discussion with FDA in 2010 and was
under review by an advisory committee in 2014. The FDA and Cleveland CBB eventually came
to a resolution and the FDA approved their BLA in 2016. The Cleveland CBB argued that the
FDA regulatory requirements created an untenable business model based on the excessive cost of
transforming manufacturing facilities to meet CGMP requirements (Laughlin, 2014). It still is
unclear, however, which aspects are considered most burdensome, while transforming a cord
blood banking operation to become CGMP compliant. For example, the hospital collection sites
where the donating mothers deliver their babies may be particularly challenging. It is also
possible that the constraints associated with working in a CGMP environment may hinder
innovations into new processes as well as new therapeutic uses. However, aside from anecdotal
16
evidence, we do not know the views of the cord blood manufacturing professionals on the new
regulatory framework that impacts almost all facets of their operations.
1.3 Purpose of the Study
The purpose of this study was to investigate the views of the cord blood industry on the
implementation of CGMP requirements contained in the FDA’s regulatory framework for
Section 351 cord blood products. The study used a novel survey instrument that incorporated
elements of implementation science and policy analysis. The survey measured the views of the
survey respondents on the process of implementing the new regulatory requirements at their
institutions. The findings from this research should help to identify where the potential
roadblocks exist and illuminate why only a few BLAs have been submitted over the last ten
years. Furthermore, the study examined to what degree respondents agree with the FDA’s
categorization of allogeneic cord blood transplant as Section 351 products and how the current
regulatory framework impedes or expedites access of licensed cord blood products to patients. A
secondary framework for biotechnology policy analysis was used to probe specific elements that
may be most impacted by the new regulatory requirements.
1.4 Importance of the Study
Understanding the challenges faced by the cord blood industry in implementing the
CGTP/CGMP regulatory framework will be useful as regulators look to apply licensure
requirements on other Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps).
In addition, cord blood manufacturing institutions, which are the focus of this study, will be
instrumental in the new generation of cellular products in that these institutions will likely be
responsible for collecting the initial starting material. The recent approvals of first-in-class CAR
T products presage a robust pipeline with many potential new products. The cellular collection
17
hospitals and processing institutions as well as other stakeholders must, therefore, anticipate a
growing need to support these new products and comply with all the requirements associated
with CMC sections of BLAs. The results of this study should provide an understanding of the
challenges faced by the cord blood industry in its efforts to comply with CGMP in a clinical
environment. This upfront knowledge may be useful to the sponsors as they make tactical
decisions like which clinical trial sites to select or audit, as well as strategic decisions, like which
manufacturing processes to develop or implement.
The findings from this study could also provide policymakers with a current assessment
of the FDA’s Section 351 regulatory pathway for cord blood. The views of the respondents
involved in the cord blood manufacturing process -- researchers, clinicians and practitioners -- on
the implementation of the current regulatory framework serve to gauge the success of the current
regulatory policy. Policymakers have many tools with which to promote public health and this
study evaluated the success and challenges of enforcing a new regulatory framework onto an
existing medical practice. Science and medicine typically move much faster than regulation is
enforced. Therefore, it is valuable to examine the downstream impact that legal categorization
decisions and their resulting regulations ultimately have on individual therapies and products
such as cord blood.
1.5 Delimitations, Limitations, Assumptions
This study was delimited to cord blood manufacturing professionals who have had
experience with Section 351 biologic drug product manufacturing. It was further delimited to
cord blood manufacturing institutions such as hospitals that collect cord blood and/or conduct
cord blood research, CBBs, laboratories, and affiliated non-profit organizations that sponsor
biologic drug IND applications for which CGMP manufacturing of biologic drugs is a new
18
requirement. Pharmaceutical companies and their employees have an inherent industry
familiarity and knowledge of CGMP manufacturing requirements which could obfuscate the
survey results. Therefore, biopharmaceutical companies that manufacture biologic drugs such as
Novartis were not included in the study, limiting the potential number of survey respondents.
The study was delimited to the United States. International licensing processes for cord blood
vary widely from the FDA’s BLA process or are nonexistent, preventing data inclusion. Another
important delimitation was the length of the survey. Restricting the number of survey questions
is crucial to ensuring survey completion; however, the scope of potential data collection was
therefore restricted.
An important limitation for this study was the small population of potential respondents
to draw from. There are approximately 25 public or hybrid CBBs operating in the United States.
I address this limitation by surveying the banks as well as the CBBs’ affiliated contract
manufacturers and non-profit organizations that perform regulated parts of the cord blood
manufacturing process. A potential limitation for this research was the number of cord blood
products currently categorized as Section 351 biologic drug products, and by extension, the
number of individuals capable of providing meaningful input to this study. Only a small subset
of biologic products is fully licensed and marketed. Most of the remaining products are currently
in development and/or under study. Manufacturing in this investigational pre-market
environment must also comply with the dual CGTP and CGMP requirements. However,
expectations about the level of rigor for CGMP compliance is scaled according to the maturity of
the activities conducted at a site. Sites in an investigational phase typically have quality
expectations much lower than what we see applied to full-scale production manufacturing. Thus,
the perspectives of respondents on quality compliance may vary according to the development
19
stage of their products. I assume that respondents answered honestly to all survey questions
about their current or past experience with biologic product manufacturing. However, it is
possible that some of the respondents are involved in only one part of the product collection and
manufacturing process and were unable to answer some questions. This study is a snapshot of the
time period over which the survey was open. The results are therefore representative of the
respondent’s views occurring during that time.
1.6 Organization of Thesis
Chapter 1 provides an overview of the research problem to be explored in this
dissertation and explains the approach taken in the study. Chapter 2 outlines the literature
relevant to the field of biologic product manufacturing; specifically, cord blood products and sets
up the implementation framework through which to examine the questions of interest. Chapter 3
defines the methods by which the survey was developed and conducted. Chapter 4 reviews the
results of the study. Chapter 5 discusses the significance and validity of the findings.
1.7 Definitions
Autologous Stem Cell Transplant
A transplant in which the donor of the stem cells and the recipient of the stem cell
product is the same individual.
Allogeneic Stem Cell Transplant
A transplant in which the donor of the stem cells is not the same individual as the
recipient of the stem cells.
20
CD34
The cluster of differentiation 34 is a group of cell surface markers, specifically
transmembrane glycoproteins, that is expressed on Hematopoietic Progenitor Cells (HPCs).
Hematopoietic Progenitor Cells (HPCs)
Primitive pluripotent hematopoietic cells that are capable of self-renewal or
differentiation as well as maturation into any of the hematopoietic lineages (Areman and Loper,
2009).
Hematopoietic Progenitor Cells, Cord Blood (HPC, Cord Blood)
Refers to the final drug product (cryopreserved or thawed) of minimally manipulated
HPCs from placental/umbilical cord blood, sourced from an unrelated allogeneic donor and
intended for hematopoietic and immunologic reconstitution in patients with disorders affecting
the hematopoietic system that are inherited, acquired, or result from myeloablative treatment
(FDA, 2014)
Homologous use
The use of a cellular or tissue-based product for a normal function that is analogous to
that of the cells or tissues being replaced or supplemented (Areman and Loper, 2009).
Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps)
Products that contain human cells or tissues or any cell or tissue-based component of
such a product that is intended for implantation, transplantation, infusion, or transfer into a
recipient (Areman and Loper, 2009).
21
Minimally Manipulated
For cells or nonstructural tissue - Processing that does not alter the relevant biological
characteristics of cells or tissues (FDA, 2014)
22
Chapter 2. Literature Review
This chapter establishes the state of the literature regarding cord blood’s medical history
and its regulatory evolution. Using the USC online libraries as a starting point, a literature search
was conducted with key search terms for peer-reviewed studies involving cord blood research
and regulation. The search initially yielded over 100,000 citations. After narrowing the search to
landmark studies and texts which appeared most relevant to cord blood manufacturing and
CGTP/CGMP regulation, the remaining 52 were used as a basis for the review developed here.
In addition, the FDA website, relevant cord blood institution websites, and professional
organization websites were valuable to this research. These resources were searched for
presentations and reference materials concerning current cord blood industry views and are
included in this literature review.
2.1 Cord Blood History
“Science has presented us with a hope called stem-cell research, which may provide our
scientists with many answers that have for so long been beyond our grasp” (Reagan, 2004). This
quote from Nancy Reagan, an outspoken supporter of cellular research, captures the promise
associated with stem cell investigation and reflects the growing public interest that cellular topics
came to enjoy over the subsequent decade. Perhaps the first commercialized stem cell “product”
was that carried in the cord blood of infants. Researchers first started collecting and studying
cord blood that was then administered under the practice of medicine starting in the 1950s. Over
the next 50 years, medical research institutions and universities primarily conducted cord blood
research and case studies under institutional protocols with very little limelight or attention from
policymakers. The figure below depicts the significant historical events in cord blood medical
research through its transition into modern use.
23
Figure 3: Timeline of Cord Blood Medical Research
Early use of cord blood was primarily diagnostic in nature and explored the safety of collection
methods. In the mid-1980s, a transition occurred into modern cord blood use, characterized by
research and transplant specifically for hematopoietic reconstitution or immune system self-
renewal.
2.1.1 Early History
The first use of cord blood, recorded in medical journals of the early 1950s, was for
analytical samples that could provide biomarkers to reflect a newborn’s state of immunity (Barr,
1950). A notable example was the use of cord blood samples to determine the rate at which
infants lose “their maternally conferred antitoxin” for diphtheria (Barr, 1950). This study
collected hundreds of samples across South-East London in order to determine the best
immunization schedule for infants. They demonstrated that cord blood could be used as an
alternative sample source to avoid drawing newborn blood. Cord blood continued to be used for
24
newborn sample analysis until the 1970s, when researchers began to investigate other unique
properties of cord blood that might expand its potential therapeutic use.
The broader use of cord blood required that collection methods and use be standardized.
Discussion of cord blood collection methodology and use can be identified, for example, in a
1979 U.S. study by Charles Paxson that sought to provide an alternative source of blood for
newborns suffering hypotensive shock or blood loss at the time of delivery (Paxson, 1979).
Rapid blood sources are very limited for newborns. Further, donated blood must be type matched
and then processed to a higher hematocrit to be compatible with the newborn system (Paxson,
1979). The Paxton study explored the benefits of immediate collection and infusion of cord
blood back into delivered newborns experiencing blood loss. The study detailed a safe method of
collection using “an adaptation of the federal regulations for heparin collection of human blood
products” promulgated by the FDA in 1977 (Paxson, 1979).
Investigations of safe cord blood collection continued in the 1980s. One such study on
neonatal bacteremia utilized a sterile technique, in which meticulous use of sterile needles and
careful preparation and handling of the cord segment could be shown to reduce the incidence of
bacteria-positive cord blood cultures to 0.5% (Polin et al., 1981). This represented a dramatic
decrease from the range of 9 to 47% contaminated cord blood cultures reported in previous
studies (Polin et al., 1981). Researchers concluded that the “noninvasive and nontraumatic”
sterile collection method could prevent sample contamination and ultimately derived a greater
blood volume than could be collected previously from the newborn babies (Polin et al., 1981).
Later investigation into the cellular properties of cord blood revealed the potential for
therapeutic use in hematopoietic stem cell transplants because of their multipotent stem cell
25
content. In 1988, prominent transplant physicians began investigating whether cord blood could
be a viable source of stem cells for immune system self-renewal (Broxmeyer et al., 1989). The
study compared the number of progenitor cells present in cord blood with the range known to be
necessary for successful engraftment by the standard-of-care bone marrow transplant
(Broxmeyer et al., 1989). Broxmeyer and his team found that cord blood was a sufficient source
of cells if used within 3 days of collection, or under certain storage conditions (Broxmeyer et al.,
1989). They tested a cryopreservation protocol to determine if cells would remain viable after
being frozen for 1 – 10 months (Broxmeyer et al., 1989). Their work resulted in the first
publication of stability methods for cord blood, including processing, time-limited freezing, and
storage in 100 ml bags (Broxmeyer et al., 1989). Researchers concluded that cord blood
appeared to be a viable alternative source to bone marrow and opened the door for its modern
use in hematopoietic reconstitution.
2.1.2 Modern Use
Soon after the groundbreaking studies by Broxmeyer, a French and American research
collaboration conducted the first cord blood transplant in 1988 (Gluckman et al., 1989). This
transplant was particularly significant because the research documented more than just the results
of the intervention. It also detailed the methods for cord blood collection, cryopreservation, pre-
transplantation conditioning, and transplantation (Gluckman et al., 1989). Specifically, the cord
blood was collected in the United States from a Human Leukocyte Antigen (HLA) matched
newborn for her 5-year-old brother who suffered from a rare blood disorder, Fanconi’s Anemia.
The collection was banked in New York and shipped to Paris, France, two weeks prior to the
transplantation (Gluckman et al., 1989). This endeavor, which resulted in a successful patient
outcome, ushered in the modern use of cord blood for immune system reconstitution.
26
Cord blood provided an important therapeutic alternative in a case where harvesting bone
marrow from a newborn would have been unethical. Bone marrow collection, carried out since
the 1970s, requires the use of general anesthesia in order to aspirate the marrow from the donor’s
hip region. Another option, Hematopoietic Progenitor Cell Apheresis [HPC (A)], first used in the
late 1980s, is carried out by dosing the donor with a mobilizing drug to draw the stem cells out of
the bone marrow into the peripheral blood. The progenitor cells then are collected through
apheresis, in a manner similar to that used to collect blood platelets. Both of these methods pose
some risk to the donor. The probability of adverse events from either a bone marrow or apheresis
procedure is low but the transplant community is obligated to mitigate donor risks where
possible (Be The Match, 2019b). The cord blood process is unique in that it is a safe donation
process for both the consenting mother and the newborn infant.
The first cord blood transplant also represented the first successful banking attempt. This
experience led to the first public storage of cord blood in 1991 when New York Blood Center
(NYBC) began publicly storing cord blood (Areman and Loper, 2009). With banked product
now readily available for physicians, unrelated allogeneic transplants began to take place across
the nation. NYBC began the Placental Blood Program in 1992 to study the feasibility of using
banked cord blood for unrelated HLA-matched patients (Kurtzberg et al., 1996). The study
followed the first 25 unrelated transplants, from 1992 -1996, using the Placental Blood
Program’s banked products (Kurtzberg et al., 1996). Patients involved in the study were
indicated for the same variety of diseases treated by contemporary bone marrow transplant
including “some hematologic cancers, bone marrow failure syndromes, immunodeficiency
disorders, and inborn errors of metabolism” (Kurtzberg et al., 1996). Kurtzburg and colleagues
27
concluded that cord blood was a suitable alternative source of stem cells for pediatric allogeneic
transplant (Kurtzberg et al., 1996).
Methods and indications for the use of cord blood had focused on allogeneic transplant
between HLA matched donors and patients. This changed near the turn of the millennium when
the Placental Blood Program at NYBC conducted an outcomes study in which it analyzed all 562
transplants facilitated by the Placental Blood Program between 1992 and 1998 (Rubinstein et al.,
1998). Investigators found that partially HLA matched cord blood could be used in patients
without HLA identical donor options (Rubinstein et al., 1998). This finding expanded the options
for unrelated transplants. Previously, autologous and allogeneic related cord blood use was
managed by the patient’s physician under the practice of medicine at their hospital or institution.
Now, the transplant physician could search the Cord Blood Bank (CBB) inventory and order
HLA-identical and HLA-partially matched product as needed for their patients.
As allogeneic use increased, it became apparent that methods for managing allogeneic
transplant materials should be standardized. To achieve this end, a prospective study was needed
to standardize the wide variety of techniques being implemented at public CBBs for processing,
freezing, storing, and shipping. The National Heart, Lung, and Blood Institute therefore
sponsored the Cord Blood Transplantation Study, termed COBLT, to establish standard
operating procedures for cord blood products (Kurtzberg et al., 2008). At the outset of the study,
a steering committee collectively wrote COBLT standard operating procedures based on the
current literature for cord blood processing and cryopreservation. Investigators used the
standardized procedures for thawing, washing, and processing cord blood products across the 26
participating public CBBs (Kurtzberg et al., 2008). This landmark study collected transplant data
from 1999 through 2003. The standardized procedures culminated in usable study data for
28
comparing transplant outcomes. The COBLT study provided the necessary depth of analysis to
present cord blood as a viable alternative source of stem cells and established the use of cord
blood as a therapeutic product. Within the cord blood industry, cord blood transitioned to its
product name, Hematopoietic Progenitor Cells, Cord Blood (HPC, Cord Blood).
2.1.3 Current Use of Cord Blood Products
The central factor to determine a successful cord blood transplant is the degree of HLA
agreement between stem cells of patient and donor. Certain cell-surface marker proteins are
known to be responsible for immune system function. Matching these proteins, or alleles,
increases the chances of patient survival. The connection between patient outcome and HLA
match is now so well understood that transplant physicians and medical centers will select the
cellular product based on the degree of HLA match available to the patient (Be The Match,
2019a). Cord blood products have a rich concentration of stem cells that have an important
advantage in that the recipients can tolerate a lower degree of allele matching for a given gene.
Hence, patients can transplant successfully with only 4 out of 6 allele matches. This is compared
with the minimum requirement of 6 out of 8 allele matches for bone marrow patients. However,
the overall volume of cell-rich product is limited by the nature of the umbilical cord source, and
this constitutes a challenge for the use of the product in adult patients. Patient dosing is
determined as a ratio of total nucleated cells (TNC) per kilogram of the patient’s weight to
ensure adequate product potency. Most banked cord blood samples have a TNC count sufficient
only to support engraftment in pediatric patients. Therefore, cord blood therapy was limited for
the pediatric patient population until 2005 when researchers explored the feasibility of
combining two cord blood products in a single adult transplant. The study provided compelling
evidence that a “double cord” blood transplant could be safe and effective (Barker et al., 2005).
29
Researchers had to balance the need to assure the best HLA match with the need to achieve a
satisfactory dose. This necessitated selecting the largest available set of HPC, Cord Blood
products that would be matched only partially to the patients (Barker et al., 2005). The double
cord blood transplant effectively expanded the available donor pool and provided an important
transplant alternative for the adult patient population.
After engraftment, Graft Versus Host Disease (GVHD) in both its acute and chronic form
is the most common cause of transplant-related adverse events and mortality. The body’s
immune system self-identifies cells by examining the HLA markers and attacks foreign or un-
matched cells. To reduce this problem, most patients receive high dose myeloablative
chemotherapy prior to stem cell transplant, in a conditioning regimen that reduces the body’s
inflammatory response to donor stem cells and allows for engraftment. Such an approach is
critical for post-transplant survival. However, not all stem cells appear to be equally likely to
produce GVHD. An important study looked at transplant outcomes, including GVHD, by
analyzing data reported to central registries such as the Center for International Blood and
Marrow Transplant Research (CIBMTR). In this work, Rocha and colleagues compared GVHD
outcomes in transplants between children with an HLA-identical cord blood transplant and
children with an HLA-identical bone marrow transplant (Rocha et al., 2000). They showed that a
patient transplanted with cord blood had less chance of developing both acute and chronic
GVHD than those transplanted with bone marrow (Rocha et al., 2000). The characteristic low
cell volume of cord blood was typically associated with slower engraftment, but the lower
incidence of GVHD was a compelling counterpoint (Rocha et al., 2000). Unsurprisingly, the
transplant community embraced cord blood transplant as a preferred therapy in particularly high-
risk GVHD circumstances. The lower rates of GVHD in comparison to those associated with
30
alternative stem-cell sources led to the medical community acceptance of cord blood for
unrelated transplants in adult patients without a sibling or a fully matched donor.
Cord blood can be cryopreserved and banked, and therefore be made available rapidly for
procurement and transplant. This convenience gives it another advantage over the use of both
bone marrow and peripheral blood stem cells that rely on careful timing to contact, prepare and
collect the donor material while the transplant physician manages the patient and their
conditioning regime. A one-year comparison study conducted on the stem-cell searches for all
blood-cancer transplants at the University of Minnesota showed that clinicians took an average
of 13.5 days to search registries for a matching cord blood product but 49 days for a bone-
marrow donor (Barker et al., 2002).
Why does it take so long to find a bone-marrow source? Donor availability is a major
factor impacting the time needed to find appropriate stem-cell products. When a search takes
place for a bone-marrow donor, a short list of potential HLA matched donors is identified in a
digital registry. The potential donors must then be contacted and evaluated for suitability and
eligibility (Be The Match, 2019a). Donor samples are tested for infectious disease according to
the CGTP regulations and confirmatory HLA matching. A health-history questionnaire and
physical exam then are carried out to assure the donor’s suitability for the donation process.
After the cells are removed from the donor, they are hand couriered and infused into the patient
as a fresh product as soon as possible. The results of the Barker study point to the much easier
process to retrieve a frozen banked cord blood product. Gluckman and Rocha discussed this
comparison in a 2009 perspective article on the state of cord blood donation. They opined that
HPC, Cord Blood offered “substantial logistic” advantages for urgent transplants (Gluckman and
Rocha, 2009).
31
Cord blood’s processing, storage, and delivery procedures are in many ways similar to
traditional pharmaceutical manufacturing approaches. Because much time is usually available
between the initial collection and subsequent use of cord blood, it is possible to process the
product in a manner that satisfies the regulatory requirements of CGMP for pharmaceutical
products. Cord blood products can go through a lot release process at the point of collection,
where they can be tested for safety, purity, and potency, and identity prior to cryopreservation
(FDA, 2014). Specifications such as the cell surface marker cluster of differentiation (CD),
CD34, is tested via flow cytometry to establish potency (FDA, 2014). CD34 is expressed on
HPCs and is the defining characteristic of cell viability. The transplant community relies on the
number of cells expressing CD34 (CD34+ cell count) as a key predictor of initial engraftment
success. Thus, clinicians selecting a cord blood product can access HLA and product
specifications well before transplant.
Cord blood products are also controlled through approved cryopreservation methods for
storage and shipment and undergo a validated process for thawing at the point-of-care. The
availability of cord blood products is thus more like that of traditional pharmaceutical products in
that the banked products are inventoried and listed on searchable registries, such as the Be The
Match Registry, where they are available for physicians to order (Be The Match, 2019a). This
key similarity to the pharmaceutical industry may be one of the factors that influenced
policymakers to categorize cord blood as a therapeutic product under Section 351 and require
premarket approval in a way not dissimilar to that for drugs.
2.2 Evolution of Biologic Product Regulation
The FDA’s first approval of a cord blood BLA by New York Blood Center in 2011 took
place more than a century after regulations for biologics first appeared in the early 20
th
century.
32
At that time vaccines were the primary biological products. These products, like all biologics, are
“generally derived from living material--human, animal, or microorganism-- are complex in
structure, and thus are usually not fully characterized” (FDA, 2015). Their complicated features
and production processes have the potential of introducing myriad risks of contamination. Two
such high-profile contamination incidents related to the production of diphtheria antitoxin and
smallpox vaccine were responsible for driving the first biologics legislation, the Biologics
Control Act of 1902.
Over the decades, scientific advances in virus, blood, and blood component research and
products diversified the playing field of biologics and prompted more federal oversight of
biologic products. The following timeline graphic, Figure 4, highlights the sequence of key
biologic product innovations in relation to legislative and regulatory acts where oversight was
expanded or clarified. Product and regulatory history details will be explored in subsequent
sections.
33
Figure 4: Biologic Product Regulatory Evolution
34
2.2.1 The Beginnings of Biologics Legislation
Regulation of biologics was first introduced to safeguard the early use of immune
treatments. Immunology is defined as the science that deals with the immune system and the
cell-mediated and humoral aspects of immunity and immune responses (Merriam-Webster). The
therapeutic implications of immunology was first evidenced in Emil von Behring’s landmark
clinical study on diphtheria published in the late 19
th
century (Behring and Kitasato, 1890).
Researcher, Terry Coleman, explored the impact of Behring’s 19
th
century research on biologic
regulation in the Food and Drug Law Journal. Coleman described the diphtheria bacterium’s
protein toxin secretion that caused the disease’s adverse effects in 1890 including particularly
high pediatric fatality rates (Coleman, 2016). Behring, among others, revealed that animals
exposed to the diphtheria bacterium produced “antitoxins” in their blood that could be
transferred to other animals in a serum, preventing the disease effects (Coleman, 2016). A
Britannica article on immunology’s historical figures describes Behring as a pioneer in the “the
20
th
century fight against infectious disease” (Rogers, 2010). Behring would receive the Nobel
Prize for his work developing a serum-based therapy at the Institute for Hygiene in Berlin
(Rogers, 2010); his colleague, Paul Ehrlich, would subsequently earn his Nobel Prize for
developing a technique to measure serum effectiveness and method of collecting the blood of
live horses (Rogers, 2010). Ehrlich coined the term ‘antibodies’ to describe antitoxins in his
prize-winning studies (Himmelweit et al., 1956) but ‘antitoxins’ continued to be the commonly
used term throughout the early twentieth century. The results of animal and clinical trials for
diphtheria antitoxin serum were published in 1894, prompting commercial production of
antitoxin serum for diphtheria and also for tetanus (Coleman, 2016). According to the FDA
historian, Dr. Suzanne Junod, the mortality rates for these diseases dropped across the European
continent (Junod, 2002). Publications from the National Institutes of Health (NIH) researchers
35
emphasize the important role that 19
th
century national laboratories played in addressing
diphtheria (Morens and Fauci, 2012). Prominent immunologists such as Robert Koch at the
Institute for Hygiene in Berlin and Louis Pasteur at his laboratory in Paris continued to publish
promising studies from their nationally supported laboratories (Morens and Fauci, 2012).
The United States, also plagued by the spread of diphtheria and tetanus, followed the
European example by establishing laboratories dedicated to the study of immunology and
infectious disease prevention. The Marine Hospital Service (MHS) established the nation’s first
infectious disease laboratories on New York’s Staten Island quarantine station in 1887 (Morens
and Fauci, 2012). It was later moved to Washington D.C., where it mass-produced the diphtheria
antitoxin among others (Morens and Fauci, 2012). With the development of vaccine mass
production came problems. Most notably, in 1901, contaminations introduced during
manufacturing of diphtheria antitoxin and smallpox vaccine caused fatalities. In the first
instance, thirteen children in St. Louis died of tetanus when they were immunized with
diphtheria antitoxin produced from a sick horse with that disease. The vaccine that they received
was mislabeled and did not undergo the required laboratory testing prior to distribution
(Coleman, 2016). This incident was publicized extensively and convinced many parents to opt
out of treating their children with the antitoxin. As a result, there was an increased rate of
mortality from diphtheria (Coleman, 2016). Later in that same year, in Camden, New Jersey, a
manufacturer of smallpox vaccine was also investigated for contamination of its product with
tetanus, resulting in approximately eighty cases and eleven fatalities (Coleman, 2016). These
incidents revealed the challenging nature of manufacturing biologics and a need for further
controls to ensure consistent vaccine quality. Unlike drug products composed of chemical small
molecules, biologics are highly heterogeneous and contain large protein moieties. Slight
36
variability in the manufacturing process can result in an entirely different product; even with
careful production, variability is inherent to the live organisms in which the products are raised
(FDA, 2015).
The United States government responded to the above incidents with the passage of the
first federal biologic legislation, the Biologics Control Act of 1902. The Act regulated the sale of
“virus, therapeutic serum, toxin, antitoxin, or analogous product” in interstate and international
commerce by requiring manufacturers to obtain an annual establishment license and submit to
inspection from the MHS, renamed the Public Health Service (U.S. Congress, 1902). The
Hygienic Laboratory took responsibility for setting production standards and issuing licenses
(Junod, 2002). For example, the Hygienic Laboratory published their tetanus toxin production
methods for manufacturers to follow (Anderson and Leake, 1915). The Biologics Control Act
also prohibited false statements and required that products be labeled with the license number
and product expiration date (U.S. Congress, 1902). This first example of federal oversight and
specific requirements set the trajectory for eventual FDA regulation of other biologics.
2.2.2 Virus, Blood, and Blood Component Products
In the relative calm of the 1930s, framed between the two World Wars, a new era of
biologic development became centered on several new types of biological products. War had
highlighted a need to provide fresh blood and blood plasma. The novel method of blood
fractionation, introduced by the scientist, Edwin Cohn, was able to separate proteins from the
blood plasma. The new blood protein products, termed plasma derivatives (Zoon, 2002), could
be pooled for storage. This was a benefit for medical treatment but introduced the risk that a
single infected donor could contaminate an entire batch of product and thus could cause adverse
events in a large group of people (Zoon, 2002).
37
The invention of the electron microscope and the development of new techniques for
growing tissue cultures in the 1930s ushered in the option to image and reproduce viruses in the
laboratory. The new approaches allowed advances in viral vaccine production that could be used
to develop preventive treatments for such diseases as yellow fever and influenza (Rogers, 2010).
Vaccines to the viral agents could then be manufactured from either a weakened live virus or a
killed virus (Rogers, 2010). Like the problems with bacterial vaccines, early viral vaccines had
risks. A historical research paper describing the evolution of early viral risks for biologic
products was published for a 2011 joint conference between the pharmaceutical industry and
FDA. The research highlighted early 20
th
century vaccine contamination risks from bacterial and
fungal contamination of raw materials, manufacturing processes, and non-sterile packaging
(Lubiniecki, 2011). During the same time period, FDA oversight of food, drugs, and cosmetics
was greatly expanded through the passage of the 1938 Food, Drug, and Cosmetic (FD&C) Act
(FDA, 1938). Drug manufacturers were now required to show safety and efficacy of their
products through a premarket application process.
At the end of World War II, the need to strengthen further the regulatory oversight of
biologics became apparent following an incident in which approximately 2.5 million Allied
military personnel were given contaminated yellow fever vaccine. The vaccine sickened 20,000
and caused 26 deaths (Lubiniecki, 2011). This tragedy drew attention to the need for greater
manufacturing controls including improved aseptic processing technologies (Lubiniecki, 2011).
Congress responded by passing the Public Health Service (PHS) Act of 1944. The PHS Act
formally granted the Surgeon General authority to promulgate regulation regarding biologic
products, defined there as a
38
virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, protein (except any chemically synthesized
polypeptide), or analogous product, or arsphenamine or derivative of
arsphenamine (or any other trivalent organic arsenic compound), applicable
to the prevention, treatment, or cure of a disease or condition of human beings
(PHS, 1944).
Importantly, the PHS Act required premarket licensing of biologic products to assure
their safety, purity, and potency (PHS, 1944). Although the process for licensing has changed
and been updated over time, an important component is the attention paid to the manufacturing
process. Clearly defined and controlled manufacturing processes are critical to characterizing the
biologic product itself and preventing contamination. The PHS Act and associated regulations
established that manufacturing controls, including a combination of contamination detection
technologies, would have to be implemented for large molecule biologic products that could not
survive the traditional thermal processes for drug sterilization (Lubiniecki, 2011).
Although the PHS Act expanded the scrutiny of manufacturing controls, significant
regulatory gaps remained. The need for more oversight became obvious when Cutter
Laboratories released several lots of incompletely inactivated poliovirus that caused almost 150
cases of poliomyelitis in the mid-1950s (Nathanson and Langmuir, 1963). This public health
crisis highlighted the need for companies to validate viral clearance and institute ways to test the
final product for residual infectious virus during a lot release (Lubiniecki, 2011).
By the end of the 1960s, the FDA had already introduced the requirement for rigorous
pharmaceutical quality assurance and control, termed the Current Good Manufacturing Practices
or CGMPs, described in 21 CFR Part 210 and 21 CFR Part 211. By this time, FDA had become
the preeminent therapeutic regulatory authority by virtue of its extensive experience regulating
drug products for both safety and efficacy under the FD&C Act. By contrast, the PHS Act lacked
39
the efficacy language of the FD&C Act. Without the legal authority to require proof of efficacy,
ineffective biologic products were able to enter the market between 1944 and 1972. A General
Accounting Office (GAO) investigation in 1971 revealed that twenty-eight percent of PHS
licensed products, including vaccines, were known to be ineffective (Coleman, 2016). These
investigative findings prompted the transfer of biologic regulatory oversight from the PHS to the
FDA in 1972 (Coleman, 2016).
If FDA was to oversee biologic products, amendments and updates would have to be
made to both the PHS and FD&C Acts. As part of the change, the PHS Act was amended to
introduce two different product categories. The ‘Section 351’ products such as vaccines and
blood products would need to submit extensive dossiers to obtain product licensing while
‘Section 361’ products, which were primarily cellular and tissue-based products like cartilage,
bone, skin, and embryos did not require licenses prior to sale and use. In 1972, the FDA created
the Center for Biologics Evaluation and Research (CBER) and promulgated biologic licensing
regulations for Section 351 products in the 21 CFR Part 600 series, as the foundational body of
the FDA’s biologic regulation. The Section 361 products, on the other hand, were subject only to
regulations intended to prevent transmission of communicable diseases. However, the ‘Section
361’ products escaped even that level of oversight because the FDA, distracted by the Acquired
Immune Deficiency (AIDS) epidemic of the 1980s, did not promulgate these “tissue regulations”
until many years later. During the AIDS epidemic, CBER researchers contributed to the
development of the first test kit detecting Human Immune Deficiency Virus (HIV) in donated
blood products in 1985 (Zoon, 2002). CBER also prioritized regulations to support the detection
of the disease in the blood supply. In 1985, FDA produced blood and blood-component GMPs as
an additional part, 21 CFR Part 606, in the biologic regulations. These testing requirements for
40
HIV and other infectious diseases heralded the creation of formalized tissue manufacturing
regulation.
2.2.3 Regulatory Oversight of Human Cellular and Tissue-Based Products
Cord blood and other HCT/Ps such as bone, vascular, and ligament tissue products, can
cause serious problems for patients if the donor tissues are contaminated either from the donor
source or the subsequent methods used to process the tissue. As cellular and tissue-based
products rapidly achieved therapeutic acceptance in the 1990s and 2000s, the need to mitigate
the risks of product contamination became paramount. The Center for Disease Control and
Prevention (CDC) confirmed cases of HIV transmission from tissue transplanted in the early
1990s from human cadavers (Areman and Loper, 2009). These cadaver tissues were distributed
directly to the hospitals from tissue banks responsible for their storage and processing. In one
well publicized case, a 23-year-old college student died in 2001 from a routine surgical repair of
their knee cartilage when implanted with contaminated cadaver tissue (Kohn, 2002). This
incident highlighted the potential risk that nonsterile tissue products might be provided by the
underregulated tissue banks with questionable systems to detect contamination (Kohn, 2002).
Unlike blood products that are stored for a maximum of 42 days in refrigeration, HCT/Ps, such
as cord blood, can be frozen for long-term storage. Cryopreservation presented new processing
risks related to improper storage conditions, bag breakage, and improper labeling. New HCT/P
regulations were also needed to assure that products would remain stable and would bear
expiration dates, in order to assure the continued effectiveness of inventoried products. When
double cord blood transplants became the standard of care for adult patients in 2005, the
contamination risks from inappropriate donors and improper processing were magnified.
41
To prevent contamination by HIV and hepatitis, the FDA published an Interim Rule for
Human Tissue Intended for Transplantation, in 1993, requiring banking institutions to conduct
donor eligibility testing and screening for these diseases (FDA, 1997). For transplants using cord
blood, particular risks may be present because a donor’s infectious or hereditary diseases could
be transmitted when patient’s cells are replaced with the donors. Finalized in 2005 as the Current
Good Tissue Practice (CGTP) regulations, the FDA required institutions to establish downstream
processing controls and quality controls to assure the release of safe final products (FDA,
2004a). The CGTP requirements reflected a risk-based, tiered approach by FDA to minimize the
potential for spreading Relevant Communicable Disease Agents or Diseases (RCDADs) carried
by cellular or tissue products (FDA, 2004a). The CGTP requirements were finalized in 2005, the
same year as the first successful double cord blood transplant and were implemented throughout
the cellular and tissue banking industries. Table 2 below outlines and briefly describes the
relevant sections of CGTP regulation.
Table 2: History of HCT/P Final Rules and Location in 21 CFR 1271
Ruling Title 21 CFR 1271
1st Final Rule
69 FR 5447
Jan 19 2001
Human Cells, Tissues, and Cellular and
Tissue-Based Products; Establishment
Registration and Listing
Subparts A and B
2nd Final Rule
69 FR 29786
May 25 2004
Eligibility Determination for Donors of
Human Cells, Tissues, and Cellular and
Tissue-Based Products
Subpart C
3rd Final Rule
69 FR 68612
Nov 24 2004
Current Good Tissue Practice for
Manufactures of Human Cells, Tissues,
and Cellular and Tissue-Based Products;
Inspection and Enforcement
Subpart D, E, and F
42
Under FDA’s CGTP regulations, all organizations involved in cellular and tissue product
“manufacturing,” -the collection, processing, storage and distribution of HCT/Ps- are obligated
to register their establishments with FDA in accordance with Subparts A and B of 21 CFR 1271
(FDA, 2001). FDA’s CBER personnel, together with local FDA inspection offices, use the
establishment registration listing to perform routine and risk-based audits on both the clinical
institutions registered as collection sites and the CBBs responsible for cell storage and
distribution. These inspections and enforcement activities are described in Subpart F (FDA,
2004a).
Donor eligibility requirements to prevent infectious disease in HCT/Ps are established in
Subpart C of 21 CFR 1271 (FDA, 2004b). All cord blood products, for example, must follow
these requirements for donor screening, testing, and eligibility determinations. Infectious Disease
Marker (IDM) testing should reflect the FDA’s current thinking and the available guidance for
infectious and communicable diseases that could affect the transplant patient and the greater
public health. Cord blood for autologous use is not required to comply with 21 CFR 1271
Subpart C, Donor Eligibility, but it is recommended (FDA, 2004b).
21 CFR 1271 Subpart D and E describe the GTP regulations and additional requirements
such as reporting and labeling (FDA, 2004a). This subpart is intended to control the introduction,
transmission, or spread of communicable diseases during HCT/P manufacturing. Subpart D and
E are referred to as the ‘core GTP’. The core GTP require manufacturers to create a quality plan
that ensures the proper management and validation of each step in the manufacturing process
(FDA, 2004a). Specific requirements address the management of equipment, personnel, critical
supplies, and labeling, among others (FDA, 2004a). All cord blood products and their
manufacturing facilities must adhere to the core GTPs to ensure proper disease risk mitigation.
43
The CGTPs are the modern regulatory solution to the original mandate of the PHS, to
prevent transmission of communicable diseases (PHS, 1944). They are applied to both Section
351 and Section 361 products. However, Section 351 and Section 361 products continue to differ
according to the need to satisfy FDA’s premarket approval regulations. The modern definitions
below reflect the FDA’s current thinking for HCT/P regulation and were the rationale behind
requiring premarket approval for cord blood for allogeneic transplant. The product definitions in
Section 361 and Section 351 of the PHS Act determine the applicable body of FDA regulation.
Section 361 products must meet three principal criteria listed below to be governed solely by
CGTPs. They must be:
● minimally manipulated and intended for homologous use
● not combined with a drug, device or biologic product or other article that presents new
clinical safety concerns
● not have a systemic or metabolic effect unless:
o administered to the original donor (autologous use)
o administered to a first-degree or second-degree blood relative
o administered or used for reproductive purposes
Manufacturers can self-designate their products as Section 361 HCT/Ps and place them
on the market without seeking FDA consult. Some products, such as bone, skin, and embryos are
straightforward and fall clearly within the Section 361 definition provided above. However, self-
designation of cellular products is complicated by the requirement that Section 361 products be
‘minimally manipulated’ and intended for ‘homologous use’. Both of these terms appear to leave
room for interpretation. It is clear that self-designation as a Section 361 product can be
advantageous for manufacturers, so that manufacturers often attempt to shoehorn their products
into this category even if the fit is poor. If the FDA disagrees with the Section 361 determination,
it could use its enforcement authority to require Section 351 premarket approval. The FDA
44
issues warning letters to the most egregious cases of misrepresentation. Most recently, the FDA
gave warnings to several companies that they are out of compliance with regard to the wrongful
designation of their products as Section 361 products, and thus skipping premarket review (FDA,
2019d). For example, a warning letter to a group of stem cell clinics in Arizona stated that the
clinics have used “questionable marketing campaigns to take advantage of vulnerable patients
and their families with unproven claims about their unapproved stem cell products” (FDA,
2019b).
Section 351 HCT/Ps must demonstrate their safety and efficacy by meeting the
requirements for premarket approval regulations in addition to the CGTPs. A HCT/P would be
designated as a Section 351 product if any one of the following criteria are met:
● The product is more than minimally manipulated
● The product is not employed for homologous use
● The product is combined with a drug, device or biologic product in a way that raises new
clinical safety concerns
● The product is genetically modified or expanded ex vivo
● The product exerts a systemic effect unless for autologous use, allogeneic first-degree or
second-degree blood relative, or reproductive use
Cord blood products intended for most transplant applications fall under Section 351
because they are provided to an unrelated patient and thus considered to be allogeneic.
Allogeneic products are subject not only to the tissue requirements spelled out in the CGTPs but
also the drug CGMP and other requirements associated with premarket approval. Table 3 depicts
the current regulatory framework for cord blood.
45
Table 3: Cord Blood Product Regulation
Although all cord blood product manufacturing must adhere to the CGTP regulations, the
additional requirements listed above for allogeneic cord blood place significant additional
constraints and responsibilities on the institutions that collect and register products for allogeneic
transplant. However, the distinction is not always clear to the sites at which the cord blood is
collected. Hospital facilities performing collection and cryopreservation may do so without
knowing whether the final product will eventually meet the licensing requirements. To meet
BLA processing and labeling requirements, the clinical staff must apply the CGMP requirements
to product collection and initial processing steps. Further, the activities required of cord blood
manufacturing facilities have also had to change. Until the FDA published the draft guidance for
Transplant
Type
Autologous
Transplanted
cord blood
back into the
donor
Allogeneic -
Related
Transplanted
cord blood
from first-
degree or
second-
degree blood
relative
Allogeneic - Unrelated
Transplanted cord blood from an unrelated
donor
Regulation
21 CFR
Part 1271
Current Good Tissue Practice
(CGTP)
21 CFR
Part 1271
Current
Good
Tissue
Practice
(CGTP)
21 CFR
Parts 210, 211
Current Good
Manufacturing
Practice
(CGMP)
21 CFR
Part 312
Parts 600, 610
Parts 201, 202
Investigational
New Drug
(IND), Biologic
License
Application
(BLA), labeling
&
advertisement
requirements
among others
46
cord blood BLA submission in 2009, facilities were operating as Section 361 facilities, solely in
compliance with CGTPs (FDA, 2009). These facilities are now attempting to comply with the
modern framework of layered regulation required for BLA.
FDA met and collaborated with advisory committees and cord blood stakeholders to
understand the full scope of previous cord blood use under medical practice and to examine
opportunities for standardization. FDA acknowledged the need for extensive cord blood banking
comment and input on their draft guidance for cord blood BLA submissions (FDA, 2009). Its
final guidance relating to cord blood BLA submission in 2014 states that, while both CGMP and
CGTP compliance are required, “for the most part, in the manufacture of HPC, Cord Blood, the
CGMP regulations will be applied because they are more broadly drafted and subsume the CGTP
regulations” (FDA, 2014). One example of the gap between tissue and drug manufacturing
regulations is the nature of requirements for a CGMP Quality Control Unit (QCU) enunciated in
21 CFR Part 211.22. Whereas the tissue practices require a quality plan for the facility, they do
not specify that an independent organizational element must be responsible for the QCU. The
CGMP regulations require, for example, that the QCU be responsible for product approval and
rejection prior to HPC, Cord Blood distribution (FDA, 2014). This authority implies that
independent quality control personnel are staffed within the facility. This level of CMC detail
represents a dramatic transition from treating cord blood as though it were a part of the practice
of medicine to regarding it as a biologic product. Modern cord blood products for allogeneic
transplant are subject to the biologic regulations and certain aspects of the drug CGMPs, as well
as the tissue CGTPs. Institutions must navigate this complicated landscape of regulation in order
to secure licensure and keep their products on the market.
47
2.3 Current Regulatory Landscape for Cord Blood Banks
The HCT/P regulatory framework does not address the heterogeneity that exists in the
cord blood industry. Currently, the CBBs are divided into three categories, public, private, and
hybrid, each needing to adhere to different levels of regulatory compliance. Approximately 20
private, 20 public, and 5 hybrid CBBs in the United States offer both private and public storage.
Private banks are “for-profit companies that facilitate storage of cord blood for personal or
family use” (Scaradavou, 2013). Banks in this group charge fees for initial collection and
subsequent annual storage fees for future private family use. Hence, the private banks primarily
handle autologous or related transplants (Section 361 products) and are subject to CGTP
requirements. On the other hand, public banks do not charge donation or storage fees and require
that the donating mother consent to make the cord blood available publicly for an unrelated
patient. In this case, the cord blood product would fall under Section 351 and need to comply
with both CGTP and CGMP requirements. In addition, the product would need to be
administered under IND or an approved BLA submission. These public cord blood products are
listed on the National Cord Blood Inventory (NCBI) so that they can be searched and then
acquired by transplant centers and physicians (NCBI, 2015). In the third category, the hybrid
CBBs typically provide both private and public banking and, hence, must manage both Section
351 and Section 361 products. The existence of multiple banking models with their differing
levels of regulatory oversight may be unclear to both donors and patients. Furthermore, the
business models are vastly different for the three categories of CBBs, creating a stressful
environment due to disparities across regulatory burden, collection priorities, and financial
sustainability.
48
Public CBBs listed under the NCBI are subject to overlapping layers of compliance
oversight by the FDA and the Health Resources and Services Agency (HRSA). The HRSA, a
sister agency to the FDA under the U.S. Department of Health and Human Services (HHS),
operates the NCBI. As part of its mandate to increase public’s access to cord blood, HRSA
distributes funding to CBBs through competitive five year congressional contracts that cover
150,000 new cord blood collections (NCBI, 2020). Hence, public and hybrid CBBs must meet
contractual requirements for cord blood collection and storage to qualify for continued HRSA
funding.
There is growing evidence that the priorities of the HRSA and the FDA differ when it
comes to cord blood products. Insights into HRSA’s approach can be gained through the 2016
publications on meetings convened by the HHS Advisory Council on Blood Stem Cell
Transplantation (ACBSCT). As a requirement for the reauthorization of the Stem Cell
Therapeutic and Research Act in 2015, the HRSA must report to the ACBSCT on the financial
state of the public cord blood banks (HRSA, 2016a). During these meetings, the HRSA heard
from leaders across cord blood industry and concluded that funding should be prioritized to
support CBBs that are FDA licensed or working toward licensure and actively collecting
products from underrepresented ethnic minorities (HRSA, 2016b). For public and hybrid CBBs,
the HRSA funding for cord blood collection is an important component of their budget, but they
also depend on the sale of individual products to transplant hospitals; and prioritizing FDA
licensure represents an enormous burden on the finances and resources of these organizations.
Dr. Colleen Delaney, leading cord blood researcher at the Fred Hutchinson Cancer Research
Center, shared her perspectives as a medical practitioner. She opined that FDA licensure is not a
consideration for clinicians when they select a cord blood product, but price is. A higher price
49
point for a licensed product would, in fact, discourage its selection (HRSA, 2016b). Thus, there
is not an increased demand for licensed products even though the HRSA has prioritized funding
for obtaining BLA approvals. Furthermore, despite calls by the CBB industry for the FDA to
have a uniform regulatory framework for all CBBs, either to have the licensure standards be
required for all or none, the FDA responded by stating that it had “no deadline for achieving
licensure” (HRSA, 2016a). Public and hybrid banks must, therefore, navigate the policies of both
agencies as they make business development decisions. The FDA statement in 2016 was a
critical piece of information for CBBs as they no longer had a timeline to meet. Since that
statement, only one new CBB has received BLA approval and most cord blood products
continue to be distributed and transplanted under IND rules.
Accreditation organizations also play an oversight role within the cord blood
manufacturing process. Accreditation is granted at the facility level rather than the product level,
because a contaminated product can quickly spread the risk of infection to the entire facility.
Facilities for collection, banking, or transplant may choose to seek accreditation through a
recognized organization. In the United States, the leading accreditation programs are the
American Association of Blood Banks (AABB) (AABB, 2019) and the Foundation for the
Accreditation of Cellular Therapy (FACT) (FACT, 2019). Both organizations provide
accreditation certificates for quality standards and audits of the facilities, including clinical and
laboratory operations. The accreditation process predates the FDA’s regulatory framework and
does not distinguish between Section 351 and Section 361 quality standards. Moreover,
accreditation is currently considered voluntary and not required as part of FDA compliance.
While for historical reasons, accreditation is well-regarded within the industry, it is not an
indicator of CGMP compliance. For transplant physicians, accreditation provides a measure of
50
comparing relative quality across the different CBBs (HRSA, 2016b). The HRSA also uses
accreditation as a requirement for its NCBI funding contracts. In a 2015 journal article studying
US policy on cord blood banking, researchers Matsumoto and Matthews concluded that
“uniform accreditation for both public and private CB banks” should be required to “maximize
the number of high-quality CB units that are stored, promoting patient safety and medical
efficacy” (Matsumoto and Matthews, 2015).
In addition to securing facility accreditations, the cord blood banks must also meet the
FDA’s regulatory requirements and address compliance issues as they are raised. Regulatory
assessments by the FDA are primarily conducted through facility audits. Public banks are
inspected to see if they are in compliance with both CGTP and CGMP regulations relevant to
cord blood; and if they have proper documentation to support BLAs or INDs as appropriate
(FDA, 2014). If there are findings from the FDA inspections, CBBs must respond in a timely
manner to avoid enforcement actions that could include warning letters and product recalls.
Because failures to assure accreditation and regulatory compliance could damage the reputation
of a CBB and jeopardize its standing as a license holder, institutions must dedicate considerable
resources to maintain compliant facilities and upfront costs for accreditation and, if appropriate,
INDs and BLAs. Hence, the regulatory framework for licensed cord blood depends on
financially viable cord blood banks. Examination of financial health of CBBs at the 2016
Advisory Council on Blood Stem Cell Transplantation (ACBSCT) revealed that most institutions
surveyed by the National Marrow Donor Program (NMDP) had not been profitable since 2009
and 80% of the surveyed public CBBs saw reductions in cord blood collections between 2012
and 2014 (HRSA, 2016a). Financial concerns over the BLA user fees and CGMP compliance
were cited as reasons for reduced banking activity (HRSA, 2016a). The NMDP survey also
51
revealed that many public CBBs were considering alternate product business and considering
transitioning into the hybrid model to be profitable (HRSA, 2016a). The results of the NMDP
survey were corroborated by a 2017 study conducted by the RAND Corporation to investigate
the financial sustainability of public cord blood banks (Kapinos et al., 2017). The study
participants pointed to the high cost of licensed HPC, Cord Blood as “a major deterrent to its
use” and “attributed recent increases in costs of cord blood to the costs associated with FDA
licensure” (Kapinos et al., 2017).
It is clear from the literature that the current regulatory framework for cord blood
products presents challenges and confusion for the industry. Recently, FDA issued a warning
letter to Cord for Life, a hybrid CBB in Florida, for marketing cord blood for unrelated use
without having submitted either an IND or a BLA (FDA, 2019e). This disregard, ignorance, or
misunderstanding of the Section 351 premarketing requirements is surprising to see from an
AABB accredited CBB that has been operating for more than 20 years. The following statement
by the FDA inspector points to the severe inadequacies in CGMP compliance: “Cord for Life’s
unvalidated manufacturing processes, uncontrolled environment and inadequate personnel
aseptic practices…pose a significant risk that your products may be contaminated with
microorganisms or have other serious product quality defects.” (FDA, 2019e)
This warning letter in addition to the low number of CBB licenses may reflect the
implementation challenges faced by the broader industry. Matsumoto and Matthews alluded to
these widespread challenges, concluding that surveys were needed to “address knowledge gaps”
at the CBBs and maintain public support for the National Cord Blood Inventory (NCBI)
(Matsumoto and Matthews, 2015).
52
2.3.1 Exploring CBB Industry Views
Cord blood industry professionals perform the various aspects of cord blood product
manufacturing. Manufacturing occurs at several types of institutions including collection and
research hospitals, CBBs, laboratories, and affiliated non-profit organizations. Affiliated non-
profits can serve as IND sponsors, perform manufacturing facility audits, and distribute product
to transplant centers. This research aims to understand how the regulatory framework for cord
blood has impacted the industry professionals who collect and manage those products. Product
collection is typically facilitated by clinical institutions with labor and delivery facilities. Initial
processing could occur in different settings -- directly in the delivery room by clinical staff or in
the facility’s clinical laboratory by medical technologists (Areman and Loper, 2009). Laboratory
technicians will test maternal and product samples for infectious disease (Areman and Loper,
2009). All processing steps for the product may be completed in the facility’s clinical laboratory
or be transferred to a CBB for final testing and processing. Typically, a cord blood product
undergoes minimal manipulation in the clinical laboratory, including cell washing, separation,
and centrifugation (Areman and Loper, 2009). After the product undergoes final testing for lot
release, it is cryopreserved and stored at the CBB. As requested, the CBB may utilize private
courier services and other affiliated non-profit organizations to manage distribution of frozen
product to hospitals for transplant. In the new regulatory framework, a CBB, as the BLA license
holder, would be responsible for managing affiliated organizations including contract
manufacturers. Ensuring CGMP compliance across the entire supply chain, from initial
collection to final transplantation involving differing settings and parties, would be challenging
for most CBBs and may keep them from pursuing BLA submissions.
53
The cord blood regulatory framework, now finalized through FDA guidance, has been
positioned to serve as a roadmap for developing new Section 351 HCT/Ps. As with any
regulatory policy, it is important to understand how effective that policy has been in achieving its
goals and whether it is sufficient to address the new issues that will come when products become
more sophisticated. In part, its success will depend on whether the end users who are affected by
that policy can work successfully as businesses under its constraints. This evaluation has two
different aspects that deserve special exploration.
First, how successful has the policy been to achieve its objectives with regard to creating
a sustainable cord blood banking system? To some extent, this might be inferred from certain
available metrics, such as the percentage of CBBs operating under licensure or the percentage of
annual transplanted licensed cord blood product versus product under IND. While outcome
measures like these may indicate the regulation’s state of success at a point in time, a more
thorough evaluation would benefit from a systematic study of the views of users.
Second, how effective will this roadmap be for more sophisticated biologics that may
require banked cord blood products as starting materials? Cellular product manufacturing
professionals, policymakers, and regulators may look to the cord blood guidance as a baseline
interpretation of how to apply drug CGMPs to biologic manufacturing. A recent publication from
the California-based Cord Blood Registry, described the possibilities of using banked cord blood
as starting material for next generation immunotherapy products (Brown et al., 2019). As the
cellular product industry continues to explore new product opportunities, it would be informative
to investigate current views of cord blood professionals on the implementation of CGMP
requirements at their manufacturing sites.
54
For this study, the views of the CBB industry may be aided by evaluating systematically
how the issues of CGMP compliance and licensure were viewed at different stages of
implementation. To define these stages, it was useful to apply some of the tools available
through a growing academic field of implementation research. Implementation research, initially
developed for social work, was advanced by the National Implementation Research Network into
a body of frameworks, applicable to a variety of fields (Fixsen et al., 2005). Applying
implementation research to the cord blood regulatory framework should reveal more specific
information about the current state of CGMP compliance across cord blood manufacturing and to
what degree CBBs have adopted their new status as biologic drug manufacturers.
2.3.2 Applying Implementation Science
Implementation research defines the process steps for initiating a new program. Dr. Dean
Fixsen, working with the National Implementation Research Network, is perhaps the foremost
implementation researcher of the past 15 years. Fixsen set the modern implementation definition
as a set of specified activities “designed to put into practice an activity or program of known
dimensions” and then broke the implementation process down into stages: exploration and
adoption, program installation, initial implementation, full operation, innovation, and
sustainability (Fixsen et al., 2005). These stages were revised during the Global Implementation
Conference in 2011 to exclude innovation which should only be planned once the new program
has reached target outcomes (Bertram et al., 2015).
Each phase of the implementation process is seen to have a beginning and end, though
there may be overlap in the requisite activities. During exploration and adoption, options are
considered and assessed for their potential fit within the environment (Fixsen et al., 2005).
Cross-functional stakeholder inclusion and participation are critical to understanding the
55
environment to be changed. This stage concludes with a decision about whether to continue
implementing the change or innovation (Fixsen et al., 2005).
If stakeholders decide to continue, then the process enters the program installation stage.
Program installation is characterized by the initial activities that must be accomplished before
any change can occur (Fixsen et al., 2005). Drafting new policies, creating reporting structures,
and setting expectations for success are all examples of program installation. This stage
consumes “startup costs” and resources to prepare for implementation (Fixsen et al., 2005).
The initial implementation stage is where the new program begins, and the associated
changes take place. Initial implementation is filled with complex changes for the individual,
organization, and industry levels to attempt (Fixsen et al., 2005). The tenets of change
management are relevant to the initial implementation stage. Leaders must champion multi-level
changes while dealing with individuals’ fear of change and overcoming organizational inertia
(Fixsen et al., 2005).
Full operation is the point at which the implemented changes are considered standard
practice (Fixsen et al., 2005). Full operation implies a level of mastery with new techniques and
acceptance across the implementation environment. Full operation is a steady state from which
innovative improvements can be launched (Fixsen et al., 2005). The last stage of sustainability
necessitates a long term approach to maintaining effectiveness as changes shift the environment
(Fixsen et al., 2005).
Continuous evaluation and iterative improvements are a critical component of
implementation research. All stages utilize iterative feedback loops that depend on outcomes
analysis of each implementation site (Fixsen et al., 2005). This results in lengthy feedback
56
cycles, typically spanning several years, to correct concerns at implementation sites (Fixsen et
al., 2005). In subsequent research, Fixsen and colleagues clarified that the stages were not linear
because each stage can be impacted by the others (Fixsen et al., 2009). Researchers suggested
that implementation be “thought of as components of a tight circle with two-headed arrows from
each to every component” (Fixsen et al., 2009). Based on this refined description, the figure
below depicts the implementation stages.
Figure 5: Implementation Stages
The implementation stage framework was additionally refined to integrate sustainability
into each phase of the process (Bertram et al., 2015). The activities inherent to each stage should
be conducted with a sustainability focus (Bertram et al., 2015). This long-term focus on program
operation must be considered up front to achieve sustainability.
57
Implementation research suggests that understanding the environment is critical to
success at individual implementation sites and industry-wide. However, within each type of
business or organization will be additional models or frameworks that can break the overall
program into subsectors of interest relevant to the overall policy under study. Researchers
Susanne Haga and Huntington Willard at the Institute for Genome Sciences and Policy published
a framework to categorize such policy issues in the biotechnology sector. Although created for
genomics, gene therapy products are also regulated as Section 351 products and must satisfy the
dual CGTP and CGMP FDA requirements. Therefore, the framework appears to be relevant for
cord blood products as well and was adopted and modified for this study (Haga and Willard,
2006). Policy areas are introduced as a “complex network of issues” capable of influencing each
other (Haga and Willard, 2006). Nevertheless, they regard it as useful to decompose the set of
issues into four policy analysis elements, illustrated in Figure 6, that include: operational issues,
legal & regulatory issues, economic issues, and education issues (Haga and Willard, 2006).
58
Figure 6: Biotechnology Policy Analysis Elements
This framework for approaching biotechnology policies helps identify the potential range
of policy issues on which stakeholders may have important and competing views. In the
biotechnology context, issues like these may take precedence over purely scientific concerns
(Haga and Willard, 2006). Therefore, it may be helpful to understand how the stakeholder
interests are likely to influence policy creation and ultimately shape the new strategy or direction
for a given program.
2.4 Framing the Study of Cord Blood Regulatory Policy
Fixsen’s framework of implementation stages could be an effective tool for examining
cord blood regulation using the date of draft BLA guidance as a clear starting point. The
exploration and adoption stage require all CBB industry professionals to consider the options for
distributing cord blood products under either an IND or a BLA. In this stage, CBBs decide
59
whether to pursue a license and affiliated organizations must evaluate their CGMP capabilities.
Subsequent implementation stages will increase compliance activities across the cord blood
manufacturing process. The culminating full implementation stage represents readiness for
licensure. To understand the implementation stages in context, I also consider Haga and
Willard’s biotechnology policy analysis elements. The variety of analysis issues in this
framework is intended to effectively engage all affected organizations and manufacturing
institutions. Engagement is also critical to our research questions regarding CGMP compliance
across the spectrum of cord blood collection, processing, storage, and distribution. Therefore, I
have developed a novel framework based on the combination of Fixsen’s implementation stages
and Haga and Willard’s policy analysis.
This novel research framework integrates the biotechnology policy analysis issues across
the stages of implementation. While the cord blood regulatory framework itself was established
by final guidance, our research question explores CBB industry views on the implementation of
the quality standards necessary for BLA. Current literature such as the 2017 public cord blood
banking sustainability study and 2019 FDA warning letter and consumer updates supports a
variety of implementation stages at the manufacturing sites. To understand CBB industry’s
implementation views we must, therefore, ask questions across the exploration and adoption,
program initiation, initial implementation, and full implementation stages. Fixsen’s framework
could help decompose where the adoption roadblocks are for the cord blood pathway to
licensure. The policy analysis framework is broken down into relevant issue areas that drive
consideration of multiple stakeholders impacted by these policies. This secondary framework
could help to guide areas where roadblocks might be most important. Using a combination of
implementation research framework & biotechnology policy analysis framework literature, I
60
have created the Table 4 below. The research framework’s bullet points are grouped and targeted
for the applicable respondent group. The first bullet in each box of the research framework
reflects a critical activity necessary for BLA processes. Therefore, the research survey’s
associated BLA questions were targeted to the CBB survey respondents, through branching skip
logic. The affiliated organizations responsible for product collection, distribution, and other
aspects of product manufacturing also received a group of specific survey questions. The
research framework’s second bullets reflect activities indicative of CGMP compliance. The
associated CGMP survey questions were targeted to the affiliated respondents.
61
Table 4: Research Framework
Stages of
Implementation
Operational Issues
Legal &
Regulatory Issues
Economic Issues Education Issues
Assessment
• Evaluate contract
manufacturers’
capabilities
• Explore BLA
submission
requirements
• Assess licensure
business model
• Consult with
external licensure
experts
• Evaluate
feasibility of
implementing
CGMP across
processes
• Explore CGMP
requirements for
IND product
distribution
• Assess Section
351 product
supply & demand
• Consult with
internal clinical
experts for IND
conduct
Preparation
• Implement
process control
& final product
checks
• Apply BLA
guidance &
regulatory
framework to
institution
• Consume startup
costs for
operational
changes
• Create compliant
training around
managing
product quality
• Implement
standard donor
suitability and
eligibility
requirements
• Distribute
Section 351
product under
compliant IND
• Consume
resources for
CGMP
standardization
• Create standard
training for
operations
Implementation
• Proceduralize
full CMC
standards
internally & with
contract
manufacturers
• Engage FDA in
Pre-BLA talks
• Plan for BLA
product pricing
& patent
• Establish
dedicated
personnel for
independent
Quality Control
Unit
• Proceduralize
IDM lot release
testing standards
• Engage
regulatory
agencies in
ongoing advisory
committees
• Plan for HRSA
reimbursement
for product
collection
• Establish Quality
Control Unit
capabilities
Sustainment
• Manage fully
compliant
Quality Systems
• Target BLA
submission to
FDA
• Forecast long-
term supply &
demand of
licensed product
• Sustain
compliant
procedures and
training for BLA
changes
• Manage CGMP
requirements for
collection,
processing,
storage, &
distribution
• Target
sustainable
clinical pathway
for remaining
inventoried &
novel product
• Forecast long-
term use of
investigational
inventoried
product
• Sustain CGMP
annual training
62
2.5 Summary and Research Direction
While the available literature in this chapter describes the scientific and regulatory history
of cord blood, it also points to a gap in our understanding of how the current regulatory
framework is viewed by the CBB industry. With very few institutions pursuing the BLA path for
their products, there is a clear need to understand the perceptions by the cord blood
manufacturers on challenges they face in obtaining BLA licensure. CBB industry views are also
important in identifying the barriers to CGMP compliance across the product development
implementation stages from the IND to the BLA. As highlighted in the Matsumoto and
Matthews article, continued data analysis is critical to addressing issues with “public awareness,
training, resource allocation, and other aspects” (Matsumoto and Matthews, 2015). Our research
examines these issues, and others, within the research framework using a survey methodology to
gather perspectives across the manufacturing institutions.
63
Chapter 3. Methodology
3.1 Introduction
This study used a focus group and an internet survey to investigate the CBB industry’s
views regarding the implementation of the FDA’s cord blood regulatory framework. The current
literature outlined in Chapter 2 and informal discussions with cord blood professionals helped
steer initial survey development. A focus group further refined and validated the survey
questions and the overall survey instrument to help gain the necessary data collection. The focus
group’s feedback was evaluated and implemented through associated survey changes. The
survey was administered to pre-screened professionals whose past or current positions indicated
experience with cord blood manufacturing. Respondents were guaranteed that their identities and
responses will be protected. Interested respondents were provided a copy of the survey summary
after the analysis was completed. After the survey was conducted, selected respondents were
interviewed to further understand their comments.
3.2 Survey Development and Finalization
The survey was created using the web-based survey tool, Qualtrics (www.Qualtrics.com).
The draft survey included about 25 questions in several formats, such as matrix, scaled, rank-
order, and open text. Initial questions gathered demographic information from respondents and
established their backgrounds and affiliations. Subsequent questions were organized around
assessment, preparation, implementation, and sustainment stages according to our previously
discussed framework. These implementation questions were categorized into the biotechnology
issue areas: operations, legal and regulatory, economic, and education. The current literature
drove question development to focus on quality standards necessary for licensure and the CGMP
compliance and sustainability issues at each implementation stage.
64
3.3 Focus Group Input to Survey Development
A focus group was assembled to review and provide feedback on the final survey
questions included in the Qualtrics instrument. The purpose of the focus group was to review and
approve the draft survey by critiquing its question content, clarity, and digital format. The focus
group held a live, 90-minute, meeting using online web conferencing. The meeting began with a
summary of the proposed research study, followed by a detailed discussion of the survey
questions. The meeting concluded with focus group suggestions for survey improvement. The
focus group included a combination of individuals with academic, regulatory, and business
backgrounds. The group also included three members with extensive Section 351 product
experience.
The survey was validated by multiple individuals, students and/or faculty, from the
regulatory science doctoral program. Validation confirmed that email notifications functioned
properly, responses were returned, and analysis was performed correctly. Any survey
functionality issues were identified and resolved prior to the survey launch.
3.4 Survey Deployment and Data Analysis
Potential survey respondents were selected based on their publicly available work
experience with cord blood and professional associations. These individuals were contacted prior
to survey deployment to confirm that they were appropriate to take the survey and gauge their
inclination to participate. A survey was disseminated to all willing respondents through the
researcher’s academic email. Qualtrics Insights Platform software was used to create and send an
introductory invite, a follow-up reminder message for individuals who had not completed the
survey, and a closing thank you message. The survey could be forwarded by respondents to other
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individuals whom they felt were appropriate respondents given their knowledge of Section 351
products, specifically HPC, Cord Blood.
The survey link was also shared in person with attendees of the National Marrow Donor
Program (NMDP) ONE Forum annual conference held November 7-9, 2019. This conference’s
stated goal was to educate cellular therapy industry professionals on emerging technology and
best practices (Be The Match, 2019c) and is typically well attended by our desired respondent
pool of public CBB professionals. Attendees were approached during unscheduled time used for
professional networking. They either accessed the survey in person on a provided iPad or
accessed the survey via invitation email at a later time.
A summary of survey results was offered to all respondents who completed the survey as
an incentive for their participation. Respondents were assured that all identifying data was
anonymized in the survey summary as well as any future publications. Qualtrics sent confirmed
respondents an email link to the survey. The target response rate for this study was 50 surveys in
which the respondents answered at least 75% of questions. Qualtrics sent a follow-up reminder
email to encourage individuals who had not responded to complete the survey. Final reminder
emails were also sent prior to the survey closure.
Survey results were collected and stored electronically. The survey instrument, Qualtrics,
automatically calculated the statistical data including percentages, counts, minimums,
maximums, standard deviations, variances, and means. The responses to open-ended questions
underwent content analysis for trends or commonalties.
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Chapter 4. Results
4.1 Survey Logistics
The survey was distributed from early November through early December 2019 to 72
individuals. The individuals who received the survey were identified as having suitable
credentials to participate through the researcher’s professional network, through search and
connections of a public social media platform, or additional recommendations from survey
respondents. The survey period closed on December 2, 2019. Fifty-six messages with personal
and anonymous survey links were opened and started, and 55 (98%) of the respondents
completed the survey. Hence, the overall response rate is 76% (55/72). One respondent
concluded the survey through a follow-up interview, providing additional thoughts on the BLA
pathway. Transcribed quotes from the interview were manually added to the participant’s
individual survey comments and are denoted with an asterisk (*) in their associated data.
4.2 Profiles and Background of Respondents
Survey respondents were cord blood bank and/or affiliated organization personnel who
have had experience with Section 351 biologic drug product manufacturing. When asked to
select the department or function that best described their current role, most respondents reported
Administrative/Director/Program Manager (36%, 20/55) or Quality Assurance, Quality Control,
and/or Regulatory Affairs (29%, 16/55) with eight respondents in the Clinical Affairs and/or
Medical Researcher role and five in the Laboratory Technologist Services department. Six
respondents listed Other, of whom two identified themselves as consultants and another two as
retired administrative roles (Figure 7).
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Figure 7: Distribution of Respondents by Department
What department or function best describes your current role? Choose one option. (n=55)
Respondents who selected Administrative/Director/Program Manager were also asked to
specify their full title in the space provided. Of the 20, more than half were at the director level
(60%,12/20), with 30% (6/20) at the manager level, and 10% (2/20) at the executive level
(Table 5).
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Table 5: Administrative/Director/Program Manager Titles
Title
Assistant Director of Cord Blood
CBB Collection Manager
Cell Therapy Manager
Chief Operating Officer
Collection Experience Manager
Cord Blood Program Manager
Director
Director
Director
Director Quality Management
Director, Laboratory Services
Director, RA & Quality
Executive Director
Laboratory Manager
Medical Director
Regional Director, Donor Services
Senior Director
Senior Manager of Operations
Sr. Admin Director Processing
Vice President
To gauge their level of experience, survey respondents were asked about the length of
time that they were employed in their current role. Around half of respondents had six years or
more in their current role (51%, 28/55), 31% (17/55) reported three to six years and 18% (10/55)
reported between zero to two years of experience (Figure 8).
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Figure 8: Respondent Experience in Current Role
I have been working in this role for… (n=55)
To understand the distributions of organizational affiliations represented by the
respondents, they were asked to select the type of organization that best represented their work
experience from the list provided in Figure 9. Most respondents were employed by a CBB (45%,
25/55), followed by non-profit organizations that sponsor INDs, distribute product, and/or audit
manufacturing facilities (33%,18/55), collection hospitals or facilities (11%, 6/55), free-standing
or hospital/university-based laboratories (7%, 4/55), and Other (4%, 2/55). The two in the Other
category specified that they were regulatory consultants.
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Figure 9: Distribution of Respondents by Organizational Affiliation
What type of organization/company best represents your work experience? Choose one option.
(n=55)
4.3 Experiences with BLA Process
Survey respondents were asked whether they were experienced with supporting licensed
CBBs. A majority of respondents were experienced with supporting one or more of the licensed
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CBBs (60%, 31/21) while 40% (21/52) did not have such experience and their work was
confined to IND manufacturing (Figure 10).
Figure 10: Experience Supporting a Licensed CBB
In your current or past experience, has your work supported a CBB holding an approved BLA
from FDA for HPC, Cord Blood? (n=52)
The 31 respondents from above with experience supporting licensed CBBs were queried
further regarding their direct BLA involvement. The division of responses was similar with
slightly more than half of respondents (55%, 17/31) reporting that they did not have direct
involvement with a CBB’s BLA, while 45% (14/31) of respondents reported that they did have
direct BLA involvement (Figure 11). These 14 respondents with direct involvement in a BLA
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were asked five additional questions described below to further probe their views on the BLA
process.
Figure 11: Experience with the BLA Process
Were you directly involved with a CBB’s BLA to FDA? (n=31)
4.3.1 Views of Respondents with BLA Experience
To understand organizational motivations for pursuing BLAs, the 14 respondents above
(Figure 11) who reported that they were involved with the planning and/or submission of a BLA
to FDA were asked to select their views on the drivers for applying for the BLA (Figure 12).
Because respondents were instructed to select all that applied, the total number of responses (32)
exceeded the number of respondents (14). Most respondents selected FDA expectations (38%,
12/32) as a BLA driver, followed by internal organization expectations (34%, 11/32), and Other
(16%, 5/32). Three of the five who selected other specified the driver of government NCBI
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funding in the space provided. The remaining drivers were customer expectations (9%, 3/32) and
patient expectations (3%, 1/32).
Figure 12: BLA Application Drivers
What were the drivers for applying for BLA (select all that apply)? (n=14)
The respondents in this group were asked to share their views regarding the performance
of the FDA’s review division by providing their level of agreement with four statements listed.
As can be seen in Figure 13, almost all respondents agreed with three out of the four statements.
The highest level of agreement was associated with the statement FDA was willing to work with
sponsors to find feasible solutions (strongly agree: 43%, 6/14; somewhat agree: 50%, 7/14;
disagree: 7%, 1/14), followed by FDA was knowledgeable about the cord blood product
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(strongly agree: 21%, 3/14; somewhat agree: 58%, 8/14; disagree: 21%, 3/14), and FDA was
knowledgeable about the transplant industry (strongly agree: 14%, 2/14; somewhat agree: 65%,
9/14; disagree: 21%, 3/14). In contrast, only half of the respondents agreed with the statement
The FDA submission and review process were straightforward and navigable for sponsors
(strongly agree: 14%, 2/14; somewhat agree: 36%, 5/14; disagree: 50%, 7/14).
Figure 13: FDA Review Division Viewpoints
Thinking about your BLA experience with FDA’s review division, please rank your agreement
with the following statements. (n=14)
Provided with a list of seven resources, the respondents were asked to what extent they
were helpful when deciding to pursue a BLA (Table 6). Of the three FDA resources, direct
discussion/meetings with the FDA was thought to be most helpful (very helpful: 83%, 10/12;
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helpful: 17%, 2/12), followed by the FDA guidance documents (very helpful: 50%, 6/12; helpful:
50%, 6/12), and the FDA website (helpful: 75%, 9/12; not helpful: 25%, 3/12).
Of the three industry resources, dialogue with industry peers was thought to be most
helpful (very helpful: 42%, 5/12; helpful: 42%, 5/12; not helpful: 17/%, 2/12) followed by
consultant groups/firms (very helpful: 17%, 2/12; helpful 66%, 8/12; don’t know: 17%, 2/12)
and industry association recommendations (very helpful: 17%, 2/12; helpful: 58%, 7/12; not
helpful: 25%, 3/12).
Literature, advisory meetings, and seminars/ conferences were viewed as less helpful
than FDA and industry resources. Two out of three respondents (66%, 8/12) considered literature
publications as helpful while one out of three found them not helpful (34%, 4/12). Views
regarding advisory committees and minutes were equally divided between helpful (very helpful:
17%, 2/12; helpful: 33%, 4/12) and unhelpful (50%, 6/12). Similarly, half of respondents found
seminars/conferences as not helpful (50%, 6/12), while 42% (5/12) found them as helpful, and
one respondent selected “I do not know”.
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Table 6: Helpful BLA Resources
To what extent were these resources helpful when deciding to pursue a BLA? (n=12)
When this subgroup of respondents was asked whether more FDA guidance materials
were needed to help with the decision to apply for BLAs, 12 out of the 14 provided their
responses (Figure 14). 75% (9/12) of the response group did not think that additional FDA
guidance materials were needed while 25% (3/12) did.
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Figure 14: Necessity of Additional FDA Guidance
In your opinion, are more FDA guidance materials needed to help with the decision to apply for
BLA? (n=12)
This subgroup of respondents was also asked to provide suggestions for additional
resources that might be helpful for making BLA decisions. Of the six respondents who provided
full text comments, four felt some type of additional FDA access would be helpful (Table 7).
Table 7: Additional Resource Suggestions
What additional resources might be helpful? (n=6)
Additional Resources
Time and money
Expanded FDA personnel resources to support application process
Someone who has been through the BLA process is essential
Online chat for timely responses
More FDA conferences for direct guidance on filings, etc. FDA info not info from
peers.
FDA consulting arm to assist inexperienced organizations with their initial
submissions
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4.3.2 Views of Respondents without BLA Experience
Using survey skip logic, the 25 respondents who identified as CBB professionals
(Figure 9) were cross analyzed against the 21 respondents who reported no experience with
licensed CBBs (Figure 10). The resulting subgroup was composed of 11 respondents who both
identified as CBB professionals and were inexperienced with BLAs. These respondents were
asked to select if their organizations were planning to submit a BLA in the short term (1-5 yrs),
in the future (6-10 yrs), or not at all (Figure 15). Most respondents in this group indicated that
they were not planning to pursue BLAs (55%, 6/11), while 27% (3/11) indicated that they were
considering BLAs in the short term (1-5 yrs), and 18% (2/11) in the mid-term future (6-10 yrs).
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Figure 15: Current Stage of BLA Planning
What is your organization’s current stage of planning for BLA? (n=11)
The six respondents above who indicated that their organization was not planning to
pursue BLAs were asked to rank order the barriers that impacted this decision. The respondents
were provided with a list of four barriers, operational, legal & regulatory, financial & economic,
and education & training, which were derived from the policy area issues in my research
framework from Table 4. Respondents participated by ranking these barriers from one to four
with one being the top barrier (Table 8). To understand how the respondents viewed the different
barriers, the rankings were weighted with one being the top barrier and four being the lowest. For
each item, the weighted scores were added and then divided by number of respondents to obtain
the weighted mean. Of the five who provided their responses, most ranked the financial &
economic barrier as the top barrier (weighted mean: 1.2; #1: 4/5; #2: 1/5; #3: 0/5; #4: 0/5),
followed by operational (weighted mean: 1.8; #1: 1/5; #2: 4/5; #3: 0/5; #4: 0/5), legal &
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regulatory (weighted mean: 3.2; #1: 0/5; #2: 0/5; #3: 4/5; #4: 1/5), and education & training
(weighted mean: 3.8; #1: 0/5; #2: 0/5; #3: 1/5; #4: 4/5).
Table 8: Ranked Barriers to Pursuing a BLA
Your organization is not planning to pursue BLA. Please rank the barriers that influenced this
decision. (n=5)
Barriers
Rank 1 2 3 4
Weighted
Mean
Weight 1 2 3 4
Financial & economic
4 1 0 0 1.20
Operational
1 4 0 0 1.80
Legal & regulatory
0 0 4 1 3.20
Education & training
0 0 1 4 3.80
4.4 Views on Current FDA Requirements
All survey respondents were asked a series of questions to probe their views on the
stringency of the current FDA requirements for HPC, Cord Blood as they are applied to the IND
and BLA regulatory frameworks. The questions were categorized into manufacturing process
requirements, manufacturing distribution requirements, and submission, reporting, and
inspection requirements.
4.4.1 Manufacturing Process Requirements
The seven manufacturing process requirements displayed in Figure 16 (IND) and
Figure 17 (BLA) were derived from literature and FDA regulation. For IND manufacturing
process requirements, 73%-90% of respondents thought that the level of stringency was about
right for all items listed. Specifically, Infectious Disease Marker (IDM) testing requirements
received the highest about right response (about right: 90%, 43/48; too strict: 6%, 3/48; don’t
know: 4%, 2/48), followed by product collection requirements (about right: 86%, 43/50; too
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lenient: 6%, 3/50; don’t know: 6%, 3/50; too strict: 2%, 1/50), and product testing requirements
(about right: 78%, 39/50; too lenient: 8%, 4/50; don’t know: 8%, 4/50; too strict: 6%, 3/50). The
batch record requirement was viewed similarly (about right: 80%, 39/49; too strict: 4%, 2/49; too
lenient: 6%, 3/49; don’t know: 10%, 5/49). The requirements for production and processing
controls received slightly lower about right response (about right: 74%, 36/49; too strict: 6%,
3/49; too lenient: 6%, 3/49; don’t know: 14%, 7/49), followed by quality control unit
requirements (about right: 73%, 35/48; too lenient: 15%, 7/48; too strict: 6%, 3/48; don’t know:
6%, 3/48), and process validation requirements (about right: 66%, 32/49; too lenient: 10%, 5/49;
too strict: 8%, 4/49; don’t know: 16%, 8/49). The batch record, production & processing, and
production and processing requirements received the highest responses for do not know.
Figure 16: Views on IND Manufacturing Process Requirements
In your opinion, do you think the FDA’s IND manufacturing process requirements for HPC,
Cord Blood products in the following areas are:
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Following the same question format, respondents were asked to provide their views on
the BLA manufacturing process requirements. Compared to the IND requirements, the views of
the respondents on the BLA manufacturing process requirements were more varied across the
different items (Figure 17). While product collection and Infectious Disease Marker (IDM)
testing requirements for the BLA were viewed similarly to the IND requirements as about right,
the three items under manufacturing quality system requirements were viewed as too strict by
nearly half of the respondents. Specifically, the highest about right response for the BLA was
product collection (about right: 74%, 34/46; too strict: 9%, 4/46; too lenient: 4%, 2/46; don’t
know: 13%, 6/46), followed by IDM testing requirements (about right: 39/46; too strict: 7%,
3/46; don’t know: 9%, 4/46), with required product testing (about right: 74%, 34/46; too strict:
9%, 4/46; too lenient: 4%, 2/46; don’t know: 13%, 6/46), and batch record requirement (about
right: 62%, 29/47; too strict: 17%, 8/47; too lenient: 2%, 1/47; don’t know: 19%, 9/47). In
contrast to the IND requirements, the BLA production and processing controls were considered
too strict (too strict: 41%, 19/46; about right: 35%, 16/46; too lenient: 2%, 1/46; don’t know:
22%, 10/46), followed by the BLA quality control unit requirement (too strict: 36%, 17/47; about
right: 47%, 22/47; too lenient: 2%, 1/47; don’t know: 15%, 7/47), and the BLA process
validation requirement (too strict: 45%, 21/47; about right: 32%, 15/47; too lenient: 4%, 2/47;
don’t know: 19%, 9/47). The batch record, production & processing, and production and
processing requirements also received the highest responses for do not know.
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Figure 17: Views on BLA Manufacturing Process Requirements
In your opinion, do you think the FDA’s BLA manufacturing process requirements for HPC,
Cord Blood products in the following areas are:
4.4.2 Manufacturing Distribution Requirements
Respondents were asked to gauge the stringency of FDA’s manufacturing distribution
requirements using the four-point scale shown in Figure 18 (IND) and Figure 19 (BLA). For IND
manufacturing distribution, most respondents found the requirements to be about right (between
78-88%). Specifically, the highest about right responses were for packaging and labeling controls
(about right: 88%, 43/49; too strict: 2%, 1/49; too lenient: 2%, 1/49; don’t know: 8%, 4/49) and
the storage and distribution requirement (about right: 88%, 43/49; too lenient: 6%, 3/49; don’t
know: 6%, 3/49), followed by the vendor management and qualification requirement (about
right: 78%, 38/49; too strict: 6%, 3/49; too lenient: 8%, 4/49; don’t know: 8%, 4/49).
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Figure 18: Views on IND Manufacturing Distribution Requirements
In your opinion, do you think the FDA's IND manufacturing distribution requirements for HPC,
Cord Blood products in the following areas are: (n=48)
Following the same question format, respondents were asked to gauge the level of
stringency for the BLA manufacturing distribution requirements (Figure 19). While respondents
generally agreed that the BLA manufacturing distribution requirements were about right (52%-
81%), vendor management and qualification was specifically viewed as more challenging. The
highest about right responses for the BLA were for the packaging and labeling controls
requirement (about right: 81%; 39/48; too strict: 6%, 3/48; don’t know: 13%, 6/48) and storage
and distribution requirement (about right: 79%, 37/47; too strict: 8%, 4/47; too lenient: 2%, 1/47;
don’t know: 15%, 7/48). By contrast, about half of the respondents viewed vendor management
and qualification requirements as about right (about right: 52%, 25/48; too strict: 31%, 15/48; too
lenient: 2%, 1/48; don’t know: 15%, 7/48).
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Figure 19: Views on BLA Manufacturing Distribution Requirements
In your opinion, do you think the FDA's IND and BLA manufacturing distribution requirements
for HPC, Cord Blood products in the following areas are:
4.4.3 Submission, Reporting, and Inspection Requirements
Respondents were also asked to gauge the level of stringency of FDA’s submission,
reporting, and inspection requirements for INDs (Figure 20) and BLAs (Figure 21). For IND
requirements, most respondents (66%-76%) found the requirements to be about right for all
items listed. Specifically, the highest about right response was for the IND reporting requirement
(about right: 76%, 37/49; too strict: 10%, 5/49; too lenient: 4%, 2/49; don’t know: 10%, 5/49),
followed by the IND submissions requirement (about right: 68%, 33/49; too strict: 10%, 5/49;
too lenient: 10%, 5/49; don’t know: 12%, 6/49), and the IND inspection requirement (about
right: 66%, 32/49; too strict: 8%, 4/49; too lenient: 12%, 6/49; don’t know: 14%, 7/49).
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Figure 20: Views on IND Submission, Reporting, and Inspection Requirements
In your opinion, do you think the FDA's IND regulatory requirements for HPC, Cord Blood
products in the following areas are: (n=49)
The respondents were then asked to gauge the level of stringency of FDA’s submission,
reporting, and inspection requirements for BLAs (Figure 21). In contrast to the IND
requirements, only 33-44% of respondents viewed the submissions, reporting, and inspections
requirements for BLAs as about right. Most respondents viewed two out of the three
requirements to be too strict. The highest about right response was for reporting requirements
(about right: 44%, 20/46; too strict: 37%, 17/46; too lenient: 2%, 1/46; don’t know: 17%, 8/46).
In comparison, most respondents viewed submissions as too strict (too strict: 46%, 21/49; about
right: 33%, 15/49; too lenient: 2%, 1/49; don’t know: 19%, 9/49), followed by inspections (too
strict: 42%, 19/46; about right: 35%, 16/46; too lenient: 4%, 2/46; don’t know: 19%, 9/46).
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Figure 21: Views on BLA Submission, Reporting, and Inspection Requirements
In your opinion, do you think the FDA's BLA regulatory requirements for HPC, Cord Blood
products in the following areas are: (n=49)
4.5 Views on the BLA Framework
In this section, the respondents were asked about their views on the positive impact and
the challenges posed by the existing BLA regulatory framework.
4.5.1 The Impact of BLA Requirements
The respondents were asked whether the FDA’s BLA regulatory requirements resulted in
improvement with respect to patient safety, product quality, CBB differentiation, as well as
standardization across CBBs and collection hospitals (Figure 22). Most commonly, respondents
identified that the requirements had improved standardization across CBBs (agree: 47%, 23/49;
disagreed: 16%, 8/49; neutral: 37%, 18/49), product quality (agreed: 42%, 21/49; disagreed:
29%, 14/49; neutral: 29%, 14, 49), and standardization across collection hospitals (agree: 37%,
18/49; disagree: 26%, 13/49; neutral: 37%, 18/49). In comparison, respondents were more
commonly neutral about the impact of the BLA requirements to differentiate across CBBs
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(neutral: 45%, 22/49; agree: 31%, 15/49; disagree: 24%, 12/49) and more commonly disagreed
that the requirements improved patient safety (disagree: 40%, 20/49; agree: 27%, 13/49; neutral:
33%, 16/49).
Figure 22: BLA Regulatory Requirement Impacts
In my opinion/experience, FDA's BLA regulatory requirements for HPC, Cord Blood has had the
following impacts. (n=49)
4.5.2 The Challenges of Pursuing a BLA
To understand the nature of challenges associated with obtaining a BLA, respondents
were asked to reflect on the adequacy of resources available to pursue licensure, the level of
difficulty associated with the transition from the IND to the BLA, and the overall barriers to
BLA adoption.
Most respondents identified that they did not have sufficient resources in all five areas
provided in Figure 23. Funding was overwhelmingly viewed as an area in which they did not
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have sufficient resources (no: 82%, 40/49; yes: 4%, 2/49, don’t know: 14%, 7/49), followed by
personnel (no: 65%, 32/49; yes: 25%, 12/49; don’t know: 10%, 7/49), regulatory expertise (no:
59%, 29/49; yes: 29%, 14/49; don’t know: 12%, 6/49), CGMP expertise (no: 57%, 28/49;
yes:35%, 17/49; don’t know: 8% 4/49), and facility and equipment (no: 49%, 24/49; yes: 35%,
17/49; don’t know: 16%, 8/49).
Figure 23: CBB Industry Resources to Meet BLA Requirement
Do you think the public Cord Blood Banking industry has adequate resources to meet the FDA's
regulatory requirements for HPC, Cord Blood products? (n=49)
Respondents were also asked to reflect on the level of difficulty to transition from CGMP
for IND to CGMP for BLA (Figure 24). All but one respondent viewed the transition as difficult
(very difficult: 39%, 19/49; moderately difficult: 43%, 21/49; slightly difficult: 16%, 8/49; not
difficult at all: 2%, 1/49), and most viewed it as very to moderately difficult.
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Figure 24: Level of Difficulty Transitioning CGMP from IND to BLA
In your view, what is the level of difficulty to transition from CGMP for cord blood
investigational studies (IND) to CGMP for cord blood Biologic License Application (BLA)?
(n=49)
Finally, respondents were asked to rank order the barriers to obtaining a BLA (Table 9).
Respondents participated by ranking these barriers from one to four with one being the top
barrier. To understand how the respondents viewed the different barriers, the rankings were
weighted with one being the top barrier and four being the lowest. For each item, the weighted
scores were added and then divided by number of respondents to obtain the weighted mean. The
majority of respondents ranked the top barrier as financial & economic (weighted mean: 1.8; #1:
28/47; #2: 7/47; #3: 5/47; #4: 7/47), followed by operational (weighted mean: 1.9; #1: 12/47; #2:
25/47; #3: 9/47; #4: 1/47), legal & regulatory (weighted mean: 2.7; #1: 5/47; #2: 10/47; #3:
25/47; #4: 7/47), and education & training (weighted mean: 3.4; #1: 2/47; #2: 5/47; #3: 8/47; #4:
32/47).
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Table 9: Ranked Barriers to Obtaining a BLA
What is the most significant barrier to obtaining a BLA in your view? Please rank the following.
(n=47)
Barriers
Rank 1 2 3 4
Weighted
Mean
(SD)
Weight 1 2 3 4
Financial & economic
28 7 5 7
1.8
(0.03)
Operational
12 25 9 1
1.9
(0.04)
Legal & regulatory
5 10 25 7
2.7
(0.05)
Education & training
2 5 8 32
3.4
(0.06)
4.6 Barriers to BLA Implementation
Survey skip logic was employed to sub stratify the respondent pool based on their
employment. Respondents who self-identified with Cord Blood Banks received a block of
questions regarding the BLA process. Respondents who self-identified with an affiliate
organization involved in aspects of cord blood manufacturing received a separate block of
questions regarding CGMP compliance. The affiliated subset of respondents included
professionals responsible for product collection, distribution, and other aspects of cord blood
manufacturing. The questions were composed based on the research framework detailed in
Table 4.
4.6.1 Views of CBBs
Survey respondents who were employed by CBBs (45%, 25/55) were asked a subset of
questions to obtain their views and experiences associated with the BLA activities across
different stages of implementation. This subset of survey questions was completed by 80%
(20/25) of the CBB respondents.
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4.6.1.1 Assessment and Preparation Stages of BLA
The CBB respondents were asked to gauge the level of difficulty faced during the
assessment stage of the BLA process (Figure 25). To take into consideration varying numbers of
“do not know” responses and the levels difficulties, the responses were weighted with one for
“very difficult”, two for “difficult”, three for “not difficult”, and zero for “do not know”. For
each activity, the weighted scores were added and then divided by number of respondents to
obtain the weighted mean. The most difficult activity is shown with the lowest weighted mean
score. The majority of CBB respondents found all four activities to be “very difficult” or
“difficult”.
The highest degree of difficulty was associated with securing funding for operational
changes (weighted mean: 1.3; very difficult: 65%, 13/20; difficult: 25%, 5/20; do not know:
10%, 2/20), followed by evaluating collection hospitals’ ability to meet CGMP requirements
(weighted mean: 2.0; very difficult: 20%, 4/20; difficult: 50%, 10/20; not difficult: 25%, 5/20; do
not know: 5%, 1/20), and assessing the BLA submissions requirements (weighted mean: 2.0;
very difficult: 20%, 4/20; difficult: 55%, 11/20; not difficult: 25%, 5/20). The activity evaluating
Cord Blood Bank’s ability to meet CGMP requirements was also viewed as difficult (weighted
mean: 2.3; very difficult: 5%, 1/20; difficult: 55%, 11/20) but received the most responses (40%)
for not difficult (8/20).
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Figure 25: Difficulty of BLA Assessment Activities
When a Cord Blood Bank initially assesses the BLA process, how difficult are the following
activities in your opinion? (n=20)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
Following the same question format, the CBB respondents were asked to gauge the level
of difficulty faced during the preparation stage of the BLA (Figure 26). The majority of
respondents found three of the four activities to be “very difficult or “difficult”. When the same
weighting structure was applied to the responses, the highest degree of difficulty was associated
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with implementing facility changes (weighted mean: 1.5; very difficult: 50%, 10/20; difficult:
45%, 9/20; not difficult: 5%, 1/20), followed by developing a BLA business model (weighted
mean: 1.8; very difficult: 25%, 5/20; difficult: 55%, 11/20; not difficult: 10%, 2/20; do not know:
10%, 2/20), and implementing process controls & final product testing (weighted mean: 1.9;
very difficult: 30%, 6/20; difficult: 50%, 10/20; not difficult: 5%, 1/20). In contrast to the other
activities, the majority of respondents viewed training personnel on CGMP as not difficult
(weighted mean: 2.5; not difficult: 60%, 12/20; very difficult: 10%, 2/20; difficult: 30%, 6/20).
Figure 26: Difficulty of BLA Preparation Activities
When a Cord Blood Bank prepares for the BLA process, how difficult are the following
activities? (n=20)
Weighted means and standard deviations are displayed next to each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
These respondents were asked to share any additional comments they may have regarding
the assessment and preparation for the BLA process. Comments were received from six
respondents (30%, 6/20) of whom four referred to financial and economic challenges as reflected
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in the bolded words, “money” and “expensive”. The complete comments are displayed below in
Table 10.
Table 10: CBB Comments on BLA Assessment & Preparation
Please provide any additional comments regarding the assessment and preparation for the BLA
process. (n=6)
Additional Comments
It is helpful if the facility can afford to dedicate staff to completing the BLA process
only. We are a small organization and we had to handle daily activities in addition to
preparing for the BLA submission. (Respondent 44)
My responses are specific to my organization and/or are insights shared with me by
others who have already been down the BLA path. We hired a consultant to help
advise on exactly what's required, because it's not very clear or evident and very little
literature is available on details concerning documents created for submission. Our
IND experience has also been difficult so far, but not as confusing as getting
acquainted with specific BLA requirements. (Respondent 29)
It all takes time and money that most banks can't afford. (Respondent 26)
Very expensive up front. (Respondent 22)
This process is very time consuming and expensive. In my experience it has been very
difficult to secure funding for cord blood BLA in a time when cord blood
transplantation is in decline. The business case just doesn't outweigh the cost of the
BLA right now. (Respondent 14)
There was value in going through the BLA process for our facility. In the laboratory,
we are manufacturing other products that are being used as raw material and going
into regulated products. So there was value in learning the GMP language and
establishing good relationships at FDA. This has been beneficial when we put in other
INDs. However, it is much more expensive to run the bank. This is a unique product
with lots of IND product still in use, so we’ve kept track of the data and there is no
difference in either the quality of the units or outcomes of the patients. FDA is
encouraging manufacturers to use licensed raw material for further manufacturing so,
in that way, we are differentiated. Today there is more attention paid to regulation and
the FDA continues to say that we should all move in the right direction, meaning
pursue BLA, but they aren’t enforcing it. I think the fact that they aren’t enforcing it
has hurt the industry’s impression of the regulations. With the new MSC and CAR-T
products, there is attention paid to the administration of the product in the clinic being
GMP. However, I think there is still work to be done establishing the line between
practice of medicine and regulations. It is better for the patient to have flexibility.
(Respondent 11)
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4.6.1.2 Implementation and Sustainment Stages of BLA
The CBB respondents were asked to gauge the level of difficulty faced during the
implementation stage of the BLA process (Figure 27). The responses were weighted with one for
“very difficult”, two for “difficult”, three for “not difficult”, and zero for “do not know”. The
highest degree of difficulty was associated with responding to FDA’s BLA submission review
requests (weighted mean: 2.1; very difficult: 15%, 3/20; difficult: 30%, 6/20; not difficult: 25%,
5/20; do not know: 30%, 6/20), followed by standardizing processes across collection hospitals
and vendors (weighted mean: 2.2; very difficult: 15%, 3/20; difficult: 45%, 9/20; not difficult:
30%, 6/20; do not know: 10%, 2/20), establishing product pricing & reimbursement (weighted
mean: 2.2; difficult: 45%, 9/20; not difficult:15%, 3/20; do not know: 40%, 8/20), training a
Quality Control Unit for product release (weighted mean: 2.5; very difficult: 5%, 1/20; difficult:
35%, 7/20; not difficult: 50%, 10/20; do not know: 10%, 2/20), and engaging FDA in pre-BLA
dialogue (weighted mean: 2.5; very difficult: 10%, 2/20; difficult: 10%, 2/20; not difficult: 45%,
9/20; do not know: 35%, 7/20).
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Figure 27: Difficulty of Implementing BLA Activities
When a Cord Blood Bank implements a BLA, how difficult are the following activities in your
opinion? (n=20)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
The CBB respondents were asked to gauge the level of difficulty faced during the
sustainment stage of the BLA process (Figure 28). Most respondents viewed all four activities as
difficult (“very difficult” and “difficult” responses)”. When the same weighting structure was
applied to the responses, the highest degree of difficulty was associated with forecasting product
supply & demand (weighted mean: 1.7; very difficult: 25%, 5/20; difficult: 35%, 7/20; not
difficult: 5%, 1/20; do not know: 35%, 7/20), followed by performing BLA process change
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management (weighted mean: 1.8; very difficult: 25%, 5/20; difficult: 50%, 10/20; not difficult:
10%, 2/20; do not know: 15%, 3/20), and responding to FDA inspection (weighted mean: 2.1;
very difficult: 20%, 4/20; difficult: 35%, 7/20; not difficult: 30%, 6/20; do not know (15%, 3/20).
The lowest degree of difficulty was associated with sustaining CGMP compliant Quality Systems
(weighted mean: 2.3; very difficult: 15%, 3/20; difficult: 30%, 6/20; not difficult: 40%, 8/20; do
not know (15%, 3/20).
Figure 28: Difficulty of Sustaining BLA Process Activities
When a Cord Blood Bank works to sustain BLA processes, how difficult are the following
activities in your opinion? (n=20)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
These respondents were asked to share any additional comments regarding the
implementation and sustainment of the BLA processes. Comments were received from four
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respondents (20%, 4/20). Three of the four comments referred to operational barriers and legal
and regulatory challenges as reflected in the bolded words “changes” or “change management”.
The complete comments are displayed below in Table 11.
Table 11: CBB Comments on BLA Implementation & Sustainment
Please provide any additional comments regarding implementing a BLA and sustaining the BLA
processes. (n=4)
Additional Comments
Sustaining is time consuming and costly overhead but not in context of difficulty.
(Respondent 24)
Understanding time and personnel requirements at the outset of the BLA project has
not been as straightforward as our executive team imagined it should be.
Communicating regulatory constraints and resource deficiencies is impossible without
an impartial consultant SME. While we are far from submission, the experience of
other licensed banks that we work with has almost always been harrowing--at
preparation, planning and execution, but most certainly and even more painfully with
regard to sustaining licensure requirements and the increased reporting, change
management, and other multifarious maintenance procedures that quickly drain
energy and resources required for day-to-day operations. (Respondent 29)
Managing aging equipment and/or no longer supported equipment/supplies is
challenging after a BLA licensure is awarded. The amount of work and time to
support any change to the process can be burdensome. Plan ahead as much as
possible. (Respondent 44)
Amendments to the original BLA are very challenging. New requirements and
interpretations of regulation/guidance introduced by FDA reviewers during review
process have caused delays in over a year to implement changes. (Respondent 26)
*The FDA’s Team Biologics inspects one-year post-licensure and then every two
years after. There were inconsistences between the inspector’s interpretation of
CGMP for operations and the pre-established interpretation with CBER’s BLA
reviewers. The directors of all licensed banks and a representative from NMDP met
with FDA to discuss inconsistencies. The resolution was to send a CBER
representative with Team Biologics on all post-licensure audits. (Respondent 11)
4.6.2 Views of the Affiliated Organizations
Survey respondents who were employed by affiliated organizations in Figure 9 (55%,
30/55; non-profit organizations that sponsor INDs, distribute product, and/or audit manufacturing
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facilities: 33%,18/55, collection hospitals or facilities: 1%, 6/55, free-standing or
hospital/university-based laboratories: 7%, 4/55, and regulatory consultants: 4%, 2/55) were
asked a subset of questions to obtain their views and experiences associated with CGMP
compliance activities across different stages of implementation. This subset of survey questions
was completed by 90% (27/30) of the affiliated respondents and followed the same question
format as the CBB subgroup questions.
4.6.2.1 Assessment and Preparation Stages of CGMP
The affiliated respondents were asked to gauge the level of difficulty faced during the
assessment and preparation stages for CGMP compliance (Figure 29). To take into consideration
varying numbers of “do not know” responses and the levels difficulties, the responses were
weighted with one for “very difficult”, two for “difficult”, three for “not difficult”, and zero for
“do not know”. The majority of affiliated respondents found three out of the four activities to be
“very difficult” or “difficult”. When the weighting structure was applied to the responses, the
highest degree of difficulty was associated with the activity performing vendor qualification
(weighted mean: 1.9; very difficult: 22%, 6/27; difficult: 59%, 16/27; not difficult: 15%, 4/27; do
not know: 4%, 1/27), followed by assessing CGMP requirements for IND conduct in operations
(weighted mean: 2.0; very difficult: 19%, 5/27; difficult: 48%, 13/27; not difficult: 22%, 6/27; do
not know: 11%, 3/27), and evaluating the facility’s ability to meet CGMP requirements
(weighted mean: 2.0; very difficult: 30%, 8/27; difficult: 26%, 7/27; not difficult: 33%, 9/27; do
not know: 11%, 3/27). In contrast to the other activities, most respondents found assessing
product supply & demand to be not difficult (weighted mean: 2.4; very difficult: 11%, 3/27;
difficult: 33%, 9/27; not difficult: 45%, 12/27; do not know: 11%, 3/27).
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Figure 29: Difficulty of Assessing CGMP Compliance Activities
When an organization initially assesses CGMP compliance, how difficult are the following
activities in your opinion? (n=27)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
Following the same question format, the affiliated respondents were asked to gauge the
level of difficulty faced during the preparation stage for CGMP compliance (Figure 30). The
majority of respondents found all four activities to be “very difficult” or “difficult”. When the
same weighting structure was applied to responses, the highest degree of difficulty was
associated with securing funding for any operational changes (weighted mean: 1.4; very
difficult: 52%, 14/27; difficult: 33%, 9/27; do not know: 15%, 4/27), followed by implementing
facility changes (weighted mean: 1.5; very difficult: 44%, 14/27; difficult: 37%, 10/27; not
difficult: 4%, 1/27; do not know: 15%, 4/27), establishing standard operating procedure training
(weighted mean: 2.3; very difficult: 7%, 2/27; difficult: 56%, 15/27; not difficult: 33%, 9/27; do
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not know: 4%, 1/27), and standardizing donor suitability & eligibility processes (weighted mean:
2.3; very difficult: 7%, 2/27; difficult: 48%, 13/27; not difficult: 41%, 11/27; do not know: 4%,
1/27). The activities establishing standard operating procedure training and standardizing donor
suitability & eligibility processes received relatively high “not difficult” responses.
Figure 30: Difficulty of Preparing for CGMP Compliance Activities
When an organization prepares for CGMP compliance, how difficult are the following activities
in your opinion? (n=27)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
These respondents were asked to share any additional comments regarding the
assessment and preparation for CGMP compliance. Comments were received from nine
respondents (33%, 9/27). Six of the nine comments referred to education and training challenges
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as reflected in the bolded words and phrases “unfamiliar”, “without prior experience”, and “lack
of training”. Three referred to financial and economic challenges as reflected in the underlined
and italicized words “financial” or “funding”. The complete comments are displayed below in
Table 12.
Table 12: Affiliated Comments on CGMP Assessment & Preparation
Please provide any additional comments regarding the assessment and preparation for CGMP
compliance. (n=9)
Additional Comments
When first assessing and preparing, CBBs had limited knowledge of CGMP in the
actual workplace. Reading about and operating under CGMP are very different. To
begin with, most CBB personnel are from clinical diagnostic labs, not pharmaceutical
companies. The FDA speaks in a language that is unfamiliar to clinical blood
bankers/quality management personnel who generally fill these roles. It's critical to
understand that CGMP is about control of processes and facilities and does not require
clean rooms.
Using the experience of the early adopters, CBBs now realize the dangers of being too
specific and too 'perfect' in their submissions. The FDA doesn't generally advise if a
bank has gone overboard in their BLA. Once approved, a facility is held fast to those
details until they submit evidence to change practice. (Respondent 4)
Facilities know what is required but find it difficult to get the financial support to
meet the need when product banked can still be used without the license.
(Respondent 5)
I think collection hospitals lack CGMP trained staff. Unless the bank does an external
audit, we don’t really know where we are lacking. (Respondent 32)
Our lab supports multiple collection hospitals. It is true that IND SOPs make the
product testing and processes more standardized across the different facilities.
Collection kits do the most to standardize product samples. It prevents staff error from
lack of training or turnover. (Respondent 34)
Securing funding for any operational changes in the research hospital is a lengthy and
difficult process. (Respondent 38)
The cord blood industry is unfamiliar with CGMP regulations. (Respondent 46)
The answers to the above questions regarding CGMP compliance depend on the
experience of professional staff and the funding available for each facility.
(Respondent 48)
Again, without prior experience in a GMP environment, it is difficult to properly
prepare for GMP compliance. (Respondent 51)
The industry as a whole struggles with standardization. Terms like "phase appropriate
GMP compliance" have variable interpretations. (Respondent 53)
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4.6.2.2 Implementation and Sustainment Stages of CGMP
The affiliated respondents were asked to gauge the level of difficulty faced during the
implementation and sustainment stages for CGMP compliance (Figure 31). The responses were
weighted with one for “very difficult”, two for “difficult”, three for “not difficult”, and zero for
“do not know”. Most respondents found all four activities to be “very difficult” or “difficult”.
The highest degree of difficulty was associated with establishing Quality Control Unit
capabilities for product releases (weighted mean: 1.7; very difficult: 41%, 11/27; difficult: 44%,
12/27; not difficult: 11%, 3/27; do not know: 4%, 1/27), followed by establishing IND product
reimbursement/cost recovery (weighted mean: 2.0; very difficult: 15%, 4/27; difficult: 41%,
11/27; not difficult: 18%, 5/27; do not know: 26%, 7/27), engaging FDA in pre-IND dialogue
(weighted mean: 2.3; very difficult: 11%, 3/27; difficult: 33%, 9/27; not difficult: 33%, 9/27; do
not know: 23%, 6/27), and standardizing infectious disease testing & final product testing
(weighted mean: 2.4; very difficult: 4%, 1/27; difficult: 48%, 13/27; not difficult: 44%, 12/27; do
not know: 4%, 1/27).
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Figure 31: Difficulty of Implementing CGMP Compliance Activities
When an organization implements CGMP, how difficult are the following activities in your
opinion? (n=27)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
The affiliated respondents were asked to gauge the level of difficulty faced during the
sustainment stage of CGMP compliance (Figure 32). The majority of respondents found two out
of the four activities to be “very difficult” or “difficult”. When the same weighting structure was
applied to responses, the highest degree of difficulty was associated with the activity performing
IND process change management (weighted mean: 1.9; very difficult: 22%, 6/27; difficult: 56%,
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15/27; not difficult: 11%, 3/27; do not know: 11%, 3/27), followed by sustaining CGMP
complaint Quality Systems (weighted mean: 2.0; very difficult: 26%, 7/27; difficult: 41%, 11/27;
not difficult: 26%, 7/27; do not know: 7%, 2/27), and engaging FDA in ongoing dialogue about
product indications for use (weighted mean: 2.2; very difficult: 11%, 3/27; difficult: 33%, 9/27;
not difficult: 26%, 7/27; do not know: 30%, 8/27).
In contrast to the other activities, most respondents found sustaining annual CGMP
personnel training to not be difficult (weighted mean: 2.3; very difficult: 19%, 5/27; difficult:
26%, 7/27; not difficult: 48%, 13/27; do not know: 7%, 2/27).
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Figure 32: Difficulty of Sustaining CGMP Compliance Activities
When an organization works to sustain compliant processes, how difficult are the following
activities in your opinion? (n=27)
Weighted means and standard deviations are displayed on top of each column
(very difficult = 1; difficult = 2; not difficult = 3; do not know = 0)
These respondents were asked to share any additional comments regarding the
implementation and sustainment stages for CGMP compliance. Comments were received from
eight respondents (30%, 8/27). Five of the eight comments referred to operational challenges as
reflected in the bolded words “Quality Control Unit”, “QCU”, and “changes”. Additionally, three
referred to education and training challenges as reflected in the underlined and italicized words
“training” and “experience”. The complete comments are displayed below in Table 13.
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Table 13: Affiliated Comments on CGMP Implementation & Sustainment
Please provide any additional comments regarding implementing CGMP and sustaining the
compliant processes. (n=8)
Additional Comments
IND requirements aren't nearly as rigorous and when operating under them, a bank
may falsely believe CGMP is a simple next step. In the clinical setting, the MD has
the last word. In the BLA setting, it's the Quality Control Unit. Banks may not have
the personnel resources to staff a full QCU that is independent of all other functions
of the bank. Under IND, it's expected that a sponsor will modify processes as the data
indicates to make improvements in design, safety, efficacy, efficiency. But that's not
the case with a BLA. A facility is absolutely committed to the content details of the
BLA until a change is requested and approved. (Respondent 4)
Once in place, sustaining compliance isn't too difficult. Performing IND process
changes can be difficult to know all of the impacts of a single change and managing
the process. (Respondent 5)
As clinicians, focused on patient care, we are constantly improving treatment plans
and making changes based on a variety of product and patient concerns. This runs
counter to the IND process where we must follow the Protocol and approved SOPs. It
becomes difficult for us to recommend changes to the collection process. On the other
hand, the dissemination of collection kits made the process very easy and clear.
(Respondent 32)
The Quality Control Unit is not focused on CGMP compliance in the hospital, they
are doing patient outcomes. So, I think lab staff fill this GMP need but they are
primarily lab staff. The requirement is met by hospital and lab staff wearing multiple
hats. (Respondent 33)
CGMP is built into the lab SOPs, but we don't have specific annual training around it.
We train to lab requirements. We have been inspected by the FDA, but they were not
looking at CGMP for a specific product. (Respondent 34)
QCU duties are done within the lab with a final sign off by the Medical Director. I've
heard from the Cord Bank labs that that isn't acceptable for BLA. For our facility, we
don't have a staff member at the right level to take responsibility for releasing the
product other than the Medical Director. (Respondent 35)
The staff responsible for collecting product are not specifically trained in GMP
compliance. The Cord Blood bank is responsible for that type of compliance although
we must follow protocols. (Respondent 38)
The above answers to implementing CGMP and sustaining compliant processes
assume the professional staff are experienced and the facilities have the funding
needed to implement and sustain the cord blood bank operations. If the staff do not
have adequate experience or financial support, it is very difficult to implement and
maintain CGMP. (Respondent 48)
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4.6.3 Most Difficult Activities Across Implementation Stages
The two groups surveyed in this study were the CBBs and the affiliated organizations. To
understand if the two groups had different views on the most challenging aspects of BLA
implementation, Table 14 was constructed comparing the two groups across the implementation
stages.
Table 14: Most Difficult Activities Across Implementation Stages
Implementation
Stages
Cord Blood Bank
Subset
Affiliated Organization
Subset
Most Difficult BLA Process Activities
Most Difficult CGMP Compliance
Activities
Assessment
Securing funding for operational changes
Figure 25
Performing vendor qualification
Figure 29
Preparation
Implementing facility changes
Figure 26
Securing funding for any operational
changes
Figure 30
Implementation
Responding to FDA’s BLA submission review
requests .
Figure 27
Establishing Quality Control Unit
capabilities for product release
Figure 31
Sustainment
Forecasting product supply & demand
Figure 28
Performing IND process change
management
Figure 32
4.6.4 Views on Requiring BLA Submission
At the end of the subgroup questions, each group of respondents were asked whether all
public CBBs should be required to submit a BLA to FDA (Figure 33). The majority of CBB
respondents did not think BLAs should be required (no: 71%, 12/17; yes: 29%, 5/17).
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Figure 33: CBB Opinion on Requiring BLA Submission
Given what you know today, do you think all public Cord Blood Banks should be required to
submit a BLA to FDA? (n=17)
An equivalent majority of affiliated respondents did not think that BLAs should be
required (no: 71%, 17/24; yes: 29%, 7/24) (Figure 34).
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Figure 34: Affiliated Organization Opinion on Requiring BLA Submission
Given what you know today, do you think all public Cord Blood Banks should be required to
submit a BLA to FDA? (n=24)
4.7 Additional Thoughts on the BLA Pathway
The survey concluded by asking all respondents to share any additional comments on the
FDA’s regulatory framework for cord blood. Comments were received from 17 respondents
(31%, 17/55). Their comments are divided into three themes according to their views on HPC,
Cord Blood regulation: positive, negative, and mixed (Table 15).
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Table 15: Additional Comments on FDA’s Regulation
Is there anything else you would like to say related to this topic of FDA regulation of HPC, Cord
Blood? (n=17)
Positive:
We applied later in the game in 2015. FDA/CBER had already learned certain lessons about
reality of cord blood regulation, and they were very accommodating in finding acceptable
middle ground between regulations and feasibility of adequate implementation of CGMP. We
are a better CBB because of it, but the banks that applied before us had a much harder time.
(Respondent 26)
For research staff, we need to keep the translational possibilities of our studies in mind. Any
cell therapy product we collect could be used “raw” or manipulated later. It benefits everyone
if we can collect them to the highest CGMP standards. (Respondent 33)
Unless you go through this process, you don’t appreciate the process controls necessary to
prove your product and testing is in control from CGMP perspective. (Respondent 24)
Cord blood is now routinely used in the practice of medicine. It is beneficial to any
organization to go through the process of submitting a BLA. (Respondent 51)
Negative:
The entire FDA process is overkill. The level of complexity is not necessary and thus in
tresses costs and complexities in necessarily. Especially given that licensing does not provide
any advantage. Units are selected based on matching and cell dose. (Respondent 47)
I think the cord blood industry is over regulated and costly to maintain a BLA. We are a very
small percentage of the all transplants performed, and we need transplanting physicians to
consider cord blood more when finding treatments for their patients. (Respondent 44)
I feel that there is no difference in whether or not your bank holds a BLA for cord blood. If
you ask a transplant physician in my experience they do not care if the cord blood is a
licensed unit. IND units engraft just as well as licensed units. (Respondent 14)
I don't think it would be possible for some of the banks to manage a BLA process. They are
already combining inventory and changing their business models to stay afloat. (Respondent
35)
Transplant physicians select product based on the donor patient match. We can assess supply
and demand for cord products, but we can't predict them. We can only slightly increase the
changes of selection by getting a good collection that meets the requirements and is the best
volume possible. Training on the collection process is the biggest factor to improve the
quality of collected products. But, as I said, the quality of the product is second place to the
match. (Respondent 37)
I am concerned that this model would be applied to Peripheral Blood Stem Cells. We have not
seen a real improvement in patient outcomes with BLA and there are not sufficient resources
to pursue the bad players such as those that market stem cells for all sorts of ailments.
(Respondent 53)
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In my opinion, the original concept of a standards-based approach to HPC, Cord Blood
licensure would have been more feasible in regard to maintaining a flow of licensed products
meeting standardized criteria. (Respondent 55)
Table 15: Additional Comments on FDA’s Regulation (Continued)
Mixed:
A cord blood bank producing a licensed HPC, Cord Blood product, with a single unit being
one lot, is very different than a drug company manufacturing thousands of pills that constitute
one lot. Working with inspectors who are not used to this difference can be challenging and at
times frustrating. Not all regulations can be directly translated to cord blood banking and
release.
As far as if all cord blood banks should be licensed, that's a tough question. Since I work for a
bank that has worked very hard to obtain a license, then yes, I think it should be required.
However, I understand why many banks simply cannot afford to go through the process or
have the resources to keep up with the strict requirements. (Respondent 22)
If licensure were purely optional, I think the long-term goals of the organization would be a
key consideration for whether to obtain a BLA or not. Unless the organization plans to pursue
INDs or has aspirations to bring other novel cell therapy products to market, having a BLA
seems superfluous to the mission to build a robust NCBI. Banks have been doing this (more
or less) successfully for decades, regardless of licensure. A BLA could better position a
company in a solid regulatory pathway that, according to the opinion of a colleague whose
bank is licensed, could help expedite future therapies or attract stronger partnerships toward
innovation and the eventual democratization of cell therapy. (Respondent 29)
The learning curve for clinical personnel transitioning to a BLA setting cannot be understated.
There's a language barrier as mentioned previously. The rigid application of the requirements
to a biologic product that is anything but standardized results in failures that would not
adversely affect SQuIPP.
Has licensure improved patient safety - the data doesn't support that. Has licensure improved
product quality? Perhaps, in that processes are clearly more controlled and standardized.
A drawback of licensure is that change, even process improvements or incorporation of
updated technology and supplies, requires approval from the FDA - a process that takes time
and effort, and places a hold on products manufactured with the new methods. Reluctant to
submit a CBE or supplement, banks may forego those improvements. In this way, licensure
could be seen as stifling innovation.
Licensure is a differentiating feature for banks, but physicians will choose what matches their
patients. I predicted around 2012 that in 5 years, MDs would only choose licensed products,
but these units only represent 10% of the total inventory even 6-8 years later.
Would the industry have gotten here on its own without the BLA requirement? It would have
likely evolved but probably not as quickly due to the cost of implementing rigid
environmental monitoring, disinfection effectiveness, supply qualification... It's definitely
made us smarter! But as soon as techs are trained, they're scooped up by higher paying pharm
companies or engage in startups.
Lastly, all banks should be required to submit a BLA. I don't read it as optional, but the law!
(Respondent 4)
BLA provides the transplant program receiving the product with more of a known product;
the quality, size, purity of the CBU received is less of a question, and the assurance of FDA
inspections occurring at the CBB is valuable. This can also be achieved by accrediting bodies,
so alternative assurance are a possibility as well that aren't as costly! (Respondent 5)
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Cord blood licensure did improve the quality of the products to some extent. However, the
regulatory and financial burden has negative impact on FDA because the agency allocated its
precious resources to the area that is not risky because the accumulated experience by the
banks and clinicians. License posed significant financial challenges to the cord blood banks
and increased the cost of cord blood transplantation significantly. Full CGMP compliance is
unnecessary for products that are minimally manipulated using functionally closed system.
(Respondent 46)
Cross tabulation was not included in this Chapter due to the small respondent numbers
remaining in each sub stratified group but the full set of additional cross tabulations can be found
in Appendix B.
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Chapter 5. Discussion
5.1 Overview
The purpose of this study was to explore the views of cord blood industry views on the
current BLA regulatory framework in order to identify areas that present challenges. The
licensure pathway and issuance of a BLA as described in 21 CFR Part 601 “constitutes a
determination that the establishment(s) and the product meet applicable requirements to ensure
the continued safety, purity, and potency of such products”. Yet the majority of CBBs have not
pursued this path. The results of this study support the current notion that adopting the BLA
requirements for CGMP as well as the CGTP present challenges for CBBs and other affiliated
organizations. Moreover, the composition of respondents reflected CBBs at different stages of
BLA implementation in that some were already operating under approved BLAs while others
were planning to pursue licensure in the short term, contemplating the licensure option, or have
no plans to seek the BLA option. According to the study results, the challenges faced by the
respondents are different across the various stages of implementation. Furthermore, the CBBs
not pursuing BLAs have likely been deterred following their initial assessment or have
confronted challenges during the planning stages. The CBBs that are licensed have fully
implemented manufacturing processes and quality systems but still face ongoing challenges to
sustain the BLA. The findings from this study point to the economic barriers and operational
challenges as the most difficult areas for both the CBBs and affiliated organizations.
5.2 Methodological Considerations
This study was delimited to cord blood manufacturing professionals with experience in
Section 351 manufacturing for HPC, Cord Blood. It was further delimited to cord blood
manufacturing institutions within the United States who should be familiar with the dual CGMP
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and CGTP manufacturing regulations and the general FDA process for obtaining BLAs. This
scope encompassed a pool of approximately 25 public and/or hybrid CBBs and their associated
collection hospitals, laboratories, and non-profit organizations that sponsor biologic drug IND
applications as described in Chapter 2. The HCT/P transplant physicians were not included in
this research because their viewpoints on patient safety, product indications, and clinical
outcomes were previously highlighted in FDA advisory committees (HRSA, 2016b) and past
studies (Kapinos et al., 2017).
A potential limitation to the study of concern at the outset of the research was the small
number of public CBBs that could limit the number of potential survey respondents. The pool of
potential respondents was selected based on publicly available job title and employment history
information. The targeted population was invited to participate in the survey through in person
request or invitation email. These methods of selection ensured that the survey was accessed
only by the targeted population and, in fact, the demographics of respondents revealed an
experienced group at director level or above. Furthermore, the survey was shared through the
researcher’s academic email to present it as an academic endeavor and encourage the
respondents to express their personal viewpoints rather than those of their employers (Groves et
al., 2000). The extensive and detailed nature of comments received indicate that the respondents
felt free to express not only the experiences within their organizations but to opine on the greater
CBB industry.
The methods of survey invitation also presented another potential limitation related to
respondent selection in that the survey might be completed mostly by like-minded participants
who would overrepresent one viewpoint of the larger CBB field. It is possible that respondents
with direct BLA experience would be more driven to respond to the survey in order to share their
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views according to survey leverage-saliency (Groves et al., 2000). This could skew the results by
increasing the weight of the licensed CBB respondents who represent less than half of the overall
CBB population. Where possible, this potential for bias was mitigated by targeting respondents
from both licensed as well as unlicensed CBBs that resulted in a reasonable mix of respondents
with and without direct experience with the BLA process.
The strict criteria used to identify qualified participants, however, also raised a concern
that the respondent group may be too small or that the response rate too low to assure a
representative sample. Fortunately, we saw an overall response rate of 76% in this study, which
was much higher than typically observed for electronic surveys (Fincham, 2008) and the
responses for most questions reached saturation (Weller, 2018). Still, some caution should be
exercised when skip logic is used to direct a small subpopulation of respondents to specific
questions. For example, there were six respondents in a subgroup whose ranked responses could
have easily inverted by an additional response. Therefore, care must be taken when interpreting
exploratory results whose validity should be strengthened by further research. The focus group
input on demographics, question order, and subset creation were critical to maximize
participation from this survey population. For example, Groves suggests that “a single survey
design attribute will have different “leverages” on the cooperation decision for different persons”
(Groves et al., 2000). In this case, focus group recommendations promoted accurate self-
identification through precise wording of demographic titles and categories of respondents. Self-
identification was also critical for survey sub stratification. In addition, the focus group feedback
helped identify the appropriate affiliated organizations to survey.
Respondent fatigue was a concern at the outset of survey creation and the survey length
delimited. The survey was designed so that individual respondents had to answer no more than
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33 questions. In addition, the use of skip logic to concentrate each of the questions around the
area of expertise of the respondent. This technique may also have promoted survey rapport and
interest and decreased burdensome questions, which encouraged respondents to continue
participating, as noted elsewhere (Pew Research, 2020). The fact that almost every survey
respondent finished the survey seems to indicate that this topic is highly engaging to the
participants. The opportunity to add open text responses was also taken by many respondents,
suggesting a high level of engagement. However, this opportunity can have drawbacks as well
because it adds to the time needed to finish the survey. The fact that one respondent was not able
to add additional comments within a reasonable timeframe and requested a follow-on interview
may be telling. It is possible that other respondents intended to include comments but could not
allocate sufficient time for those optional questions.
The focus of this study was on the experience of CBB industry in implementing the BLA
regulations including challenges associated with complying with CGMP requirements. The
biopharmaceutical industry was intentionally excluded from the survey based on the assumption
that the industry has been operating under CGMP regulation for almost sixty years and, hence,
should have a mature understanding of Chemistry Manufacturing and Controls (CMC). It should
be noted, however, that as more biopharmaceutical companies include Section 351 biologic
products in their product portfolios, it would be interesting in the near future to study the
performance and suitability of CBBs as suppliers of cellular material for the biopharmaceutical
industry.
Because the survey was delimited to a specific time period of early November to early
December 2019, the study findings will reflect the views held during that specific time point. It is
unclear whether the same views will be held over time. The subjects of Section 351 legislation,
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CBB standardization, and regulation harmonization are all being actively discussed by the Cord
Blood Association , a non-profit that specializes in cord blood advocacy issues (CBA, 2020).
Under CBA’s influence, the current regulatory landscape may continue to transition the CBBs
toward licensure. In addition, the current COVID-19 crisis may also increase the stringency of
certain CGMP and CGTP regulations as other epidemics have in the past. For example, the AIDs
epidemic in the 1980s and the more recent ZIKA response drove the creation of new CGMP and
CGTP regulations. Although we do not expect respiratory illness, like COVID-19, to spread
through transplantation, CBER will likely generate new regulation and guidance based on their
experiences with this highly transmissible disease. In particular, the IDM testing requirements
may be updated for both cord blood donor screening and final product testing.
5.3 Consideration of Results
An objective of this survey was to understand why less than half of the public CBBs had
achieved BLAs in the decade since the regulatory framework was created. Our findings reveal
that CBBs across the industry are at different stages of BLA implementation. Some have been
operating under approved BLAs, but others are only now planning to submit or still assessing the
situation. Some have decided against the pursuit of the BLA pathway altogether. The
examination of results points to a lack of clarity regarding how CGMP are to be applied to the
cord blood manufacturing process and gives rise to two general themes: a) the most significant
challenges to the BLA process are the limited regulatory and economic incentives and b) these
and other challenges have resulted in ineffective implementation of the cord blood regulatory
framework.
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5.3.1 Limited Regulatory Incentive for BLAs
The study findings show that transitioning CGMP compliance from the IND environment
to the BLA environment is a significant barrier. Although the regulations are technically
unchanged from IND to BLA, they are applied with different levels of rigor. We know that the
pivotal Cord Blood Transplantation Study (Kurtzberg et al.) used validated procedures for
collection, processing, and storing product (Kurtzberg et al., 2008). However, the use of a CGMP
compliant lot release process wasn’t seen until the first CBBs pursued their license approvals
(Cassata, 2013). This difference in the compliance rigor between IND and BLA was recognized
by the respondents of this study. Results indicate that the industry generally views the IND
manufacturing requirements to be appropriately stringent for cord blood. By contrast, it seems to
view corresponding BLA requirements as too strict or opaque. The respondents’ additional
comments highlighted this compliance disparity between INDs and BLAs.
Interestingly, respondents generally agreed that Infectious Disease Marker (IDM) testing
was appropriate for both the IND and the BLA requirements. This is notable because IDM
testing is required not only by CGMP regulations but also by CGTP, which was phased in 23
years ago. And, hence, the industry has a long history with and a deeper understanding of the
CGTP requirements (FDA, 1997). Study respondents viewed as most difficult the areas of
production and processing controls, process validation, and quality control requirements needed
to support a BLA when compared with those for an IND. According to CGMP, the Quality
Control Unit (QCU) is solely responsible for checking all product documentation and conducting
final product release, as described in 21 CFR 211. Here the results of this study seem to
contradict the perspectives of leading transplant physicians that processing and release
procedures are “extensively published” and transparent (Gluckman and Rocha, 2009). Transplant
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physicians may feel that the requirements are met because of the tendency to rely on their
hospital’s FACT accreditation as the means to satisfy cord blood requirements (Gluckman and
Rocha, 2009). By contrast, the CBB’s scope of product requirements must move beyond CBB
industry accreditations to meet the FDA’s requirements for CGMP compliance. Unfamiliarity
with CGMP may, in fact, be the root cause of many implementation challenges, driving the
CBBs and affiliated organizations to resist pursuing BLAs. The comments from the survey serve
to reinforce the idea that full CGMP compliance remains unfamiliar.
This study also sought to draw comparisons between licensed cord blood products and
cord blood products manufactured under IND. One might have expected that the licensed
products, which require more rigorous CGMP compliance, would be viewed by the respondents
as improving product quality and patient safety. Interestingly, this was not the case. The results
of this survey indicate that the CBB industry generally does not view the BLA process as
providing meaningful improvements to the product quality or patient safety. Although somewhat
surprising, these results are actually consistent with the findings in the literature. For example, a
study conducted in 2005 by the University of Minnesota found that, out of sixteen CBBs, 54% of
products had quality control issues (McCullough et al., 2005). When the study was conducted
again in 2016, post-FDA guidance for cord blood, the results showed that 49% of products still
had quality control issues (Murphy et al., 2016). In a more recent study, unlicensed and licensed
cord blood products sourced through the NMDP were compared and found that the licensed
products were not superior to investigational products as measured by safety and efficacy
metrics, including engraftment and patient survivability (Ballen et al., 2020). Collectively, my
results and those of related studies seem to indicate that while there are opportunities for quality
control improvements, there may also be aspects of the product collection process and/or product
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itself that cannot be improved through the traditional CMC process inherent in the BLA. The
additional comments provided by survey respondents further conveyed lukewarm views on the
impact of the BLA process in improving product quality.
Vendor qualification is another key component of product quality that depends on a
quality control relationship between the manufacturer and supplier. Our study findings reveal
that vendor qualification is a particularly challenging area for CBBs and their affiliated
organizations. Vendor qualification and the requirements surrounding a manufacturer’s supply
chain are areas that have only recently been defined for drug and biologic manufacturers by the
FDA through its 2016 final guidance, “Contract Manufacturing Arrangements for Drugs: Quality
Agreements” (FDA, 2016). This guidance makes it clear that CGMP applies to both the sponsor
and its contract facilities and laboratories (FDA, 2016). In addition, the guidance describes the
method for drafting a Quality Agreement between the contracted entities to specify which
facilities are responsible for each aspect of CGMP in a given product’s manufacturing process
(FDA, 2016). While the Quality Agreement should be signed by a senior quality representative at
each site, the study comments indicate that CBBs may lack quality representatives capable of
representing the facility in this type of agreement:
“In the clinical setting, the MD has the last word. In the BLA setting, it's the
Quality Control Unit. Banks may not have the personnel resources to staff a
full QCU that is independent of all other functions of the bank” (Respondent
4).
Although INDs have always required a list of contract manufacturing facilities, the
contract manufacturing guidance introduced tangible quality control mechanisms that are
expected for those facilities. And it is the sponsor’s responsibility to audit and qualify its contract
manufacturers. Our study findings point to difficulties associated with the FDA’s vendor
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qualification requirements from the perspectives of both the CBB sponsor and the affiliated
organization. It is not clear how CGMP requirements can be applied to the hospital setting where
the collection of cord blood takes place. In this case, the hospital would be acting as a contract
manufacturer and the CBB will need to address any gaps in meeting the CGMP requirements
prior to establishing a compliance agreement between the CBB and the collection hospital. These
findings that point to challenges faced by CBBs with vendor qualifications are likely behind the
quality initiatives launched in 2018 by the NMDP. The NMDP’s Quality Systems Audit Program
(QSAP) functions as a contract auditing service available for sponsors including
biopharmaceutical companies unfamiliar with applying CGMP to the clinical facilities collecting
HCT/P material (Be The Match, 2018). It follows that if biopharmaceutical companies are
enlisting the NMDP to audit their collection hospitals, then individual CBBs with limited staff
may be struggling to audit and manage their own network of collection hospitals and
laboratories.
The auditing of contract manufacturers by the CBBs should mirror their own facility
audits by the FDA (FDA, 2016). However, the FDA has limited capacity to conduct routine CBB
inspections and applies a risk-based approach to HCT/P enforcement actions. Consequently, the
agency’s inspection and enforcement activities currently seem to prioritize organizations that
market unapproved stem cell therapies, including cord blood (FDA, 2019c). One such warning
letter directed to Stemell Inc., a small biotechnology company in San Juan Capistrano,
California, was marketing cord blood products that have been manipulated using unproven
methods (FDA, 2019f). As described in the FDA’s warning letter, the firm was found to be
deficient in “donor eligibility determinations, aseptic process validation, validation of the
manufacturing processes, your stability program, cleanroom qualification, and the
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responsibilities of your quality unit”. The FDA’s focus on errant stem cell manufacture certainly
seems appropriate from a risk standpoint and understandably takes precedence over routine CBB
inspection. However, without any prior CGMP inspection experience, a pre-BLA inspection
would likely be a daunting hurdle.
Ultimately, the question of how best to improve the regulatory case for pursuing BLAs
remains open when the FDA fails to provide an implementation deadline or effective
enforcement (HRSA, 2016a). The FDA could consider revising their statement from 2016
indicating that there was no deadline for CBBs to transition to BLAs (HRSA, 2016b). The
comments by respondents of this study shown below echoed the frustration shared during that
2016 HRSA advisory committee meeting:
“The FDA continues to say that we should all move in the right direction,
meaning pursue BLA, but they aren’t enforcing it. I think the fact that they
aren’t enforcing it has hurt the industry’s impression of the regulations”
(Respondent 11).
The results of this study indicate that regulators may need to further clarify policy and provide
direction. Warning letters such as the Stemell example above may not be a sufficient means of
enforcing and policing the greater CBB industry. The FDA’s HPC, Cord Blood guidance
document is relatively new, which may help explain why most of the respondents preferred
direct communication with the FDA over other resources. Direct dialogue allows for more
concrete understanding and CBB professionals clearly desire timely FDA consult. More dialogue
between the FDA and cord blood professionals could be useful to help CBBs translate IND
protocols for the collection hospital and laboratory staff into effective SOPs under the BLA. As
there are just few (less than 20) unlicensed CBBs, it should be feasible for the FDA to provide
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not only educational opportunities but also forums to discuss how CBBs can apply specific cord
blood CGMP requirements to their facilities and contract manufacturers.
5.3.2 Limited Economic Incentive for BLAs
The results of this study indicate that the upfront investment necessary for manufacturing
changes associated with BLA submission was a top challenge, especially during the assessment
and preparation stages of implementation. These costs escalate as the company looks to modify
equipment and facilities, hire consultants, or assign in-house personnel who could be otherwise
engaged (Kapinos et al., 2017). The added costs would then have to be passed on to the clients as
part of the product. Previous literature, such as the RAND study, highlighted the high cost of
HPC, Cord Blood product was attributed, in part, to the BLA regulatory framework and as a
potential deterrent to its use (Kapinos et al., 2017). The results of our study are consistent with
those of the RAND study but provide additional insights into which factors are considered
important as a CBB makes the decision to either pursue or abandon BLA submission. According
to our results, the CBB industry may view the upfront cost as a large barrier to entry.
Furthermore, the current transplant environment does not reward CBBs for having licensure and,
in fact, may favor investigational products for being more economical. The lack of
differentiation between licensed and unlicensed product is highlighted by the comment from a
respondent as provided below:
“I feel that there is no difference in whether or not your bank holds a BLA for
cord blood. If you ask a transplant physician in my experience they do not care
if the cord blood is a licensed unit. IND units engraft just as well as licensed
units” (Respondent 14).
The existence of “access and distribution” clinical trials, through INDs held by
organizations like the NMDP and Center for International Bone and Marrow Research has
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created an environment that allows products to be collected and banked for transplant (CIBMTR,
2011). This unique paradigm provides an ample supply of IND products in the marketplace with
lower prices. While it is clearly important for regulators to support patient access to
investigational products with the best HLA match, the inventory of investigational product does
weaken the CBB business case to transition from the IND to the BLA. This is especially true
when the transition itself is viewed as financially challenging. The Journal of Clinical Medicine
published a recent article emphasizing that public CBBs only recover costs when a product is
released from their inventory rather than at the time of cryopreservation (Brown et al., 2019).
The inherently unpredictable nature of HLA matching, therefore, makes the budget process of a
CBB very unpredictable. From the patient perspective, the cord blood product can appear cost
prohibitive because adult patients frequently need two doses of cord blood products to meet their
transplant requirements (Brown et al., 2019). The Brown article would seem to indicate that the
CBB business model does not lend itself to productization. My study’s findings confirm that the
current financial situation for CBBs is tenuous at best. Respondents overwhelmingly felt that
funding for the transition to a BLA was inadequate across the CBB industry. The affiliated
organizations faced similar challenges as the CBBs in that they also viewed securing funding for
operational changes as the most difficult activity during the preparation stage of CGMP
implementation. It is clear from the study’s additional comments that affiliated organizations,
such as collection hospital representatives, echo the CBB perspective on these funding
challenges.
Attempts to reduce the financial and economic burden on public CBBs and their affiliated
organizations have had limited success. One outcome of the 2016 Advisory Council on Blood
Stem Cell Transplantation (ACBSCT) was the prioritization of licensing as a criteria for NCBI
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funding (HRSA, 2016b). That initiative has since resulted in the selection of six licensed CBBs
out of the nine possible contracts (NCBI, 2020). These NCBI contracts represent a significant
financial resource for CBBs and it is meaningful that all three sponsors of the most recent BLAs
won contracts. My results confirm that NCBI funding is a major incentive in the decision to
apply for a BLA. However, the nine CBBs with NCBI contracts represent only 36% of the public
CBBs. It will be interesting to see in the coming years whether competition for NCBI contracts
will continues to serve as incentives for CBBs to pursue the BLA process. In the most recent
ACBSCT meeting, held November 2019, discussions centered on opportunities for novel
partnerships between transplant centers and non-profit initiatives to grow the selection and use of
cord blood products overall (HRSA, 2019). The success of these ventures could improve product
demand and remedy some economic concerns for CBBs. However, these initiatives would still
not tilt the balance with respect to improving the business case for pursing a license or address
the existing disparity between licensed and unlicensed CBBS.
5.3.3 Ineffectual Implementation of the Regulatory Framework
The FDA finalized the guidance for HPC, Cord Blood in 2014, by clarifying the draft
CMC requirements (FDA, 2014). Perhaps pointing to the effectiveness of that final guidance,
two out of the three most recent BLAs were approved without major amendments. The findings
from this study indicate that the industry relies on its interactions with the agency to mitigate
BLA challenges. However, surmounting the upfront obstacles to pursing licensure is only the
first step towards full implementation. We would expect to see licensed CBBs demonstrating not
only full mastery of new CGMP operations but also managing iterative feedback loops to
incorporate changes and innovation across their facilities (Fixsen et al., 2009). But according to
my survey results, licensed CBBs continue to struggle with sustaining their operations after BLA
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licensure has been obtained. For example, the regulatory submission, reporting, and inspection
requirements were generally viewed as more challenging under a BLA than an IND. One
respondent’s comments highlighted post market tensions between the CBER submission review
team and post-market inspections from Team Biologics:
“The FDA’s Team Biologics inspects one-year post-licensure and then every
two years after. There were inconsistences between the inspector’s
interpretation of CGMP for operations and the pre-established interpretation
with CBER’s BLA reviewers. The directors of all licensed banks and a
representative from NMDP met with FDA to discuss inconsistencies. The
resolution was to send a CBER representative with Team Biologics on all post-
licensure audits” (Respondent 11).
The current CBER inspection manual confirms the need for ongoing coordination by
recommending Team Biologic’s inspectors align with CBER’s CMC review representatives and
attend pre-approval inspections of CBBs in order to facilitate their post-market inspections and
the evaluation of subsequent changes (FDA, 2020). Given the fact that change control is a central
feature to post market operations under license (FDA, 2014), it is notable that so many survey
respondents viewed this manufacturing activity as a significant burden for both CBBs and
affiliated organizations. Further exploration of post-market inspection challenges in the future
could be helpful. Due to the small number of survey respondents, it is difficult to judge how the
entire CBB industry perceives change control and sustainment activities.
Part of the difficulty when applying CGMP regulations on the CBB environment may be
attributed to a disconnect in quality cultures. Many of the professionals performing cord blood
manufacture are, in fact, clinicians who have historically viewed the process of collecting and
processing cord blood as practice of medicine (Areman and Loper, 2009). Indeed, even in the
leading cellular therapy manual published by AABB, FDA regulations are given a separate
generic HCT(P) chapter instead of being integrated throughout the cord blood collection and
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processing chapters (Areman and Loper, 2009). This organization may be indicative of the
mindset that CGMP regulations are just another checklist of requirements rather than an
approach that should be integrated across the entire manufacturing process. It is evident, from
comments throughout the study, that there is a tendency to view quality from a clinical outcome
perspective rather than from a manufacturing control (CGMP) perspective:
“The learning curve for clinical personnel transitioning to a BLA setting
cannot be understated. There's a language barrier” (Respondent 4).
One respondent shared that the line between medical practice and regulated
manufacturing was still quite formative for cord blood. We know that controlling product
manufacturing processes and operations is at the heart of CGMP and only increases under the
BLA. It could be that the CBBs’ difficulty with CGMP is representative of the challenges any
clinical facility faces when adapting to FDA regulation.
5.4 Future Directions and Concluding Thoughts
The results of this study provide the views of cord blood manufacturing professionals on
the most difficult aspects of the BLA process across the stages of implementation. Transitioning
manufacturing from the IND to the BLA is challenging both operationally and financially. The
CMC requirements such as QCU product release and vendor qualification exist in a less stringent
form under IND and pose challenges for institutions wishing to transition to a BLA. If the
industry does not see the BLA process as improving the product quality or patient safety, as the
results of this study suggest, and the FDA does not provide a deadline for obtaining licensure, the
rationale for pursuing BLAs for cord blood may no longer exist. The results of this study could
stimulate the regulators to reconsider the section 351 categorization for HCT(P)s and ask
whether changes to the rule may be appropriate. At a minimum, a more detailed translational
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guidance or roadmap to scale CGMP compliance under INDs would be helpful. A lack of a
stepwise approach to full CGMP compliance presents challenges for unlicensed CBBs and
lingering problems for licensed CBBs, preventing effective implementation of the cord blood
regulatory framework.
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References
AABB (2019) Standards & accreditation [Online]. American Association of Blood Banks
(AABB). Available: http://www.aabb.org/sa/Pages/default.aspx [Accessed July 1 2019].
Anderson, J. F. & Leake, J. P. (1915) A method of producing tetanus toxin. The Journal of
Medical Research, 33(2), 239-241.
Areman, E. M. & Loper, K. (eds.) (2009) Cellular therapy: principles, methods, and regulations,
Bethesda, Maryland: AABB.
Ballen, K., Logan, B., Chitphakdithai, P., Kuxhausen, M., et al. (2020) Unlicensed umbilical
cord blood units provide a safe and fffective graft source for a diverse population: a study
of 2456 umbilical cord blood recipients. Biol Blood Marrow Transplant, 26(4), 745‐757.
Barker, J. N., Krepski, T. P., Defor, T. E., Davies, S. M., et al. (2002) Searching for unrelated
donor hematopoietic stem cells: availability and speed of umbilical cord blood versus
bone marrow. Biology of Blood and Marrow Transplantation, 8, 257-260.
Barker, J. N., Weisdorf, D. J., Defor, T. E., Blazar, B. R., et al. (2005) Transplantation of 2
partially HLA-matched umbilical cord blood units to enhance engraftment in adults with
hematologic malignancy. Blood, 105, 1343-1347.
Barr, M. (1950) A cord-blood survey of diphtheria immunity; comparison of 2 populations.
Lancet, 1, 1110-2.
Be the Match (2018) Be The Match Biotherapies® announces launch of quality system audit
program to enable faster onboarding of cell collection facilities [Online]. National
Marrow Donor Program. Available: https://bethematchbiotherapies.com/newsroom/be-
the-match-biotherapies-announces-launch-of-quality-system-audit-program/ [Accessed
April 20 2020].
Be the Match (2019a) Donor or cord blood unit search process [Online]. National Marrow
Donor Program. Available: https://bethematchclinical.org/transplant-therapy-and-donor-
matching/donor-or-cord-blood-search-process/ [Accessed June 25 2019].
Be the Match (2019b) Donor safety and support [Online]. National Marrow Donor Program.
Available: https://bethematch.org/support-the-cause/donate-bone-marrow/donor-safety-
and-support/ [Accessed June 25 2019].
Be the Match (2019c) The ONE forum 2019 [Online]. National Marrow Donor Program.
Available: https://network.bethematchclinical.org/education/the-one-forum/ [Accessed
April 19 2020].
Behring, E. V. & Kitasato, S. (1890) The mechanism of diphtheria immunity and tetanus
immunity in animals. Molecular Immunology, 28 (12), 1317, 1319–1320.
Bertram, R. M., Blase, K. A. & Fixsen, D. L. (2015) Improving programs and outcomes:
implementation frameworks and organization change. Research on Social Work Practice,
25, 477-487.
Brown, K. S., Rao, M. S. & Brown, H. L. (2019) The future state of newborn stem cell banking
[Online]. Journal of Clinical Medicine. Available:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352006/ [Accessed July 2 2019].
Broxmeyer, H. E., Douglas, G. W., Hangoc, G., Cooper, S., et al. (1989) Human umbilical cord
blood as a potential source of transplantable hematopoietic stem/progenitor cells.
Proceedings of the National Academy of Sciences, 86, 3828-32.
Cassata, R. (2013) The second anniversary of HPC, Cord Blood BLA requirements – a
regulatory review. Regulatory Focus.
132
CBA (2020) Advocacy [Online]. The Cord Blood Association. Available: https://www.cb-
association.org/advocacy [Accessed April 20 2020].
CIBMTR (2011) A multicenter access and distribution protocol for unlicensed cryopreserved
cord blood units [Online]. NIH U.S. National Library of Medicine. Available:
https://clinicaltrials.gov/ct2/show/record/NCT01351545?term=NMDP%2C+cord+blood
&draw=2&rank=5&view=record [Accessed April 20 2020].
Coleman, T. S. (2016) Early developments in the regulation of biologics. Food and Drug Law
Journal, 71, 544-607.
FACT (2019) What FACT accreditation means to patients and their families [Online].
Foundation for the Accreditation of Cellular Therapy (FACT). Available:
http://www.factwebsite.org/Inner.aspx?id=351 [Accessed July 1 2019].
FDA (1938) Federal Food, Drug, and Cosmetic Act of 1938 [Online]. Office of the Law
Revision Counsel. Available:
http://uscode.house.gov/browse/prelim@title21/chapter9/subchapter5&edition=prelim
[Accessed June 26 2019].
FDA (1997) Proposed approach to regulation of cellular and tissue-based products [Online].
FDA. Available: https://www.fda.gov/media/70704/download [Accessed April 20 2020].
FDA (2001) Human cells, tissues, and cellular and tissue-based products; establishment
registration and listing [Online]. Federal Register, Vol. 66, No. 13, Government
Publishing Office. Available: https://www.govinfo.gov/content/pkg/FR-2001-01-
19/pdf/FR-2001-01-19.pdf [Accessed June 27 2019].
FDA (2004a) Current good tissue practice for human cell, tissue, and cellular and tissue-based
product establishments; inspection and enforcement; final rule [Online]. Federal
Register, Vol. 69, No. 226, Government Publishing Office. Available:
https://www.govinfo.gov/content/pkg/FR-2004-11-24/pdf/04-25798.pdf [Accessed June
27 2019].
FDA (2004b) Eligibility determination for donors of human cells, tissues, and cellular and
tissue-based products; final rule and notice [Online]. Federal Register, Vol. 69, No. 101,
Government Publishing Office. Available: https://www.govinfo.gov/content/pkg/FR-
2004-05-25/pdf/FR-2004-05-25.pdf [Accessed June 27 2019].
FDA (2009) Guidance for industry: minimally manipulated, unrelated allogeneic
placental/umbilical cord blood intended for hematopoietic reconstitution for specified
indications [Online]. Federal Register. Available:
https://www.federalregister.gov/documents/2009/10/20/E9-25135/guidance-for-industry-
minimally-manipulated-unrelated-allogeneic-placentalumbilical-cord-blood [Accessed
June 25 2019].
FDA (2014) Guidance document: biologics license applications for minimally manipulated,
unrelated allogeneic placental/umbilical cord blood intended for hematopoietic and
immunologic reconstitution in patients with disorders affecting the hematopoietic system
[Online]. FDA. Available:
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/CellularandGeneTherapy/UCM357135.pdf [Accessed June 25
2019].
FDA (2015) Frequently asked questions about therapeutic biological products [Online]. FDA.
Available: https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/frequently-
asked-questions-about-therapeutic-biological-products [Accessed June 26 2019].
133
FDA (2016) Guidance document: contract manufacturing arrangements for drugs: quality
agreements guidance for industry [Online]. Available: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/contract-manufacturing-arrangements-
drugs-quality-agreements-guidance-industry [Accessed April 20 2020].
FDA (2019a) Approved cellular and gene therapy products [Online]. FDA. Available:
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-
cellular-and-gene-therapy-products [Accessed May 24 2019].
FDA (2019b) FDA puts company on notice for marketing unapproved stem cell products for
treating serious conditions [Online]. FDA. Available: https://www.fda.gov/news-
events/press-announcements/fda-puts-company-notice-marketing-unapproved-stem-cell-
products-treating-serious-conditions [Accessed July 2 2019].
FDA (2019c) FDA sends warning to companies for offering unapproved umbilical cord blood
products that may put patients at risk [Online]. Available: https://www.fda.gov/news-
events/press-announcements/fda-sends-warning-companies-offering-unapproved-
umbilical-cord-blood-products-may-put-patients-risk [Accessed April 20 2020].
FDA (2019d) FDA warns about stem cell therapies [Online]. FDA. Available:
https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies
[Accessed June 27 2019].
FDA (2019e) Warning letter, Cord for Life, Inc. MARCS-CMS 572770 [Online]. FDA.
Available: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/cord-life-inc-572770-03292019 [Accessed May 29 2019].
FDA (2019f) Warning letter, Stemell Inc. MARCS-CMS 579013 [Online]. FDA. Available:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/stemell-inc-579013-08282019 [Accessed April 20 2020].
Fincham, J. E. (2008) Response rates and responsiveness for surveys, standards, and the Journal.
American Journal of Pharmaceutical Education, 72(2).
Fixsen, D. L., Blase, K. A., Naoom, S. F. & Wallace, F. (2009) Core implementation
components. Research on Social Work Practice, 19, 531–540.
Fixsen, D. L., Naoom, S. F., Blase, K. A., Friedman, R. M., et al. (2005) Implementation
research: a synthesis of the literature [Online]. National Implementation Research
Network. Available: https://nirn.fpg.unc.edu/resources/implementation-research-
synthesis-literature [Accessed May 28 2019].
Gluckman, E., Broxmeyer, H. E., Auerbach, A. D., Friedman, H. S., et al. (1989) Hematopoietic
reconstitution in a patient with Fanconi's Anemia by means of umbilical-cord blood from
an HLA-identical sibling. New England Journal of Medicine, 321, 1174-1178.
Gluckman, E. & Rocha, V. (2009) Cord blood transplantation: state of the art. Haematologica,
94, 451-454.
Groves, R. M., Singer, E. & Corning, A. (2000) Leverage-saliency theory of survey
participation, description and an illustration. Public Opinion Quarterly, 64, 299-308.
Haga, S. B. & Willard, H. F. (2006) Defining the spectrum of genome policy. Nature Reviews
Genetics, 7, 966.
Himmelweit, F., Marquardt, M. & Dale, H. H. (eds.) (1956) The collected papers of Paul
Ehrlich: in four volumes, including a complete bibliography, London; New York:
Pergamon Press.
HRSA (2016a) Advisory Council on Blood Stem Cell Transplantation (ACBSCT), March 3 2016
[Online]. U.S. Department of Health and Human Services. Available:
134
https://bloodstemcell.hrsa.gov/sites/default/files/bloodstemcell/about/advisory-
council/meetings/acbsct-minutes-2016-mar.pdf [Accessed July 1 2019].
HRSA (2016b) Advisory Council on Blood Stem Cell Transplantation (ACBSCT), September 13
2016 [Online]. U.S. Department of Health and Human Services. Available:
https://bloodstemcell.hrsa.gov/sites/default/files/bloodstemcell/about/advisory-
council/meetings/acbsctmeetingsummary2016sept.pdf [Accessed July 1 2019].
HRSA (2019) Advisory Council on Blood Stem Cell Transplantation (ACBSCT), September 10
2019 [Online]. U.S. Department of Health and Human Services. Available:
https://bloodstemcell.hrsa.gov/about/advisory-council/meetings/september-10-2019
[Accessed April 20 2020].
Junod, S. W. (2002) Biologics centennial: 100 years of biologics regulation [Online]. FDA.
Available:
https://www.fda.gov/downloads/AboutFDA/History/ProductRegulation/UCM593491.pdf
[Accessed June 26 2019].
Kapinos, K. A., Briscombe, B., Gracner, T., Strong, A., et al. (2017) Challenges to the
sustainability of the U.S. public cord blood system [Online]. RAND Corporation.
Available:
https://www.rand.org/content/dam/rand/pubs/research_reports/RR1800/RR1898/RAND_
RR1898.pdf [Accessed July 2 2019].
Kohn, D. (2002) What killed Brian Lykins? A problem with tissue transplants? [Online]. CBS
News. Available: https://www.cbsnews.com/news/what-killed-brian-lykins/ [Accessed
June 27 2019].
Kurtzberg, J., Laughlin, M., Graham, M. L., Smith, C., et al. (1996) Placental blood as a source
of hematopoietic stem cells for transplantation into unrelated recipients. The New
England Journal of Medicine, 335, 157-166.
Kurtzberg, J., Prasad, V. K., Carter, S. L., Wagner, J. E., et al. (2008) Results of the Cord Blood
Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord
blood transplantation in pediatric patients with hematologic malignancies. Blood, 112,
4318-27.
Laughlin, M. J. (2014) Cleveland Cord Blood Center Biologics License Application (BLA)
[Online]. Available:
https://bloodstemcell.hrsa.gov/sites/default/files/bloodstemcell/about/advisory-
council/meetings/laughlin-ccbcbla-application.pdf [Accessed].
Lubiniecki, A. S. (2011) Evolution of approaches to viral safety issues for biological products.
PDA Journal of Pharmaceutical Science and Technology.
Matsumoto, M. M. & Matthews, K. R. W. (2015) A need for renewed and cohesive US policy on
cord blood banking. Stem Cell Reviews and Reports, 11, 789-797.
Mccullough, J., Mckenna, D., Kadidlo, D., Schierman, T., et al. (2005) Issues in the quality of
umbilical cord blood stem cells for transplantation. Transfusion, 45(6), 832‐841.
Merriam-Webster (2020) Definition of immunology [Online]. Merriam-Webster. Available:
https://www.merriam-webster.com/dictionary/immunology [Accessed 2020 April 20].
Morens, D. M. & Fauci, A. S. (2012) The forgotten forefather: Joseph James Kinyoun and the
founding of the National Institutes of Health. mBio, 3.
Murphy, A., Mckenna, D. & Mccullough, J. (2016) Cord blood banking and quality issues.
Transfusion, 56(3), 645‐652.
135
Nathanson, N. & Langmuir, A. D. (1963) The Cutter incident. Poliomyelitis following
formaldehyde-inactivated poliovirus vaccination in the United States during the Spring of
1955. Relationship of poliomyelitis to Cutter vaccine. American Journal of Hygiene, 78,
29-60.
NCBI (2015) National Cord Blood Inventory (NCBI) [Online]. Health Resources and Services
Administration. Available: https://bloodstemcell.hrsa.gov/about/contracts [Accessed
April 20 2020].
NCBI (2020) National Cord Blood Inventory (NCBI) Contract Summary [Online]. Health
Resources and Services Administration. Available:
https://bloodcell.transplant.hrsa.gov/about/contracts/ncbi/index.html [Accessed April 20
2020].
Paxson, C. L. (1979) Collection and use of autologous fetal blood. American Journal of
Obstetrics and Gynecology, 134, 708-710.
Pew Research (2020) U.S. survey research: questionnaire design [Online]. Pew Research
Center, Methods. Available: https://www.pewresearch.org/methods/u-s-survey-
research/questionnaire-design/ [Accessed April 20 2020].
PHS (1944) The Public Health Service Act [Online]. Office of the Law Revision Counsel.
Available: http://uscode.house.gov/browse/prelim@title42/chapter6A&edition=prelim
[Accessed June 26 2019].
Polin, J. I., Knox, I., Baumgart, S., Campman, E., et al. (1981) Use of Umbilical Cord Blood
Culture for Detection of Neonatal Bacteremia. Obstetrics & Gynecology, 57, 233-237.
Reagan, N. (2004) Juvenile Diabetes Research Foundation Event Speech [Online]. Available:
https://www.latimes.com/archives/la-xpm-2004-may-09-me-nancy9-story.html
[Accessed June 20 2020].
Rocha, V., Wagner, J. E. J., Sobocinski, K. A., Klein, J. P., et al. (2000) Graft-versus-host
disease in children who have received a cord-blood or bone marrow transplant from an
HLA-identical sibling. New England Journal of Medicine, 342, 1846-1854.
Rogers, K. (2010) Medicine and healers through history, New York, Britannica Educational
Publishing.
Rubinstein, P., Carrier, C., Scaradavou, A., Kurtzberg, J., et al. (1998) Outcomes among 562
recipients of placental-blood transplants from unrelated donors. New England Journal of
Medicine, 339, 1565-1577.
Scaradavou, A. (2013) Chapter 83 - Cord blood banking. In: Shaz, B. H., Hillyer, C. D., Roshal,
M. & Abrams, C. S. (eds.) Transfusion Medicine and Hemostasis. 2nd ed.: Elsevier Inc.
St. Martin, K. (2019) FDA regulation of cord blood products. In: Reis, R. L. & Gomes, M. E.
(eds.) Encyclopedia of Tissue Engineering and Regenerative Medicine. Amsterdam:
Elsevier.
U.S. Congress (1902) Session I. Chapter 1378, Biologics Control Act [Online]. NIH. Available:
https://history.nih.gov/display/history/Legislative+Chronology?preview=%2F1016866%
2F30736768%2FPL106-113.pdf [Accessed April 20 2020].
Weller, S. C. (2018) Open-ended interview questions and saturation. PloS one, 13(6).
Zoon, K. C. (2002) Science and the regulation of biological products: from a rich history to a
challenging future [Online]. FDA. Available:
https://www.fda.gov/media/108536/download [Accessed April 25 2020].
136
Appendix A: Survey
Start of Block: Survey Introduction
Intro:
Thank you for your participation in this survey. I appreciate your willingness to share your
thoughts regarding the current cord blood regulatory framework for traditional transplant
indications.
This survey is part of research associated with the Doctor of Regulatory Science degree at the
University of Southern California. Your candid answers are important to the success of this study
and are anonymous. I will provide respondents with a brief summary of the survey results once
the study is completed. I hope you will find the information valuable.
This survey should take approximately 15 minutes to complete.
End of Block: Survey Introduction
Start of Block: Demographics
Intro:
In this section, please tell me about your role and experience within your organization.
137
Q1 What department or function best describes your current role? Choose one option.
▢ Clinical Affairs and/or Medical Researcher
▢ Quality Assurance, Quality Control, and/or Regulatory Affairs
▢ Laboratory Technologist Services
▢ Administrative / Director / Program Manager (please specify your title)
________________________________________________
▢ Other ________________________________________________
Q2 I have been working in this role for...
o 0-2 Years
o 3-6 Years
o > 6 Years
Q3 What type of organization/company best represents your work experience? Choose one
option.
o Cord Blood Bank (including laboratory personnel)
o Collection hospital or facility
o Laboratory (free standing or hospital/University affiliated)
o Non-profit organization that sponsors INDs, distributes products, and/or audits cord
blood manufacturing institutions
o Other ________________________________________________
138
Q4 In your current or past experience, has your work supported a Cord Blood Bank holding an
approved BLA (license) from FDA for HPC, Cord Blood?
For your reference, the following is a list of FDA's currently licensed banks:
o Yes, my work has supported one or more of the licensed Cord Blood Banks
o No, my work has supported organizations operating under cord blood investigational
studies (IND)
o I don't know
Display This Question:
If Q4 = Yes, my work has supported one or more of the licensed Cord Blood Banks
Q5 Were you directly involved with a Cord Blood Bank's Biologic License Application (BLA)
to FDA?
o Yes, I was involved with the planning and/or submission of a BLA to FDA
o No
o I don't know
139
Display This Question:
If Q5 = Yes, I was involved with the planning and/or submission of a BLA to FDA
Q6
What were the drivers for applying for BLA (select all that apply)?
▢ FDA expectations
▢ Customer expectations
▢ Patient expectations
▢ Internal organization expectations
▢ Other (please specify)
________________________________________________
140
Display This Question:
If Q5 = Yes, I was involved with the planning and/or submission of a BLA to FDA
Q7 Thinking about your BLA experience with FDA's review division, please rank your
agreement with the following statements.
Strongly agree Somewhat agree Do not agree Don't know
FDA was
knowledgeable
about the cord
blood product
o o o o
FDA was
knowledgeable
about the
transplant
industry
o o o o
FDA was willing
to work with
sponsors to find
feasible solutions
o o o o
The FDA
submission &
review process
was
straightforward
and navigable
for sponsors
o o o o
141
Display This Question:
If Q3 = Cord Blood Bank (including laboratory personnel)
And Q4 = No, my work has supported organizations operating under cord blood
investigational studies (IND)
Q8 What is your organization's current stage of planning for BLA?
o Planning BLA in short term (1-5 yrs)
o Considering BLA in future (6-10 yrs)
o Not planning to pursue BLA
o I don't know
Display This Question:
If Q8 = Not planning to pursue BLA
Q9 Your organization is not planning to pursue BLA.
Please rank the barriers that influenced this decision.
______ Operational barriers
______ Legal & regulatory barriers
______ Financial & economic barriers
______ Education & training barriers
End of Block: Demographics
Start of Block: Critical Questions
Intro:
The FDA has requirements that govern the manufacturing of minimally manipulated, unrelated
cord blood for hematopoietic and immunologic reconstitution. CGMP compliance is required for
manufacturing cord blood under both Investigational New Drug (IND) clinical studies and
Biologics License Application (BLA). However, there are additional FDA requirements for BLA
operations.
The following questions are intended to gather your views on FDA requirements for HPC, Cord
Blood.
142
Q10 In your opinion, do you think the FDA's IND and BLA manufacturing process requirements
for HPC, Cord Blood products in the following areas are:
IND requirements BLA requirements
Too
strict
About
right
Too
lenient
Don't
know
Too
strict
About
right
Too
lenient
Don't
know
Product
collection o o o o o o o o
Infectious
Disease
Marker
Testing
o o o o o o o o
Required
Product
Testing
o o o o o o o o
Quality
Control
Unit
o o o o o o o o
Production
&
Processing
Controls
o o o o o o o o
Process
Validation o o o o o o o o
Batch
Records o o o o o o o o
143
Q11 In your opinion, do you think the FDA's IND and BLA manufacturing distribution
requirements for HPC, Cord Blood products in the following areas are:
IND requirements BLA requirements
Too
strict
About
right
Too
lenient
Don't
know
Too
strict
About
right
Too
lenient
Don't
know
Packaging
& Labeling
Controls
o o o o o o o o
Storage &
Distribution o o o o o o o o
Vendor
management
and
qualification
o o o o o o o o
Q12 In your opinion, do you think the FDA's IND and BLA regulatory requirements for HPC,
Cord Blood products in the following areas are:
IND requirements BLA requirements
Too
strict
About
right
Too
lenient
Don't
know
Too
strict
About
right
Too
lenient
Don't
know
FDA
submissions o o o o o o o o
FDA
reporting o o o o o o o o
FDA
inspections o o o o o o o o
144
Q13 What is the most significant barrier to obtaining a BLA in your view? Please rank the
following.
______ Operational barriers
______ Legal and regulatory barriers
______ Financial and economic barriers
______ Education & training barriers
Q14
In my opinion/experience, FDA's BLA regulatory requirements for HPC, Cord Blood has had the
following impacts.
Agree
Neither agree nor
disagree
Disagree
Improved patient
safety o o o
Improved product
quality o o o
Improved
standardization across
Cord Blood Banks
o o o
Improved
standardization across
collection hospitals
o o o
Improved Cord Blood
Bank differentiation o o o
145
Q15 Do you think the public Cord Blood Banking industry has adequate resources to meet the
FDA's regulatory requirements for HPC, Cord Blood products?
Yes No I don't know
Funding
o o o
Personnel
o o o
Facility & Equipment
o o o
Regulatory expertise
o o o
CGMP expertise
o o o
Q16 In your view, what is the level of difficulty to transition from CGMP for cord blood
investigational studies (IND) to CGMP for cord blood Biologic License Application (BLA)?
o Very difficult
o Moderately difficult
o Slightly difficult
o Not difficult at all
146
Display This Question:
If Q5 = Yes, I was involved with the planning and/or submission of a BLA to FDA
Q17 To what extent were these resources helpful when deciding to pursue a BLA?
Very helpful Helpful Not helpful I do not know
FDA website
o o o o
FDA guidance
documents o o o o
Direct
discussion/meeting
with FDA
o o o o
Industry association
recommendations o o o o
Literature
publications o o o o
Consultant
groups/firms o o o o
Dialogue with
industry peers o o o o
Seminars/conferences
o o o o
Advisory Committee
meetings & minutes o o o o
147
Display This Question:
If Q5 = Yes, I was involved with the planning and/or submission of a BLA to FDA
Q18
In your opinion, are more FDA guidance materials needed to help with the decision to apply for
BLA?
o Yes
o No
o No opinion
Display This Question:
If Q5 = Yes, I was involved with the planning and/or submission of a BLA to FDA
Q19 What additional resources might be helpful?
________________________________________________________________
End of Block: Critical Questions
Start of Block: Cord Blood Banks
Intro:
The following questions are intended to gather your perceptions and/or experience on the process
of implementing BLA requirements at Cord Blood Banks. Your views are important regardless
of direct experience with a BLA.
148
CBB_Q20
When a Cord Blood Bank initially assesses the BLA process, how difficult are the following
activities in your opinion?
Very difficult Difficult Not difficult Do not know
Evaluating
collection
hospitals’ ability
to meet CGMP
requirements
o o o o
Evaluating Cord
Blood Bank’s
ability to meet
CGMP
requirements
o o o o
Assessing the
BLA submission
requirements
o o o o
Securing funding
for operational
changes
o o o o
149
CBB_Q21
When a Cord Blood Bank prepares for the BLA process, how difficult are the following
activities in your opinion?
Very difficult Difficult Not difficult Do not know
Implementing
facility changes o o o o
Implementing
process controls
& final product
testing
o o o o
Developing a
BLA business
model
o o o o
Training
personnel on
CGMP
o o o o
CBB_Q22
Please provide any additional comments regarding the assessment and preparation for the BLA
process.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
150
CBB_Q23 When a Cord Blood Bank implements a BLA, how difficult are the following
activities in your opinion?
Very difficult Difficult Not difficult Do not know
Standardizing
processes across
collection
hospitals and
vendors
o o o o
Training a
Quality Control
Unit for product
release
o o o o
Engaging FDA
in pre-BLA
dialogue
o o o o
Responding to
FDA's BLA
submission
review requests
o o o o
Establishing
product pricing
&
reimbursement
o o o o
151
CBB_Q24 When a Cord Blood Bank works to sustain BLA processes, how difficult are the
following activities in your opinion?
Very difficult Difficult Not difficult Do not know
Sustaining
CGMP
compliant
Quality Systems
o o o o
Performing BLA
process change
management
o o o o
Responding to
FDA inspection o o o o
Forecasting
product supply
& demand
o o o o
CBB_Q25 Please provide any additional comments regarding implementing a BLA and
sustaining the BLA processes.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
152
CBB_Q26 Given what you know today, do you think all public Cord Blood Banks should be
required to submit a BLA to FDA?
o Yes
o No
o I don't know
CBB_Q27 Is there anything else you would like to say related to this topic of FDA regulation of
HPC, Cord Blood?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
End of Block: Cord Blood Banks
Start of Block: Affiliated Stakeholders
Intro:
The following questions are intended to gather your views on the process of implementing
CGMP requirements for HPC, Cord Blood at your organization and the experience of supporting
cord blood collection, processing, storage, and distribution under an IND or BLA.
Your views are important regardless of direct experience with an IND or BLA.
153
AS_Q28 When an organization initially assesses CGMP compliance, how difficult are the
following activities in your opinion?
Very difficult Difficult Not difficult Do not know
Assessing
CGMP
requirements for
IND conduct in
operations
o o o o
Evaluating the
facility's ability
to meet CGMP
o o o o
Assessing
product supply
& demand
o o o o
Performing
vendor
qualification
o o o o
AS_Q29 When an organization prepares for CGMP compliance, how difficult are the following
activities in your opinion?
Very difficult Difficult Not difficult Do not know
Standardizing
donor suitability
& eligibility
processes
o o o o
Securing funding
for any
operational
changes
o o o o
Implementing
facility changes o o o o
Establishing
standard
operation
procedure
training
o o o o
154
AS_Q30 Please provide any additional comments regarding the assessment and
preparation for CGMP compliance.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
AS_Q31 When an organization implements CGMP, how difficult are the following activities in
your opinion?
Very difficult Difficult Not difficult Do not know
Standardizing
infectious disease
testing & final
product testing
o o o o
Establishing
Quality Control
Unit capabilities
for product release
o o o o
Engaging FDA in
pre-IND dialogue o o o o
Establishing IND
product
reimbursement/cost
recovery
o o o o
155
AS_Q32 When an organization works to sustain compliant processes, how difficult are the
following activities in your opinion?
Very difficult Difficult Not difficult Do not know
Sustaining
CGMP
compliant
Quality Systems
o o o o
Performing IND
process change
management
o o o o
Engaging FDA
in ongoing
dialogue about
product
indications for
use
o o o o
Sustaining
annual CGMP
personnel
training
o o o o
AS_Q33 Please provide any additional comments regarding implementing CGMP and
sustaining compliant processes.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
156
AS_Q34 Given what you know today, do you think all public Cord Blood Banks should be
required to submit a BLA to FDA?
o Yes
o No
o I don't know
AS_Q35 Is there anything else you would like to say related to this topic of FDA regulation of
HPC, Cord Blood?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
End of Block: Affiliated Stakeholders
Start of Block: End of survey
End:
Thank you for your support of this survey. I appreciate your time and value your perspective on
this topic. If you would like a brief summary of the results when the study concludes, specify
your preferred email below:
_____________________________________________________________
End of Block: End of survey
157
Appendix B: Survey Cross Tabulation
Cross tabulation results were not statistically significant
Experience Supporting Licensed CBB: BLA Manufacturing Process Requirements
Comparison between the “Too Strict” and “About Right” responses
Experience Supporting Licensed CBB: BLA Manufacturing Distribution Requirements
Comparison between the “Too Strict” and “About Right” responses
Total
Total Count 43 17 26
Too strict 4 2 (12%) 2 (8%)
About right 34 14 (82%) 20 (77%)
Too strict 3 0 3 (11%)
About right 38 17 (100%) 21 (81%)
Too strict 11 8 (47%) 3 (11%)
About right 27 7 (41%) 20 (77%)
Too strict 17 9 (53%) 8 (31%)
About right 20 6 (35%) 14 (54%)
Too strict 19 7 (41%) 12 (46%)
About right 16 7 (41%) 9 (35%)
Too strict 21 10 (58%) 11 (42%)
About right 15 5 (29%) 10 (38%)
Too strict 8 3 (18%) 5 (19%)
About right 29 12 (70%) 17 (65%)
In your current or past experience, has your work
supported a Cord Blood Bank holding an approved BLA?
No Yes
In your opinion, do you think the FDA's BLA product
collection requirements for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA batch
record requirements for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA Infectious
Disease Marker testing requirements for HPC, Cord
In your opinion, do you think the FDA's BLA required
product testing requirements for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA Quality
Control Unit requirements for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA production
& processing control requirements for HPC, Cord Blood
In your opinion, do you think the FDA's BLA process
validation requirements for HPC, Cord Blood are
Total
Total Count 45 18 27
Too strict 3 1 (6%) 2 (7%)
About right 39 16 (88%) 23 (85%)
Too strict 4 2 (11%) 2 (7%)
About right 37 14 (78%) 23 (85%)
Too strict 15 8 (44%) 7 (26%)
About right 25 8 (44%) 17 (63%)
In your opinion, do you think the FDA's BLA vendor
management & qualification for HPC, Cord Blood are
In your current or past experience, has your work
supported a Cord Blood Bank holding an approved BLA?
No Yes
In your opinion, do you think the FDA's BLA packaging
& labeling controls for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA storgage &
distribution requirements for HPC, Cord Blood are
158
Experience Supporting Licensed CBB: BLA Submission, Reporting, & Inspection
Comparison between the “Too Strict” and “About Right” responses
Type of Organization: BLA Manufacturing Process Requirements
Comparison between the “Too Strict” and “About Right” responses
Total Count No Yes
44 18 26
Too strict 21 10 (56%) 11 (42%)
About right 15 5 (28%) 10 (38%)
Too strict 17 7 (39%) 10 (38%)
About right 20 8 (44%) 12 (46%)
Too strict 19 9 (50%) 10 (38%)
About right 16 4 (22%) 12 (46%)
In your opinion, do you think the FDA's BLA
reporting requirements for HPC, Cord Blood are
In your opinion, do you think the FDA's BLA
inspection requirements for HPC, Cord Blood are
In your current or past experience, has your work
supported a Cord Blood Bank holding an approved BLA?
In your opinion, do you think the FDA's BLA
submission requirements for HPC, Cord Blood are
Total
Total Count 45 17 20 5 4
Too strict 4 1 (5%) 1 (5%) 1 (20%) 1 (25%)
About right 34 10 (58%) 17 (85%) 4 (80%) 3 (75%)
Too strict 3 2 (11%) 0 0 1 (25%)
About right 39 11 (64%) 20 (100%) 5 (100%) 3 (75%)
Too strict 11 2 (11%) 5 (25%) 4 (80%) 0
About right 27 7 (41%) 15 (75%) 1 (20%) 4 (100%)
Too strict 17 3 (17%) 7 (35%) 4 (80%) 3 (75%)
About right 22 9 (52%) 11 (55%) 1 (20%) 1 (25%)
Too strict 19 4 (23%) 9 (%) 4 (80%) 2 (50%)
About right 16 4 (23%) 11 (%) 0 1 (25%)
Too strict 21 4 (23%) 9 (45%) 5 (100%) 3 (75%)
About right 15 3 (17%) 11 (55%) 0 1 (25%)
Too strict 8 2 (22%) 5 (25%) 0 1 (25%)
About right 29 7 (78%) 15 (75%) 5 (100%) 2 (50%)
In your opinion, do you think the FDA's BLA
process validation requirements for HPC,
Cord blood are
In your opinion, do you think the FDA's BLA
batch record requirements for HPC, Cord
blood are
What type of organization/company best represents your
work experience? Choose one option.
Non-
profit &
Other CBB
Collection
Hospital Laboratory
In your opinion, do you think the FDA's BLA
product collection requirements for HPC,
Cord blood are
In your opinion, do you think the FDA's BLA
Infectious Disease Marker testing
requirements for HPC, Cord blood are
In your opinion, do you think the FDA's BLA
required product testing requirements for
HPC, Cord blood are
In your opinion, do you think the FDA's BLA
Quality Control Unit requirements for HPC,
Cord blood are
In your opinion, do you think the FDA's BLA
production & processing controls
requirements for HPC, Cord blood are
159
Type of Organization: BLA Manufacturing Distribution Requirements
Comparison between the “Too Strict” and “About Right” responses
Type of Organization: BLA Submission, Reporting, & Inspection
Comparison between the “Too Strict” and “About Right” responses
Total
Total Count 47 19 20 5 3
Too strict 3 1 (5%) 0 1 (20%) 1 (25%)
About right 39 12 (57%) 20 (100%) 4 (80%) 3 (75%)
Too strict 4 1 (5%) 3 (12%) 0 0
About right 37 12 (57%) 17 (68%) 5 (100%) 3 (100%)
Too strict 15 3 (14%) 6 (24%) 3 (60%) 3 (75%)
About right 25 8 (38%) 14 (56%) 2 (40%) 1 (25%)
In your opinion, do you think the FDA's
BLA packaging & labeling controls for
HPC, Cord Blood are
In your opinion, do you think the FDA's
BLA storage & distribution requirements
for HPC, Cord Blood are
In your opinion, do you think the FDA's
BLA vendor management & qualification
requirements for HPC, Cord Blood are
What type of organization/company best represents your
work experience?
Non-profit &
Other CBB
Collection
Hospital Laboratory
Total
Total Count 46 17 20 5 4
Too strict 21 3 (14%) 13 (52%) 3 (60%) 2 (50%)
About right 15 7 (33%) 6 (24%) 1 (20%) 1 (25%)
Too strict 17 4 (19%) 9 (36%) 2 (40%) 2 (50%)
About right 20 6 (29%) 10 (40%) 2 (40%) 2 (50%)
Too strict 19 4 (19%) 9 (36%) 3 (60%) 3 (75%)
About right 16 5 (24%) 9 (36%) 1 (20%) 1 (25%)
In your opinion, do you think the
FDA's BLA submission requirements
for HPC, Cord Blood are
In your opinion, do you think the
FDA's BLAreporting requirements for
HPC, Cord Blood are
In your opinion, do you think the
FDA's BLA inspection requirements
for HPC, Cord Blood are
What type of organization/company best represents your
work experience? Choose one option.
Non-profit
& Other CBB
Collection
Hospital Laboratory
160
Type of Organization: BLA Regulatory Requirement Impacts
Type of Organization: CBB Industry Resources to Meet BLA Requirements
Total
Total Count 49 20 20 5 4
Agree 13 9 (45%) 3 (15%) 1 (20%) 0
Disagree 20 3 (25%) 12 (60%) 3 (60%) 2 (50%)
Neither agree or disagree 16 8 (48%) 5 (25%) 1 (20%) 2 (50%)
Agree 21 10 (50%) 6 (30%) 4 (80%) 1 (25%)
Disagree 14 4 (20%) 9 (45%) 0 1 (25%)
Neither agree or disagree 14 6 (30%) 5 (25%) 1 (20%) 2 (50%)
Agree 23 9 (45%) 9 (45%) 2 (40%) 3 (75%)
Disagree 8 2 (10%) 5 (25%) 0 1 (25%)
Neither agree or disagree 18 9 (45%) 6 (30%) 3 (60%) 0
Agree 18 6 (30%) 4 (20%) 5 (100%) 3 (75%)
Disagree 13 3 (15%) 9 (45%) 0 1 (25%)
Neither agree or disagree 18 11 (55%) 7 (35%) 0 0
Agree 15 8 (40%) 6 (30%) 0 1 (25%)
Disagree 12 4 (20%) 7 (35%) 0 1 (25%)
Neither agree or disagree 22 8 (40%) 7 (35%) 5 (100%) 2 (50%)
In my opinion/experience, FDA's BLA regulatory requirements for HPC,
Cord Blood has had the following impact on improving patient safety
In my opinion/experience, FDA's BLA regulatory requirements for HPC,
Cord Blood has had the following impact on improved product quality
In my opinion/experience, FDA's BLA regulatory requirements for HPC,
Cord Blood has had the following impact on improved standardization
across CBBs
In my opinion/experience, FDA's BLA regulatory requirements for HPC,
Cord Blood has had the following impact on improved standardization
across collection hospitals
In my opinion/experience, FDA's BLA regulatory requirements for HPC,
Cord Blood has had the following impact on improved CBB
differentiation
What type of organization/company best represents your work
experience? Choose one option.
Non-profit
organization &
Other CBB
Collection
Hospital Laboratory
Total
Total Count 49 5 20 4 17 3
I don't know 7 2 (40%) 1 (5%) 0 4 (23%) 0
No 40 3 (60%) 19 (95%) 4 (100%) 12 (71%) 2 (67%)
Yes 2 0 0 0 1 (6%) 1 (33%)
I don't know 5 0 0 0 4 (24%) 1 (33%)
No 32 5 (100%) 13 (65%) 3 (75%) 10 (59%) 1 (33%)
Yes 12 0 7 (35%) 1 (25%) 3 (18%) 1 (33%)
I don't know 8 1 (20%) 0 1 (25%) 5 (29%) 1 (33%)
No 24 3 (60%) 11 (55%) 0 9 (53%) 1 (33%)
Yes 17 1 (20%) 9 (45%) 3 (75%) 3 (18%) 1 (33%)
I don't know 6 0 0 1 (25%) 4 (24%) 1 (33%)
No 29 4 (80%) 11 (55%) 1 (25%) 11 (65%) 2 (67%)
Yes 14 1 (20%) 9 (45%) 2 (50%) 2 (12%) 0
I don't know 4 0 0 0 3 (18%) 1 (33%)
No 28 5 (100%) 8 (40%) 2 (50%) 11 (65%) 2 (67%)
Yes 17 0 12 (60%) 2 (50%) 3 (18%) 0
Do you think the public Cord Blood Banking industry has
adequate funding resources to meet the FDA's
regulatory requirements for HPC, Cord Blood products?
Do you think the public Cord Blood Banking industry has
adequate personnel resources to meet the FDA's
regulatory requirements for HPC, Cord Blood products?
Do you think the public Cord Blood Banking industry has
adequate facility & equipment resources to meet the
FDA's regulatory requirements for HPC, Cord Blood
products?
Do you think the public Cord Blood Banking industry has
adequate regulatory expertise resources to meet the
FDA's regulatory requirements for HPC, Cord Blood
products?
Do you think the public Cord Blood Banking industry has
adequatecGMP expertise resources to meet the FDA's
regulatory requirements for HPC, Cord Blood products?
What type of organization/company best represents your work
experience? Choose one option.
Collection
Hospital or
Facility CBB Laboratory
Non-profit
Organization Other
161
Appendix C: Respondent Identification
Abstract (if available)
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Asset Metadata
Creator
St. Martin, Katherine Elizabeth
(author)
Core Title
Examining the cord blood industry views on the biologic license application regulatory framework
School
School of Pharmacy
Degree
Doctor of Regulatory Science
Degree Program
Regulatory Science
Publication Date
09/19/2020
Defense Date
07/16/2020
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
biologic drug regulation,Biologics License Applications,cord blood banks,current good manufacturing practices,current good tissue practices,Food and Drug Administration,OAI-PMH Harvest,stem cell therapy,umbilical cord blood
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Richmond, Frances (
committee chair
), Church, Terry (
committee member
), Pacifici, Eunjoo (
committee member
), Pire-Smerkanich, Nancy (
committee member
)
Creator Email
kstmarti@usc.edu,stmartinkatherine@gmail.com
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c89-371304
Unique identifier
UC11666349
Identifier
etd-StMartinKa-8982.pdf (filename),usctheses-c89-371304 (legacy record id)
Legacy Identifier
etd-StMartinKa-8982.pdf
Dmrecord
371304
Document Type
Dissertation
Rights
St. Martin, Katherine Elizabeth
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
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Repository Location
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Tags
biologic drug regulation
Biologics License Applications
cord blood banks
current good manufacturing practices
current good tissue practices
Food and Drug Administration
stem cell therapy
umbilical cord blood