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A survey of US industry views on implementation of decentralized clinical trials

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A survey of US industry views on implementation of decentralized clinical trials

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A SURVEY OF US INDUSTRY VIEWS ON IMPLEMENTATION OF
DECENTRALIZED CLINICAL TRIALS

by

Wendi Marie Lau

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

August 2020

Copyright 2020 Wendi Marie Lau

ii
Dedication……

I dedicate this dissertation to my family and friends. Your continual support and
encouragement throughout this process helped provide me the strength and perseverance
I needed to fulfill my dream.
To my parents, Len and Judi, thank you for standing by me and encouraging me
during the ups and downs of my educational process. I would not be where I am today
without your unconditional support.
To my husband, David, and children, Conrad, Hannah and Stephanie, I appreciate
the sacrifices you made to accommodate my need and drive and look forward to giving
back to support your dreams and ambitions, wherever they may lead.

iii
Acknowledgements

I would like to thank all of those who helped to encourage me along my journey.
First being the professors and staff at the University of Southern California. The five
years I participated in this program went fast. I enjoyed every minute, mostly, and
appreciate the support provided as a distance student. I wasn’t sure how this would work,
and I was smitten on the first day of class! In particular, I would like to thank my thesis
supervisor, Dr. Nancy Pire-Smerkanich, for providing me the inspiration to achieve my
goal. Your guidance, advice, encouragement and stories were motivating and helped put
things into perspective when needed. I would also like to thank Dr. Frances Richmond
for her words of encouragement and support throughout my 5 years at USC. Your
positive words helped to motivate me through sleepless nights and weekends filled with
lectures and homework. The program you created has provided me a world-class
experience and I look forward to continuing to support the program in any way I can.
I would also like to acknowledge my colleagues and mentors at Astellas for
supporting me through this journey. Your encouragement and flexibility allowed me to
dedicate myself to this experience. I could not have done this without the commitment
you made to me, and for that I am deeply humbled and honored.
I would like to acknowledge my industry peers, including Craig Lipset and Dr.
Lisa DiMolfetto, for their support of the survey used for this research. Your input and
insights strengthened this research. And for those peers who helped provide responses, I
look forward to sharing the results and continuing to add to your knowledge in this space,
just as you have added to my knowledge.

iv
And finally, for the colleagues in the doctoral cohort of 2016. I am honored to be
part of your team. I will cherish the friendships I have made and the unending
encouragement. I will be your biggest advocate and strongest supporter to help get you
over the finish line!

v
Table of Contents
Dedication…… .................................................................................................................... ii
Acknowledgements ............................................................................................................. iii
Table of Contents ................................................................................................................. v
List of Tables ..................................................................................................................... viii
List of Figures ...................................................................................................................... x
Abstract………. ................................................................................................................ xiii
Overview ......................................................................................................... 1
1.1 Overview Introduction ................................................................................... 1
1.2 Statement of the Problem ............................................................................... 3
1.3 Purpose of the Study ...................................................................................... 4
1.4 Importance of the Study ................................................................................. 5
1.5 Limitation, Delimitations, Assumptions ........................................................ 5
1.6 Organization of Thesis ................................................................................... 6
1.7 Definitions ...................................................................................................... 7
Literature Review .......................................................................................... 10
2.1 Literature Search .......................................................................................... 10
2.2 Introduction .................................................................................................. 11
2.3 History of Clinical Drug Development in a Regulated Environment .......... 13
2.3.1 The Introduction of the Clinical Trial to Evaluate US Drugs ................. 13
2.3.1.1 Regulation of the Investigational Use of New Drugs ................... 15
2.3.1.2 Marketing Approval of New Drugs .............................................. 17
2.3.2 The Evolving Regulation of Drugs in the US ......................................... 18
2.3.3 Regulation of Drugs Outside the US ...................................................... 23
2.3.4 Evolution of Good Clinical Practices ..................................................... 26
2.3.5 The Emergence of Technology in Clinical Trials and Regulatory
Filings ..................................................................................................... 28
2.4 Current State of Clinical Drug Development ............................................... 32
2.4.1 Protocol Complexity is Reducing Productivity ...................................... 33
2.4.2 Patient Enrollment and Patient Retention Impacting Productivity ......... 35
2.5 Decentralized Clinical Trials in Drug Development and Stakeholder
Views on Implementation ............................................................................ 37
2.5.1 Evolution of Regulatory Views on Decentralized Trials ........................ 41
2.5.2 CTTI Recommendations for Decentralized Clinical Trials .................... 43
2.5.2.1 Telemedicine and Mobile Healthcare Providers ........................... 45
2.5.2.2 Investigator Delegation and Oversight.......................................... 46
2.5.2.3 Clinical Trial Drug Supplies ......................................................... 47
2.5.2.4 Safety Monitoring ......................................................................... 47
2.5.3 Current Implementation of Decentralized Clinical Trials by Industry
Sponsors .................................................................................................. 47
2.6 Approach to the Research Project ................................................................ 51
2.6.1 The Innovation-Decision Process ........................................................... 52
2.6.2 Attributes of Innovation .......................................................................... 53
2.6.3 Rate of Adoption and Adopter Categories .............................................. 54

vi
Methodology ................................................................................................. 56
3.1 Identification of Study Participants .............................................................. 56
3.2 Data Collection Methodology ...................................................................... 57
3.2.1 Focus Group ............................................................................................ 57
3.2.2 High-Level Survey Content .................................................................... 59
3.2.3 Definition of Decentralized Clinical Trials............................................. 60
3.3 Survey Deployment ..................................................................................... 61
3.4 Data Analysis Methodology......................................................................... 62
Results ........................................................................................................... 63
4.1 Survey Participation ..................................................................................... 63
4.2 Demographic Profile of Respondents .......................................................... 63
4.3 Innovation Decision Process and Implementation Strategy ......................... 69
4.3.1 Level of Knowledge About Decentralized Clinical Trials ..................... 69
4.3.2 Implementation Stage for Decentralized Clinical Trials ........................ 74
4.4 Rate of Innovation ........................................................................................ 88
4.5 Factors Influencing Decisions to Implement Some or All Elements of
Decentralized Clinical Trials ....................................................................... 91
4.6 Factors Affecting the Use of Approaches to Decentralized Clinical
Trials ............................................................................................................ 97
4.6.1 Approaches to Study Conduct by Type of Interventional Clinical
Trial 97
4.6.2 Approaches to Study Conduct by Location of Clinical Trial and
Types of Procedures ............................................................................. 102
4.6.3 Approaches to Study Conduct by Patient Population ........................... 105
4.6.4 Approaches to Study Conduct by Characteristics of the Drug
Product .................................................................................................. 109
4.7 Experience with Decentralized Clinical Trials .......................................... 113
4.7.1 Experience with FDA ........................................................................... 114
4.7.2 Experience with Trial Participants ........................................................ 115
4.8 Additional Comments Elicited by the Study .............................................. 117
Discussion ................................................................................................... 119
5.1 Methodological Considerations ................................................................. 119
5.1.1 Limitations ............................................................................................ 119
5.1.1.1 Identifying and Engaging Representative Participants ............... 120
5.1.1.2 Assuring Completion of the Survey ............................................ 121
5.1.2 Delimitations ......................................................................................... 123
5.2 Consideration of Results ............................................................................ 125
5.2.1 Knowledge and Persuasion ................................................................... 126
5.2.2 Decision, Implementation and Confirmation ........................................ 131
5.3 Conclusions and Future Direction .............................................................. 133
References…….. .............................................................................................................. 136
Appendix A. Survey.......................................................................................................... 150
Appendix B. Data Tables .................................................................................................. 180
Appendix C. Rank Order Calculations ............................................................................. 201

vii
Appendix D. Cross-tabulations ......................................................................................... 206

viii
List of Tables
Table 1: Regulations Enacted in the 21
st
Century to Facilitate FDA Support of
Efficient Access to Innovative Drugs and Biologics ......................................21
Table 2: Public, Private and Academic Collaborations Sponsored by FDA ................22
Table 3: Factors Negatively Affecting Patient Recruitment and Retention in
Clinical Studies ...............................................................................................36
Table 4: Lessons Learned from the Execution of the REMOTE Trial .........................40
Table 5: General Theme of Comments Received from Pharmaceutical
Companies on FDA Public Docket FDA-2015-N-3579 ................................42
Table 6: Themes from the CTTI Expert Meeting on Legal and Regulatory
Issues Affecting Adoption of Mobile Clinical Trials .....................................44
Table 7: Attributes of Innovation ..................................................................................54
Table 8: Focus Group Participants ................................................................................58
Table 9: Size of Company Based on Number of Employees ........................................68
Table 10: Number of Interventional Clinical Trials Conducted/Year ............................68
Table 11: Priority for Implementing Approaches to Decentralized Clinical
Trials ...............................................................................................................90
Table 12: Ranking of Priority for Implementing Approaches to Decentralized
Clinical Trials by Size of Company ...............................................................91
Table 13: Ranking of Organizational Challenges or Barriers to Implementation
of Approaches to Decentralized Clinical Trials .............................................92
Table 14: Ranking of Organizational Challenges or Barriers to Implementation
of Approaches to Decentralized Clinical Trials by Size of Company ...........93
Table 15: Outcome of Discussions with FDA on Fully Decentralized Clinical
Trial or Hybrid Approaches .........................................................................115
Table 16: Outcome of Discussions with Trial Participants or Caregivers on
Fully Decentralized Clinical Trial or Hybrid Approaches ...........................117
Table 17: Open-Ended Comments on Positive Experiences or Challenges with
Decentralized Clinical Trial Approaches .....................................................118
Table 18: Any Other Open-Ended Comment From Any Respondent ..........................118

Appendix C Table 1: Rank of Organizational Challenges/Barriers (Q9),
Overall and By Size of Company (Q24) ......................................................201
Appendix C Table 2: Rank of Implementation Priority for Decentralized
Approaches (Q30), Overall and By Size of Company (Q24) .......................204

ix
Appendix D Table 1: Cross-Tabulation of Implementation Stage of
Decentralized Clinical Trial (Q4 and Q5) by Size of Company (Q24) ........206
Appendix D Table 2: Cross-Tabulation of Decentralized Approaches (Q6)
by Size of Company (Q24) ...........................................................................208
Appendix D Table 3: Cross-Tabulation of Knowledge of Decentralized
Approaches (Q2) by Size of Company (Q24) ..............................................211

x
List of Figures
Figure 1: Overview of the New Authorities Granted to FDA by the Kefauver-
Harris Amendment of 1962 ............................................................................15
Figure 2: Phases of Clinical Studies ...............................................................................17
Figure 3: Average Length of Clinical Development Time for Small-Molecules
Approved by FDA from 1970-2001 ...............................................................19
Figure 4: Overview of ICH Good Clinical Practice .......................................................27
Figure 5: CDISC Standards for Clinical Trial Data .......................................................30
Figure 6: Median Time (in Months) from Final Protocol Approval to Final
Study Report for Phase 2 and 3 Studies in 2006-2008 Compared with
2013-2015 .......................................................................................................32
Figure 7: Mean Number of Procedures for Phase 2 and Phase 3 Clinical Trials
from 2001-2015 ..............................................................................................34
Figure 8: Mean Total Cost per Study Participant per Study Visit for Phase 2
and Phase 3 Clinical Trials from 2001-2015 ..................................................34
Figure 9: Cost of Site Initiation and 1-Year Maintenance Costs for Study Sites
that Under Enroll or do not Enroll Patients into a Phase 3 Study ..................37
Figure 10: Flow of Potential Participants through the Screening Process for the
REMOTE trial ................................................................................................40
Figure 11: Projects within the CTTI Mobile Clinical Trials Program .............................43
Figure 12: Patient-Centric Initiatives Evaluated in the DIA/Tufts CSDD Survey ..........50
Figure 13: Innovation-Decision Process ..........................................................................52
Figure 14: Categorization of Adopters Over Time ..........................................................55
Figure 15: Overview of Survey ........................................................................................60
Figure 16: Department/Function Represented by Respondents .......................................65
Figure 17: Role Played by Respondents in Deciding to Implement Decentralized
Clinical Trials .................................................................................................66
Figure 18: Organizational Level of Respondents .............................................................67
Figure 19: Knowledge of Approaches Related to the Conduct of Decentralized
Clinical Trials .................................................................................................71
Figure 20: Decentralized Approaches Respondents Have Knowledge of and
Have Used by Size of Company .....................................................................73
Figure 21: Mechanisms Used to Reference or Learn About Decentralized
Clinical Trials .................................................................................................74
Figure 22: Implementation Stage for Fully Decentralized Clinical Trials .......................75

xi
Figure 23: Implementation Stage for a Hybrid Approach to Decentralized
Clinical Trials .................................................................................................76
Figure 24: Implementation Stage for Fully Decentralized Clinical Trials by Size
of Company ....................................................................................................78
Figure 25: Implementation Stage for a Hybrid Approach to Decentralized
Clinical Trials by Size of Company ...............................................................80
Figure 26: Decentralized Approaches to Clinical Trials Considered or Used by
Those Considering or Pursuing Implementation of Decentralized
Trials ...............................................................................................................82
Figure 27: Implementation of Fully Decentralized Clinical Trials by Size of
Company ........................................................................................................83
Figure 28: Implementation of Virtual Trial Sites Plus Traditional Trial Sites by
Size of Company ............................................................................................84
Figure 29: Implementation of Telemedicine by Size of Company ..................................85
Figure 30: Implementation of Mobile Healthcare Providers by Size of Company ..........86
Figure 31: Implementation of Local Healthcare Providers by Size of Company ............87
Figure 32: Implementation of Direct Shipment of Study Drug or Materials to the
Trial Participant by Size of Company ............................................................88
Figure 33: Timing for Conduct of Fully Decentralized Clinical Trials (n=14) ...............89
Figure 34: Timing for Conduct of Hybrid Approaches to Decentralized Clinical
Trials ...............................................................................................................90
Figure 35: Influence of Feasibility Factors Which May Impact Decision to
Implement Approaches to Decentralized Clinical Trials ...............................94
Figure 36: Influence of External Factors On Decisions to Implement
Decentralized Clinical Trials or Hybrid Approaches to Decentralized
Clinical Trials .................................................................................................96
Figure 37: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Type of Clinical Trial ..........................................98
Figure 38: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Type of Clinical Trial ...................................................................................101
Figure 39: Approaches to Decentralized Clinical Trials Based on Regions of
Study Conduct ..............................................................................................103
Figure 40: Approaches to Decentralized Clinical Trials Based on Requirement
for Specialized Procedures ...........................................................................105
Figure 41: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Characteristics of the Population Included
in the Trial ....................................................................................................107

xii
Figure 42: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Characteristics of the Population Included in the Trial ................................109
Figure 43: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Characteristics of the Product Being
Evaluated ......................................................................................................111
Figure 44: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Characteristics of the Product Being Evaluated ...........................................113
Figure 45: Discussion of Fully Decentralized Clinical Trial or Hybrid
Approaches with FDA ..................................................................................114
Figure 46: Discussion of Fully Decentralized Clinical Trial or Hybrid
Approaches with Trial Participants ..............................................................116

xiii
Abstract……….

Decentralized clinical trials offer great potential to reduce the cost and time that it takes
to obtain marketing authorization of a new drug. However, it is unclear how industry
stakeholders perceive opportunities and barriers associated with the use of decentralized
trials. This study evaluated how, why and at what rate decentralized clinical trials are
being adopted by industry using a survey-based approach based on the diffusion of
innovation framework. A total of 72 respondents with backgrounds in clinical
development from a range of small and large pharmaceutical companies completed at
least one question and 50% of respondents completed all questions. Half identified that
their companies had decided to implement fully decentralized clinical trials and two-
thirds to implement hybrid approaches. The primary barriers to implementation were
lack of clear regulatory guidance and insufficient organizational readiness. Priorities for
implementation included the use of virtual trial sites in additional to traditional trial sites,
telemedicine, mobile healthcare providers and direct shipment of study drug or materials
to the participant; a fully decentralized approach was rated as lowest priority.
Decentralized approaches were considered less commonly for early-stage clinical trials
and pivotal studies for non-marketed products. Additionally, studies of products
requiring oversight by healthcare professionals or for products which require special
handling considerations were less likely to be conducted using hybrid approaches.

1
Overview
1.1 Overview Introduction
The approval of a new drug pivots on the outcome of preliminary testing in
humans to provide essential evidence of safety and effectiveness. Over the last thirty
years, these trials have become increasingly lengthy and costly, contributing to an overall
clinical development program taking 15 years and costing as much as 2 billion dollars or
more to get a drug to the market (DiMasi et al., 2016; Tufts Center for the Study of Drug
Development, 2016). Durations and costs escalate when trials recruit more slowly than
anticipated or when participants drop out before the study is over (Getz and Kaitin,
2015). The increasing complexity of protocols also affects the likelihood that patients
will find it difficult to participate. Pharmaceutical companies and regulators agree that
improvements in the current drug development process are needed to get effective
medical products to patients faster (FDA, 2019b). They are now looking to modern
technological tools such as telemedicine and mobile health platforms as novel adjuncts to
clinical research conduct that might encourage better patient engagement. These new
tools allow the decentralization of study conduct away from the traditional clinical study
site and expand opportunities to engage local healthcare providers into the clinical trial
environment. Today, the term “decentralized design” describes the conduct of clinical
trials using telemedicine and mobile/local healthcare providers rather than the traditional
in-clinic based setting. It offers a way for patients to fit study participation into their life
rather than fitting their life around the clinical trial (CTTI, 2018).

2
The new approaches are in some ways revolutionary. Since the late 1940s, the
randomized-controlled trial has been viewed as the “gold standard”, the most rigorous
method to control bias and subjective evaluations (Jenkins and Hubbard, 1991). In the
United States, their use was embedded into regulatory expectations by the 1962
Kefauver-Harris amendment to the Food, Drug and Cosmetic Act, which required proof
of efficacy through adequate and well-controlled trials as a prerequisite to drug approval
(Greene and Podolsky, 2012). The burden of proof to satisfy these requirements fell
upon drug manufacturers and increased the time and cost that it took to develop new
drugs. Food and Drug Administration (FDA) took steps to ease the burden to facilitate
access and the development of products for life-threatening indications (Darrow et al.,
2014). “Treatment-use” INDs allowed patient access to an investigational drug outside a
formal protocol or clinical trial; “fast-track” programs allowed early and frequent
meetings with FDA as well as the use of surrogate endpoints to support marketing
approval while obtaining data on clinically relevant endpoints after marketing
authorization (Darrow et al., 2014). However, these routes are not available for those
novel products that cannot pass the bar of treating serious or life-threatening diseases
with insufficient treatment options. Further, even with these pathways, concerns exist
about the challenges of completing the expensive clinical trials that have traditionally
been required to assure market approval. An evolution of the clinical trial operating
model, taking advantage of advances in technology such as precision medicine and
mobile health applications, has taken place more recently to improve operational
efficiencies and ensure the right drug is given to the right patient at the right time.
Additionally, a focus on the patient experience has been promoted to encourage better

3
participation by the general population. Decentralized clinical trials offer an innovative
opportunity to improve the way we approach the development of drugs.
The first decentralized clinical trial with regulatory oversight was conducted by
Pfizer in 2011 (Hirsch et al., 2017). The study used web-based technology and
smartphones to manage the study. This allowed patients to participate remotely, without
regard to the location of the clinical study site (Roehr, 2011b). Logistically, the study
managed all aspects of a traditional clinical trial by using mechanisms that did not rely on
site visits (Orri et al., 2014). The study used web-based technology to administer and
document informed consent; study drug was shipped to the patient’s home; samples for
laboratory tests were collected by nurses who visited the patient’s home or by visits to
local clinics; and physicians associated with the study were accessible by phone 24 hours
a day. The trial demonstrated the technical feasibility of a remote trial and prompted
additional interest by regulators and industry.
1.2 Statement of the Problem
Although the first decentralized clinical trial was conducted by Pfizer nearly a
decade ago, the pharmaceutical and biotechnology industry has been slow to accept and
use this operating model. In a survey conducted in 2016 by DIA and Tufts Center for the
Study of Drug Development (CSDD), for example, the use of various patient-centric
initiatives appeared to be modest at best. The approaches that have been most attractive
to date have been patient-centric initiatives, such as home nursing networks, that have
tended to offer a quick return on investment and were able to be applied across multiple
therapeutic areas. In contrast, telemedicine and direct-to-patient clinical trials were much

4
less likely to be implemented (Lamberti and Awatin, 2017). The primary barriers to the
implementation of patient-centric initiatives identified by that study were lack of
company support and authority by senior leadership to implement. Other barriers
included lack of readiness by the sponsor, low risk tolerance and lack of resources
(people, time and money). Even though the survey was limited in scope to 22 companies,
it seemed clear that the enthusiasm and perceived benefits of decentralized clinical trials
were not driving companies to implement this novel conduct approach. Nevertheless,
some companies are embracing decentralization as an effective way to reach patients.
Companies such as Science 37 have conducted several clinical trials in a decentralized
setting. Therefore, while in 2016 the trend seemed as if adoption would be slow, the
adoption of decentralized trials may be gaining momentum, particularly as regulators,
such as FDA, focus on furthering innovation in clinical development.
The research presented here aimed to extend the understanding of the views of
industry stakeholders on perceived opportunities and barriers associated with the
adoption of decentralized clinical studies.
1.3 Purpose of the Study
The purpose of this study was to survey professionals within the pharmaceutical
and biotechnology industry in the United States (US) on their views and observations
regarding the use of decentralized clinical trials as an innovative way to improve the drug
development process. Using the diffusion of innovation framework as a basis for
collecting information, this study evaluated how, why and at what rate decentralized
clinical trials were being adopted by industry (Rogers, 1983). This study used the

5
electronic survey tool, Qualtrics, to disseminate the survey, collect and compile the
responses and assist with simple statistical analyses.
1.4 Importance of the Study
The results of this study provide industry stakeholders with a better understanding
of current trends in the adoption of decentralized clinical trials. The results may also help
stakeholders understand how to evaluate the value of decentralized clinical trials and
overcome barriers that may be restraining sponsors from adopting decentralized clinical
trial. Sharing observations and expectations can help interested sponsors to understand
how to deal with any uncertainties that may influence adoption.
The results of this study may also be important to regulators, who also have been
concerned about the dampening effects that traditional clinical trials might have on access
to innovative new medicines. It provides information about areas in which regulatory
guidance could be fortified, guiding revisions of available materials based on a better
understanding of industry needs. Information to help guide industry may assist those
who are initiating such trials to anticipate and deal with areas that may be confusing or
lack clarity.
1.5 Limitation, Delimitations, Assumptions
Several limitations were considered for this study, including the ability to identify
enough respondents to participate in the survey. Because such trials are relatively new,
the numbers and availability of the respondents with sufficient experience and
understanding were limited. Additionally, participants were typically busy professionals,
therefore, the length of the survey was kept as short as possible to reduce the potential

6
drop-out. The number of questions posed in the survey may have been too few to allow
this topic to be fully explored, constraining the depth and breadth of the exploration.
The survey was delimited to managers or executives working in clinical trial
operations, regulatory or clinical quality assurance functions at pharmaceutical or
biotechnology companies in the United States. Opinions from industry peers outside of
the US were not included since the regulatory pathway in support of a decentralized
approach is not as consistently available as in the US. Additionally, opinions from
sponsors of medical device trials were not included since the regulatory pathway is not
consistently applied across the various types of medical devices. Additionally, views
from other stakeholders, such as study site personnel, research participants, IRB
representatives or regulatory authority representatives were not included. The survey
responses were collected over a limited period of time which may have impacted the
number of participants willing or able to participate. Its scope focused only on the
process of adoption of decentralized clinical trials and the attributes which may impact
the decision to adopt within the industry.
1.6 Organization of Thesis
This thesis is organized into 5 chapters as follows:
• Chapter 1 introduces the problem to be studied and briefly summarizes the
rationale for the approach that will be taken for this thesis.
• Chapter 2 reviews relevant literature and provides an overview of the
history of regulations in the US, Europe and Japan with respect to drug

7
development; the current state of drug development; and the current state
of decentralized clinical trials, including industry and regulatory views.
• Chapter 3 describes the methodology used in conducting the survey and
includes all questions developed and used to gather the data.
• Chapter 4 describes the results of the study in the form of a narrative,
tables and graphs.
• Chapter 5 discusses the implications of the research and provides an
interpretation of the results in the context of other literature with
conclusions and recommendations for implementation and further
research.
Appendices to this thesis include a draft survey (Appendix A), tabulation of
results from the survey (Appendix B), calculations for rank order questions (Appendix C)
and cross-tabulation results (Appendix D).
1.7 Definitions
Decentralized Clinical Trial clinical trials “…executed through telemedicine and
mobile/local healthcare providers (HCPs) using procedures
that vary from the traditional clinical trial model (e.g., the
investigational medicinal product [IMP] is shipped directly to
the trial participant.” (CTTI, 2018, p. 2)

8
Hybrid Approaches to
Decentralized Clinical Trials
Hybrid approaches to decentralized clinical trials could
include one or more of the following options:
• Use of a virtual trial site in addition to traditional trial
sites,
• Use of telemedicine for at least parts of the trial or
some study visits,
• Use of mobile HCP for at least parts of a trial or some
study visits,
• Use of a local HCP, either in addition to traditional
trial sites or instead of traditional trial sites, the
difference from virtual is that there is some direct
contact with the participant,
• Shipment of study drug and materials direct to
participant in the absence of a fully virtual trial.
Abbreviations
FDA Food and Drug Administration
CTTI Clinical Trial Transformation Initiative
US United States
IND Investigation New Drug Application
PDUFA Prescription Drug User Fee Act
FDAMA Food and Drug Administration Modernization Act
EMA European Medicines Agency
CPMP Committee for Proprietary Medicinal Products
GCP Good Clinical Practices
ICH International Conference on Harmonization
IRB Institutional Review Board
IEC Independent Ethics Committee
NDA New Drug Application
EDC Electronic Data capture
RDE Remote Data Entry
CDISC Clinical Data Interchange Standards Consortium
PRO Patient-reported outcomes
CSDD Center for the Study of Drug Development
FDARA FDA Reauthorization Act

9
REMOTE Research on Electronic Monitoring of Overactive Bladder
Treatment Experience
HCP Healthcare Provider

10
Literature Review
2.1 Literature Search
As a first research step, a review of current information in literature was
conducted to establish the state of literature related to decentralized clinical trials. The
University of Southern California library search tool was utilized to conduct an internet
search using the following search terms: “virtual clinical trial”, “remote clinical trial”,
“decentralized clinical trial”, “decentralised clinical trial”, “virtual clinical study”,
“remote clinical study” or “decentralized clinical study”. A total of 452 articles
published between 1997 to May 24, 2019 were identified. Limiting the search to
English-language peer-reviewed journals reduced the number to 232 articles. To reduce
duplications, the search was limited to PubMed and Elsevier databases, yielding 143
articles. Articles that were not relevant to the research, such as simulation studies,
artificial intelligence applications and/or modeling approaches using “virtual patients”,
were excluded. This left 41 articles of relevance from the literature search. Relevant
literature references from these 41 articles were also used to provide further context into
some topics.
Other references used within this research included regulations, guidance
documents, directives and/or communications from national regulatory authorities such
as FDA; recommendations and information from industry consortiums, such as the
Clinical Trial Transformation Initiative (CTTI); industry news outlets; and information
from vendor websites, such as Science 37.
And finally, a book entitled “Re-Engineering Clinical Trials” by Peter Schüler
and Brendan M. Buckley was reviewed and found to be a good resource.

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2.2 Introduction
The field of clinical research is not new. Experimentation within the medical
field can be traced back to 500 BC (Bhatt, 2010). One of the first published comparative
evaluations, conducted by James Lind in 1753, examined the effect of various diets on
scurvy in sailors (Bothwell and Podolsky, 2016). Nevertheless, until the late 1940s,
opinions on medical treatment were made using, at best, uncontrolled, often retrospective
medical observations of individuals and, at worst, trial and error.
Nevertheless, the challenges to patient safety posed by new drug treatments over
the last century have been a driving force for increasingly rigorous approaches to the
conduct and oversight of clinical trials. This progression was punctuated, and to a great
extent shaped, by a series of unfortunate events that prompted specific changes in the
requirements for clinical research. If that timeline were to be mapped from the first
formal regulation of drugs in the US, it would start with a tragedy related to the
formulation of a new class of antibiotics, the sulfa drugs, in the late 1930s. In 1937,
sulfanilamide, a drug used to fight streptococcal infections, underwent formulation
changes to create a liquid that could be taken easily by young children (Junod, 2008).
The formulation was based on the use of the solvent, diethylene glycol, a poison related
to antifreeze. Over 100 people in the US died when that product was commercialized and
distributed widely. In the face of the sulfanilamide crisis, the Food, Drug and Cosmetic
(FDC) Act was enacted in 1938 to enhance the safety of drugs being marketed in the US
(Junod, 2008). The FDC Act gave FDA formal authority to review safety data of all new
drugs prior to marketing. While no specific regulations were in place to define the type
of safety information required for submission, “adequate data” was to be submitted in a

12
formal New Drug Application. FDA had 60 days to provide a response to the sponsor; if
no response was received the drug could be marketed.
The FDC Act of the 1930s did not, however, give FDA the authority to require
data from clinical trials. Although FDA scientists were interested in promoting a
standardized approach to the conduct of clinical trials, the progress of science was
primarily in the hands of the physician and medical industry for the next twenty-five
years. Nevertheless, clinical design began to adopt structures more aligned with
scientific principles. Many view the first randomized controlled trial to be the study
conducted in 1946 at the Medical Research Council in the United Kingdom by Austin
Bradford Hill. The study evaluated streptomycin versus bed-rest in the treatment of
patients with pulmonary tuberculosis. The study contained many elements of design
considered standard in today’s clinical trials, including double-blind randomization,
prospective identification of criteria for enrollment, objective endpoint measures
evaluated by an independent panel of experts who were not aware of randomization
assignment and ethical review of the trial prior to its conduct (Bhatt, 2010; Jenkins and
Hubbard, 1991). The study helped to shine a light on the bias that was introduced
without prospective randomization and established a higher level of expectation in the
medical community when it came to study design and clinical testing (Jenkins and
Hubbard, 1991). The success of the clinical trial conducted by Hill and colleagues in
1946 highlighted the opportunity of randomized clinical trials to provide better data, and
a new standard was set in the medical community.
Scientists used the Hill study as a guide and created general criteria for clinical
trial design, which were consistent with the ethical standards of the time, including the

13
use of formal inclusion criteria, randomization of patients into separate treatment and
control groups, the use of double-blind trials, the use of objective measures and
diagnostics, standardized dosing schedule, and uniform observation schedules (Junod,
2008).
2.3 History of Clinical Drug Development in a Regulated Environment
2.3.1 The Introduction of the Clinical Trial to Evaluate US Drugs
Even though the current standard for clinical trial design was established more
than 70 years ago, regulation of medicinal products utilizing controlled clinical trials has
only been in place for a little more than half a century (Bhatt, 2010). From a regulatory
perspective, it was not until the approval of the Drug Amendments Act of 1962, also
known as the Kefauver-Harris Amendment, that adequate and well-controlled trials
establishing both safety and efficacy were required as a prerequisite to drug approval in
the US (Greene and Podolsky, 2012).
The Drug Amendments Act of 1962 was, in part, a product of the thalidomide
disaster (Junod, 2008). Thalidomide was a non-barbiturate hypnotic synthesized in 1953
by a German pharmaceutical company and commercialized in nearly every major country
as a sleeping tablet and as an antiemetic for pregnant women (Sherman and Strauss,
1986; Fintel et al., 2009). In 1960, adverse reports of polyneuritis, characterized by
tingling of hands, sensory and motor disturbances and thumb atrophy, began to appear in
German medical journals. In 1961, physicians in West Germany noticed an alarming
number of infants born with deformities of the arms and legs, a condition known as

14
phocomelia, and a link to the use of thalidomide was established. In March 1962, the
drug was pulled from most markets (Sherman and Strauss, 1986).
Thalidomide was not yet approved in the US and was under review by FDA when
it was linked to phocomelia (Fintel et al., 2009). A persistent FDA reviewer, Frances
Kelsey, delayed approval of thalidomide in the US due to the neuropathic adverse effects
noted in Germany. Dr. Kelsey requested additional safety data, particularly data
supporting the use in pregnant women for which the applicant was seeking an indication.
Without marketing approval, the drug was not made highly available to the US market,
although the drug was available for “investigational” use. The thalidomide crisis sparked
change in the regulation of the drug development process in the US and worldwide
(Sherman and Strauss, 1986).
Although passage of the 1962 amendment was spurred by the thalidomide events,
this was not the only reason why bills relating to clinical trials were introduced.
Congressional inquiries on the effectiveness and price of new drugs had been initiated as
early as the late 1950s. They prompted an earlier bill, sponsored by Senator Kefauver,
that would not only require proof of efficacy of a drug, but would impose stricter
limitations on patents and require that “me too” drugs demonstrate a significantly greater
effect than their predecessor (Greene and Podolsky, 2012; Ceccoli, 2002). In his
consumer protection speech in March 1962, President Kennedy expressed concern about
the lack of proof that new drugs could have to support marketing claims (Ceccoli, 2002).
Nonetheless, this initial bill garnered insufficient support to be passed. Instead, it served
as a foundation for the later omnibus legislation that was spurred by the thalidomide

15
crisis. An overview of the authorities granted to FDA by the Kefauver-Harris
Amendment is provided in Figure 1.
Figure 1: Overview of the New Authorities Granted to FDA by the Kefauver-
Harris Amendment of 1962

Source: adapted from (FDA, 2012)

While the enacted 1962 Drug Amendment Act was silent on the topic of patents,
the amendment strengthened the scientific standards required for new drugs to be
investigated and marketed. Standards enacted by this amendment which had an impact
on clinical trials are described in the following sections.
2.3.1.1 Regulation of the Investigational Use of New Drugs
Prior to the 1962 amendment, FDA had no formal mechanism to track clinical
trials or investigational agents in the US. As stated previously, thalidomide was
distributed under “investigational” pretenses to approximately 20,000 patients across the
nation, including approximately 3,760 women of childbearing age, and at least 207
pregnant women. More than 1200 physicians dispensed thalidomide as part of a
“clinical” trial; few kept track of their patients after thalidomide was dispensed (Fintel et
al., 2009; FDA, 2012).

16
With the enactment of the 1962 amendment, the Investigational New Drug
application was created. The Act required that FDA be notified of any investigational
trial of a new drug prior to conduct of the trial through a written request titled “Notice of
Claimed Investigational Exemption for a New Drug” (FDA, 1962; FDA, 1963a). As per
the regulation, the written request was to include a description of manufacturing
information of the drug, preclinical data sufficient to justify the proposed clinical testing
plan, an outline of the clinical testing plan, and information on the investigators who will
conduct the clinical trials.
Once the written request was submitted to FDA, sponsors could proceed with the
investigation unless FDA informed them to withhold the clinical trial. The new drug
regulation also required sponsors to provide ongoing progress reports to FDA, at least
annually. Additionally, the sponsor and Investigator were expected to track and control
distribution of the clinical trial materials throughout the course of the investigational
plan.
Regulatory requirements were amplified in 1963 when the FDA published its new
drug regulations to support the Kefauver Amendment. FDA created the phased approach
to clinical trials utilized today and described in Figure 2 (FDA, 1963b; FDA, 2018a).

17
Figure 2: Phases of Clinical Studies

Source: adapted from (FDA, 2018a)

2.3.1.2 Marketing Approval of New Drugs
As mentioned previously, the 1962 amendment gave FDA the ability to refuse
marketing approval of a new drug if the applicant was not able to demonstrate evidence
of safety or effectiveness in accordance with the proposed labeling. The amendment
further explained that substantial evidence of effectiveness is required through “adequate
and well-controlled” trials(US Congress, 1962, p. 781). To market a new drug, the
evidence to support safety and effectiveness was to be submitted to FDA. With this
amendment, applicants could not market the drug until approval was obtained. This
clause transitioned the 60-day default approval originally enacted through the FDC Act
into a pre-market approval that typically took much more time (Junod, 2008).
The 1962 amendment required all drugs approved on safety alone between 1938
and 1962 under the FDC Act to be re-reviewed for evidence of efficacy, also known as
the Drug Efficacy Study Implementation (DESI) reviews (Junod, 2008). Through these
reviews, FDA defined “substantial evidence" in two ways. First, FDA defined "adequate
and well-controlled clinical investigations” as placebo-controlled, active-controlled, or

18
historical-controlled studies with a clearly designed protocol; uncontrolled studies were
not considered acceptable to support a claim of effectiveness (FDA, 1969, p. 14596).
Second, FDA confirmed that positive results from two clinical studies were required to
establish effectiveness (FDA, 1979). The DESI process helped to establish the regulatory
paradigm that exists today for development of new drugs in the US.
2.3.2 The Evolving Regulation of Drugs in the US
Prior to the 1970s, the data submitted to support approval of a new drug was less
rigorous and often lacked the standards for a well-controlled study (Junod, 2008). As the
sponsor companies and FDA worked under the new standards, FDA supported the efforts
by conducting workshops and working with outside advisory committees. By the late
1970s, FDA had developed specific guidelines describing expectations for study designs
and data needed to support approval for certain therapeutic areas (Junod, 2008). These
traditional designs were typically rigorous and resulted in substantial delays in the access
to new drugs (Junod, 2008).
The requirements of the 1962 amendment in the US and its subsequent
regulations resulted in increased costs to the development of new products as well as an
increase in time required to develop the necessary data for regulatory submissions. As
displayed in Figure 3, the length of the clinical development phase for new drugs steadily
increased since the 1970s and the approval phase often took between 2-3 years (Reichert,
2003). In the 1980s, the need to treat the rampant diseases associated with the human
immunodeficiency virus prompted the FDA and its stakeholders to address concerns
related to drug access for severe diseases. One outcome was the implementation of a
simpler type of clinical trial, the Treatment Investigational New Drug Application (FDA,

19
2019a) by which individual patients could gain access to investigational new drugs in an
unblinded yet traceable manner without having to meet some of the criteria associated
with a traditional protocol. The Orphan Drug Act of 1983 was also passed to provide
incentives for the development of treatments for rare diseases, an area more or less
abandoned by industry due to the costs to develop these products with little commercial
return (Sicherman, 2018).
Figure 3: Average Length of Clinical Development Time for Small-Molecules
Approved by FDA from 1970-2001

Clinical phase is the time the sponsor took to conduct clinical trials. The Clinical + Approval Phase
includes the sponsor clinical phase and the time FDA took to review and approve the New Drug
Application.
PDUFA: Prescription Drug User Fee Act of 1992; FDAMA: Food and Drug Administration Modernization
Act of 1997.
Source: modified from (Reichert, 2003)

Additionally, in the 1980s, FDA began to evaluate the value of surrogate
endpoints as supporting evidence for clinical effectiveness in the absence of data to
support the actual clinical outcome. For example, the first statin was approved in 1987
based on data demonstrating the ability of the drug to lower blood cholesterol, a surrogate
endpoint for the clinical endpoint of decreased heart disease or stroke. The use of surrogate

20
endpoints was officially implemented as part of the Prescription Drug User Fee Act
(PDUFA) in 1992 to support accelerated approval; it provided flexibility to sponsors and
FDA to address unmet medical needs for life-threatening indications (Darrow et al.,
2014). In an attempt to reduce the time that FDA took to review and approve a marketing
application, PDUFA also introduced user fees that would allow FDA to improve its
reviewing capabilities, tied to performance goals of reducing regulatory review times.
Due to amendments to the FD&C Act in the 1980s and 1990s, the FDA review time
decreased to approximately 12-18 months in the mid-1990s.
In 1997, the Food and Drug Administration Modernization Act (FDAMA)
amended the Federal Food, Drug, and Cosmetic Act to allow FDA the ability to approve
a New Drug Application (NDA) based on one adequate and well-controlled trial if the
evidence is sufficient to justify effectiveness (US Congress, 1997). FDA issued a
guidance document in 1998 to clarify situations in which a single study could be used to
support efficacy claims (FDA, 1998). FDAMA also codified the accelerated approval
process and added the fast-track designation for serious or life-threatening diseases
(Reichert, 2003).
FDA continues to evaluate opportunities to improve the regulatory process and
ensure access to important innovations are available to the public in a timely manner.
Additional amendments to the FD&C Act and other initiatives sponsored by FDA that
could have a positive impact on the clinical development time frame and access to new
products are described in Table 1.

21
Table 1: Regulations Enacted in the 21
st
Century to Facilitate FDA Support of
Efficient Access to Innovative Drugs and Biologics
Title of Law, Year Enacted Relevant Mandates for Drugs/Biologics
Best Pharmaceutical for
Children Act (BPCA), 2002
• Incentive to complete pediatric clinical studies by
providing additional marketing exclusivity to sponsors
• Pediatric plan agreement in advance of conduct through
Written Request
Pediatric Research Equity Act
of 2003 (PREA), 2003
• Requires evaluation of safety and effectiveness of new
drugs and biological products in relevant pediatric
subpopulations
• Waivers or partial waivers permissible under certain
conditions
Food and Drug Administration
Amendments Act (FDAAA) of
2007
• Reauthorized BPCA and PREA
• Requirement to publicly register clinical trials and
disclose results to clinicaltrial.gov database
Biologics Price Competition
and Innovation Act of 2009
(BPCI) included in the Patient
Protection and Affordable
Care Act, 2010
• Established abbreviated approval pathway for biosimilars
Food and Drug Administration
Safety and Innovation Act
(FDASIA), 2012
• Established Breakthrough Therapy designation
• Established patient-focused drug development program to
obtain patient input on outcomes relevant to patients to
inform FDA review and decision-making
• Gather input to inform the creation of a risk-based
regulatory framework for health information technology
21st Century Cures Act, 2016 • FDA to incorporate perspectives of patients into decision-
making for development of drugs, biologics and devices
• Modernize clinical trial designs and clinical outcome
assessments, including use of real-world evidence to
support new uses of approved drugs
• Established new expedited Regenerative Medicine
Advanced Therapy and Breakthrough Devices programs
FDA Reauthorization Act of
2017 (FDARA), 2017
• Encourage diversity in clinical trials through relevant
evaluation and guidance on inclusion/exclusion criteria
• Improve expanded access criteria and pediatric study plan
development, expand evaluation of cancer therapies to
pediatric cancers
Source: (US Congress, 2002; US Congress, 2003; US Congress, 2007; US Congress, 2010; US Congress,
2012; US Congress, 2016; US Congress, 2017)

In 2004 FDA issued a report entitled “Challenge and opportunity on the critical
path to new medical products”. In it, they acknowledged that increasing drug
development costs were driving a decline in the number of innovative medical products

22
(FDA, 2004). Innovators were focusing efforts on products with a higher chance for
market return and reducing efforts to meet the medicinal needs of less common diseases.
Additionally, traditional tools used to discover and assess medical products were not able
to take advantage of newer technology, thus reducing success rates and impeding true
discovery and advances in medicine. FDA initiated a strategy for modernizing the drug
development paradigm through the creation of various collaborations between FDA and
industry, academia and other stakeholders (FDA, 2004; Woosley, 2013). Three of the
collaborations relevant to this research are described in Table 2.
Table 2: Public, Private and Academic Collaborations Sponsored by FDA
Name of Collaboration Primary Purpose
The Critical Path Institute

Focuses on biomarkers, patient-reported outcomes and
quantitative disease models.
Clinical Trial Transformation
Initiative
Focuses on clinical trials and developing efficiencies.
Center for Biomedical
Innovation
Focuses on post-market surveillance methodologies
Source: (Woosley, 2013)

FDA continues to express its commitment to exploring opportunities for
innovation in the regulatory process without reducing the role they play in protecting the
public health. FDA review times now are the shortest in the world. Nearly two-thirds of
drugs approved by FDA between 2012 and 2017 were approved under one or more
expedited pathways (Grignolo and Siu, 2018). Despite these attempts, however, the cost
of drug development has steadily increased and today, each drug approved in the US
comes with a price tag estimated to be as high as $2.6 billion-dollars (DiMasi et al.,
2016).

23
2.3.3 Regulation of Drugs Outside the US
The regulation of drugs in Europe lacked formal procedures for drug approval
until thalidomide uncovered the flaws in those systems (Milmo, 2014). In 1965, a
European directive was issued requiring authorization of a medicinal product based on
quality, safety and efficacy prior to marketing (Council of the European Economic
Community, 1965). However, it was not until 1975 that more specific requirements were
provided in terms of the type of data required from nonclinical and clinical studies to
support authorization (The Council of the European Communities, 1975). The 1975
directive indicated that controlled clinical trials were required to use double-blind, active-
or placebo-controlled designs, but the number of studies was not specified. Additionally,
the directive provided flexibility in the amount and type of data provided, allowing for
less comprehensive data for less common indications.
While the burden of proof appeared less specifically defined in Europe compared
with the US, the process for obtaining marketing authorization in Europe was more
demanding (Vogel, 1998). Prior to 1975, the authorization process for each country was
managed independently, requiring a sponsor to submit applications in each country in
which they wished to market the drug. This process increased redundancy and cost as
industry sponsors tried to obtain separate marketing authorizations in numerous member
states of the European Union (EU). In 1975, a new system for drug review was
developed, that redirected some of the more challenging and novel products to the
relatively new European Medicines Agency (EMA). Within that Agency, the Committee
for Proprietary Medicinal Products (CPMP) was formed by drawing members from each
Member State within the European Union. The CPMP was given the responsibility to

24
ensure that marketing applications met the standards required to support quality, safety
and efficacy of a medicinal product. Initially, the CPMP provided an advisory role and,
while they offered an opinion, official authorization to market a product was still required
by each Member State independently.
A mutual recognition procedure was also introduced in 1975 which allowed a
sponsor to submit an application to one country for review and approval; once that
country provided approval, the application could subsequently be sent to other Member
States for review. This process was to expedite the review process for the subsequent
Member States as they were to take the initial reviewer’s opinion into account during
their own review. In reality, the process was not as impactful as expected; sponsors were
still burdened with managing applications across multiple countries. A centralized
procedure, implemented in 1993, finally provided a way for sponsors to obtain marketing
authorization throughout the EU on the basis of a single marketing authorization and
single review process. The centralized procedure was a way to reduce the cost and
burden of drug approvals across EU member states and was initially mandatory for
biotechnology products while optional for medicines (Milmo, 2014). Today, the
centralized procedure is required for new products to treat serious diseases such as HIV
and cancer, diabetes, neurodegenerative and autoimmune diseases; products for viral
diseases; genetically engineered products; advanced therapies such as gene and cell
therapy; and products for orphan diseases (EMA, 2019). Other products are also able to
use this procedure, such as new active substances or significant innovative products or
products that contribute to the interest of public health.

25
Regardless of route, EU drug submissions need to provide the results of clinical
testing. With respect to investigational products, each clinical study historically needed
to be reviewed and authorized by each individual health authority of European member
states in which the study will be conducted. This duplicative process required sponsors
to maintain and manage individual country-level submissions and requests within
Europe. The burden resulted in a 25% reduction in the number of clinical trials
conducted in the European Union between 2007 and 2011 (Tenti et al., 2018). In 2009,
to address the burden, a voluntary, harmonized procedure to be managed by the Paul‐
Ehrlich Institute was implemented by the Heads of Medicines Agencies through its
Clinical Trials Facilitation Group (CTFG) (CTFG, 2016; CTFG, 2010). The procedure
offered a way to centralize the clinical trial authorization process and reduce redundancy
by consolidated the list of questions received from member states. Approximately 16-
23% of multinational clinical trials used the VHP procedure between 2013 and 2018
(HMAs Clinical Trials Facilitation Group, 2019). In 2014, a new Clinical Trial
Regulation (CTR) was established to centralize and harmonize the approach for review
and approval of investigational studies in the EU. The CTR will create efficiency by
having one review process for investigational studies across the European member states.
The CTR will also increase transparency of clinical trials conducted in the European
Union by providing a publicly available database, still under development at time of
writing, that will host information about the clinical trials (EU, 2014).
In Japan, regulation of pharmaceuticals was also minimal until the 1960s
(Neimeth, 2017). The Pharmaceutical Affairs Law, enacted in 1943, required relatively
modest evidence from clinical trials and no preclinical data (Neimeth, 2017; Japan

26
Pharmaceutical Manufacturers Association, 2015). However, the impact of the
thalidomide experience sparked a change in policy as it did elsewhere. In 1965, Japan
instituted requirements for animal teratogenicity studies as well as controlled clinical
trials in the form of double-blind and pharmacokinetic studies. A drug development
guideline was published in 1967 to expand the guidance on policies for approval of
drugs. Unfortunately, the policies established in Japan were not consistent with those
implemented in the US and Europe. Additionally, Japan specifically required clinical
data from patients in Japan. Therefore, multiple, often duplicative, studies were required
if a single drug were to obtain approval in multiple countries. To reduce the burden of
duplicate studies, regulatory authorities in Japan have encouraged the incorporation of
Japanese patients into multinational clinical trials (Tanimoto, 2015). Nevertheless,
challenges exist with conducting clinical trials in Japan. Historically, academic
institutions had a strong basic science research paradigm and have not accepted clinical
trials as scientifically sound, likely due to the single-arm nature of many clinical trials
used to support market authorization in Japan (Chiu, 2013). Additionally, it is difficult to
recruit participants in Japanese clinical trials. Socialized medicine already provides good
access to treatments for Japanese patients and provides only modest resources to conduct
and oversee trials. Thus, incentives are insufficient to motivate most physicians in Japan
to conduct trials and patients to participate in clinical trials. Sponsors also face
operational challenges such as language barriers and higher costs.
2.3.4 Evolution of Good Clinical Practices
Although drug regulations vary by country, ethical principles that govern the
rights of research subjects have been recognized quite consistently worldwide through the

27
publication and acceptance of the Nuremburg Code. Created in 1947, the Nuremburg
Code was a listing of 10 principles that evolved from improper medical research
performed during World War II (Shuster, 1997). In 1964, the Nuremburg Code was
incorporated into the Declaration of Helsinki (Pick and Gilbert, 2013), a document seen
to provide the basic principles that make up the Good Clinical Practices (GCP) adopted
today (van Oijen et al., 2017).
In 1990, the CPMP issued a GCP guideline for members of the European Union
(Switula, 2000). Further, in 1995, the World Health Organization issued an internally
accepted set of GCPs. These two sets of guidelines, along with the principles of the
Declaration of Helsinki, would become the basis for the GCP guideline implemented by
the International Conference on Harmonization (ICH) in 1996. The ICH GCP was
created by representatives from the US, Europe and Japan and has become the standard
for clinical trial conduct for regulated clinical research (Bhatt, 2010). An overview of the
ICH Good Clinical Practices is provided in Figure 4.
Figure 4: Overview of ICH Good Clinical Practice

IRB: Institutional Review Board; IEC: Independent Ethics Committee.
Source: (ICH E6(R2), 2016)

In Japan, the concept of GCP was challenging to adopt because cultural
differences existed in the relationships between physicians and patients compared with

28
those typical in the US and Europe (Nagata and Rafizadeh-Kabe, 2002). However,
progress has been made and ICH GCPs have since been adopted by ICH founding and
standing regulatory members, including the regulatory authorities from the European
Union, Japan, the United States, Canada and Switzerland and more recently by new ICH
members that include China, South Korea and Brazil.
2.3.5 The Emergence of Technology in Clinical Trials and Regulatory Filings
For much of the history of clinical trials, data was gathered through laborious data
collection methods that generated reams of paper. As submissions grew, review of those
paper-based submissions became more and more time consuming and difficult to
navigate (Kubick, 2015). In 1997, FDA issued a regulation allowing for the use of
electronic signatures and electronic records, paving the way for the electronic submission
of marketing applications (FDA, 1997). Two years later, they began accepting electronic
NDAs (Racher Press, 1998). This action helped to provide industry with the support
needed to justify a conversion from paper-based processes to electronic processes.
One of the first targeted applications of electronic methods was the capture of
data on case report forms at clinical sites. Even though the tools for electronic data
capture (EDC) were available in the late 1980s, it was not until the early 2000s that this
technology became adopted on a relatively wide scale. EDC depended on Remote Data
Entry (RDE) tools allowing sponsors to convert their paper-based case report forms into
computer-based software tools into which study site personnel could directly transfer data
from source documents. Initially, the RDE tools were loaded onto computers or laptops
that were then provided to each study site for data entry purposes. However, this method
was burdensome for sites that worked with several sponsors. In such a case, the study

29
site would have multiple laptops and require training across multiple systems in order to
provide the data needed for each study (Marks et al., 2001). In 2004, only about 25% of
clinical trials were using RDE or EDC tools because implementing and maintaining the
systems were challenging (Pavlović et al., 2009). As the internet became more
accessible, RDE tools evolved into internet-based EDC tools that were easier to use
(Marks et al., 2001). Nonetheless, only about 50% of clinical trials were using EDC in
2013, despite a clear return on investment related to the reductions in data errors, labor
costs associated with the double-data entry process and travel costs for onsite monitoring,
(Shewale and Parekh, 2013; Mitchel et al., 2015). Today, use of EDC is at or near 100%,
although it is not the sole means for collecting data (Wilkinson et al., 2019).
Despite the implementation of EDC, industry-wide standards for collecting,
storing and reporting of data were not applied universally across industry, so challenges
remained for FDA. In 1998, the Clinical Data Interchange Standards Consortium
(CDISC) was established with a goal to provide a global data standard for clinical trial
data (Wood and Fitzsimmons, 2001). CDISC has created standards that support the
collection, organization and analysis of clinical trial data as described in Figure 5.
However, industry did not begin adopting these standards until 2013, nearly a decade
later, when FDA issued a statement indicating CDISC would be required (Kubick, 2015).
EMA and Pharmaceuticals and Medical Devices Agency have also adopted CDISC
standards.

30
Figure 5: CDISC Standards for Clinical Trial Data

Source: adapted from (Clinical Data Interchange Standards Consortium, 2019)

Patient-reported outcomes (PROs), self-assessments of disease-related symptoms
or quality of life, have also been affected by the transition to computerized methods
(Hufford et al., 2002). PROs are important to capture data that cannot be obtained
objectively through examination or medical testing. Patients typically provide
information using diaries to record how they feel in order to measure a treatment effect
(Patrick et al., 2007). The quality of paper-based diaries has been criticized because
patients sometimes completed the diaries just prior to a study visit rather than at the time
the data was to be recorded, thus introducing recall bias (Hufford et al., 2002). A study
by Stone et al. demonstrated compliance for patients using a paper-based diary was 11%
compared with 94% for patients instead provided with electronic diaries (Stone et al.,
2002). The ePRO systems are also cost-effective, estimated by one study to be 37.5% of
the cost of a comparable paper-based system (José and Langel, 2010).

31
The use of mobile devices, wearables and sensors to capture data in real-time has
the potential to increase data quality, minimize resource efforts along the data chain of
command and improve how researchers monitor and manage outcomes (Mitchell, 2018a).
Regulators support the utilization of eSource, a system in which data from subjects are
collected digitally without recording the data on paper first (Mitchel et al., 2015). Direct
entry of data into an electronic case report form, either from medical devices or electronic
health records, is supported by FDA and EMA. However, regulation of mobile devices
and apps to support clinical trial data collection and capture is not straightforward
(Buckley, 2015b; Buckley, 2015a). Additional effort is needed to document the merit of
clinical data collected through these routes and to ensure the mobile devices consistently
deliver quality data (Perry et al., 2018).
Technological tools such as EDC and ePRO have facilitated operational and
tactical processes related to study conduct. They have also created opportunities to
enhance the integrity and quality of data collected in clinical trials. ICH GCP, often
identified by its document number, E6, was updated in 2016 to take into account the
changing technological landscape and its impact on oversight of clinical trials (ICH
E6(R2), 2016). Updates to ICH GCP allow sponsors to put more effort and resources
into activities that provide higher value and reduce risk associated with study conduct.
One of the biggest changes in ICH E6 has been its focus on the implementation of risk-
based control over study conduct and data integrity. The emphasis on the use of technical
tools and techniques to identify potential risk faster attempts to remedy gaps observed
historically in the ability to manage data integrity.

32
2.4 Current State of Clinical Drug Development
Today, it takes on average ten years to gather the information necessary to
achieve regulatory approval for a new drug (Getz and Kaitin, 2015). Clinical trial
conduct makes up most of that time and has continued to show increases. The KMR
Group, a group of consultants who study benchmarking and advocate process
improvement, reported that the median length of phase 2 and 3 trials from 2013-2015 was
about 6 months longer than in 2006-2008 [See Figure 6] (Martin et al., 2017a).
Figure 6: Median Time (in Months) from Final Protocol Approval to Final
Study Report for Phase 2 and 3 Studies in 2006-2008 Compared with
2013-2015

Source: adapted from (Martin et al., 2017a)

KMR also analyzed over 700 interventional trials conducted by 7 major
pharmaceutical companies from 2010-2015 and found that the median cost for
conducting phase 2 and phase 3 clinical trials was $8.6 million and $21.4 million,
respectively (Martin et al., 2017b). The reasons for increasing cost and time were
multifactorial - increased complexity of study designs, increased sample sizes, longer
treatment duration, changes in outsourcing strategy and increased use of study sites
0
5
10
15
20
25
30
35
40
45
2006-08 2013-15
Median Time from Protocol Approval
to Final Study Report (months)
Phase 2 Phase 3

33
located in emerging markets, for example (Martin et al., 2017a; Martin et al., 2017b).
Factors relating to protocol complexity and impact to patient enrollment and retention are
described in more detail below. These factors offer tangible targets for process
improvement as it relates to study management and conduct.
2.4.1 Protocol Complexity is Reducing Productivity
Clinical studies have become more complex, as drugs for complex or chronic
disease states demand multiple, complicated clinical endpoints (Getz et al., 2011; Getz et
al., 2015). Protocol complexity is also driven by the need to support reimbursement by
payers who demand that the newer and more expensive alternative products differentiate
themselves from other treatments. Unfortunately, more complex protocols are more
difficult for participants and have been associated with poor recruitment and retention
rates (Lamberti et al., 2018).
Tufts CSDD conducted a study evaluating the trends in complexity of protocol
design, comparing 5-year averages in the number of procedures, number of study visits,
work effort for the study sites and cost per study volunteer between 2001 and 2015 (Getz
and Campo, 2018). Results demonstrated that the mean number of planned study visits
per participant rose 23% and 25% for phase 2 and phase 3 studies respectively from the
period between 2001-2005 and 2011-2015. As displayed in Figure 7, the mean number
of distinct procedures in phase 2 and phase 3 studies increased by 54% and 59%,
respectively, from 2001-2005 to 2011-2015. The increase in number of study procedures
was driven by a slight increase in number of lab tests and patient-reported outcomes
collected in these studies. The changes increased the mean number of total procedures
per-participant per-study by 67% and 70% for phase 2 and 3 studies, respectively.

34
Figure 7: Mean Number of Procedures for Phase 2 and Phase 3 Clinical Trials
from 2001-2015

Source: adapted from (Getz and Campo, 2018)
Increases in study procedures and visits has increased the average costs for each
patient visit by 61% for phase 2 studies and 34% for phase 3 studies (Figure 8) (Getz and
Campo, 2018).
Figure 8: Mean Total Cost per Study Participant per Study Visit for Phase 2
and Phase 3 Clinical Trials from 2001-2015

Source: adapted from (Getz and Campo, 2018)

$-
$200
$400
$600
$800
$1,000
$1,200
$1,400
$1,600
2001-5 2006-10 2011-15
Phase 2 Phase 3

35
Additional data points also contributed to higher costs for the study sites, Contract
Research Organizations (CROs) and sponsors. Essentially, protocol complexity drives
poor performance (Shaw, 2019). Protocol complexity has been linked to an increased
number of protocol amendments. A study published by Tufts CSDD demonstrated that
studies with at least one substantial amendment tended to be more complex, had more
patients to enroll and included more investigative sites (Getz et al., 2016). They were
also slower to enroll fully and to the time between last patient last visit to database lock
was longer. A substantial amendment was associated with an average increase in direct
costs of over $500,000 for a phase 3 study.
2.4.2 Patient Enrollment and Patient Retention Impacting Productivity
In addition to operational challenges, several studies have shown an increase in
study complexity takes a toll on enrollment and retention. Recruitment targets are missed
by nearly 40% of clinical studies (Hirsch et al., 2017). Patient retention is also an issue
with almost half of enrolled patients failing to complete a study.
Trial complexity reduces the likelihood that a healthcare professional will
recommend a clinical study to a patient or that a patient would agree to participate (Getz
et al., 2015; Ross et al., 1999; Madsen et al., 1999). Patients are more reluctant to join a
clinical trial when there is more intensive trial-related testing or if the treatment duration
is more than 6 months (Martin et al., 2013). Additional factors associated with
recruitment and retention problems are provided in Table 3.

36
Table 3: Factors Negatively Affecting Patient Recruitment and Retention in
Clinical Studies
Distrust of the research enterprise Fear something bad might happen
Inconvenience of participation Lack of information on studies for which they
may be eligible
Clinicians unaware of trials or do not
encourage participation
Costs may be incurred that are not covered by
insurance
Complexity of enrollment, compliance and
participation
Fatigue or boredom with study participation
Non-native language speaker Low health literacy or cultural aversion to
clinical studies due to historical issues
Source: adapted from (Weisfeld, 2011)

In an attempt to reduce the enrollment period, the number of study sites involved
in the larger and more complex trials has increased (Getz, 2018). In 2002, the typical
phase 3 study was conducted in 11 countries and included 124 study sites; 10 years later
the typical phase 3 study was conducted in 34 countries and 196 study sites (Getz and
Kaitin, 2015). Unfortunately, 11% of study sites never enrolled a single participant and
over two-thirds under-enroll. These shortfalls appear to add over $1 million to the cost of
an average phase 3 study [See Figure 9] (Getz, 2018; Buckley, 2015a). Tufts CSDD has
found that the current global study sites are lacking in adequate staff, patient volume and
infrastructure to support the demands of today’s clinical trial needs (Getz, 2018). The
typical study site is a clinical care facility where healthcare management is the primary
responsibility with clinical trial conduct a far secondary role (Buckley, 2015a). Access to
patients varies depending on the type of institution, and primary care physicians are still
an important, yet untapped, factor in the management of healthcare options (Getz, 2018;
Trizna, 2015). And, since most clinical studies are not located at study sites that treat the
underserved socioeconomic population, diversity in clinical trials is challenging (Ojha et
al., 2018).

37
Figure 9: Cost of Site Initiation and 1-Year Maintenance Costs for Study Sites
that Under Enroll or do not Enroll Patients into a Phase 3 Study

Assumptions: Costs calculated based on an average phase 3 study conducted at 196 study sites. Average
initiation cost of $10,000/site and average monthly maintenance costs of $1,500/month/site based on data
from (Buckley, 2015a).
Opportunities exist to reduce the burden of clinical study recruitment and
retention. These efforts may require sponsors to consider new ways to manage how
clinical trials are conducted.
2.5 Decentralized Clinical Trials in Drug Development and Stakeholder Views on
Implementation
All of the factors identified above have shone a bright light on the need to
decrease the costs and time associated with clinical testing. Not surprisingly many have
looked to the potential role of technology to increase trial efficiency, not just through
logistical approaches to replace labor intensive steps in the data capture but more
generally in trial design. One important way that technology can be used is to connect
more effortlessly to patients, not only in a clinical setting but anywhere, through the use
$0
$200,000
$400,000
$600,000
$800,000
$1,000,000
Site Initiation Cost Site Maintenance Costs for 1 year
Never Enroll Under Enroll

38
of internet communication and social media. These tools have driven researchers to
consider how to reconstruct clinical design. At the same time, patients have been
increasingly recognized as potential partners in the clinical trial. Much has been written
about the patient voice and the importance of patient focused drug development.
As information becomes easier to access, and social media provides a means of
sharing experiences in real-time, the role of the patient in making decisions about their
healthcare is evolving (Du Plessis et al., 2017). The impact of this culture shift affects
how biopharmaceutical companies view the incorporation of patient-focused or patient-
centric activities into clinical research. One such outcome of these converging threads of
change is the introduction of the “virtual” clinical trial, also called the “decentralized”
clinical trial. Decentralized clinical trials attempt to transition the conduct of clinical
trials away from the traditional clinical study site concept, taking advantage instead of
local or virtual healthcare providers to understand how the research opportunity impacts
the patient and makes participation simpler.
The first decentralized clinical trial with regulatory oversight was conducted by
Pfizer in 2011 (Hirsch et al., 2017). The study used web-based technology and
smartphones to manage the study, allowing patients to participate remotely, without
regard to the location of the clinical study site (Roehr, 2011a). Pfizer’s goal in piloting
this type of trial was to identify whether such methods to reduce the barriers to
participation affected the outcomes from this type of trial compared to that of traditional
clinical trials (Roehr, 2011a; Jadhav, 2016). Another goal of the trial was to pilot the
processes implemented as part of this study to ensure feasibility. Logistically, the study
managed all aspects of a traditional clinical trial by using mechanisms that did not rely on

39
site visits (Orri et al., 2014). For example, electronic means were used to administer and
document informed consent; study drug was shipped to the patient’s home; samples for
laboratory tests were collected by nurses who visited the patient’s home or by visits to
local clinics; and physicians associated with the study were accessible by phone 24 hours
a day.
For this trial, entitled REMOTE, Research on Electronic Monitoring of
Overactive Bladder Treatment Experience, Pfizer reproduced the essential design features
of a previously conducted trial of tolterodine ER 4 mg, an FDA-approved product for the
treatment of overactive bladder (Orri et al., 2014). One of the goals of the REMOTE trial
was to compare results from the web-based trial to those captured from the traditional
trial. The REMOTE trial aimed to randomize about 600 patients, whose recruitment was
initiated through online advertising. Interested individuals were directed to an
information website. Various checks were implemented during the recruitment process
to verify identity, confirm eligibility and obtain consent, demonstrated in Figure 10.

40
Figure 10: Flow of Potential Participants through the Screening Process for the
REMOTE trial

Source: adapted from (Orri et al., 2014)

In the end, only 18 participants were randomized and entered the double-blind
portion of the trial (Orri et al., 2014). The study was terminated because of its low
enrollment after about a year (Coons, 2017). Despite the disappointing recruitment, the
study provided valuable lessons, depicted in Table 4.
Table 4: Lessons Learned from the Execution of the REMOTE Trial
Positive Findings Improvements Identified
Electronic data capture tools generally worked
well
Multi-step recruitment process not
participant-friendly; identify verification
processes required information not available
publicly
Video-based informed consent worked well Verification emails sent to spam folders
Recruitment tools funneled a high volume of
participants to the informational website
Study procedures were complicated
Treating physicians not involved, marketing
of trial did not connect with how population
managed their health
Equipment not user-friendly
Source: (Coons, 2017; Dolgin, 2018; Hirsch et al., 2017; Orri et al., 2014)

Pfizer was able to confirm that web-based tools, such as electronic informed
consent and data capture tools, could be used successfully in a clinical trial (Dolgin,

41
2018). Enrollment was the biggest issue, likely due to the multiple steps required to enter
the trial (Orri et al., 2014). Pfizer also indicated that the security measures to verify
identification could have been simpler. Despite these challenges, the trial demonstrated
the technical feasibility of a remote trial and prompted additional interest by regulators
and industry.
2.5.1 Evolution of Regulatory Views on Decentralized Trials
FDA acknowledges that the drug development environment created by the
Kefauver-Harris amendment has created limited information in terms of how medical
products will react in the real world (Califf et al., 2016). Finding novel ways to ensure
that trials can reach a diverse population and employ clinically relevant endpoints will
help inform how a product will add value once available on the market. Amendments to
the FD&C Act, including the 21
st
Century Cures Act and FDARA as described in
Table 1, continue to facilitate the evolution of regulatory thinking toward the use of
novel, cost-effective clinical trials. To this end, in 2015, FDA opened a public docket
(Docket No. FDA–2015–N–3579) to obtain input on the perceived barriers when
attempting to use technology and innovative methodologies to support clinical trials
(FDA, 2015; Jadhav, 2016). Comments were received from 40 individuals and
organizations, including pharmaceutical companies, CROs, technology vendors and
industry organizations. Comments from five pharmaceutical companies generally
highlighted the need for guidance from FDA regarding use of mobile technologies in
clinical research (Table 5).

42
Table 5: General Theme of Comments Received from Pharmaceutical
Companies on FDA Public Docket FDA-2015-N-3579
Guidance from FDA needed to better
understand evidence needed, such as
validation, calibration, authenticity and
attributability, to support use of mobile
technology in a clinical trial
1, 2, 3, 4

Definition of primary source data, particularly
when ‘bring your own device’ (BYOD) is
used for data collection; how will data from
BYOD be audited during an inspection?
1, 2, 3, 4

Anonymization of data and concerns about
patient privacy
1, 2, 3, 4

Lack of a globally harmonized regulatory
view with use of mobile devices may hamper
implementation
1, 3, 4

Technology is new and evolving, any
regulation or guidance provided must be
flexible enough to evolve with the
technology
3, 4

How to address consistency of results if
different methodologies are used (paper,
electronic, mobile) in a single study
1

Source:
1
(Lipset, 2015),
2
(Paporello, 2015),
3
(Smith, 2015),
4
(Benecky, 2015)

FDA has since provided several guidance documents relevant to the evolving use
of technology in clinical trials. These include “Use of Electronic Informed Consent in
Clinical Investigations” (2016), “Use of Electronic Records and Electronic Signatures in
Clinical Investigations Under 21 CFR Part 11” (2017), and “Use of Electronic Health
Record Data in Clinical Investigations” (2018) (FDA, 2016; FDA, 2017; FDA, 2018c).
In November 2018, FDA announced a digital platform called MyStudies, a tool that can
be used to develop mobile applications (apps) that can collect real world data in a secured
environment (FDA, 2018b). By offering this platform, FDA hopes that the information
collected using this platform can increase data quality, improve safety monitoring and
speed up the drug development process. Further, in January 2019, the former FDA
Commissioner, Scott Gottlieb, indicated that a formal working group had been created to
establish guidance documents that will outline the FDA’s approach on decentralized trials
going forward (Gottlieb, 2019).
An important group in the drive to diversify approaches to clinical trials has been
the Clinical Trials Transformation Initiative (CTTI), a public-private partnership between

43
Duke University and FDA co-founded in 2007. This organization aims to create best
practices to increase the efficiency of clinical-trial conduct (Hirsch et al., 2017). One of
the programs on which CTTI is working is the Mobile Clinical Trials program (CTTI,
2016). This program examines ways in which mobile technologies can be used to
increase the quality and efficiency of FDA-regulated clinical trials by allowing
participants to conduct some or all study activities remotely and by developing novel
endpoints. Four areas of focus in this initiative are listed in Figure 11. Each project
contributes to an overall set of recommendations to sponsors when considering the use of
mobile technologies in FDA-regulated clinical trials.
Figure 11: Projects within the CTTI Mobile Clinical Trials Program

Source: adapted from (CTTI, 2020)
2.5.2 CTTI Recommendations for Decentralized Clinical Trials
In July 2017, CTTI held an expert meeting with several stakeholders to discuss
perceived legal and regulatory barriers to conducting DCTs through telemedicine and
mobile healthcare providers (CTTI, 2017). Topics covered during the meeting included
FDA and IRB readiness, delegation and oversight by Investigators, monitoring of safety,

44
shipment and receipt of investigational products and state licensing issues relevant to
telemedicine and medication management. In addition to understanding the practical
barriers to conducting DCTs, the meeting was used to identify ways to clarify and inform
policies that might facilitate the implementation of DCTs. Table 6 describes a few
themes from the meeting that were used to develop recommendations.
Table 6: Themes from the CTTI Expert Meeting on Legal and Regulatory
Issues Affecting Adoption of Mobile Clinical Trials
State laws and regulations regarding drug supply vary; a thorough understanding is needed in
an easily accessible location
Investigator responsibilities of patient oversight and delegation of responsibility as it relates to
a decentralized study model needs to be addressed in current regulatory guidance documents
(i.e., Good Clinical Practices)
Some issues identified for mobile clinical trials are common to all clinical trials and should not
be a hindrance and hold mobile clinical trials to a higher standard
Tasks or activities provided by third-party vendors may be leveraged when thoughtfully
integrated in MCT design.
Regulatory and patient engagement should be established early in the protocol design stage
Definitions relevant to the design and conduct of mobile clinical trials should be standardized
across industry and stakeholders
Use prior and current experience from remote clinical trials to drive the design and conduct of
mobile clinical trials
Integrate and leverage third-party vendors into the design of mobile clinical trials
Source: adapted from (CTTI, 2017)

In September 2018, CTTI issued recommendations for decentralized clinical trials
(CTTI, 2018). DCTs were defined by CTTI as clinical trials: “… executed through
telemedicine and mobile/local healthcare providers (HCPs) using procedures that vary
from the traditional clinical trial model (e.g., the investigational medicinal product [IMP]
is shipped directly to the trial participant.” (CTTI, 2018, p. 2)
According to CTTI, the benefits of DCTs include faster recruitment, improved
retention, more convenience and greater comfort for trial participants for whom care will
be offered locally or at home. In addition, such methods were seen as potential ways to
increase participant diversity and to capture experiences in an environment more

45
representative of the real world. CTTI further suggested that these benefits, clearly
desirable for any clinical trial in any disease area, might be particularly important for rare
diseases due to the limited number of patients who are typically dispersed geographically.
CTTI recommends that a DCT does not have to approach change in an all or
nothing way (CTTI, 2018). Rather, implementation can be flexible, adopting different
elements of a DCT in a hybrid approach. The main principle is to remove barriers and
provide participants with a more flexible way to participate in a clinical trial. When
planning a DCT, sponsors should engage with various stakeholders as early as possible.
Sponsors should meet with FDA to discuss any questions related to study conduct using
DCT components to be sure that they are aligned with respect to strategy and approach.
Using vendors with experience in DCTs will also help to ensure that best practices are
incorporated. The protocol design and conduct will need to consider how trial-specific
procedures related to DCT aspects will be documented and explained.
2.5.2.1 Telemedicine and Mobile Healthcare Providers
When implementing DCT, CTTI recommends partnering with sites that are
already familiar with the principles of telemedicine and have incorporated such
approaches into their normal practice (CTTI, 2018). Clearly, healthcare professionals
must be licensed in the state in which they practice medicine but they may also need to be
licensed in the state in which the patient receives treatment. Therefore, it is important to
ensure that the study satisfies the legal requirements for each state. Since the legal status
of telemedicine is evolving, investing in expert resources, such as legal advisors, will be
helpful to ensure compliance with local laws. When considering the use of telemedicine,
CTTI also recommends that it be implemented preferentially in therapeutic areas where

46
telemedicine is more commonly applied, such as dermatology, psychiatry, cardiology or
radiology.
Mobile healthcare providers (HCP) can also be useful in easing burdens on
participants by reducing the number of clinic visits required in the clinical study (CTTI,
2018). A mobile HCP can provide flexibility by scheduling visits at the convenience of
the participant. Their engagement is especially valuable when patients who have
mobility issues cannot leave the home easily. Mobile HCPs should be trained to exercise
their clinical trial responsibilities and should be licensed to perform the tasks required by
the protocol. Vendors and study sites familiar with implementation of mobile HCPs are
better able to assure trial success because of their experience with logistics and
challenges from previous situations.
2.5.2.2 Investigator Delegation and Oversight
Delegation and oversight by the investigator should be no different for a DCT
than for any other traditional study model (CTTI, 2018). The protocol should detail those
activities taking place remotely. Local HCPs collecting data as part of normal standard
of care do not need to be considered as subinvestigators. However, local HCPs who
perform study-specific procedures should be trained on clinical trial practice. The scope
of their authority and way that the investigator will train associated HCPs and oversee
their assigned activities should be documented. Clarity regarding the role of the local
HCP in the collection and management of study-related data will help to ensure the study
does not violate GCP requirements.

47
2.5.2.3 Clinical Trial Drug Supplies
The laws that govern drug distribution vary by state, but some distributional
practices may also be regulated federally depending on the registration status of the
product. Therefore, a thorough review and understanding of relevant legislation will be
needed (CTTI, 2018). All procedures for drug dispensing should be clearly documented
in the protocol, and the use of vendors with experience in managing direct-to-patient
shipment of investigational product should be considered.
2.5.2.4 Safety Monitoring
Any safety monitoring procedures under a DCT should not be held to a different
standard than would be expected in a more traditional clinical trial (CTTI, 2018). The
protocol should specify how safety monitoring is to be performed in a remote setting and
participants should have a clear path for communicating any safety concerns. The
communication plan should be well understood by all of the HCPs and personnel directly
involved with the study.
2.5.3 Current Implementation of Decentralized Clinical Trials by Industry Sponsors
Since the first remote trial conducted by Pfizer in 2011, other sponsors have been
interested in innovating the investigational trial procedures. In 2016, Sanofi and three
other organizations sponsored a phase 4 trial called the VERKKO study to evaluate a
wireless 3G glucose meter in patients with diabetes (Jadhav, 2016). This virtual study,
conducted in Finland, enrolled 60 patients with an average age of 56 years (ClinPal,
2016). The virtual study took one-third of the time to manage as the same trial conducted
using a traditional approach (Mitchell, 2018b). Additionally, patients were recruited 56%
faster and had a similar drop-out rate using the decentralized approach compared with the

48
traditional model using 8 study sites (Langel, 2017). One of the key challenges faced in
the decentralized trial was the support needed for participants who were technically-
challenged (Learner, 2015). Nevertheless, 90% of patients expressed satisfaction with
the virtual trial (Langel, 2017).
Science 37, a company that specializes in conducting decentralized clinical trials,
recently conducted a phase 2b placebo-controlled trial of a topical probiotic spray to treat
acne. Science 37 used a virtual approach and served as the only study site (Dolgin,
2018). It enrolled 372 patients, 41% of whom were non-Caucasian, across ten states.
The study was completed in 12 months, faster than expected by the sponsor, AOBiome
(Science 37, 2017). Science 37 not only provided the technology, an iPhone-based
platform called NORA™ (Network Oriented Research Assistant) to record data, schedule
reminders and communicate with remote study staff. They also had company-affiliated
physicians and coordinators who kept in touch with the participants and offered a human
face to the trial (Dolgin, 2018; Science 37, 2017).
Genentech used a hybrid approach in a study of rituximab to treat pemphigus
vulgaris, a rare skin-blistering disease (Dolgin, 2018). Science 37 was a study site in this
trial along with over 60 traditional study sites. Science 37 was able to enroll 10 patients
in the same time frame that 21 traditional study sites needed to enroll that same number.
Top pharmaceutical companies like Novartis, Sanofi, Otsuka and UCB have
joined forces with Science 37 and have committed to implementing decentralized clinical
trials in fields as varied as neurology, dermatology, oncology, psychiatry and
immunology (Dolgin, 2018; Smalley, 2018). One benefit of the decentralized approach

49
conducted by Science 37 is its ability to recruit 40% of its participants from minority
populations, consistent with the general minority population in the US.
In late 2018, UCB initiated a phase 3b study with Science 37 to study rotigotine in
adolescents with restless leg syndrome, a study that UCB initially dismissed because it
feared that recruitment would take more than 7 years (Smalley, 2018). UCB now hopes
that by using the virtual approach with the help of Science 37, the study will enroll in less
than 2 years. Science 37 is also conducting a phase 4 study with Sanofi to characterize a
diabetic treatment that will focus on enrolling minority populations in the US, including
participants of African-Americans, Hispanic and Asian descent. Other companies such
as Center Point Clinical Services in Fargo, North Dakota and Clinpal in Scotland, offer
decentralized approaches. Interestingly, however, the decentralized model has yet to be
utilized for a pivotal phase 3 trial.
In 2016, the DIA and Tufts CSDD co-sponsored a survey to quantify the patient-
centricity initiatives that were being implemented into clinical research efforts across 22
biopharmaceutical companies and CROs (Lamberti and Awatin, 2017). The organizers
saw value in providing this quantitative information to support other companies as they
decide whether, how and when to implement patient-centric initiatives. The survey
evaluated 25 different patient-centric initiatives as described in Figure 12. Each initiative
was evaluated as either implemented, piloted, planned or not implemented.

50
Figure 12: Patient-Centric Initiatives Evaluated in the DIA/Tufts CSDD Survey

Source: adapted from (Lamberti and Awatin, 2017)

Three of the initiatives evaluated in the survey, direct-to-patient clinical trials,
telemedicine and home nursing networks and logistics assistance, are relevant to the
evaluation of decentralized clinical trials. In this survey, home nursing networks were
rated as the most commonly implemented initiatives; 9/22 (41%) companies implemented
this approach (Lamberti and Awatin, 2017). However, direct-to-patient clinical trials and
telemedicine were included in the list of most-common initiatives that were not being
implemented; 12/22 (55%) companies reported that they were not considering
telemedicine approaches and 9/22 (41%) companies were not considering direct-to-
patient clinical trials.
The survey revealed that the patient-centric initiatives most commonly
implemented, such as patient advisory boards and panels, were cost effective and could
be applied to any therapeutic area, thus offering a faster return on investment. However,
the implementation of patient-centric initiatives faced several barriers. At the top of the
list were challenges related to a lack of company support. This was paralleled by
problems in obtaining the needed authority to implement the initiatives, suggesting that
senior leadership did not appreciate the opportunity that such initiatives presented. Other

51
barriers included a lack of readiness by the sponsor, low risk tolerance and lack of
resources (people, time and money). Even though the survey was limited in scope to 22
companies, it is clear that the level of enthusiasm and perceived benefits associated with
decentralized clinical trials was often insufficient to drive the implementation of this
novel approach. Since the survey was conducted, several companies have initiated the
use of a decentralized setting in clinical trials.
Therefore, while in 2016 the trend seemed to indicate adoption would be slow.
Yet in 2019, the adoption of decentralized trials has been gaining momentum, particularly
as regulators, such as FDA, focus on furthering innovation in clinical development.
2.6 Approach to the Research Project
Low recruitment and high drop-out rates are among the biggest contributors to the
longer development time for medicinal products (Getz and Kaitin, 2015). The increasing
complexity of protocols has contributed to the increased costs and more importantly,
reduced patient engagement. Decentralized clinical trials have been promoted as a way
to reduce the cost and amount of time it takes to gather enough evidence required for
marketing authorization of a new drug. As stated in Section 2.5.3, several companies
have used decentralized approaches in the conduct of clinical trials. Additionally,
regulatory authorities, such as FDA, have openly advocated for more innovative
approaches. The work that has been done to date regarding the implementation of
decentralized clinical trials has focused on the fact that they have not been viewed with
enthusiasm as reflected by difficulties in obtaining company support to implement these
approaches. This study expanded upon prior research to evaluate how companies have

52
progressed along the path to adoption, and to the extent that they have begun
considerations, what have been their experiences and impediments along the adoption
pathway.
The diffusion of innovation framework has been used frequently for evaluating
how innovative ideas are adopted (Rogers, 1983). This framework, as published by
Everett M. Rogers, provides a way to evaluate the impact of the social process on the
communication of new ideas to potential adopters over time. New ideas, or innovation,
represent uncertainty to the potential adopters and uncertainty can influence adoption.
This framework offers ways to evaluate how, why and at what rate innovations are
adopted by individuals or organizations.
2.6.1 The Innovation-Decision Process
The process by which potential adopters decide whether to implement an
innovation is made by following a 5-step process as described in Figure 13 (Rogers,
1983). Each stage considers how much information a stakeholder has about an
innovation and the decision they make based on the information available. As
stakeholders progress along the process, uncertainty surrounding the innovation reduces
and the advantages and disadvantages become clearer.
Figure 13: Innovation-Decision Process

Source: adapted from (Rogers, 1983)

In the first stage, a stakeholder may have knowledge of a new idea or innovation
and may have some basic understanding of how it works. In this step, a stakeholder may

53
or may not do anything with the knowledge. In the persuasion stage, a stakeholder is
actively engaged with learning more about the innovation and is generating a general
perception on the characteristics of the innovation. The decision stage is where a
stakeholder initiates activity which lead to adoption or rejection of the innovation. A
stakeholder may conduct a small-scale pilot during this stage to further understand the
uncertainties and support the decision-making process. During the implementation stage,
a stakeholder puts the innovation into practice. Not all uncertainties will be known when
entering the implementation stage, therefore re-invention can occur during this stage to
improve the innovation. The confirmation stage is used to gather evidence to reinforce
the decision to adopt. A reversal of the decision to adopt can also be made if conflicting
evidence is obtained.
The communication channels used to promote an innovation can influence
adoption. Although mass media can be effective in providing information about an
innovative idea, interpersonal communication is more effective in promoting and
influencing change.
This study evaluated where participants were in the innovation-decision process.
The survey also evaluated the ways participants have learned about decentralized clinical
trials and the effort they have made to seek more information.
2.6.2 Attributes of Innovation
How information is perceived is an important part of the innovation process and
impacts the rate of adoption. The diffusion of information framework suggests that the
rate of adoption can be impacted by 5 main factors, relative advantage, compatibility,

54
trialability, observability and complexity (Rogers, 1983). Further explanation and
examples of each of the factors is provided in Table 7.
Table 7: Attributes of Innovation
Attribute Definition Example(s)
Relative
Advantage
Perceived degree to which an
innovation is better than current
state or predecessor
Degree of profitability, cost of
implementation, impact to timelines,
impact on effort, immediacy of reward
or impact
Compatibility Perceived degree to which
innovation is consistent with
existing knowns
Cultural values/beliefs, fit with prior
ideas/ways of working, fit to perceived
need for innovation
Trialability Degree to which
experimentation can take place
Ability to pilot components or all of a
process/technology
Observability Degree to which others can see
the results of innovation
Impact on relevant metrics
Complexity Perceived degree of difficulty to
understand and use
Impact to processes, need to develop
new skills or understanding
Source: adapted from (Rogers, 1983)

This study evaluated the participants views on the attributes that have impacted
their decision-making process. For those participants who have reached the decision,
implementation or confirmation stage, current thinking on how aspects of decentralized
clinical trials are prioritized, for example, by study type, indication, patient population
and region, was explored.
2.6.3 Rate of Adoption and Adopter Categories
Adoption of innovation does not happen all at once. The rate of adoption is the
relative speed of adoption of an innovation (Rogers, 1983). Stakeholders can be classified
based on their rate of adoption. This classification ranks the degree of innovativeness of
an adopter based on the time of adoption. Rogers categorized adopters into innovators,
early adopters, early majority, late majority and laggards and has demonstrated that the
distribution of these categories follows a bell-shaped curve as depicted in Figure 14.

55
Figure 14: Categorization of Adopters Over Time

Source: adapted from (Rogers, 1983)

This study attempted to qualitatively identify where participants were in the
adoption process.

56
Methodology
The purpose of this exploratory study was to survey professionals within the
pharmaceutical and biotechnology industry in the US on their views and observations
regarding the use of decentralized clinical trials as an innovative way to improve the drug
development process. Using the diffusion of innovation framework as a basis for
collecting information, this study used an electronically administered survey to evaluate
how, why and at what rate decentralized clinical trials are being adopted by industry
(Rogers, 1983).
3.1 Identification of Study Participants
The study sought to obtain opinions from professionals working at sponsor
companies within the pharmaceutical and biotechnology industry in the US. Participants
included representatives with experience in the conduct of clinical trials and may have
represented functions such as clinical development or operations, regulatory or clinical
quality assurance. Participants targeted were mid to senior level employees familiar with
the views of their company with respect to the topic.
The solicited participants were delimited to sponsor companies since these
stakeholders ultimately make the decision to adopt innovation. Thus, representatives
from regulatory authorities, CROs, other vendor companies, study sites and clinical trial
participants were excluded from the study. Representatives from medical device
companies were also excluded from the study, not because the decentralized tools are
irrelevant to this industry, but because the regulatory approaches are handled by a
different part of the regulatory agency and are subject to different constraints.

57
Similarly, representatives working outside of the US were excluded from the trial
since the regulatory approach and framework for the implementation of decentralized
clinical trials in regions outside of the US is not as well established.
To ensure that a broad range of opinions are gathered, participants were identified
through a variety of channels, including my LinkedIn network, personal referrals, social
networking platforms, professional associations or attendance at industry meetings.
Potential participants were contacted through LinkedIn messages or email to determine
their willingness to participate. Interested parties were encouraged to nominate others to
participate, using the snowball technique to further expand the pool of potential
participants (Streeton et al., 2004).
3.2 Data Collection Methodology
A self-administered online survey instrument was utilized to collect data. The
survey length was controlled to ensure it could be completed within a 15-minute time
period. A final version of the survey is provided in Appendix A.
3.2.1 Focus Group
Prior to issuing the survey, a focus group comprised of 7 participants from
industry and academia was used to provide input on the overall organization of the
survey, relevance and clarity of each question and any potential gaps in the set of
questions. The focus group participants were selected based on their knowledge and/or
experience in the conduct of decentralized trials. Participants with extensive survey
preparation and development were also invited to provide insights on the overall structure
of the survey. The invited members of the focus group are listed in Table 8.

58
Table 8: Focus Group Participants
Name Title Institution
Nancy Pire- Smerkanich,
DRSc
Assistant Professor, Dept. of
Regulatory and Quality
Sciences
University of Southern
California
Frances Richmond, PhD Director, D K Kim
International Center for
Regulatory Science
University of Southern
California
Craig Lipset Former Head of Clinical
Innovation at Pfizer
Not Applicable
Lisa DiMolfetto, PhD Vice President, Regulatory
Affairs
Science 37
Laura Kupsch Vice President Quality
Assurance;
Regulatory Science Doctoral
Student
Passage Bio;
University of Southern
California
Katherine St Martin Regulatory Affairs &
Compliance Instructor;
Regulatory Science Doctoral
Candidate
University of California
Irvine;
University of Southern
California
April Armstrong, MD MPH* Associate Dean and Professor University of Southern
California
* not able to attend, comments were received in advance of the focus group

The focus group was convened on October 11, 2019. Prior to the focus group
meeting, an initial draft survey, together with the abstract and chapter 1 of this research,
was circulated to the focus group participants. The focus group was held at the
University of Southern California’s Center for Health Professionals, 1540 Alcazar St, Los
Angeles. A WebEx link was provided for those participants who had scheduling
conflicts or geographic constraints, and the proceedings were recorded. Three
individuals were physically present at the meeting, three participated via WebEx and one
was not able to attend.
The meeting lasted 90 minutes and the focus group discussed each question
sequentially. The focus group suggested improvements to the survey, including
suggestions for defining terms and statements to avoid ambiguity, expansion of the topics

59
covered, and alternative ways to collect data, either through clarifying Likert scales or
other forms of ranking. The survey was updated based on this feedback.
3.2.2 High-Level Survey Content
The survey collected data in three main groups: demographics of the respondents,
the current implementation status of decentralized clinical trials or hybrid approaches to
decentralized clinical trials within the company and general perceptions on further
implementation strategies based on whether the respondent indicated decentralized
clinical trials has been implemented or not within the company. For respondents who
were actively seeking information and beginning to plan pilots of decentralized clinical
trials or hybrid approaches, questions exploring the implementation strategy further were
included. Additionally, feedback on how decentralized clinical trials approaches have
been perceived by FDA as well as trial participants was solicited. The final survey is
provided in Appendix A.
The survey included a total of 28 questions organized into 6 blocks (Figure 15).
Fourteen of these questions were given to all respondents. An additional 14 questions
used “skip logic” so that they would be displayed for a selected subgroup that identified
that they were in some active state of implementation, such as actively seeking
information, starting an initiative, piloting or implementing decentralized clinical trials in
some way. At the end of the survey, respondents could provide their email if they wished
to receive a summary of the results once the thesis was completed.

60
Figure 15: Overview of Survey

3.2.3 Definition of Decentralized Clinical Trials
For the purpose of this study, a fully decentralized clinical trial was defined as a
trial conducted fully virtually with no direct contact with the participant. Contact with
study particpants would be through remote means, such as telemedicine or web-
conferencing capabilities.
The survey also defined hybrid approaches to decentralized clinical trials which
could include one or more of the following options:
• Use of a virtual trial site in addition to traditional trial sites,
• Use of telemedicine for at least parts of the trial or some study visits,
• Use of mobile HCP for at least parts of a trial or some study visits,

61
• Use of a local HCP, either in addition to traditional trial sites or instead of
traditional trial sites, the difference from virtual is that there is some direct
contact with the participant,
• Shipment of study drug and materials direct to participant in the absence of a
fully virtual trial.
3.3 Survey Deployment
The final survey was configured in the web-based survey platform, Qualtrics
(http://www.qualtrics.com/). Validation of the survey was conducted by me and Dr.
Nancy Pire-Smerkanich to ensure that the display logic worked as expected. Data
collected during the validation process were deleted from the survey results.
The survey was deployed on November 7, 2019 to the target population and was
planned to be open for data collection for approximately 2 months, or until a minimum of
50 participants responded. The survey was sent via multiple approaches. Participants for
whom I had personal contact information were sent an email directly from Qualtrics with
a personal link to the survey.
Additionally, an anonymous link was posted on my LinkedIn profile with
information regarding the purpose of the research and the target audience. Participants
who engaged with the survey through this process self-selected to participate. I shared
the original LinkedIn post three times in the first two months the survey was open to
continue to encourage additional participants to respond.
After 2 months, responses from approximately 40 participants were logged in
Qualtrics. To expand the number of participants, I posted the survey in the “Clinical
Research Professionals” group on LinkedIn, a group with over 99,000 members on
January 12, 2020. I also solicited support from the AVOCA group to distribute the

62
survey. The AVOCA group distributed the survey on January 13, 2020 through their
LinkedIn group as well as Aha!. Reminders were posted multiple times.
The survey was closed on February 1, 2020.
3.4 Data Analysis Methodology
Results were collected anonymously and saved electronically within Qualtrics.
Results were summarized using descriptive statistics. Descriptive text, tables, and/or
figures were utilized to display the data. Any open text and comment fields were
examined and analyzed to identify any trends or common elements.
For rank order questions where respondents sorted options by priority, a rank
score was calculated by applying a weight to each response. For example, if 6 options
were provided for ranking, the number of responses where an option was ranked as first
priority was multiplied by 6, the number of responses where an option was ranked as
second priority was multiplied by 5, and so on. The total weighted score was summed to
get the final rank score for the option. The score was then sorted from highest to lowest
with the option with the highest score ranked as 1. Data and calculations for rank scores
are provided in Appendix C.
Cross tabulation analyses were conducted to evaluate how the size of company,
based on number of employees, affected influenced responses to the research questions.
Results are provided in Appendix D.

63
Results
4.1 Survey Participation
The survey was active from November 7, 2019 through February 1, 2020. Links
to the survey were sent directly to 30 participants for whom I had personal contact
information. Of the 30 potential participants, 15 started the survey and 14 completed at
least one question providing a response rate of 47%. A larger group of 75 participants
accessed the survey using the anonymous link, and 58 of these participants completed at
least 1 question giving a drop-out rate of 23% (17/75). Combining both methods of
participation, 72 respondents completed at least one question.
Half of respondents (36/72) answered all questions. Most of the drop-offs
occurred in two main areas of the survey, first at the end of the demographics section of
the survey (19%, 14/72) and second at the end of questions dealing with the decision to
introduce decentralized trial approaches (19%, 14/72), labeled as the “innovation-
decision” block of questions.
4.2 Demographic Profile of Respondents
The first block of questions collected demographic information including the
department or function that the respondents represented within their company; the role
that they play in the decision-making process to implement decentralized clinical trials;
their titles or levels within their organizations; and the size of their organization in terms
of number of employees as well as the number of interventional clinical trials conducted
in a year.

64
Many respondents worked in clinical research including clinical operations (40%,
29/72), clinical development (11%, 8/72) and data management/statistics/programming
(4%, 3/72) (Figure 16). Functions outside of clinical areas in which respondents worked
included regulatory affairs (10%, 7/72), quality assurance (10%, 7/72), project leadership
or project management (7%, 5/72) and digital/innovation services (7%, 5/72). Functions
such as information technology and clinical supply chain were also represented by one
respondent (1%) in each category. Six respondents indicated that their function was
considered something other than those listed and included “clinical development
operations” (1%, 1/72), “business development” (3%, 2/72), “medical affairs” (1%, 1/72),
“change management focused on development technology” (1%, 1/72) and “regulatory
legal” (1%, 1/72).

65
Figure 16: Department/Function Represented by Respondents
Which statement best describes the department or function you represent within your
company?

Other: My Dept is called “Clinical Development Operations (aka DevOps)”; “Business Development”
(n=2); “Medical Affairs”; “Change management focused on development technology to enable efficient
clinical trials”; “Regulatory Legal”
Most of the respondents (63%, 43/68) considered that they influence decisions
within their company and 25% of the respondents (17/68) considered themselves to be
decision makers (Figure 17). The rest of the respondents (12%, 8/68) were not
responsible for decisions related to implementation of decentralized clinical trials.

11%
40%
4%
10%
10%
7%
7%
1%
1%
8%
0 5 10 15 20 25 30
Clinical Development
Clinical Operations
Data Management/ Statistics/ Clinical
Programming
Regulatory Affairs
Quality Assurance/ Quality Control/
Compliance
Project Leadership or Project
Management
Digital/ Innovation Services within R&D
Information Systems/Technology
Clinical Supply Chain
Other, specify
Number of Respondents
n=72

66
Figure 17: Role Played by Respondents in Deciding to Implement Decentralized
Clinical Trials
What role would do you play if/when the decision is made to implement decentralized
clinical trials within your company?

Respondents identified their positions within their organizations (Figure 18). The
majority of respondents (47%, 32/68) were Directors, 25% (17/68) were Managers or
Senior Managers, 15% (10/68) were Vice Presidents or Presidents and 6% (4/68) were in
the C-suite. Seven percent of respondents were at other levels, which included a
Coordinator (1/68), two CRAs (2/68), a senior officer to the executive level (1/68) and a
medical writer (1/68).
25%
63%
12%
0
5
10
15
20
25
30
35
40
45
50
Responsible for making
decision
Influences decision, not
necessarily final decision
maker
Not responsible for
decisions related to
implementation of
decentralized clinical trials
Number of Respondents
n=68

67
Figure 18: Organizational Level of Respondents
At what level is your role within your organization?

Respondents were employed by companies across a full range of sizes. About a
third (35%, 23/66) worked at companies with up to 250 people, 21% (14/66) with 251-
2000 people, 11% (7/66) with 2001-10,000 people, 14% (9/66) with 10,000-25,000
people and 20% (13/66) with more than 25,000 people (Table 9). For the purposes of
cross-tabulations, respondents were combined to form 3 groups based upon size of
company containing approximately similar numbers: small companies with < 250
employees (35%, 23/66), mid-sized companies with 251-<10,000 employees (32%,
21/66) and large companies with > 10,000 employees (33%, 22/66).

6%
15%
47%
25%
7%
0
5
10
15
20
25
30
35
C-Suite Vice President/
President
Director/ Senior
Director/
Executive
Director
Manager/ Senior
Manager
Other, specify
Number of Respondents
n=68

68
Table 9: Size of Company Based on Number of Employees
Which statement best describes the size of your organization?
Number of Employees Count %
Categories and Sample Size
(%) for Cross Tabulations
Fewer than 250 23 35% Small 23 (35%)
251-2000 14 21%
Mid-Sized 21 (32%)
2001-10,000 7 11%
10,000-25,000 9 14%
Large 22 (33%)
More than 25,000 13 20%
Total 66 100%

The number of interventional clinical trials conducted in a year were broadly
distributed as well; 26% (16/62) of respondents worked at companies that conducted 5 or
fewer clinical trials/year, 26% (16/62) that conducted 6-20 clinical trials/year, 21%
(13/62) that conducted 26-100 clinical trials/year and 23% (14/62) that conducted more
than 100 clinical trials/year (Table 10). Five percent of respondents (3/62) were not
aware of how many clinical trials were conducted at their company.
Table 10: Number of Interventional Clinical Trials Conducted/Year
Which statement best describes the average number of interventional trials your company
conducts in a year?
Number of Clinical Trials Count %
5 or less 16 26%
6 – 20 16 26%
26 – 100 13 21%
More than 100 14 23%
I don’t know 3 5%
Total 62 100%

69
4.3 Innovation Decision Process and Implementation Strategy
4.3.1 Level of Knowledge About Decentralized Clinical Trials
All participants were asked to describe their level of knowledge with respect to
the various approaches that could be utilized when conducting a decentralized clinical
trial.
Most participants felt that they had at least some level of knowledge about each of
the various approaches offered to them (Figure 19). The approach that had the highest
proportion of individuals with both knowledge and usage was the use of electronic
patient-reported outcomes or clinical outcome assessment tools (ePRO/eCOA); two-
thirds of respondents (67%, 39/58) both knew about and had used this approach. Of the
rest, 16% (9/58) knew of ePRO/eCOA but had not used it, 3% (2/58) indicated “some
knowledge” and 14% (8/58) had no knowledge of ePRO/eCOA. Other tools beyond
ePRO/eCOA, such as mobile data collection of digital endpoints were used less
commonly. Here, 43% (25/58) of respondents had both knowledge and experience using
this approach, 33% (19/58) had knowledge but had not used this approach, 19% (11/58)
had some knowledge and 5% (3/58) had no knowledge of this approach.
Most respondents also appeared to be widely familiar with the use of local
healthcare providers; they were known and used by 51% of respondents (29/57) and
known but not used by 19% (11/57). Of the remaining respondents, 21% (12/57) had
“some knowledge” and 9% (5/57) had no knowledge of this approach. In comparison,
the use of mobile healthcare providers in clinical trials was known and used by 31% of
respondents (18/58) whereas 22% (13/58) had knowledge and have not used this

70
approach, 29% (17/58) had “some knowledge” and 17% (10/58) had no knowledge of
this approach.
The majority of respondents felt that they knew about eConsent, whether they had
used it (36%, 21/58) or not (45%, 26/58). Of the rest, 12% (7/58) had “some knowledge”
and 7% (4/58) had no knowledge of eConsent.
Knowledge about how to ship study drug and other materials directly to clinical
trial participants was identified by 70% of respondents. It was used by 41% (24/58) and
not used by 29% (17/58). About 22% (13/58) had “some knowledge” of shipping to
study participants and 7% (4/58) had no knowledge of this approach.
The use of telemedicine in clinical trials was the least utilized approach; only 21%
of respondents (12/58) knew and had used telemedicine in a clinical trial. However, 36%
of respondents (21/58) had knowledge of telemedicine approaches in clinical trials but
had not used this approach, 26% (15/58) had “some knowledge” and 17% (10/58) had no
knowledge of this approach.

71
Figure 19: Knowledge of Approaches Related to the Conduct of Decentralized
Clinical Trials
Please indicate your level of knowledge about the following approaches as they related
to the conduct of a decentralized clinical trial of an investigational product in an
interventional trial.

A cross-tabulation was performed to explore whether the results for respondents
who knew and had used the decentralized approaches described above were influenced
by the size of company. As displayed in Figure 20, each approach has been used by all
sizes of companies.
eConsent, ePRO/eCOA, mobile data collection of digital endpoints and
telemedicine were used more often by large companies. eConsent was used by 52% of
36%
67%
43%
21%
31%
51%
41%
45%
16%
33%
36%
22%
19%
29%
12%
3%
19%
26%
29%
21%
22%
7%
14%
5%
17%
17%
9%
7%
0 20 40 60
eConsent (n=58)
ePRO/eCOA (n=58)
Mobile data collection of digital endpoints
(n=58)
Telemedicine (n=58)
Mobile Healthcare Provider (n=58)
Local Healthcare Provider (n=57)
Direct shipment of study materials to
participant (n=58)
Number of Respondents
Knowledgeable HAVE USED Knowledgeable HAVE NOT USED
Some knowledge No knowledge

72
respondents (11/21) representing large companies relative to 19% (14/21) representing
mid-sized companies and 29% (6/21) representing small companies. ePRO or eCOA was
used by 41% of respondents (16/39) representing large companies, 31% (12/39) by mid-
sized companies and 28% (11/39) by small companies. Mobile collection of digital
endpoints was used by 48% of respondents (12/25) representing large companies, 28%
(7/25) by mid-sized companies and 24% (6/25) by small companies. Telemedicine was
used by 58% of respondents (7/12) representing large companies, 17% (2/12) by mid-
sized companies and 25% (3/12) by small companies.
Use of mobile HCPs, local HCPs and direct shipment appeared to be less
influenced by size of company. Mobile healthcare providers were used by equal
proportions of respondents, 33% (6/18), for each of the company size categories. Local
health providers were used by 34% of respondents (10/29) representing large companies,
34% (10/29) by mid-sized companies and 31% (9/29) by small companies. Direct
shipment of study drug and other materials was used by 33% of respondents (8/24)
representing large companies, 38% (9/24) by mid-sized companies and 29% (7/24) by
small companies.

73
Figure 20: Decentralized Approaches Respondents Have Knowledge of and Have
Used by Size of Company

The mechanisms used by respondents to reference or learn about the use and
conduct of fully decentralized clinical trials or hybrid approaches to decentralized clinical
trials are summarized in Figure 21. More than 50% of respondents indicated that each of
the mechanisms for learning provided as choices were modestly useful or very useful.
The two mechanisms chosen most often as modestly useful or very useful were direct
contact with peers with known practical experience (94%, 48/51) and discussion with
representatives from industry consortiums (90%, 46/51). “Consultant groups” was the
choice with the fewest respondents (51%, 26/51) indicating that this method was
modestly or very useful. All of the other mechanisms, including regulations and
guidance documents from regulatory authorities, discussion/meeting with a regulatory
authority, recommendations from industry collaborations, such as CTTI, representatives
from CRO or other vendor, patients, caregivers or patient advocate groups,
29%
28%
24%
25%
33%
31%
29%
19%
31%
28%
17%
33%
34%
38%
52%
41%
48%
58%
33%
34%
33%
0 10 20 30 40
eConsent (n=21)
ePRO/eCOA (n=39)
Mobile data collection of digital endpoints
(beyond ePRO/eCOA) (n=25)
Telemedicine (n=12)
Mobile Healthcare Provider (n=18)
Local Healthcare Provider (n=29)
Direct shipment of study drug and other
materials to participant (n=24)
Number of Respondents
Small (<251 people) Mid-sized (251-<10,000 people) Large (>10,000 people)

74
seminars/conferences and literature, publications, news articles, magazines, were chosen
by 78-88% of respondents as modestly or very useful ways to learn about decentralized
approaches.
Figure 21: Mechanisms Used to Reference or Learn About Decentralized Clinical
Trials
How useful are the following support mechanisms for referencing or learning about the
use and conduct of fully decentralized clinical trials or hybrid approaches to
decentralized clinical trials?

Total number of respondents was 51 for all choices except “Recommendations from industry
collaborations” with 50 respondents.
4.3.2 Implementation Stage for Decentralized Clinical Trials
A summary of the implementation stage for fully decentralized clinical trials is
provided in Figure 22. The majority of respondents are either not considering
51%
29%
38%
63%
59%
43%
35%
55%
65%
63%
28%
49%
46%
28%
24%
8%
59%
26%
20%
26%
0 10 20 30 40 50
Regulation/guidance from regulatory authorities
Discussion/meeting with a regulatory authority
Recommendations from industry collaborations
Discussion with industry consortiums
Representatives from CRO/other vendor
Consultant group
Direct contact with peers with practical
experience
Patients, caregivers or patient advocate groups
Seminars/conferences
Literature or other articles
Number of Respondents
Modestly useful Very useful
n=5
1

75
implementing fully decentralized trials (31%, 16/51), at the early stages of exploring the
opportunity (28%, 14/51) or actively seeking information and would consider piloting in
the future (8%, 4/51). Respondents in later stages of implementation included 4% (2/51)
whose companies were starting an initiative, 10% (5/51) that were completing a pilot and
14% (7/51) had formally implemented the approach. Six percent (3/51) were not sure of
the implementation strategy within their company.
Figure 22: Implementation Stage for Fully Decentralized Clinical Trials
Which statement best describes the implementation stage for fully decentralized clinical
trials (fully virtual trial) at your company?

A summary of the implementation stage for hybrid approaches to decentralized
clinical trials is provided in Figure 23. Most respondents were either not considering
implementing hybrid approaches (12%, 6/49), were exploring the opportunity (25%,
12/49) or were actively seeking information and would consider piloting in the future
(14%, 7/49). Respondents whose companies were in some stage of implementation
31%
28%
8%
4%
10%
14%
6%
0 2 4 6 8 10 12 14 16 18
Not considering at this time
Exploring
Actively seeking information
Resources assigned and corporate initiative
has started
Completing pilot
Have implemented processes/procedures
formally
I am not sure
Number of Respondents
n=51

76
included 8% (4/49) that were starting an initiative, 6% (3/49) completing a pilot and 27%
(13/49) formally implementing the approach. Eight percent (4/49) were not sure of the
implementation strategy within their company.
Figure 23: Implementation Stage for a Hybrid Approach to Decentralized
Clinical Trials
Which statement best describes the implementation stage for a hybrid approach to
decentralized clinical trials at your company? For example, portions of a study may be
conducted virtually.

A cross-tabulation of the implementation stage for fully decentralized clinical
trials by size of company (based on number of employees) was conducted to understand
whether there were differences based on size of company. Most respondents representing
small companies were not implementing fully decentralized clinical trials; 53% (9/17)
were not considering implementation and 29% (5/17) were exploring implementation
compared to 6% (1/17) whose companies had implemented fully decentralized clinical
trials (Figure 24). Twelve percent (2/17) were not sure of the strategy.
12%
25%
14%
8%
6%
27%
8%
0 2 4 6 8 10 12 14 16 18
Not considering at this time
Exploring
Actively seeking information
Resources assigned and corporate initiative
has started
Completing pilot
Have implemented processes/procedures
formally
I am not sure
Number of Respondents
n=49

77
Similarly, respondents representing mid-sized companies more commonly
indicated they were not to the point of implementing fully decentralized clinical trials
with 40% (6/15) indicating they would not implement, 20% (3/15) indicating they were
exploring and 7% (1/15) indicating they were actively seeking information and may pilot
in the future. Of the mid-sized companies who were in an implementation stage, 20%
(3/15) were completing a pilot and 13% (2/15) had implemented fully decentralized
clinical trials.
In contrast, respondents representing large companies only one, (5%, 1/19)
identified that the company did not intend to implement fully decentralized clinical trials
where as 32% (6/19) indicated they were exploring and 16% (3/19) that they were
actively seeking information and may pilot in the future. Of the large companies in an
implementation stage, 11% (2/19) had commenced an initiative, 11% (2/19) were
completing a pilot and 21% (4/19) had implemented fully decentralized clinical trials.
One (5%) respondent representing a large company was not sure of the implementation
strategy for fully decentralized clinical trials.

78
Figure 24: Implementation Stage for Fully Decentralized Clinical Trials by Size
of Company

A cross-tabulation of the implementation stage for hybrid approaches to
decentralized clinical trials by size of company (based on number of employees) is
provided in Figure 25. The majority of respondents representing small companies were
not implementing hybrid approaches to decentralized clinical trials; 29% (5/17) were not
considering implementing, 29% (5/17) were exploring implementation and 18% (3/17)
were actively seeking information and may pilot in the future. Twelve percent (2/17) of
respondents from a small company indicated they implemented hybrid approaches to
decentralized clinical trials and 12% (2/17) were not sure of the strategy.
53%
29%
0%
0%
0%
6%
12%
40%
20%
7%
0%
20%
13%
0%
5%
32%
16%
11%
11%
21%
5%
0 1 2 3 4 5 6 7 8 9 10
Not considering at this time
Exploring
Actively seeking information
Resources assigned and corporate initiative
has started
Completing pilot
Have implemented
I am not sure
Number of Respondents
Small <251 people (n=17) Mid-sized 251-<10,000 people (n=15)
Large >10,000 people (n=19)

79
Of respondents representing mid-sized companies, 7% (1/15) indicated they
would not implement hybrid approaches, 20% (3/15) that they were exploring their use
and 13% (2/15) that they were actively seeking information and may pilot in the future.
Of the mid-sized companies who were in an implementation stage, 7% (1/15) had
resources assigned to an initiative and would pilot in the future, 13% (2/15) were
completing a pilot and 40% (6/15) have implemented hybrid approaches to decentralized
clinical trials.
Of respondents representing large companies, none identified that they would not
implement hybrid approaches. Twenty percent (4/17) were exploring their use and 12%
(2/17) were actively seeking information and may pilot hybrid approaches in the future.
Slightly more than half were at some stage of implementation; 18% (3/17) had resources
assigned to an initiative and would pilot in the future, 6% (1/17) were completing a pilot
and 29% (5/17) had implemented fully decentralized clinical trials. Twelve percent
(2/17) were not sure of the implementation strategy.

80
Figure 25: Implementation Stage for a Hybrid Approach to Decentralized
Clinical Trials by Size of Company

Respondents who indicated that they were actively seeking information, had
resources assigned, completed a pilot or had implemented either fully decentralized
clinical trials or hybrid approaches, were asked to clarify their implementation strategy
for with regard to a number of choices that were presented earlier as tools or approaches
to decentralized clinical trials (Figure 26).
Most respondents were at least considering each of the approaches.
Direct shipment of study drug and materials was the most widely implemented
approach with 46% of respondents either piloting (4%, 1/26) or having used the approach
29%
29%
18%
0%
0%
12%
12%
7%
20%
13%
7%
13%
40%
0%
0%
24%
12%
18%
6%
29%
12%
0 2 4 6 8 10
Not considering at this time
Exploring
Actively seeking information
Resources assigned and corporate initiative
has started
Completing pilot
Have implemented
I am not sure
Number of Respondents
Small <251 people (n=17) Mid-sized 251-<10,000 people (n=15)

81
(42%, 11/26). Additionally, this method was being considered by 46% (12/26) of
respondents. One respondent (1/26) would not use the approach and one respondent
(1/26) was not sure.
The next approach to be used quite widely was that engaging local healthcare
providers; 44% of respondents were either piloting (8%, 2/25) or had used the approach
(36%, 9/25). Additionally, 32% (8/25) were considering the approach and 24% (6/25)
were not sure.
Similar distributions were observed for use of telemedicine and mobile healthcare
providers with 36% (9/25) of respondents piloting or having used telemedicine and 35%
(9/26) of respondents piloting or having used mobile healthcare providers. Telemedicine
was being considered by 44% (11/25) of respondents and mobile healthcare providers by
50% (13/26). Twenty percent (5/25) were not sure about using telemedicine and 15%
(4/26) were not sure about using mobile healthcare providers.
Virtual plus traditional sites were being piloted or used by 27% (7/26) of
respondents and would be considered by 54% (14/26) of respondents; 19% (5/26) were
not sure.
Fully decentralized clinical trials were being piloted or used by 35% (9/26) of
respondents. Twenty-seven percent (7/26) indicated that they would consider the
approach and 19% (5/26) were not sure. About a fifth of respondents (19%, 2/26)
indicated that they would not use the approach.

82
Figure 26: Decentralized Approaches to Clinical Trials Considered or Used by
Those Considering or Pursuing Implementation of Decentralized
Trials
Which statement best describes the decentralized approaches for an interventional study
that you have used or may consider using at your company?

A cross-tabulation was conducted for each approach to decentralized clinical trials
by size of company.
Respondents who indicated that they would not consider implementation of fully
decentralized clinical trials were all associated with small (60%, 3/5) or mid-sized
19%
19%
20%
15%
24%
4%
19%
0%
0%
0%
0%
4%
27%
54%
44%
50%
32%
46%
12%
12%
12%
12%
8%
4%
23%
15%
24%
23%
36%
42%
0 2 4 6 8 10 12 14
Fully decentralized clinical trial (n=26)
Virtual site plus traditional sites (n=26)
Telemedicine (n=25)
Mobile healthcare provider (n=26)
Local healthcare provider (n=25)
Direct shipment to participant (n=26)
Number of Respondents
Not sure Will not use Considering using Piloting Have used

83
companies (20%, 2/10) (Figure 27). A minority of representatives from small companies
were either considering using the approach (20%, 1/5) or had implemented the approach
(20%, 1/5). Respondents from mid-sized companies were more often considering the
approach (20%, 2/10) or have either piloted or had used the approach (40%, 4/10)
whereas 20% (2/10) were not sure. Most respondents from large companies were either
considering (36%, 4/11) or using (36%, 4/11) fully decentralized clinical trials whereas
27% (3/11) were not sure.
Figure 27: Implementation of Fully Decentralized Clinical Trials by Size of
Company

Implementation of virtual trial sites plus traditional trial sites was being
considered or implemented by all sizes of companies (Figure 28). Most representatives
from small companies identified that their companies were considering the use of virtual
trial sites plus traditional trial sites (80%, 4/5) and 20% (1/5) had implemented the
0%
60%
20%
0%
20%
20%
20%
20%
30%
10%
27%
0%
36%
0%
36%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=10)

84
approach. Those form mid-sized companies reported that their companies were
considering (30%, 3/10) or implementing them (30%, 3/10) but many (40%, 4/10) were
not sure. Respondents from large companies reported that their companies were
considering this approach (64%, 7/11) and 27% (3/11) had piloted or used it; one
respondent was not sure (9%, 1/11).
Figure 28: Implementation of Virtual Trial Sites Plus Traditional Trial Sites by
Size of Company

Implementation of telemedicine was being considered or implemented by all sizes
of companies (Figure 29). Equal numbers of representatives from small companies
identified that their companies were either considering (40%, 2/5) or had implemented
the approach (40%, 2/5); one (20%, 1/5) was not sure. Mid-sized companies were either
considering (44%, 4/9) or piloting (33%, 3/9) the approach; two respondents (22%, 2/9)
were not sure. Almost all respondents from large companies were considering or using
0%
0%
80%
0%
20%
40%
0%
30%
20%
10%
9%
0%
64%
9%
18%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=10)
Large >10,000 people (n=11)

85
telemedicine (45%, 5/11 and 36%, 4/11, respectively) but two respondents (18%, 2/11)
were not sure.
Figure 29: Implementation of Telemedicine by Size of Company

Implementation of mobile healthcare providers was being considered or
implemented by all sizes of companies (Figure 30). Representatives from small
companies identified that their companies were either considering using mobile
healthcare providers (60%, 3/5) or had used the approach (40%, 2/5). Mid-sized
companies were either considering the approach (60%, 6/10) or had piloted or used the
approach (30%, 3/10), but one respondent (10%, 1/10) was not sure. Most large
companies were also considering or using mobile healthcare providers (36%, 4/11 and
36%, 4/11, respectively); 27% (3/11) were not sure.
20%
0%
40%
0%
40%
22%
0%
44%
33%
0%
18%
0%
45%
0%
36%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=9)
Large >10,000 people (n=11)

86
Figure 30: Implementation of Mobile Healthcare Providers by Size of Company

The use of local healthcare providers was being considered or implemented by all
sizes of companies (Figure 31). Representatives from small companies identified that
their companies were either considering or using local healthcare providers (20%, 1/5 and
80%, 4/5, respectively). Mid-sized companies were either considering or had piloted or
used local healthcare providers (40%, 4/10 and 40%, 4/10), respectively); 20% (2/10)
were not sure. Large companies were considering or using this approach as well (30%,
3/10 and 30%, 3/10, respectively); 40% (4/10) were not sure.
0%
0%
60%
0%
40%
10%
0%
60%
20%
10%
27%
0%
36%
9%
27%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=10)
Large >10,000 people (n=11)

87
Figure 31: Implementation of Local Healthcare Providers by Size of Company

Implementation of direct shipment of study drug/materials to the participant was
being considered or implemented by all sizes of companies (Figure 32). Representatives
from small and mid-sized companies identified that they were mostly considering the use
of direct shipment (60%, 3/5 and 60%, 6/10, respectively) or had used the approach
(40%, 2/5 and 40%, 4/10, respectively). Respondents from large companies were also
considering or using this approach (27%, 3/11 and 54%, 6/11, respectively) whereas one
(9%, 1/11) was not sure and one (9%, 1/11) would not use direct shipment.
0%
0%
20%
0%
80%
20%
0%
40%
20%
20%
40%
0%
30%
0%
30%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=10)
Large >10,000 people (n=10)

88
Figure 32: Implementation of Direct Shipment of Study Drug or Materials to the
Trial Participant by Size of Company

4.4 Rate of Innovation
The timing of implementation for fully decentralized clinical trials is shown in
Figure 33. Nearly half (42%, 6/14) of respondents indicated that their companies have
already implemented fully decentralized clinical trials whereas 50% (7/14) indicated that
their companies would initiate a fully decentralized clinical within the next two years and
one (7%, 1/14) indicated that it might be introduced in 3 or more years.
0%
0%
60%
0%
40%
0%
0%
60%
0%
40%
9%
9%
27%
9%
45%
0 1 2 3 4 5 6 7 8 9 10
Not sure
Will not use
Considering using
Piloting
Have used
Number of Respondents
Small <251 people (n=5) Mid-sized 251-<10,000 people (n=10)
Large >10,000 people (n=11)

89
Figure 33: Timing for Conduct of Fully Decentralized Clinical Trials (n=14)
Approximately when was/will the first fully decentralized clinical trial (fully virtual)
conducted/be conducted at your company?

The introduction of hybrid approaches to decentralized clinical trials is compared
in Figure 34. Nearly half of respondents (48%, 12/25) indicated that they had already
implemented hybrid approaches to decentralized clinical trials with most implementing
them within the last 2 years; 36% (9/25) of respondents indicated that they would initiate
hybrid approaches within the next two years and 16% (4/25) predicted introduction in 3
or more years.
0% 21% 21% 50%
7%
0
1
2
3
4
5
6
7
8
9
10
>5 years ago Within the last
3-5 years
Within the last
2 years
Within the next
2 years
3+ years
Number of Respondents
n=14

90
Figure 34: Timing for Conduct of Hybrid Approaches to Decentralized Clinical
Trials
Approximately when was/will the first hybrid approach to decentralized clinical trial
conducted/be conducted at your company?

Respondents were also asked to rank the approaches to decentralized clinical
trials with the highest priority in their company. The top priorities were implementation
of virtual trial sites in addition to traditional trial sites and the use of telemedicine
(Table 11). The lowest priority was implementation of a fully decentralized clinical trial.
Table 11: Priority for Implementing Approaches to Decentralized Clinical
Trials
Rank the following approaches to decentralized clinical trials in order of implementation
priority, where #1 would be considered the highest priority in your company.
Approach
n=23
Rank Score Ranking
Virtual trial site plus traditional sites 95 1
Telemedicine 92 2
Mobile healthcare provider 87 3
Direct shipment of study drug/materials to participant 86 4
Local healthcare provider 73 5
Fully decentralized/virtual clinical trial 50 6
Priority is ranked where 1 is the highest priority.
4%
12% 32% 36% 16%
0
1
2
3
4
5
6
7
8
9
10
>5 years ago Within the last
3-5 years
Within the last
2 years
Within the next
2 years
3+ years
Number of Respondents
n=25

91

A cross-tabulation of the rank of priority for implementation of decentralized
approaches was conducted by size of company to see if any differences were observed.
Generally, the top priorities for small companies was the introduction of virtual trial site
plus traditional trial site and telemedicine (Table 12). Top priorities for mid-sized
companies were the use of mobile healthcare providers and telemedicine. Top priorities
for large companies were the use of virtual trial site plus traditional trial site and direct
shipment of materials to trial participants.
Fully decentralized clinical trials were of lowest priority for small and mid-sized
companies whereas the use of local healthcare providers was of lowest priority for large
companies. However, in all of these cross-tabulations, numbers of respondents in each
sample are small.
Table 12: Ranking of Priority for Implementing Approaches to Decentralized
Clinical Trials by Size of Company
Approach
Ranking by Size of Company
Small
<250
people
(n=4)
Mid-sized
251-10,000
people
(n=10)
Large
>10,000
people
(n=9)
Virtual trial site plus traditional sites 1 3 1
Telemedicine 1 2 3
Mobile healthcare provider 3 1 4
Local healthcare provider 4 5 6
Direct shipment of study drug/materials to participant 5 4 2
Fully decentralized/virtual clinical trial 6 6 5
Priority is ranked where 1 is the highest priority.
4.5 Factors Influencing Decisions to Implement Some or All Elements of
Decentralized Clinical Trials
When asked to rank order potential challenges or barriers to implementation of
approaches to decentralized clinical trials from a series of offered choices (Table 13), the

92
most highly ranked were unclear regulatory requirements/guidance/compliance
expectations and insufficient organizational readiness. The challenges or barriers that
were least influential were lack of company support/authority to implement and a risk
averse company mindset/culture.
Table 13: Ranking of Organizational Challenges or Barriers to Implementation
of Approaches to Decentralized Clinical Trials
The following organizational factors have been considered to contribute to the decision
to implement decentralized clinical trials (DCT) or hybrid approaches to DCT. Rate the
importance of each factor in influencing the decision to implement a DCT or hybrid
approach to DCT at your company.
Organizational Challenges/Barriers
n=44
Rank Score Ranking
Unclear Regulatory requirements/guidance/compliance
expectations
247 1
Insufficient organizational readiness (i.e., know-how, processes,
templates, etc.)
230 2
Concern about regulatory acceptability of data/study results 180 3
Unclear value proposition (i.e., reduction in time, positive return
on investment)
165 4
Concern about data privacy/security 140 5
Lack of company support/authority to implement 136 6
Risk averse company mindset/culture 134 7
Challenge/barrier with the highest rank score represents the most important factor in the decision to
implement approaches to decentralized clinical trials.
The rankings of challenges or barriers to implementation were cross-tabulated to
company size. Respondents from companies of all sizes ranked unclear regulatory
requirements/guidance/ compliance expectations and insufficient organizational readiness
as the greatest challenges (Table 14). The barrier or challenge with the lowest ranking
was concern about data privacy/security for small companies, an unclear value
proposition for mid-sized companies and a lack of company support/authority to
implement decentralized trials for large companies.

93
Table 14: Ranking of Organizational Challenges or Barriers to Implementation
of Approaches to Decentralized Clinical Trials by Size of Company
Organizational Challenges/Barriers
Size of Company
Small
<250
people
(n=16)
Mid-Sized
251-10,000
people
(n=14)
Large
>10,000
people
(n=14)
Unclear Regulatory
requirements/guidance/compliance expectations 1 1 1
Insufficient organizational readiness (i.e., know-how,
processes, templates, etc.) 2 2 2
Unclear value proposition (i.e., reduction in time,
positive return on investment) 3 7 4
Concern about regulatory acceptability of data/study
results 4 3 3
Risk averse company mindset/culture 5 6 6
Lack of company support/authority to implement 6 5 7
Concern about data privacy/security 7 4 5
Challenges/barriers were ranked where 1 is the largest challenge/barrier priority.
When asked to rank choices whose feasibility might influence the decision to
implement decentralized clinical trials, all of the offered choices were considered to have
some or great influence. From the list, the top ranked choice was the ability to identify
studies where endpoints can be captured outside of a clinic (71%, 29/41), followed by the
characteristics of the investigational product requiring specialized handling and
administration (66%, 27/41) and the ability to validate mobile device collection for
regulatory acceptance (63%, 26/41) (Figure 35). The route of administration of the
investigational product was ranked as the least influential in the decision to implement
decentralized trials (49%, 20/41).

94
Figure 35: Influence of Feasibility Factors Which May Impact Decision to
Implement Approaches to Decentralized Clinical Trials
Describe how influential the following feasibility factors have been or would be in the
decision to implement any decentralized clinical trial approaches in your company.

Respondents were also offered a list of external factors that might influence the
decision to adopt decentralized clinical trials or hybrid approaches to decentralized
clinical trials. All of these were considered by at least 75% of the respondents as
somewhat important or important (Figure 36). The most highly ranked factor was FDA
support of the approach; 100% (41/41) of respondents indicated this was somewhat
important or important. “Regulatory authority support outside the US” and “positive
experience for participants/care givers” were also given high priority; 95% (38/40 and
10%
5%
3%
5%
7%
15%
17%
27%
38%
34%
27%
34%
71%
63%
58%
54%
66%
49%
2%
5%
3%
7%
0%
2%
0 5 10 15 20 25 30
Ability to identify studies where endpoints
can be captured outside of a clinic (n=41)
Ability to validate mobile device collection
for regulatory acceptance (n=41)
Enough lead time is available to ensure
digital endpoints can be justified and
validated for use in a pivotal trial (n=40)
Procedures requiring specialized equipment
or assessments, such as imaging or biopsies
(n=41)
Characteristics of the investigational product
requiring specialized handling or
administration (n=41)
Route of administration of investigational
product (n=41)
Number of Respondents
No influence Some influence A lot of influence Not sure

95
37/39, respectively) of respondents indicated that these factors were somewhat important
or important factors.
The factors with lowest rankings included the “ability to maintain relationships
with key opinion leaders/investigators” (75%, 30/40 somewhat important or important)
and the “ability to maintain relationship with traditional study sites” (78%, 31/40
somewhat important or important).

96
Figure 36: Influence of External Factors On Decisions to Implement
Decentralized Clinical Trials or Hybrid Approaches to Decentralized
Clinical Trials
How important are the following external factors in influencing the decision to adopt
decentralized clinical trials or hybrid approaches of a decentralized clinical trial at your
company?

0%
3%
5%
10%
10%
0%
3%
0%
3%
5%
0%
3%
5%
15%
13%
5%
13%
8%
5%
10%
15%
28%
48%
35%
45%
23%
8%
25%
20%
33%
85%
68%
43%
40%
33%
72%
78%
68%
73%
53%
0 5 10 15 20 25 30 35
FDA support of approach (n=40)
Regulatory authority support outside the US
(n=40)
Availability of specific regulation/guidance on
decentralized approaches (n=40)
Ability to maintain relationship with key
opinion leaders/investigators (n=40)
Ability to maintain relationship with
traditional study sites (n=40)
Positive experience for participants/care
givers (n=39)
Security and/or privacy of data (n=40)
Higher retention rate of trial participants
(n=40)
Faster trial enrollment rate (n=40)
Increase in diversity of participants (n=40)
Number of Respondents
Not important/Somewhat not important Neutral Somewhat important Important

97
4.6 Factors Affecting the Use of Approaches to Decentralized Clinical Trials
4.6.1 Approaches to Study Conduct by Type of Interventional Clinical Trial
Interventional clinical trials can have different purposes and these purposes can
affect the likelihood of considering or using decentralized approaches. Only a few
respondents indicated that a fully decentralized clinical trial would be used for a first-in-
human patient study (5%, 1/20), a proof of concept study/dose-finding study (10%, 2/20)
or a pivotal study for a non-marketed drug (5%, 1/20) (Figure 37). For these trial types, a
traditional clinical study was most often considered (90%, 18/20 to 100%, 20/20). A
traditional clinical study was also the approach most often considered for studies of
healthy volunteers (90%, 19/21), although fully virtual trials would also be considered
(43%, 9/21).
Fully virtual trials were more often considered as an approach appropriate for a
long-term safety study (70%, 14/20), a post-market study (80%, 16/20) or a pragmatic
study (78%, 14/18).
Virtual trial sites in addition to traditional sites were considered more frequently
(60%, 12/20 to 85%, 17/20) for pivotal and post-market studies of various types than for
early-stage studies, such as first-in-human patient studies (10%, 2/20) and proof of
concept/dose finding studies (25%, 5/20).

98
Figure 37: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Type of Clinical Trial
Choose which clinical trial approach your company would generally consider using for
each of the following types of interventional clinical studies. Check all that might apply
for each type of study, understanding that decisions at an individual study level may
depend on other factors as well.

Hybrid approaches to decentralized clinical trials using telemedicine, mobile
healthcare providers, local healthcare providers or direct shipment of study materials to
the participant, were considered options for all study types (Figure 38). Long-term safety
43%
5%
10%
5%
35%
70%
80%
78%
62%
10%
25%
60%
80%
80%
85%
72%
90%
100%
95%
90%
65%
50%
50%
56%
0 2 4 6 8 10 12 14 16 18 20
Healthy volunteer study (n=21)
First-in-human patient study (n=20)
Proof of concept study or dose-finding
study (n=20)
Pivotal study for a non-marketed drug
(n=20)
Pivotal study for a marketed drug (n=20)
Long-term safety study (n=20)
Post-market study (n=20)
Pragmatic study (n=18)
Number of Respondents
Fully decentralized/ virtual clinical trial Virtual site plus traditional sites
Traditional trial conduct

99
studies and post-market studies were the most likely to use hybrid approaches such as
telemedicine (80%, 16/20 and 85%, 17/20, respectively), mobile healthcare providers
(75%, 15/20 and 80% (16/20, respectively) or local healthcare providers (85%, 17/20 for
both study types). A large proportion of respondents (80%, 16/18) would also consider
using direct shipment of study drug and other materials to participants for these types of
studies.
Similarly, 78% (14/18) would consider using telemedicine and 67% (12/18)
would consider using mobile healthcare providers, local healthcare providers or direct
shipment for pragmatic studies. The use of telemedicine (70%, 14/20), mobile healthcare
providers (65%, 13/20), local healthcare providers (75%, 15/20) and direct shipment of
study supplies to participants (65%, 13/20) would also be considered by most in pivotal
studies for a marketed product. The likelihood of using hybrid approaches was slightly
lower for pivotal studies of a product that is not yet marketed. Approximately half of the
respondents would consider using telemedicine (50%, 10/20), mobile healthcare
providers (50%, 10/20) or local healthcare providers (55%, 11/20). Fewer (40%, 8/20)
would consider using direct shipment for pivotal studies of non-marketed products.
For a study of healthy volunteers, respondents considered telemedicine and
mobile healthcare providers more often (57%, 12/21 and 62%, 13/21, respectively) than
the use of local healthcare providers (43%, 9/21). Direct shipment would be considered
by approximately half of respondents (48%, 10/21) for studies of healthy volunteers.
Hybrid approaches appeared to be considered for early stage human studies.
Proof of concept or dose finding studies were more likely to use mobile or local
healthcare providers (40%, 8/20 and 50%, 10/20, respectively) over telemedicine (25%,

100
5/20) and direct shipment of supplies (30%, 6/20). Hybrid approaches were considered
least suitable for first in-human patient studies with only 15% (3/20) of respondents
indicating that they would use telemedicine, mobile healthcare providers or local
healthcare providers and only 10% (2/20) of respondents indicated that they would use
direct shipment of supplies for this type of trial.

101
Figure 38: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Type of Clinical Trial
Choose which clinical trial approach your company would generally consider using for
each of the following types of interventional clinical studies. Check all that might apply
for each type of study, understanding that decisions at an individual study level may
depend on other factors as well.

57%
15%
25%
50%
70%
80%
85%
78%
62%
15%
40%
50%
65%
75%
80%
67%
43%
15%
50%
55%
75%
85%
85%
67%
48%
10%
30%
40%
65%
80%
80%
67%
0 2 4 6 8 10 12 14 16 18 20
Healthy volunteer study (n=21)
First-in-human patient study (n=20)
Proof of concept study or dose-finding
study (n=20)
Pivotal study for a non-marketed drug
(n=20)
Pivotal study for a marketed drug (n=20)
Long-term safety study (n=20)
Post-market study (n=20)
Pragmatic study (n=18)
Number of Respondents
Telemedicine
Mobile HCP
Local HCP
Direct shipment of study drug/ materials to participant

102
4.6.2 Approaches to Study Conduct by Location of Clinical Trial and Types of
Procedures
The countries in which a study is conducted also has bearing on the possible use
of decentralized clinical trials (Figure 39). Nearly all respondents indicated that they
would use a combination of virtual trial sites and traditional sites for studies conducted in
the US, whether global (100%, 20/20) or not (95%, 19/20) whereas less than half of
respondents (42%, 8/19) would use this option for studies conducted completely outside
the US. Instead, traditional trial structures were considered most often outside of the US
(89%, 17/19), compared to studies conducted solely in the US (80%, 16/20) and global
studies (75%, 15/20). Respondents more often indicated that a fully decentralized trial
would be considered for a study conducted in the US only (60%, 12/20) compared with
studies conducted globally with US sites (30%, 6/20) and studies conducted outside of
the US (21%, 4/19).
The countries in which the studies are conducted had a modest effect on some of
the specific approaches that can be used in a decentralized clinical trial. The use of
telemedicine would be considered by approximately 65% (13/20) of respondents for
studies conducted in the US, whether global or not, and 58% (11/19) for studies
conducted outside of the US. Similarly, the use of mobile and local healthcare providers
would be considered more frequently for studies conducted in the US (65%, 13/20 and
70%, 14/20, respectively) and for global studies with US sites (55%, 11/20 and 65%,
13/20, respectively) compared with studies conducted outside the US (42%, 8/19 and
47%, 9/19, respectively). Direct shipment of study materials would be considered more

103
frequently for studies conducted in the US (70%, 14/20) compared with studies
conducted globally (55%, 11/20) and studies conducted outside the US (47%, 9/19).
Figure 39: Approaches to Decentralized Clinical Trials Based on Regions of
Study Conduct
Choose which clinical trial approach your company would generally consider using for
each of the following location of conduct or procedural requirements of an interventional
clinical study. Check all that might apply for each location type and procedural
requirement, understanding that decisions at an individual study level may depend on
other factors as well.

The types of outcome measures required by the trial also affected the choice of
traditional versus decentralized approaches. A traditional clinical trial approach was
considered most often for studies requiring imaging (85%, 17/20) or procedures such as a
biopsy or other invasive procedures (100%, 20/20) (Figure 40). Hybrid approaches,
60%
95%
65%
65%
70%
70%
80%
21%
42%
58%
42%
47%
47%
89%
30%
100%
65%
55%
65%
55%
75%
0 2 4 6 8 10 12 14 16 18 20
Fully decentralized/ virtual clinical trial
Virtual site plus traditional sites
Telemedicine
Mobile HCP
Local HCP
Direct shipment of study drug/ materials to
participant
Traditional trial conduct
Number of Respondents
US only (n=20) Only outside US (n=19) Global study with US sites (n=20)

104
including the use of a virtual trial site plus traditional trial sites, would be considered by
60% (12/20) when a study required imaging and 50% (10/20) when a study included
biopsies or other invasive procedures. A fully decentralized clinical trial was the option
least often considered for studies requiring imaging (25%, 5/20) or invasive procedures
(20%, 4/20).
The use of hybrid approaches was considered by some but not all respondents if
studies required either imaging or invasive procedures such as biopsies. The use of a
local healthcare provider would be considered by 70% (14/20) of respondents when a
study required imaging and by 55% (11/20) when biopsies or other invasive procedures
were required. Similarly, telemedicine would be considered by 65% (13/20) and 50%
(10/20) for studies requiring imaging or invasive procedures, respectively.
Approximately half of respondents would use mobile healthcare providers or direct
shipment for studies requiring imaging (55%, 11/20) or invasive procedures (50%,
10/20).

105
Figure 40: Approaches to Decentralized Clinical Trials Based on Requirement
for Specialized Procedures
Choose which clinical trial approach your company would generally consider using for
each of the following location of conduct or procedural requirements of an interventional
clinical study. Check all that might apply for each location type and procedural
requirement, understanding that decisions at an individual study level may depend on
other factors as well.

4.6.3 Approaches to Study Conduct by Patient Population
Decentralized options were considered quite commonly for certain patient
populations. The use of virtual trial sites in addition to traditional trial sites was an
option most often selected for studies where patients depend upon a caregiver (100%,
19/19), had poor mobility (95%, 18/19), had low risk disease (85%, 17/20) or had a rare
disease (85%, 17/20) (Figure 41). Most respondents (75%, 15/20) would consider virtual
25%
60%
65%
55%
70%
55%
85%
20%
50%
50%
50%
55%
50%
100%
0 2 4 6 8 10 12 14 16 18 20
Fully decentralized/ virtual clinical trial
Virtual site plus traditional sites
Telemedicine
Mobile HCP
Local HCP
Direct shipment of study drug/ materials to
participant
Traditional trial conduct
Number of Respondents
Requires imaging (n=20) Requires biopsy or invasive procedure (n=20)

106
trial sites for studies in patients for whom mobile healthcare platforms are commonly
used or where patients with a moderate risk disease require regular visits with a
healthcare practitioner.
Traditional trials were also considered commonly for patients with a moderate
risk disease requiring regular check-ups with a healthcare practitioner (90%, 18/20),
patients with low mobility (84%, 16/19) or patients with a rare disease (80%, 16/20).
Less frequently, they were considered by respondents for studies in patients who depend
upon caregivers (74%, 14/19), for studies in patients where mobile healthcare platforms
are commonly used (60%, 12/20) and for studies in patients with a low risk disease (55%,
11/20).
Respondents indicated that a fully decentralized clinical trial would more often be
used for trials in rare diseases (60%, 12/20) or low risk diseases (65%, 13/20) than in
patients with low mobility (53%, 10/19) or patients depending upon caregivers (47%,
9/19) or where mobile healthcare platforms are more commonly used (40%, 8/20). Trials
in patients with a moderate risk disease requiring regular check-ups were least likely to
be considered for a fully decentralized approach (15%, 3/20).

107
Figure 41: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Characteristics of the Population Included
in the Trial
Choose which clinical trial approach your company would generally consider using for
each of the following population types included in an interventional clinical study. Check
all approaches that might apply for each population type, understanding that decisions at
an individual study level may depend on other factors as well.

Hybrid approaches to decentralized clinical trials, such as telemedicine, mobile
healthcare providers, local healthcare providers or direct shipment of study materials to
the participant, would be considered by most respondents for each of the populations
provide as options (Figure 42).
The use of local healthcare providers was favored particularly for studies where
patients depend upon caregivers (95%, 18/19). However, most also considered the use of
60%
53%
47%
65%
15%
40%
85%
95%
100%
85%
75%
75%
80%
84%
74%
55%
90%
60%
0 2 4 6 8 10 12 14 16 18 20
Rare disease (n=20)
Low mobility capabilities (n=19)
Dependent upon caregivers (n=19)
Relatively healthy with low risk disease
(n=20)
Moderate risk disease requiring regular
check-ups (n=20)
Mobile health platforms commonly used
with disease (n=20)
Number of Respondents
Fully decentralized/ virtual clinical trial Virtual site plus traditional sites
Traditional trial conduct

108
local healthcare providers for the other groups: by 79% (15/19) for patients with low
mobility and 75% (15/20) for each of the following groups: patients with a rare disease,
patients with a low risk disease, patients with moderate risk disease requiring regular
check-ups and in patients where mobile healthcare platforms are commonly used.
The use of mobile healthcare providers was also considered commonly for most
patients: those who depend upon caregivers (84%, 16/19), with low mobility diseases
(79%, 15/19) and with a rare disease or low risk disease, with moderate risk disease
requiring regular check-ups and where mobile healthcare platforms are commonly used
(70%, 14/20 for all).
Telemedicine was more often considered for studies in relatively healthy patients
with a low risk disease (80%, 16/20), patients who depend upon caregivers (79%, 15/19)
and patients with low mobility (79%, 15/19). However, it was also commonly considered
(75%, 15/20) for studies in patients with moderate risk disease requiring regular check-
ups and in studies of patients where mobile healthcare platforms are commonly used.
The use of telemedicine in studies of patients with rare diseases would be considered by
60% (12/20) of respondents.
Direct shipment of study materials would be considered by 84% (16/19) of
respondents for studies whose patients have low mobility, by 80% (16/20) in patients
with a low risk disease and by 79% (15/19) in patients who depend upon caregivers.
Direct shipment would be considered by 70% (14/20) of respondents for studies of a rare
disease and by 60% (12/20) for studies whose patients have moderate risk disease
requiring regular check-ups and in studies where mobile healthcare platforms are
commonly used.

109
Figure 42: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Characteristics of the Population Included in the Trial
Choose which clinical trial approach your company would generally consider using for
each of the following population types included in an interventional clinical study. Check
all approaches that might apply for each population type, understanding that decisions at
an individual study level may depend on other factors as well.

4.6.4 Approaches to Study Conduct by Characteristics of the Drug Product
The characteristics of a product may also influence whether decentralized
approaches are considered (Figure 43). Products with low risk are more likely to
consider virtual trial sites, either in addition to traditional sites (89%, 17/19) or as fully
60%
79%
79%
80%
75%
75%
70%
79%
84%
70%
70%
70%
75%
79%
95%
75%
75%
75%
70%
84%
79%
80%
60%
60%
0 2 4 6 8 10 12 14 16 18 20
Rare disease (n=20)
Low mobility capabilities (n=19)
Dependent upon caregivers (n=19)
Relatively healthy with low risk disease
(n=20)
Moderate risk disease requiring regular
check-ups (n=20)
Mobile health platforms commonly used
with disease (n=20)
Number of Respondents
Telemedicine
Mobile HCP
Local HCP
Direct shipment of study drug / materials to participant

110
decentralized sites (79%, 15/19) although a traditional trial approach would also be
considered by 68% (13/19) of respondents. Similarly, trials with a self-administered
product would more often consider virtual trial sites, either in addition to traditional sites
(84%, 16/19) or as fully decentralized sites (68%, 13/19). A traditional trial approach
would still be considered by 58% (11/19) of respondents.
Traditional study conduct was considered by 100% of respondents as an option
for products requiring direct oversight by a healthcare provider (such as an infusion)
(19/19) and for products that require specialized handling, such as cold chain
management (17/17) and by 95% (18/19) of respondents for products with a
moderate/higher risk from a safety perspective.
Few respondents indicated that they would use a fully decentralized approach for
products which require direct oversight by a healthcare provider (5%, 1/19), for products
with a moderate or high safety risk (16%, 3/19) and for products that require specialized
handling (18%, 3/17). About a third of respondents would consider to use virtual trial
sites in addition to traditional trial sites for products which require direct oversight by a
healthcare provider (37%, 7/19) and for products that require specialized handling (35%,
6/17) and 42% (8/19) would consider this approach for products that have a moderate or
high safety risk.

111
Figure 43: Use of Fully Decentralized, Virtual + Traditional Trial Sites and
Traditional Trial Based on Characteristics of the Product Being
Evaluated
Choose which decentralized clinical trial approach your company would generally
consider using for each of the following characteristics of a product evaluated in an
interventional clinical study. Check all approaches that might apply for each
characteristic, understanding that decisions at an individual study level may depend on
other factors as well.

Hybrid approaches to decentralized clinical trials, such as the use of telemedicine,
mobile healthcare providers, local healthcare providers or direct shipment of study
materials to the participant, varied according to product characteristic (Figure 44).
Telemedicine would be considered most often for studies of products with a low
safety risk (84%, 16/20) and for products that are self-administered (79%, 15/19), but less
79%
16%
68%
5%
18%
89%
42%
84%
37%
35%
68%
95%
58%
100%
100%
0 2 4 6 8 10 12 14 16 18 20
Product that is low risk from a safety
perspective (n=19)
Product that is moderate/higher risk from a
safety perspective (n=19)
Product that can be self-administered by the
participant or a caregiver (n=19)
Product requiring direct oversight by a
healthcare provider (such as an infusion)
(n=19)
Product requires specialized handling, such
as cold chain management (n=17)
Number of Respondents
Fully decentralized/ virtual clinical trial Virtual site plus traditional sites
Traditional trial conduct

112
often for studies of products with a moderate or higher risk profile (47%, 9/19), for
products requiring direct oversight by a healthcare provider (37%, 7/19) and for products
that require specialized handling, such as cold chain management (35%, 6/17).
The use of local healthcare providers was considered more often when studying
products with a low safety risk (84%, 16/20) or products that are self-administered (79%,
15/19). Local healthcare providers would be considered by nearly two-thirds of
respondents (63%, 12/19) when products have a moderate or higher risk profile or require
direct oversight by a healthcare provider (68%, 13/19). Almost half (47%, 8/17) would
use a local healthcare provider for studies of products that require specialized handling.
Mobile healthcare providers would be considered most frequently for products
with a low safety risk (79%, 15/20) or products that are self-administered (68%, 13/19).
Less frequently they would be considered for products with a moderate or higher risk
profile (53%, 10/19) or products requiring direct oversight by a healthcare provider (58%,
11/19). Almost one-third (35%, 6/17) would use a local healthcare provider for studies of
products that require specialized handling.
Direct shipment of study materials would be most often used for studies of
products with a low safety risk (84%, 16/20) and for products that are self-administered
(89%, 17/19). This approach would be used by about one-third of respondents (37%,
7/19) for studies with products requiring direct oversight by a healthcare provider. Only
a quarter (26%, 5/19) would direct ship materials when a product has a moderate or
higher safety risk profile and 18% (3/17) would consider using direct shipment for
products that require special handling.

113
Figure 44: Use of Hybrid Approaches to Decentralized Clinical Trials Based on
Characteristics of the Product Being Evaluated
Choose which decentralized clinical trial approach your company would generally
consider using for each of the following characteristics of a product evaluated in an
interventional clinical study. Check all approaches that might apply for each
characteristic, understanding that decisions at an individual study level may depend on
other factors as well.

4.7 Experience with Decentralized Clinical Trials
To gain additional insights into whether decentralized trials would be accepted by
FDA and by clinical trial participants, additional questions were asked about experiences
84%
47%
79%
37%
35%
79%
53%
68%
58%
35%
84%
63%
79%
68%
47%
84%
26%
89%
37%
18%
0 2 4 6 8 10 12 14 16 18 20
Product that is low risk from a safety
perspective (n=19)
Product that is moderate/higher risk from a
safety perspective (n=19)
Product that can be self-administered by the
participant or a caregiver (n=19)
Product requiring direct oversight by a
healthcare provider (such as an infusion)
(n=19)
Product requires specialized handling, such as
cold chain management (n=17)
Number of Respondents
Telemedicine
Mobile HCP
Local HCP
Direct shipment of study drug/ materials to participant

114
with these two stakeholders from respondents who indicated that they were actively
seeking information, had resources assigned, completed a pilot or have implemented
either fully decentralized clinical trials or hybrid approaches.
4.7.1 Experience with FDA
Of the 20 respondents in an active stage of the implementation process, only 4
(20%) had discussed the approach with either a specific review division (1/20) or a
central division (3/20) (Figure 45). Three respondents (15%, 3/20) were not sure whether
discussions were held with FDA.
Figure 45: Discussion of Fully Decentralized Clinical Trial or Hybrid
Approaches with FDA
Have you discussed the use of a fully decentralized clinical trial or a hybrid approach to
a decentralized clinical trial with the FDA?

Of the 4 respondents who held discussions with FDA, 3 indicated that FDA was
generally in favor of the approach (Table 15). A more neutral opinion (neither agreed or
disagreed) was provided by 3 respondents when asked if FDA gave sufficient information
for decision-making. For other outcomes of discussion with FDA, the responses were
65%
5%
0%
15%
15%
0 2 4 6 8 10 12 14
No
Discussed with a specific review division
Discussed with multiple review divisions
Discussed with a central division
Not sure
Number of Respondents n=20

115
split with half (2/4) indicating a neutral opinion and half (2/4) agreeing that discussions
were transparent, gave opportunity for follow-up, and understood any impact to a
marketing application or labeling claims. Further, two respondents felt that sufficient
advice was provided to ensure acceptability of data to support a marketing application.
Table 15: Outcome of Discussions with FDA on Fully Decentralized Clinical
Trial or Hybrid Approaches
Based on the outcome of the discussions with FDA, rate the level to which you agree with
the following statements related to feedback received from FDA on decentralized
approaches to clinical trials.
Outcome of Discussion (n=4) Disagree
Neither
disagree
nor agree Agree
Generally in favor 0 1 (25%) 3 (75%)
Transparent advice provided 0 2 (50%) 2 (50%)
Gave sufficient information for decision-
making
0 3 (75%) 1 (25%)
Gave opportunity for additional follow-
up/discussion
0 2 (50%) 2 (50%)
Yielded a clear understanding of potential
impact to marketing application and/or
labeling claims
0 2 (50%) 2 (50%)
Gave sufficient advice to ensure acceptability
of data to support a marketing application
0 2 (50%) 2 (50%)

4.7.2 Experience with Trial Participants
Of the 20 respondents in an active stage of the implementation process and who
answered the question, 30% (6/20) had not discussed the use of decentralized clinical trial
approaches with trial participants (Figure 46) and 20% (4/20) were not sure.
When respondents did discuss these approaches with trial participants, 40% (8/20)
held discussions while designing the trial and 20% (4/20) obtained feedback before
designing the trial. Respondents also indicated that they would seek feedback from trial

116
participants during the conduct of the trial (30%, 6/20) or after the trial conduct (15%,
3/20).
Figure 46: Discussion of Fully Decentralized Clinical Trial or Hybrid
Approaches with Trial Participants
Have you discussed the use of a fully decentralized clinical trial or hybrid approaches to
a decentralized clinical trial with trial participants and/or their caregivers? Check all
that apply.

When asked to rate the outcome of the discussions with trial participants and/or
their caregivers, most respondents (90%, 9/10) agreed that the trial participants
experienced a decrease in the burden to participate, that they were willing to participate
in a trial with decentralized approaches and that they would feel supported during the
trial; the other 10% (1/10) had a neutral opinion (Table 16). Additionally, 70% (7/10) of
the respondents agreed that trial participants generally favored the approach and
confirmed that retention in the trial would be improved; the other 30% (3/10) had a
neutral opinion of the outcome for these specific discussions.
30%
20%
40%
30%
15%
20%
0 2 4 6 8 10
No
Obtained feedback/plan to obtain feedback
prior to designing clinical trial
Obtained feedback/plan to obtain feedback
while designing clinical trial
Obtained feedback/plan to obtain feedback
during the conduct of the trial
Obtained feedback/plan to obtain feedback
after conduct of the trial
Not sure
Number of Respondents
n=20

117
Ease of use of mobile technology elicited a mixed response with 30% (3/10) of
respondents disagreeing that trial participants found the technology easy to use, 20%
(2/10) of respondents neutral and 50% (5/10) agreeing that they found the technology
easy to use.
Sufficient training was also an area where mixed responses were seen. Half
(5/10) of respondents had a neutral response, and 40% (4/10) agreed that trial participants
felt they were trained sufficiently. One respondent (10%) indicated that this discussion
was not applicable.
Table 16: Outcome of Discussions with Trial Participants or Caregivers on
Fully Decentralized Clinical Trial or Hybrid Approaches
Based on the discussions with participants and/or their caregivers, rate the level to which
you agree with the following statements about participant/caregivers opinion regarding
decentralized clinical trial approaches.
Participant/Caregiver Opinion
(n=10) Disagree
Neither
agree nor
disagree Agree
Not
applicable
Generally in favor of the approach
0 3 (30%) 7 (70%) 0
Confirmed burden of participation
was/would be decreased 0 1 (10%) 9 (90%) 0
Confirmed positive impact on
retention 0 3 (30%) 7 (70%) 0
Expressed willingness to participant
in trial using decentralized approach 0 1 (10%) 9 (90%) 0
Mobile technology was/is easy to use
3 (30%) 2 (20%) 5 (50%) 0
Training was/is sufficient
0 5 (50%) 4 (40%) 1 (10%)
Felt/would feel sufficiently supported
during the trial
0 1 (10%) 9 (90%) 0
4.8 Additional Comments Elicited by the Study
Respondents who were completing a pilot or had implemented either fully
decentralized clinical trials or hybrid approaches were asked if they could give additional

118
comments related to their positive experiences or challenges when implementing those
trials. Verbatim responses are provided in Table 17.
Table 17: Open-Ended Comments on Positive Experiences or Challenges with
Decentralized Clinical Trial Approaches
Comment Prompt Response(s)
Positive experiences with using a
decentralized approach to
conducting clinical trials
Ease of enrollment.
we are in the middle of conducting one fully virtual and
starting 3 hybrid studies. It is exciting and the
organization is gearing up quickly. it's tough to keep up
with the technology demands. the use of RWD to find
patients has been really positive and the collection of data
is going well via actigraphy.
EPRO is easy to use and fully validated
A hybrid approach is both patient and site-centric -
allowing technology to complement the process while
maintain the human element important to patients first
and foremost.
They provide patient accessible and can be ran with less
resources than traditional trials. They are convenient for
the patient.
Challenging aspect of
implementing a fully decentralized
clinical trial
Any trial that is invasive or requires much equipment
would be hard. It also may be hard for a blinded trial.

All respondents were provided the opportunity to provide any comments related
to decentralized clinical trials. Responses received are provided in Table 18.
Table 18: Any Other Open-Ended Comment From Any Respondent
Comment Prompt Response(s)
Any Other Comment on
Challenges or Benefits of
Decentralized Clinical Trials
Should utilized as much as possible to more closely
simulate real world usage
Regulatory acceptability of data is paramount and GCP
concordance documentation
Need more information at this time.
Education and awareness of the logistics and the
pros/cons is lacking.
Nothing to add
Regulations

119
Discussion
Low recruitment and high drop-out rates are among the biggest contributors to
longer development times for medicinal products (Getz and Kaitin, 2015). Thus, industry
is highly motivated to find ways to accelerate the acquisition of clinical data to satisfy
regulatory hurdles. Decentralized clinical trials represent a potential opportunity to
address the inefficiencies faced when testing medicinal products and, at the same time, to
improve the patient experience. Using the diffusion of innovation framework as a guide,
this study expanded upon prior research to evaluate how companies have progressed
along the path to adoption. For those that had progressed beyond early stages of
adoption, it also provided insight into their experiences and impediments along the
adoption pathway.
5.1 Methodological Considerations
5.1.1 Limitations
In this study, I used a survey method to gain information from industry
participants. Thus, it was important to assure enough responses from those with
appropriate knowledge and experience, in a field in which potential respondents are busy
professionals. Certain aspects of this challenge were important to assure: identifying
enough qualified respondents who will represent the industry more generally and
therefore ensure some level of external validity; engaging those respondents so that they
were willing to complete the survey; and ensuring that the survey was not so onerous that
participants dropped out of the survey prematurely.

120
5.1.1.1 Identifying and Engaging Representative Participants
Validity of results from a survey depends in part on the representativeness of the
respondents (Fincham, 2008). A larger sample size increases the likelihood that the
results reflect the experience and views of the population that the sampling is intended to
represent (Johnson and Wislar, 2012). However, in a study such as this, it can be
challenging to identify appropriate professionals because a centralized contact list is not
available for individuals involved with clinical research. As discussed in chapter two,
decentralized trial design is still in its infancy, so that the number of clinical research
professionals with experience in the implementation of decentralized clinical trials is
relatively small and could pose a limitation to the collection of a significant number of
participants (Lamberti and Awatin, 2017). It therefore seemed important to use multiple
approaches to recruit professionals who would be willing to participate, regardless of
their knowledge of the topic.
The first approach, using personal contacts, appeared to be successful in assuring
a good response rate (46%) but risked bias that may be related to the nature of my
personal network. The second method, using internet messaging boards in a professional
networking platform, had the potential to reach a broader range of individuals. However,
the background of the individuals who opened the survey through the message board
could not be filtered in advance. Additionally, a quarter of the individuals who opened
the survey may have reviewed the first few questions and subsequently excluded
themselves from the study. Thus, it is not possible with such a method to determine a
response rate since the number of responsive individuals could not be compared to those
who might have seen the survey and failed to respond. Additionally, this method of

121
obtaining respondents may have introduced bias since those who chose to participate may
have had a stronger interest in the topic more generally and therefore may have been
early adopters, or at least, more likely to be familiar with the methods (Groves et al.,
2004).
Nevertheless, the recruitment strategy resulted in a pool of well-qualified
respondents representing companies of many sizes. The fact that most were at the
manager-level and above is consistent with their self-assessments that they were either
influential in the clinical strategies or were decision-makers regarding the adoption of
trial approaches. They should therefore be well positioned to provide the kind of
information sought in this work. The survey was also able to recruit a set of individuals
who were in various stages of implementation of decentralized approaches, some of
whom were using such approaches but others who appear to have chosen deliberately to
follow a different course. This leads me to believe that the respondents were not biased
toward individuals who were early adopters of novel approaches, and who therefore
might provide a more positive picture of the use of decentralized trials than would a more
balanced population.
5.1.1.2 Assuring Completion of the Survey
It is not just important to recruit appropriate respondents but also to ensure that
they do not drop out of the survey prematurely. Thus, several approaches to question
design, ordering of the questions and length of survey were used to assure as strong a
completion rate as possible. To reduce the time the survey took to complete, most of the
28 questions were designed to be closed-ended and often used rating scales rather than
requiring text responses, as suggested by others (Moy and Murphy, 2016). Additionally,

122
matrix questions used consistent categories from one to the next so that respondents
could navigate through the questions more quickly. Other items known to improve survey
response, such as a simple first question and prenotification of estimated survey length,
were incorporated within the survey design and execution (Liu and Wronski, 2018; Moy
and Murphy, 2016). The focus group also helped to ensure clarity of questions and that
the meaning or intent of each question was interpreted as consistently as possible.
Nonetheless, the completion rate for this survey was 50%. Much of the drop-off
rate was anticipated, because many respondents from the internet messaging board might
not be sufficiently knowledgeable about decentralized approaches to feel comfortable
with the questions. This expectation was validated by results showing that nearly a
quarter of the participants who accessed the survey through the internet messaging board
failed to answer a single question, and nearly half dropped out after completing the
demographic section or the first block of questions regarding decision-making for
decentralized trials. Drop-off was not surprising and may have reflected a hesitancy to
answer questions specific to decentralized clinical trials, particularly since 37% of
respondents were either not considering implementing fully decentralized trials or were
not sure. Another reason why a subset of respondents may have been classified as partial
responders was related to a default setting in Qualtrics which marked surveys with partial
responses as “completed” after one week of last entry. Considering that respondents
were busy professionals, the opportunity to complete the survey would have been lost if
they paused the survey with the intent to complete it later.
In this study, a wide representation of respondents from companies of different
sizes gave considerable opportunity to compare the views and experience of those with

123
small- versus large-company experience. However, this opportunity was reduced to
some extent for questions regarding the implementation of decentralized trials, because
relatively few companies were at this implementation stage. Thus, attempts to stratify the
population in later parts of the survey resulted in very small subgroups that limit the
ability to draw conclusions (Petticrew et al., 2012). However, the results do provide
insights that might be used to provide a benchmark that could be used in future studies
when decentralized trials are implemented more widely.
5.1.2 Delimitations
This project studied the implementation of decentralized clinical trials to support
drug or biologic development. It does not include opinions from professionals who
support clinical trial conduct in other sectors, such as medical devices or generic drugs.
Further research would be needed to determine whether companies in those other sectors
have the same views regarding the use of decentralized approaches.
The survey was further delimited to respondents working in the United States, and
so may not represent views from other constituencies. At the time that this research was
conducted, interest and support from regulators other than FDA appeared to be at a
relatively early stage. In October 2019, an international consortium kicked off the start of
Trials@Home, an initiative to explore the opportunities of remote decentralized clinical
trials in Europe (Trials@Home, 2019). This initiative is funded jointly by the Innovative
Medicines Initiative, the European Union’s Horizon 2020 research and innovation
program and the European Federation of Pharmaceutical Industries and Associations.
Views from other regions are also evolving but many are taking a more conservative and
cautious approach (Corbin, 2019). Given that evaluation is just beginning in Europe and

124
consensus has not been achieved around the world, further research exploring views from
stakeholders outside the US would be important to collect once these approaches are
accepted more broadly.
Additionally, the focus of this project was on the views of industry sponsors. Not
included were insights from other stakeholders, such as representatives from CROs and
other vendors, study site personnel, research participants, IRB representatives or
regulatory authority representatives. This delimitation was felt to be important because
industry sponsors ultimately make the decision on how to implement a clinical trial and
thus bears the burden of the risk. Other stakeholders may have a different view. For
example, representatives from CROs or other providers may be more willing to adopt
these approaches to differentiate the services that they offer. Differences in approach
were evident in a survey conducted in 2018 by the Avoca Group where 25% of sponsor
companies had used decentralized clinical trials or telemedicine compared with 14% of
CROs or other providers (The Avoca Group, 2019). Additionally, 29% of sponsor
companies were planning to use these approaches compared with 71% of CROs and other
vendors and 30% of sponsor companies indicated they had no plans to use these
approaches compared with 10% for CROs and other vendors. The survey conducted by
Avoca demonstrated the differences in approach to decentralized clinical trials that
sponsor companies were planning to take compared with CROs.
Stakeholders in other areas of expertise, such as study site personnel, Institutional
Review Board members, and clinical research participants, may not have direct
experience with the use of decentralized approaches to clinical trials. Even fewer may be
experienced with the multiple ways in which a study could be conducted or may play a

125
role in adopting these decentralized approaches. As more such trials are implemented,
understanding the best practices and opportunities or gaps at multiple levels will help to
improve the clinical trial experience for all stakeholders and allow the use of approaches
that benefit the most stakeholders involved.
5.2 Consideration of Results
This research set out to determine how, why and at what rate innovations in
clinical trials, specifically decentralized clinical trials, are being adopted within the
pharmaceutical industry.
As indicated by Rogers, stakeholders can be classified based on their rate of
adoption into 5 main categories, innovators, early adopters, early majority, late majority
and laggards (Rogers, 1983). This present survey suggests that the adoption of
approaches to decentralized clinical trials might fit the same bell-shaped curve (See
Figure 34) that was suggested by Rogers (See Figure 14) with approximately half of the
respondents planning to implement these approaches within the next 2 years or more and
slightly less than half having already implemented approaches. This result would suggest
that adoption of decentralized clinical trial approaches falls somewhere between the early
majority and late majority stage based on a qualitative assessment.
A closer look at results relating to the five stages of the innovation-decision
process, knowledge, persuasion, decision, implementation and confirmation, gives more
insight into some of the impediments to further progression and provides lessons about
adoption from those with experience. These stages deserve exploration due to the lessons

126
that can be learned from each stage and potential impediments of advancement of
decentralized clinical trials.
5.2.1 Knowledge and Persuasion
Before a new program is installed into an already working enterprise, the program
must be understood by those who are key to the implementation and must be
communicated in a persuasive manner to the decision-makers responsible for approving
the use of decentralized approaches. To some extent, the knowledge and persuasion
stages are interlinked since stalling at either stage will block implementation. In this
survey, nearly 40% of the respondents were at one of these two stages when asked about
their implementation strategy for hybrid approaches to decentralized clinical trials and
nearly 60% were at this stage when asked about their implementation strategy for fully
decentralized clinical trials.
A prerequisite to moving forward with approaches to decentralized trials is to
understand what such trials would involve. The fact that at least 80% of the individuals
who responded here identified that they had at least some knowledge of several
components associated with decentralized clinical trials suggests that the last decade of
papers, presentations and regulations on these approaches have had a positive educational
outcome. Telemedicine and the use of mobile healthcare providers in the context of
clinical trials appeared to be the least understood with 17% of respondents not aware of
these approaches. This is not surprising since, in the US, the use of telemedicine more
generally is still in the early stages of adoption. Only 10% of healthcare consumers have
used telemedicine in 2019 (JD Power, 2019). Healthcare providers also struggle with
adoption of telemedicine due to lack of availability (29%) or lack of knowledge of

127
availability (37%) within the healthcare system in which they work. Additionally,
telehealth regulations vary from state to state with geographical as well as institutional
restrictions put into place by Medicare which, collectively, creates additional barriers to
utilization (Center for Connected Health Policy, 2019). The use of mobile healthcare
providers, or home health, has typically been associated with the support of elderly
patients, so its use for clinical trials may not be well understood by those outside of the
geriatric or homecare community (Elflein, 2019).
It is common for those in medical product industries to seek out educational
resources to understand the usefulness of a new clinical trial approach by consulting
resources such as regulatory guidance, peers, recommendations from industry
collaborations, vendors, consultants, stakeholders and news circuits or seminars. Clearly,
the respondents surveyed here were using all such sources. Regulatory guidance was
identified as one source that was used by most respondents. Such guidance is critical
because a large majority of respondents indicated that FDA’s support for decentralized
approaches was a primary consideration when deciding to adopt decentralized
approaches. However, the clarity of regulatory guidance from governmental sources
would seem to be of concern and was the top-ranked barrier to the adoption of
decentralized methods. This finding is consistent with that observed by discussions held
by CTTI in 2017 (CTTI, 2017) and suggests an area in which improvement might have a
positive outcome for the progression of decentralized approaches. The few respondents
who did discuss using a decentralized approach with FDA indicated that FDA was
generally supportive of the approach and provided the information needed to support
decision-making by the company.

128
The risk averse nature of the clinical trial industry is not surprising. Given that
drug development has followed more or less the same rules over the last 50 years, US
regulators play a large role in assuring the industry that they will accept the use of these
innovative pathways, and then provide clear expectations regarding how to assure
compliance with Good Clinical Practices in these alternative settings (Loaiza, 2019).
However, pivotal studies are typically conducted in many countries and support
marketing applications globally. Thus, adoption by industry will be affected by whether
these alternative methods can be implemented internationally, and whether they will be
accepted by the regulatory agencies in those regions, another factor identified as
important to adoption in this survey. One example of the dissonance that will be faced is
related to the implementation of electronic informed consent. Despite an FDA issued
guidance document promoting the utilization of electronic informed consent, adoption
has been slow (FDA, 2016). Adoption of electronic informed consent has been stalled by
lack of global standards and concerns around data privacy, among other things (Vanaken
and Masand, 2019). Even within this survey, only a third of respondents indicated that
they have used electronic informed consent.
As mentioned previously, FDA has brought together a formal working group to
establish guidance for decentralized approaches (FDA, 2019b). Additionally, in Europe,
the Trials@Home initiative will develop recommendations and standards for conducting
remote decentralized clinical trials in Europe (Trials@Home, 2019). And finally, ICH
released the proposed actions for the next update of the Good Clinical Practices
guideline, ICH E6 (R3), which will include an annex devoted to non-traditional
interventional clinical trials, including decentralized clinical trials (ICH E6(R3), 2019).

129
However, such efforts advance slowly. Updates to ICH E6(R3) to address decentralized
clinical trials will take more than two years to commence. Interestingly, in response to
the coronavirus pandemic (COVID-19), FDA issued a guidance document on March 18,
2020 to address the logistical challenges of conducting clinical trials as a result of
quarantines, hospital and clinic closures, travel limitations, and interruptions to the supply
chain (FDA, 2020). In this guidance, FDA acknowledged and encouraged the use of
various approaches evaluated in this survey, including telemedicine, local or mobile
providers, and direct shipment of study drug. EMA and the Medicines and Healthcare
Products Regulatory Agency in the United Kingdom responded with similar guidance
documents (EMA, 2020; Health Research Authority, 2020). While these guidance
documents were provided in response to a specific global crisis, perhaps they will provide
practical experience for all stakeholders and may provide the spark that industry is
seeking to support the use of decentralized approaches.
The barrier that ranked second across companies of all sizes was insufficient
organizational readiness. While the survey did not identify specific organizational
barriers that might be responsible for the reluctance to adopt decentralized approaches,
open comments suggest that “more information is needed”, particularly around
“logistics” as well as “pros and cons”. The Avoca Group identified similar impediments
to organizational readiness and have suggested that organizations will need to make
modifications to internal policies and procedures and assure that providers have
experience and knowledge to support these approaches (Loaiza, 2019). There will be a
need for experienced clinical trial personnel with a broader set of capabilities as these
new strategies are introduced (Fraser, 2015; ABPI, 2019). Finding ways to develop the

130
skill sets needed across all stakeholders involved with clinical trials will allow industry to
take advantage of these new capabilities in a more efficient manner (ABPI, 2019;
Hardman and Robinson, 2015; Harper and Tate, 2019).
Currently, the ways that clinical experts educate themselves about decentralized
approaches appears quite diverse and relies on many sources. It is clear from the results
that they use all of the communication channels presented here as options. However,
direct conversations with peers within known practical experience and discussions with
representatives from industry consortiums had the most influence. The social science
literature suggests that interpersonal communications can help promote and influence
change as well as educate (Rogers, 1983). Thus, the use of such channels may help to
overcome resistance and provide advice and information needed to persuade decision-
makers within their organizational structure. Interestingly, consulting groups were least
frequently identified as an information channel that was modestly or very useful. When
implementing new technology, whether through processes or systems, seeking out people
who understand the business and the impact to the organization are more influential in
promoting change than experts who may not have experience or subject matter expertise
to provide practical guidance (Furr et al., 2019). Results here seem consistent with this
observation; discussions with representatives from Contract Research Organizations or
other vendors ranked higher than consulting groups as a useful source. Representatives
from CROs may be more particularly well-placed to share practical experience with a
sponsor company that is seeking to implement decentralized approaches (Corbin, 2019;
Biopharmadive, 2019).

131
Interestingly, the barriers that were prevalent in prior surveys, lack of company
support and risk aversion (Lamberti and Awatin, 2017), were ranked last as barriers to
adoption in this survey. This observation is interesting, because it corroborates the
perceived trend that companies are more willing to consider and fund decentralized
approaches, as discussed in the next section.
5.2.2 Decision, Implementation and Confirmation
Once a decision about decentralized clinical trials is made, a new set of
considerations begin. Together, the decision, implementation and confirmation stages
form a second grouping, because they are often integrated as the new approach is
installed and used for drug development. In this survey, nearly half of the respondents
were in one of these stages for certain decentralized approaches, but only about a quarter
of them were similarly engaged in fully decentralized clinical trials.
To understand better how decisions about adoption are being made, questions
exploring the underlying considerations were revealing. Companies still appear to be
proceeding cautiously with fully decentralized clinical trials as evidenced by the findings
that some had rejected this option and most others ranked this complete approach as
lowest in priority to implement. In fact, this survey identified that most respondents
would consider using traditional trial approaches over a fully decentralized approach for
early-stage clinical studies, healthy volunteer studies and pivotal studies of non-marketed
products. Further, the likelihood of using such an approach appears to drop when trials
have complicated outcome measures, such as imaging needs. However, respondents
indicated that studies with marketed products or products in certain types of patients,
such as relatively healthy patient populations, rare diseases or patients with low mobility,

132
would be appropriate to conduct using a fully decentralized approach. Further, certain
therapeutic areas, such as dermatology, are well-suited for fully decentralized clinical
trials, since endpoints can be visibly monitored through pictures and video-visits in a
validated manner (Ali et al., 2020), a preference recognized by the respondents.
This together with the other results suggest that some companies are using
decentralized trials in very specific instances rather than as a standard approach, despite
the strongly promoted opportunities such as faster enrollment and increased retention,
factors that should translate into getting medical products to market faster and with data
of higher quality (Ali et al., 2020). This is not surprising in the context of drug
development where it may not be appropriate to administer an investigational product to
more vulnerable patients without direct oversight (Myshko, 2019).
Hybrid approaches were considered to be more acceptable than fully
decentralized trials for most study types. This differentiation was also apparent
regardless of product characteristics, location of study conduct, disease state or study
design. Hybrid approaches seemed particularly promising to support patients with
mobility issues, allowing them to participate without the discomfort or inconvenience of
travel. Additionally, hybrid approaches provide a good balance between maintaining
direct human connection in a clinical trial and offering ways to fit the trial into the
patient’s life versus fitting the patient into the trial schedule (Ali et al., 2020; Myshko,
2019). It was interesting to identify the specific approaches that appeared more likely to
be used. The top priority for implementation was virtual trial sites alongside traditional
trial sites followed by the use of telemedicine, mobile healthcare providers and direct
shipment of study drug or materials to the participant. Finding ways to reduce the burden

133
on patients participating in clinical trials through the use of hybrid approaches, taking
advantage of both virtual trial sites or telemedicine, in conjunction with the standard
operational approaches, are believed to add value for all stakeholders involved (Myshko,
2019). This view was consistent with the survey responses. Further, respondents who
had implemented decentralized approaches indicated that feedback from trial participants
was generally positive. The fact that such approaches were seen to reduce the burden of
the trial and make participation attractive suggested that patients may increasingly have
an influence over the decisions made to use such approaches. Regulatory agencies
increasingly recognize the value in the “patient voice” in making decisions about
interventions involving those patients as recognized by upcoming changes too ICH E8
(ICH E8(R1), 2019). However, this survey did not specifically ask about the actual use
of various approaches to decentralized trials for different types of trials or types of
products. This remains an area of potential investigation for the future.
5.3 Conclusions and Future Direction
The present study suggests that the implementation of decentralized trials has
made strides since the 2016 survey conducted by DIA and Tufts CSDD (Lamberti and
Awatin, 2017). However, there is still work to do if such approaches are to become a part
of mainstream clinical trials. Initial barriers related to resistance to change and the
concern about cultural issues are not entirely gone, but they are shifting toward more
practical concerns related to assuring FDA acceptance and procedural details to put the
trials into place globally. This shift puts new emphasis on some of the tools, such as
educational materials, technical training and access to experienced experts, that could

134
accelerate the understanding of these trial methods. FDA has a role in improving the
quality of its guidances and the opportunities for interaction, as suggested by the results
herein. However, companies must also take the initiative to find additional opportunities
to increase knowledge and confidence of its team to experiment with these innovative
approaches.
In hindsight, the timing of this survey was perfect. As the survey closed, news of
a novel coronavirus in China began spreading. As hospitals and clinics in China closed
their doors to noncritical visits to reduce the spread of the virus, study staff and sponsors
scrambled to find ways to ensure safety of the patients and collect the data needed to
maintain integrity of ongoing traditionally-structured clinical trials. The pandemic made
it necessary to conduct study visits through videoconferencing methods, to use local
facilities to collect vital tissue and fluid samples, and to hire shipping firms that could
deliver study drug and other materials directly to the patients. A mere six weeks later, in
the face of a pandemic, FDA responded with guidance to industry, investigators and IRBs
on ways to manage the conduct of clinical trials during the COVID-19 pandemic (FDA,
2020). EMA and MHRA responded with similar guidance. In the face of a crisis,
regulatory authorities around the world supported the use of alternative methods that
might ensure the safety of patients and maintain data integrity for the clinical trials
already underway. Hybrid approaches were formally supported by regulatory authorities.
If this survey continued to collect data while these initiatives were being introduced, the
results may have looked very different, affected by the experiences gained as the
companies attempted to maintain clinical trial continuity in the face of a crisis that would
not reflect a normal time.

135
It will be interesting to see how decentralized approaches are utilized once the
crisis of COVID-19 is behind us and sponsors transition back to a more normal state. If
the seed of decentralization has been planted, will it continue to grow and flourish, or will
companies return to traditional approaches? It will be interesting to repeat this study in
three years, the same interval as between this study and that of Lamberti and Awatin
((Lamberti and Awatin, 2017). By then, most if not all, pharmaceutical companies will
likely have had some experience in implementing hybrid approaches as they struggle to
complete their trials in the face of the COVID-19 pandemic. Additionally, the practical
experience that regulators will gain once they have the chance to review outcomes from
trials conducted during the COVID-19 pandemic may provide the experience needed to
capture best practices and points of concern in formal guidance documents.

136
References……..
ABPI. (2019) 'Bridging the skills gap in the biopharmaceutical industry (2019)'. Available at:
https://www.abpi.org.uk/publications/bridging-the-skills-gap-in-the-biopharmaceutical-
industry-2019/ (Accessed: 11 April 2020).
Ali, Z., Zibert, J. R. and Thomsen, S. F. (2020) 'Virtual clinical trials: perspectives in
dermatology', Dermatology, p.^pp. 1-8. doi: 10.1159/000506418.
Benecky, M. J. (2015) 'Comment on the Food and Drug Administration (FDA) notice: using
technologies and innovative methods to conduct Food and Drug Administration-
regulated clinical investigations of investigational drugs; establishment of a public
docket'. Available at: https://www.regulations.gov/document?D=FDA-2015-N-3579-
0007 (Accessed: 1 June 2019).
Bhatt, A. (2010) 'Evolution of clinical research: a history before and beyond James Lind',
Perspectives in Clinical Research, 1(1), pp. 6-10.
Biopharmadive. (2019) 'Decentralized clinical trials: are we ready to make the leap?'. Available
at: https://www.biopharmadive.com/spons/decentralized-clinical-trials-are-we-ready-to-
make-the-leap/546591/ (Accessed: 11 April 2020).
Bothwell, L. E. and Podolsky, S. H. (2016) 'The emergence of the randomized, controlled trial',
The New England Journal of Medicine, 375(6), pp. 501-504.
Buckley, B. M. (2015a) 'The clinical trial site', in: Schuler, P. and Buckley, B. M. (eds.) Re-
engineering clinical trials: best practices for streamlining drug development. Waltham,
MA: Elsevier, pp. 145-58.
Buckley, B. M. (2015b) 'Connected health in clinical trials: the patient as sub-investigator', in:
Schuler, P. and Buckley, B. M. (eds.) Re-engineering clinical trials: best practices for
streamlining drug development. Waltham, MA: Elsevier, pp. 199-210.
Califf, R. M., Sherman, R. E. and Slavitt, A. (2016) 'Knowing when and how to use medical
products: a shared responsibility for the FDA and CMS', The Journal of the American
Medical Association, 316(23), pp. 2485-2486.
Ceccoli, S. (2002) 'Divergent paths to drug regulation in the United States and the United
Kingdom', Journal of Policy History, 14(2), pp. 135-169.

137
Center for Connected Health Policy. (2019) 'Telehealth policy barriers'. Available at:
https://www.cchpca.org/sites/default/files/2019-
02/TELEHEALTH%20POLICY%20BARRIERS%202019%20FINAL.pdf (Accessed:
3/23/2020).
Chiu, Y. (2013) 'Conducting clinical trials in Japan'. Available at:
https://www.ppdi.com/services/industry-expertise/pharmaceutical/conducting-clinical-
trials-in-japan (Accessed: 5/20/2019).
Clinical Data Interchange Standards Consortium. (2019) 'CDISC standards in the clinical
research process'. Available at: https://www.cdisc.org/standards (Accessed: 23 June
2019).
ClinPal. (2016) 'eClinicalHealth announces successful results for an entirely remote online
clinical trial'. Available at: https://www.clinpal.com/news/eclinicalhealth-announces-
successful-results-entirely-remote-online-clinical-trial-3/ (Accessed: 6 June 2019).
Coons, S. (2017) 'OHRP/FDA offer final guidance on electronic informed consent', Research
Practitioner, 18(2), p. 21.
Corbin, A. (2019) 'Navigating the global virtual trials regulatory landscape'. Available at:
https://www.clinicalleader.com/doc/navigating-the-global-virtual-trials-regulatory-
landscape-0001 (Accessed: 29 March 2020).
Council of the European Economic Community. (1965) 'Council Directive of 26 January 1965 on
the approximation of provisions laid down by law, regulation or administrative action
relating to proprietary medicinal products', Official Journal of the European
Communities, 369(65), pp. 20-24.
CTFG. (2010) 'CTFG activity report 2008-2009'. Available at:
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2008-2009_CTFG_Activity_Report.pdf
(Accessed: 4 August 2019).
CTFG. (2016) 'Guidance document for sponsors for a voluntary harmonisation procedure (VHP)
for the assessment of multinational clinical trial applications'. Available at:
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2016_06_CTFG_VHP_guidance_for_sponsor_v4.
pdf (Accessed: 20 May 2019).

138
CTTI. (2016) 'CTTI program to increase adoption of mobile clinical trials'. Available at:
https://www.ctti-clinicaltrials.org/news/ctti-program-increase-adoption-mobile-clinical-
trials (Accessed: 1 June 2019).
CTTI. (2017) 'Legal & regulatory issues affecting the adoption of mobile clinical trials'.
Available at: https://www.ctti-clinicaltrials.org/briefing-room/meetings/legal-regulatory-
issues-affecting-adoption-mobile-clinical-trials (Accessed: 31 May 2019).
CTTI. (2018) 'CTTI recommendations: decentralized clinical trials'. Available at:
https://www.ctti-clinicaltrials.org/projects/decentralized-clinical-trials. (Accessed: 24
May 2019).
CTTI. (2020) 'Using digital health trials to improve clinical trials'. Available at:
https://www.ctti-clinicaltrials.org/programs/mobile-clinical-trials (Accessed: 15 May
2020).
Darrow, J. J., Avorn, J. and Kesselheim, A. S. (2014) 'New FDA breakthrough-drug category--
implications for patients', The New England Journal of Medicine, 371(1), pp. 89-90.
DiMasi, J. A., Grabowski, H. G. and Hansen, R. W. (2016) 'Innovation in the pharmaceutical
industry: new estimates of R&D costs', Journal of Health Economics, 47, p.^pp. 20-33.
doi: https://doi.org/10.1016/j.jhealeco.2016.01.012.
Dolgin, E. (2018) 'Industry embraces virtual trial platforms', Nature Reviews. Drug Discovery,
17(5), p.^pp. 305-306. doi: 10.1038/nrd.2018.66.
Du Plessis, D., Sake, J.-K., Halling, K., Morgan, J., et al. (2017) 'Patient centricity and
pharmaceutical companies: is it feasible?', Therapeutic Innovation & Regulatory Science,
51(4), p.^pp. 460-467. doi: 10.1177/2168479017696268.
Elflein, J. (2019) 'Home care in the U.S. - statistics & facts'. Available at:
https://www.statista.com/topics/4049/home-care-in-the-us/ (Accessed: 23 March 2020).
EMA. (2019) 'Authorisation of medicines'. Available at: https://www.ema.europa.eu/en/about-
us/what-we-do/authorisation-medicines (Accessed: 20 May 2019).
EMA. (2020) 'Guidance on the management of clinical trials during the COVID-19 (coronavirus)
pandemic'. Available at: https://www.ema.europa.eu/en/news/guidance-sponsors-how-
manage-clinical-trials-during-covid-19-pandemic (Accessed: 3 April 2020).

139
EU. (2014) Regulation (EU) no 536/2014 of the European Parliament and of the Council of 16
April 2014 on clinical trials on medicinal products for human use, and repealing
Directive 2001/20/EC (European Parliament and the Council of the European Union).
FDA. (1962) 'New drugs for investigational use', Federal Register, 27(155), pp. 7990-7993.
FDA. (1963a) 'Investigational drugs; procedure regarding biological products', Federal Register,
28(99), p. 5048.
FDA. (1963b) 'New drugs for investigational use: procedures and interpretations', Federal
Register, 28(5), pp. 179-182.
FDA. (1969) 'Hearing procedure for refusal or withdrawal of approval of new drug applications
and for issuance, amendment, or repeal of antibiotic drug regulations; interpretative
description of adequate and well-controlled clinical investigations', Federal Register,
34(180), pp. 14596-14599.
FDA. (1979) 'Warner-Lambert/Parke-Davis & Co.; Benylin; final decision', Federal Register,
44(518), pp. 51512-51539.
FDA. (1997) 'Electronic records; electronic signatures', Federal Register, 62(54), pp. 13430-
13466.
FDA. (1998) 'Guidance for industry: providing clinical evidence of effectiveness for human drug
and biological products'. Available at: https://www.fda.gov/media/71655/download
(Accessed: 06 May 2019).
FDA. (2004) 'Innovation or stagnation: challenge and opportunity on the critical path to new
medical products'. Available at: http://wayback.archive-
it.org/7993/20180125035500/https://www.fda.gov/downloads/ScienceResearch/SpecialT
opics/CriticalPathInitiative/CriticalPathOpportunitiesReports/UCM113411.pdf
(Accessed: 18 May 2019).
FDA. (2012) 'Kefauver-Harris amendments revolutionized drug development'. Available at:
https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm (Accessed: 13
April 2019).
FDA. (2015) 'Using technologies and innovative methods to conduct food and drug
administration-regulated clinical investigations of investigational drugs; establishment of
a public docket', Federal Register, 80(209), pp. 66543-66545.

140
FDA. (2016) 'Use of electronic informed consent in clinical investigations – questions and
answers'. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/use-electronic-informed-consent-clinical-investigations-questions-
and-answers (Accessed: 23 March 2020).
FDA. (2017) 'Use of electronic records and electronic signatures in clinical investigations under
21 CFR part 11'. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/use-electronic-records-and-electronic-signatures-clinical-
investigations-under-21-cfr-part-11 (Accessed: 01 June 2019).
FDA. (2018a) 'The drug development process, step 3: clinical research'. Available at:
https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
(Accessed: 06 May 2019).
FDA. (2018b) 'FDA in brief: FDA launches new digital tool to help capture real world data from
patients to help inform regulatory decision-making'. Available at:
https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm625228.htm (Accessed:
10 February 2019).
FDA. (2018c) 'Use of electronic health record data in clinical investigations guidance for
industry'. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/use-electronic-health-record-data-clinical-investigations-guidance-
industry (Accessed: 01 June 2019).
FDA. (2019a) 21 CFR 312 Investigational new drug application, Food and Drug Administration
(United States), pp.
FDA. (2019b) 'Statement by FDA commissioner Scott Gottlieb, M.D., on new strategies to
modernize clinical trials to advance precision medicine, patient protections and more
efficient product development'. Available at:
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633500.htm
(Accessed: 23 March 2019).
FDA. (2020) 'FDA guidance on conduct of clinical trials of medical products during COVID-19
pandemic'. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-
19-pandemic (Accessed: 23 March 2020).
Fincham, J. E. (2008) 'Response rates and responsiveness for surveys, standards, and the Journal',
American journal of pharmaceutical education, 72(2), p. 43.

141
Fintel, B., Samaras, A. T. and Carias, E. (2009) 'The thalidomide tragedy: Lessons for drug safety
and regulation'. Available at: https://helix.northwestern.edu/article/thalidomide-tragedy-
lessons-drug-safety-and-regulation (Accessed: 27 July 2018).
Fraser, H. (2015) 'Managing the change - you need processes, systems, and people', in: Schuler,
P. and Buckley, B. M. (eds.) Re-engineering clinical trials: best practices for
streamlining drug developmen. Waltham, MA: Elsevier, pp. 331-335.
Furr, N., Gaarlandt, J. and Shipilov, A. (2019) 'Don't put a digital expert in charge of your digital
transformation'. Available at:
http://search.ebscohost.com/login.aspx?direct=true&db=bth&AN=138408608&authtype
=sso&custid=s8983984 (Accessed: 23 March 2020).
Getz, K. (2018) 'Trends driving clinical trials into large clinical care settings', Nature Reviews
Drug Discovery, 17(10), pp. 703-704.
Getz, K., Stergiopoulos, S., Marlborough, M., Whitehill, J., et al. (2015) 'Quantifying the
magnitude and cost of collecting extraneous protocol data', American Journal of
Therapeutics, 22(2), pp. 117-124.
Getz, K. A. and Campo, R. A. (2018) 'New benchmarks characterizing growth in protocol design
complexity', Therapeutic Innovation & Regulatory Science, 52(1), pp. 22-28.
Getz, K. A., Campo, R. A. and Kaitin, K. I. (2011) 'Variability in protocol design complexity by
phase and therapeutic area', Therapeutic Innovation & Regulatory Science, 45(4), pp.
413-420.
Getz, K. A. and Kaitin, K. I. (2015) 'Why is the pharmaceutical and biotechnology industry
struggling?', in: Schuler, P. and Buckley, B. M. (eds.) Re-engineering clinical trials: best
practices for streamlining drug development. Waltham, MA: Elsevier, pp. 3-15.
Getz, K. A., Stergiopoulos, S., Short, M., Surgeon, L., et al. (2016) 'The impact of protocol
amendments on clinical trial performance and cost', Therapeutic Innovation &
Regulatory Science, 50(4), pp. 436-441.
Gottlieb, S. (2019) 'Breaking down barriers between clinical trials and clinical care:
incorporating real world evidence into regulatory decision making'. Available at:
https://www.fda.gov/news-events/speeches-fda-officials/breaking-down-barriers-
between-clinical-trials-and-clinical-care-incorporating-real-world-evidence (Accessed: 23
June 2019).

142
Greene, J. A. and Podolsky, S. H. (2012) 'Reform, regulation, and pharmaceuticals — the
Kefauver–Harris amendments at 50', The New England Journal of Medicine, 367(16), pp.
1481-1483.
Grignolo, A. and Siu, A. (2018) 'Improving drug development and patient access with the right
people, processes, and culture: what needs to happen right now to bring better medicines
to the patients who need them', Therapeutic Innovation & Regulatory Science, 53(3), pp.
398-402.
Groves, R. M., Presser, S. and Dipko, S. (2004) 'The Role of Topic Interest in Survey
Participation Decisions', Public Opinion Quarterly, 68(1), pp. 2-31.
Hardman, M. and Robinson, M. (2015) 'You need processes, systems, and people - it's all about
the people (and their competencies)', in: Schuler, P. and Buckley, B. M. (eds.) Re-
engineering clinical trials: best practices for streamlining drug development. Waltham,
MA: Elsevier, pp. 319-329.
Harper, B. and Tate, W. (2019) 'Teaching old dogs new tricks: can competency with clinical
research technologies be enhanced?'. Available at:
https://www.clinicalleader.com/doc/teaching-old-dogs-new-tricks-can-competency-with-
clinical-research-technologies-be-enhanced-0001 (Accessed: 11 April 2020).
Health Research Authority. (2020) 'Guidance about COVID-19 for sponsors, sites and
researchers'. Available at: https://www.hra.nhs.uk/covid-19-research/covid-19-
guidance-sponsors-sites-and-researchers/ (Accessed: 03 April 2020).
Hirsch, I. B., Martinez, J., Dorsey, E. R., Finken, G., et al. (2017) 'Incorporating site-less clinical
trials into drug development: a framework for action', Clinical Therapeutics, 39(5), pp.
1064-1076.
HMAs Clinical Trials Facilitation Group. (2019) 'Results of the voluntary harmonisation
procedure 2009 – 2018'. Available at:
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2019_03_CTFG_Results_Voluntary_Harmonisati
on_Procedure_2009-2018.pdf (Accessed: 15 April 2020).
Hufford, M. R., Stone, A. A., Shiffman, S., Schwartz, J. E., et al. (2002) 'Paper vs. electronic
diaries: compliance and subject evaluations', Applied Clinical Trials, 11(8), p. 38.
ICH E6(R2). (2016) 'Integrated addendum to ICH E6(R1): guideline for good clinical practice
E6(R2)'. Available at:

143
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E
6_R2__Step_4_2016_1109.pdf (Accessed: 07 September 2018).
ICH E6(R3). (2019) 'Final concept paper ICH E6(R3): guideline for good clinical practice'.
Available at: https://database.ich.org/sites/default/files/E6-
R3_FinalConceptPaper_2019_1117.pdf (Accessed: 03 April 2020).
ICH E8(R1). (2019) 'General considerations for clinical studies E8(R1)'. Available at:
https://database.ich.org/sites/default/files/E8-R1_EWG_Draft_Guideline.pdf (Accessed:
17 April 2020).
Jadhav, S. (2016) 'Virtual clinical trials: the future of patient engagement?'. Available at:
http://www.appliedclinicaltrialsonline.com/virtual-clinical-trials-future-patient-
engagement (Accessed: 31 May 2019).
Japan Pharmaceutical Manufacturers Association. (2015) 'Pharmaceutical administration and
regulations in Japan'. Available at: http://www.jpma.or.jp/english/parj/pdf/2015.pdf
(Accessed: 24 April 2019).
JD Power. (2019) 'Telehealth: best consumer healthcare experience you've never tried, says J.D.
Power study'. Available at: https://www.jdpower.com/business/press-releases/2019-us-
telehealth-satisfaction-study (Accessed: 15 April 2020).
Jenkins, J. and Hubbard, S. (1991) 'History of clinical trials', Cancer Clinical Trials, 7(4), pp.
228-234.
Johnson, T. P. and Wislar, J. S. (2012) 'Response rates and nonresponse errors in surveys', JAMA,
307(17), pp. 1805-6.
José, N. and Langel, K. (2010) 'ePRO vs. paper', Applied Clinical Trials, 19(6), pp. 68-70,72,74.
Junod, S. W. (2008) 'FDA and clinical drug trials: a short history', in: Davies, M. and Kerimani,
F. (eds.) A Quick Guide to Clinical Trials. Washington: Bioplan, Inc., pp. 25-55.
Kubick, W. (2015) 'Re-engineering clinical research with data standards', in: Schuler, P. and
Buckley, B. M. (eds.) Re-engineering clinical trials: best practices for streamlining drug
development. Waltham, MA: Elsevier, pp. 227-243.
Lamberti, M. J. and Awatin, J. (2017) 'Mapping the landscape of patient-centric activities within
clinical research', Clinical Therapeutics, 39(11), pp. 2196-2202.

144
Lamberti, M. J., Wilkinson, M., Harper, B., Morgan, C., et al. (2018) 'Assessing study start-up
practices, performance, and perceptions among sponsors and contract research
organizations', Therapeutic Innovation & Regulatory Science, 52(5), pp. 572-578.
Langel, K. (2017) 'The future of patient engagement: applying what we know now'. Available at:
http://www.appliedclinicaltrialsonline.com/future-patient-engagement-applying-what-we-
know-now?pageID=3 (Accessed: 15 April 2020).
Learner, N. (2015) 'Remote clinical trials: a goal just over the horizon'. Available at:
https://www.lifescienceleader.com/doc/remote-clinical-trials-a-goal-just-over-the-
horizon-0001 (Accessed: 15 April 2020).
Lipset, C. (2015) 'Comment on the Food and Drug Administration (FDA) notice: using
technologies and innovative methods to conduct Food and Drug Administration-
regulated clinical investigations of investigational drugs; establishment of a public
docket'. Available at: https://www.regulations.gov/document?D=FDA-2015-N-3579-
0044 (Accessed: 01 June 2019).
Liu, M. and Wronski, L. (2018) 'Examining Completion Rates in Web Surveys via Over 25,000
Real-World Surveys', Social Science Computer Review, 36(1), pp. 116-124.
Loaiza, J. (2019) 'De-mystifying the qualification of decentralized clinical trials'. Available at:
https://www.theavocagroup.com/de-mystifying-the-qualification-of-decentralized-
clinical-trials/ (Accessed: 15 April 2020).
Madsen, S., Holm, S. and Riis, P. (1999) 'Ethical aspects of clinical trials: the attitudes of the
public and out‐patients', Journal of Internal Medicine, 245(6), pp. 571-579.
Marks, R. G., Conlon, M. and Ruberg, S. J. (2001) 'Paradigm shifts in clinical trials enabled by
information technology', Statistics in Medicine, 20(17-18), pp. 2683-2696.
Martin, L., Hutchens, M. and Hawkins, C. (2017a) 'Trial watch: Clinical trial cycle times
continue to increase despite industry efforts', Nature Reviews Drug Discovery, 16(3), p.
157.
Martin, L., Hutchens, M., Hawkins, C. and Radnov, A. (2017b) 'How much do clinical trials
cost?', Nature Reviews Drug Discovery, 16(6), pp. 381-382.
Martin, S. S., Ou, F.-S., Newby, L. K., Sutton, V., et al. (2013) 'Patient- and trial-specific barriers
to participation in cardiovascular randomized clinical trials', Journal of the American
College of Cardiology, 61(7), pp. 762-769.

145
Milmo, S. (2014) 'Collaboration and innovation in European medicine regulation',
Pharmaceutical Technology, 38(8), p. 16.
Mitchel, J., Helfgott, J., Haag, T., Cappi, S., et al. (2015) 'eSource records in clinical research:
keeping it simple', Applied Clinical Trials, 24(8/9), pp. 30-38.
Mitchell, J. W. (2018a) 'Emerging trends in clinical research: The need for change', Research
Practitioner, 19(3), p. 41.
Mitchell, J. W. (2018b) 'The state of virtual clinical trials', Research Practitioner, 19(5), p. 81.
Moy, P. and Murphy, J. (2016) 'Problems and Prospects in Survey Research', Journalism and
Mass Communication Quarterly, 93(1), pp. 16-37.
Myshko, D. (2019) 'The future of decentralized trials', PharmaVoice, 19(10), pp. 46-50.
Nagata, R. and Rafizadeh-Kabe, J.-D. (2002) 'Japanese pharmaceutical and regulatory
environment', Dialogues in Clinical Neuroscience, 4(4), pp. 470-474.
Neimeth, R. (2017) Japan's pharmaceutical industry postwar evolution, Washington (DC),
National Academies Press.
Ojha, R. P., Jackson, B. E., Lu, Y., Burton, M., et al. (2018) 'Participation and retention can be
high in randomized controlled trials targeting underserved populations: a systematic
review and meta-analysis', Journal of Clinical Epidemiology, 98, pp. 154-157.
Orri, M., Lipset, C. H., Jacobs, B. P., Costello, A. J., et al. (2014) 'Web-based trial to evaluate the
efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder:
REMOTE trial', Contemporary Clinical Trials, 38(2), pp. 190-197.
Paporello, T. (2015) 'Comment on the Food and Drug Administration (FDA) notice: using
technologies and innovative methods to conduct Food and Drug Administration-
regulated clinical investigations of investigational drugs; establishment of a public
docket'. Available at: https://www.regulations.gov/document?D=FDA-2015-N-3579-
0012 (Accessed: 01 June 2019).
Patrick, D. L., Burke, L. B., Powers, J. H., Scott, J. A., et al. (2007) 'Patient-reported outcomes to
support medical product labeling claims: FDA perspective', Value in Health, 10(2), pp.
S125-S137.

146
Pavlović, I., Kern, T. and Miklavčič, D. (2009) 'Comparison of paper-based and electronic data
collection process in clinical trials: Costs simulation study', Contemporary Clinical
Trials, 30(4), pp. 300-316.
Perry, B., Herrington, W., Goldsack, Jennifer c., Grandinetti, Cheryl a., et al. (2018) 'Use of
mobile devices to measure outcomes in clinical research, 2010–2016: a systematic
literature review', Digital Biomarkers, 2(1), pp. 11-30.
Petticrew, M., Tugwell, P., Kristjansson, E., Oliver, S., et al. (2012) 'Damned if you do, damned
if you don't: subgroup analysis and equity', Journal of Epidemiology and Community
Health, 66(1), p. 95.
Pick, A. and Gilbert, K. (2013) 'Informed consent in clinical research', Nursing Standard, 27(49),
p. 44.
Racher Press, I. (1998) 'Electronic NDA filings slated for September '99', Chain Drug Review,
20(14), p. RX 17.
Reichert, J. M. (2003) 'Trends in development and approval times for new therapeutics in the
United States', Nature Reviews, 2, p. 695.
Roehr, B. (2011a) 'Pfizer launches virtual clinical trial', British Medical Journal, 342, p. d3722.
Roehr, B. (2011b) 'Pfizer launches virtual clinical trial that uses "apps"', British Medical Journal,
342(7811), p. 1333.
Rogers, E. M. (1983) Diffusion of innovations, 3rd edition, New York, The Free Press.
Ross, S., Grant, A., Counsell, C., Gillespie, W., et al. (1999) 'Barriers to participation in
randomised controlled trials: a systematic review', Journal of Clinical Epidemiology,
52(12), pp. 1143-1156.
Science 37. (2017) 'Science 37 and AOBiome complete industry-first virtual clinical trial through
Metasite™ (Decentralized) Operating Model'. Available at:
https://www.science37.com/science-37-aobiome-complete-industry-first-virtual-clinical-
trial-metasite-decentralized-operating-model/ (Accessed: 06 June 2019).
Shaw, G. (2019) 'Too many amendments, too little planning, expert says', CenterWatch Weekly,
23(12), pp. 1-4.

147
Sherman, M. and Strauss, S. (1986) 'Thalidomide: a twenty-five year perspective', Food Drug
Cosmetic Law Journal, 41(4), pp. 458-466.
Shewale, S. and Parekh, S. (2013) 'Electronic data capture in clinical trials', Applied Clinical
Trials, 22(9), pp. 28-32.
Shuster, E. (1997) 'Fifty years later: The significance of the Nuremberg Code', The New England
Journal of Medicine, 337(20), pp. 1436-1440.
Sicherman, S. (2018) 'Drug pricing, a complex issue affecting the rare disease community'.
Available at: https://www.gaucherdisease.org/blog/drug-pricing-a-complex-issue-
affecting-the-rare-disease-community/ (Accessed: 17 May 2019).
Smalley, E. (2018) 'Clinical trials go virtual, big pharma dives in', Nature Biotechnology, 36(7),
pp. 561-562.
Smith, M. A. (2015) 'Comment on the Food and Drug Administration (FDA) notice: using
technologies and innovative methods to conduct Food and Drug Administration-
regulated clinical investigations of investigational drugs; establishment of a public
docket'. Available at: https://www.regulations.gov/document?D=FDA-2015-N-3579-
0016 (Accessed: 01 June 2019).
Stone, A. A., Shiffman, S., Schwartz, J. E., Broderick, J. E., et al. (2002) 'Patient non-compliance
with paper diaries', British Medical Journal, 324(7347), p. 1193.
Streeton, R., Cooke, M. and Campbell, J. (2004) 'Researching the researchers: using a
snowballing technique.(sampling methods)', Nurse Researcher, 12(1), p. 35.
Switula, D. (2000) 'Principles of good clinical practice (GCP) in clinical research', Science and
Engineering Ethics, 6(1), pp. 71-77.
Tanimoto, T. (2015) 'A perspective on the benefit-risk assessment for new and emerging
pharmaceuticals in Japan', Drug Design, Development and Therapy, 2015, pp. 1877-
1888.
Tenti, E., Simonetti, G., Bochicchio, M. T. and Martinelli, G. (2018) 'Main changes in European
Clinical Trials Regulation (No 536/2014)', Contemporary Clinical Trials
Communications, 11, pp. 99-101.

148
The Avoca Group (2019) The 2018 Avoca industry report: perspectives on clinical innovation &
technology. In: Group, T. A. (ed.). The Avoca Group archives.
The Council of the European Communities. (1975) 'Council directive of 20 May 1975 on the
approximation of the laws of Member States relating to analytical, pharmacotoxicological
and clinical standards and protocols in respect of the testing of proprietary medicinal
products (75/318/EEC)', Official Journal of the European Communities, 147(1), pp. 1-12.
Trials@Home. (2019) 'Innovative Medicines Initiative Launches ‘Trials@Home’'. Available at:
https://trialsathome.com/innovative-medicines-initiative-launches-trialshome/ (Accessed:
3/29/2020).
Trizna, C. (2015) 'No patients - no data: patient recruitment in the twenty-first century', in:
Schuler, P. and Bbuckley, B. M. (eds.) Re-engineering clinical trials: best practices for
streamlining the development process. Waltham, MA: Elsevier, pp. 91-104.
Tufts Center for the Study of Drug Development. (2016) 'Outlook 2016'. Available at:
https://static1.squarespace.com/static/5a9eb0c8e2ccd1158288d8dc/t/abaft/152063094403
3/Outlook-2016.pdf (Accessed: 17 August 2018).
US Congress. (1962) Public Law 87-781 Drug Amendments of 1962, Senate and House of
Representatives (United States), pp. 780-796.
US Congress. (1997) Public Law 105–115 Food And Drug Administration Modernization Act of
1997, Senate and House of Representatives (United States), pp. 2296-380.
US Congress. (2002) Public Law 107–109 Best Pharmaceuticals for Children Act, Senate and
House of Representatives (United States), pp. 1408-1424.
US Congress. (2003) Public Law 108-155 Pediatric Research Equity Act of 2003, Senate and
House of Representatives (United States), pp. 1936-1943.
US Congress. (2007) Public Law 110-85 Food and Drug Administration Amendments Act of
2007, Senate and House of Representatives (United States), pp. 823-978.
US Congress. (2010) Public Law 111-148 Patient Protection and Affordable Care Act, Senate
and House of Representatives (United States), pp. 119-1024.
US Congress. (2012) Public Law 112-144 Food and Drug Administration Safety and Innovation
Act, Senate and House of Representatives (United States), pp. 993-1132.

149
US Congress. (2016) Public Law 114-255 21st Century Cures Act, Senate and House of
Representatives (United States), pp. 1033-1344.
US Congress. (2017) Public Law 115-52 FDA Reauthorization Act of 2017, Senate and House of
Representatives (United States), pp. 1005-1090.
van Oijen, J. C. F., Grit, K. J., van de Bovenkamp, H. M. and Bal, R. A. (2017) 'Effects of EU
harmonization policies on national public supervision of clinical trials: A dynamic cycle
of institutional change and institutional work', Health Policy, 121(9), pp. 971-977.
Vanaken, H. and Masand, S. N. (2019) 'Awareness and collaboration across stakeholder groups
important for econsent achieving value-driven adoption', Therapeutic Innovation &
Regulatory Science, 53(6), pp. 724-735.
Vogel, D. (1998) 'The globalization of pharmaceutical regulation', Governance, 11(1), pp. 1-22.
Weisfeld, V. (2011) Public engagement and clinical trials new models and disruptive
technologies : workshop summary, Washington, D.C., National Academies Press.
Wilkinson, M., Young, R., Harper, B., Machion, B., et al. (2019) 'Baseline assessment of the
evolving 2017 eclinical landscape', Therapeutic Innovation & Regulatory Science, 53(1),
pp. 71-80.
Wood, F. and Fitzsimmons, M. (2001) 'Clinical data interchange standards consortium (CDISC)
standards and their implementationin a clinical data management system', Drug
Information Journal, 35(3), p. 853.
Woosley, R. L. (2013) 'One hundred years of drug regulation: where do we go from here?',
Annual Review of Pharmacology and Toxicology, 53, pp. 255-273.

150
Appendix A. Survey
Survey Flow
Block: Demographics (6 Questions)
Standard: Innovation-Decision Process (5 Questions)
Standard: Rate of Innovation (3 Questions)
Standard: Attributes of Innovation (8 Questions)
Standard: Detailed Follow-up on Experience with DCT (4 Questions)
Standard: Final Comments (3 Questions)
Standard: End of Survey (1 Question)
Page Break

Start of Block: Demographics
Q1 Thank you for participating in this survey to explore the implementation of
decentralized clinical trials by industry sponsors. Your responses to this survey will be
kept confidential and presented as part of a cumulative analysis. This survey should take
approximately 15 minutes to complete.
For the purposes of this survey, a few definitions will be helpful. Here, a fully
decentralized clinical trial is defined as a trial conducted fully virtually with no direct
contact with the participant. Contact is through remote means, such as telemedicine/web-
conferencing capabilities.
Hybrid approaches can also be used and can take various forms, including:
- Use of a virtual trial site in addition to traditional trial sites,
- Use of telemedicine for at least parts of the trial or some study visits,
- Use of mobile healthcare providers (HCP) for at least parts of a trial or some study
visits,
- Use of a local HCP, either in addition to traditional trial sites or instead of traditional
trial sites, the difference from virtual is that there is some direct contact with the
participant,
- Shipment of study drug and materials direct to participant in the absence of a fully
virtual trial.

151
Q21 Which statement best describes the department or function you represent within your
company?
o Clinical Development (1)
o Clinical Operations (2)
o Data Management/Statistics/Clinical Programming (3)
o Regulatory Affairs (4)
o Quality Assurance/Quality Control/Compliance (Clinical/GCP focus) (5)
o Project Leadership or Project Management (6)
o Digital/Innovation Services within R&D (includes patient-centricity office within
R&D) (7)
o Information Systems/Technology (8)
o Clinical Supply Chain (9)
o Other, specify (10) ________________________________________________

Q22 What role would do you play if/when the decision is made to implement
decentralized clinical trials within your company?
o Responsible for making decision (1)
o Influences decision, not necessarily final decision maker (2)
o Not responsible for decisions related to implementation of decentralized clinical
trials (3)
o Other, specify: (4) ________________________________________________

152
Q23 At what level is your role within your organization?
o C-Suite (1)
o Vice President/President (2)
o Director/Senior Director/Executive Director (3)
o Manager/Senior Manager (4)
o Other, specify: (5) ________________________________________________

Q24 Which statement best describes the size of your organization?
o Fewer than 250 people (1)
o 251-2000 people (2)
o 2001-10,000 (3)
o 10,000-25,000 (4)
o More than 25,000 people (5)

153
Q25 Which statement best describes the average number of interventional trials your
company conducts in a year?
Note: Conduct is defined as a trial at any stage between final protocol approval through
final database lock. Interventional trials of medicinal products from phase 1 through
phase 4 should be included.
o 5 or less interventional clinical trials/year (1)
o 6-20 interventional clinical trials/year (2)
o 26-100 interventional clinical trials/year (3)
o More than 100 interventional clinical trials/year (4)
o I don't know (5)
End of Block: Demographics

154
Start of Block: Innovation-Decision Process
Q2 Please indicate your level of knowledge about the following approaches as they
related to the conduct of a decentralized clinical trial of an investigational product in an
interventional trial.

No
knowledge (1)
Some
knowledge (2)
Knowledgeable
HAVE NOT
USED (3)
Knowledgeable
HAVE USED (4)
eConsent (1)
o o o o
ePRO/eCOA (2)
o o o o
Mobile data
collection of
digital
endpoints
(beyond
ePRO/eCOA)
(3)
o o o o
Telemedicine
(4) o o o o
Mobile
Healthcare
Provider (5)
o o o o
Local
Healthcare
Provider (6)
o o o o
Direct
shipment of
study drug and
other materials
to participant
(7)
o o o o

155
Q3 How useful are the following support mechanisms for referencing or learning about
the use and conduct of fully decentralized clinical trials or hybrid approaches to
decentralized clinical trials?

Have not
used (1)
Not useful
(2)
Modestly
useful (3)
Very useful
(4)
Regulations and
guidance documents
from regulatory
authorities (1)
o o o o
Discussion/meeting
with a regulatory
authority (2)
o o o o
Recommendations
from industry
collaborations, such
as CTTI (3)
o o o o
Discussion with
representatives from
industry consortiums
(4)
o o o o
Representatives from
CRO or other vendor
(5)
o o o o
Consultant group
(e.g., Accenture, PWC,
Deloitte) (6)
o o o o
Direct contact with
industry peers with
known practical
experience (7)
o o o o
Patients, caregivers or
patient advocate
groups (8)
o o o o
Seminars/conferences
(9) o o o o

156

Have not
used (1)
Not useful
(2)
Modestly
useful (3)
Very useful
(4)
Literature,
publications, news
articles, magazines
(10)
o o o o
Other, specify: (11)
o o o o

Q4 Which statement best describes the implementation stage for fully decentralized
clinical trials (fully virtual trial) at your company?
o Not considering at this time (1)
o Exploring (have a basic understanding, have not actively pursued) (2)
o Actively seeking information, not ready to make a decision, may pilot in the
future (3)
o Resources assigned and corporate initiative has started, will pilot in the future (4)
o Completing pilot, assessing further implementation in a case-by-case manner (5)
o Have implemented processes/procedures formally (does not mean all studies need
to implement a decentralized approach) (6)
o I am not sure (7)

157
Q5 Which statement best describes the implementation stage for a hybrid approach to
decentralized clinical trials at your company? For example, portions of a study may be
conducted virtually.
o Not considering at this time (1)
o Exploring (have a basic understanding, have not actively pursued) (2)
o Actively seeking information, not ready to make a decision, may pilot in the
future (3)
o Resources assigned and corporate initiative has started, will pilot in the future (4)
o Completing pilot, assessing further implementation in a case-by-case manner (5)
o Have implemented processes/procedures formally (does not mean all studies need
to implement a hybrid approach to decentralized trials) (6)
o I am not sure (7)

158
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q6 Which statement best describes the decentralized approaches for an interventional
study that you have used or may consider using at your company?
Note: the choices listed below with an asterisk (*) are meant to be options that may be
used outside of a fully decentralized/virtual clinical trial.

Not sure
(1)
Will not
use (2)
Considering
using (3)
Piloting (4)
Have
used (5)
Fully
decentralized/virtual
clinical trial (1)
o o o o o
Virtual site plus
traditional sites (2) o o o o o
Telemedicine* (3)
o o o o o
Mobile healthcare
provider* (4) o o o o o
Local healthcare
provider* (5) o o o o o
Direct shipment of
study
drug/materials to
participant* (6)
o o o o o
End of Block: Innovation-Decision Process

159

Start of Block: Rate of Innovation
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Q7 Approximately when was/will the first fully decentralized clinical trial (fully
virtual) conducted/be conducted at your company?
o Was conducted more than 5 years ago (1)
o Was conducted within the last 3-5 years (2)
o Was conducted within the last 2 years (3)
o Will be conducted within the next 2 years (4)
o Will be conducted within the next 3 or more years (5)

160
Display This Question:
If Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q8 Approximately when was/will the first clinical trial conducted/be conducted utilizing
a hybrid approach to decentralized clinical trials at your company?
o Was conducted more than 5 years ago (1)
o Was conducted within the last 3-5 years (2)
o Was conducted within the last 2 years (3)
o Will be conducted within the next 2 years (4)
o Will be conducted within the next 3 or more years (5)

161
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q30 Rank the following approaches to decentralized clinical trials in order of
implementation priority, where #1 would be considered the highest priority in your
company. To rank, drag and drop each priority to sort #1 priority at the top of the list and
the lowest priority at the bottom.
Note: the choices listed below with an asterisk (*) are meant to be options that may be
used outside of a fully decentralized/virtual clinical trial.
______ Fully decentralized/virtual clinical trial (1)
______ Virtual trial site plus traditional sites (2)
______ Telemedicine* (3)
______ Mobile healthcare provider* (4)
______ Local healthcare provider* (5)
______ Direct shipment of study drug/materials to participant* (6)
End of Block: Rate of Innovation

162
Start of Block: Attributes of Innovation
Q9 Rank the following organizational challenges/barriers that limit the implementation
of decentralized clinical trial approaches for interventional trials in your company. To
rank, drag and drop each challenge to sort with the #1 challenge moved to the top of the
list and the least challenging at the bottom of the list.
______ Unclear Regulatory requirements/guidance/compliance expectations (1)
______ Insufficient organizational readiness (i.e., know-how, processes, templates, etc)
(2)
______ Unclear value proposition (i.e., reduction in time, positive return on investment)
(3)
______ Concern about data privacy/security (4)
______ Lack of company support/authority to implement (5)
______ Risk averse company mindset/culture (6)
______ Concern about regulatory acceptability of data/study results (7)

Q10 Describe how influential the following feasibility factors have been or would be in
the decision to implement any decentralized clinical trial approaches in your
company.
No influence (1)
Some influence
(2)
A lot of
influence (3)
Not sure (4)
Ability to identify
studies where
endpoints can be
captured outside
of a clinic (1)
o o o o
Ability to validate
mobile device
collection for
regulatory
acceptance (2)
o o o o
Enough lead time
is available to
ensure digital
endpoints can be
justified and
validated for use
in a pivotal trial
(3)
o o o o
Procedures
requiring
specialized
o o o o

163
equipment or
assessments,
such as imaging
or biopsies (4)
Characteristics of
the
investigational
product requiring
specialized
handling or
administration
(5)
o o o o
No influence (1)
Some influence
(2)
A lot of
influence (3)
Not sure (4)
Route of
administration of
investigational
product (6)
o o o o

164
Q11 The following organizational factors have been considered to contribute to the
decision to implement decentralized clinical trials (DCT) or hybrid approaches to
DCT. Rate the importance of each factor in influencing the decision to implement a DCT
or hybrid approach to DCT at your company.

Not
Important
(1)
Somewhat
not
important
(2)
Neutral (3)
Somewhat
important
(4)
Important
(5)
Corporate
strategy/culture
supporting
innovative
approaches (1)
o o o o o
Leadership
supportive of
innovative
approaches (2)
o o o o o
Effort/cost to
develop tools /
processes (3)
o o o o o
New skill sets
needed (4)
o o o o o
Potential to
impact current
organizational
structure (5)
o o o o o
Potential for a
long-term
return on
investment (6)
o o o o o
Potential for
competitive
advantage (7)
o o o o o

165
Q12 How important are the following external factors in influencing the decision to
adopt decentralized clinical trials or hybrid approaches of a decentralized clinical trial at
your company?

Not
important
(1)
Somewhat
not
important
(2)
Neutral
(3)
Somewhat
important
(4)
Important
(5)
FDA support of
approach (1)
o o o o o
Regulatory authority
support outside the
US (2)
o o o o o
Availability of
specific
regulation/guidance
on decentralized
approaches (3)
o o o o o
Ability to maintain
relationship with key
opinion
leaders/investigators
(4)
o o o o o
Ability to maintain
relationship with
traditional study
sites (5)
o o o o o
Positive experience
for participants/care
givers (6)
o o o o o
Security and/or
privacy of data (7)
o o o o o
Higher retention
rate of trial
participants (8)
o o o o o

166

Not
important
(1)
Somewhat
not
important
(2)
Neutral
(3)
Somewhat
important
(4)
Important
(5)
Faster trial
enrollment rate (9)
o o o o o
Increase in diversity
of participants (10)
o o o o o

167
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q13 Choose which clinical trial approach your company would generally consider using
for each of the following types of interventional clinical studies. Check all that might
apply for each type of study, understanding that decisions at an individual study level
may depend on other factors as well.
Note: the choices listed below with an asterisk (*) are meant to be options that may be
used outside of a fully decentralized/virtual clinical trial.

Fully
decentralized
/ virtual
clinical trial
(1)
Virtual
site plus
traditiona
l sites (2)
Telemedicine
* (3)
Mobil
e
HCP*
(4)
Local
HCP
* (5)
Direct
shipment
of study
drug/
materials
to
participant
* (6)
Traditiona
l trial
conduct
(7)
Healthy
volunteer
study (1)
▢ ▢ ▢ ▢ ▢ ▢ ▢
First-in-
human
patient
study (2)
▢ ▢ ▢ ▢ ▢ ▢ ▢

168

Fully
decentralized
/ virtual
clinical trial
(1)
Virtual
site plus
traditiona
l sites (2)
Telemedicine
* (3)
Mobil
e
HCP*
(4)
Local
HCP
* (5)
Direct
shipment
of study
drug/
materials
to
participant
* (6)
Traditiona
l trial
conduct
(7)
Proof of
concept
study or
dose-
finding
study (3)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Pivotal
study for
a non-
marketed
drug (4)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Pivotal
study for
a
marketed
drug (5)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Long-
term
safety
study (6)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Post-
market
study (7)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Pragmati
c study
(8)
▢ ▢ ▢ ▢ ▢ ▢ ▢

169
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q14 Choose which clinical trial approach your company would generally consider using for each
of the following location of conduct or procedural requirements of an interventional clinical
study. Check all that might apply for each location type and procedural requirement,
understanding that decisions at an individual study level may depend on other factors as well.
Note: the choices listed below with an asterisk (*) are meant to be options that may be used
outside of a fully decentralized/virtual clinical trial.

Fully
decentralized/
virtual clinical
trial (1)
Virtual site
plus
traditional
sites (2)
Telemedicine*
(3)
Mobile
HCP*
(4)
Local
HCP*
(5)
Direct
shipment of
study drug/
materials to
participant*
(6)
Traditional
trial
conduct (7)
US only (1)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Only
outside US
(2)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Global
study with
US sites (3)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Requires
imaging (4)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Requires
biopsy or
invasive
procedure
(5)
▢ ▢ ▢ ▢ ▢ ▢ ▢

170
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q15 Choose which clinical trial approach your company would generally consider using
for each of the following population types included in an interventional clinical
study. Check all approaches that might apply for each population type, understanding
that decisions at an individual study level may depend on other factors as well.
Note: the choices listed below with an asterisk (*) are meant to be options that may be
used outside of a fully decentralized/virtual clinical trial.

Fully
decentralized
/ virtual
clinical trial
(1)
Virtual
site plus
traditiona
l sites (2)
Telemedicine
* (3)
Mobil
e
HCP*
(4)
Local
HCP
* (5)
Direct
shipment
of study
drug /
materials
to
participant
* (6)
Traditiona
l trial
conduct
(7)
Rare
disease (1)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Low
mobility
capabilitie
s (2)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Dependen
t upon
caregivers
(3)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Relatively
healthy
with low
risk
disease (4)
▢ ▢ ▢ ▢ ▢ ▢ ▢

171

Fully
decentralized
/ virtual
clinical trial
(1)
Virtual
site plus
traditiona
l sites (2)
Telemedicine
* (3)
Mobil
e
HCP*
(4)
Local
HCP
* (5)
Direct
shipment
of study
drug /
materials
to
participant
* (6)
Traditiona
l trial
conduct
(7)
Moderate
risk
disease
requiring
regular
check-ups
(5)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Mobile
health
platforms
commonly
used with
disease (6)
▢ ▢ ▢ ▢ ▢ ▢ ▢

172
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q16 Choose which decentralized clinical trial approach your company would generally
consider using for each of the following characteristics of a product evaluated in an
interventional clinical study. Check all approaches that might apply for each
characteristic, understanding that decisions at an individual study level may depend on
other factors as well.
Note: the choices listed below with an asterisk (*) are meant to be options that may be
used outside of a fully decentralized/virtual clinical trial.

Fully
decentralize
d/ virtual
clinical trial
(1)
Virtual
site plus
tradition
al sites
(2)
Telemedicin
e* (3)
Mobil
e
HCP*
(4)
Loca
l
HCP
* (5)
Direct
shipment
of study
drug/
materials
to
participant
* (6)
Tradition
al trial
conduct
(7)
Product that is
low risk from a
safety
perspective (1)
▢ ▢ ▢ ▢ ▢ ▢ ▢

173

Fully
decentralize
d/ virtual
clinical trial
(1)
Virtual
site plus
tradition
al sites
(2)
Telemedicin
e* (3)
Mobil
e
HCP*
(4)
Loca
l
HCP
* (5)
Direct
shipment
of study
drug/
materials
to
participant
* (6)
Tradition
al trial
conduct
(7)
Product that is
moderate/high
er risk from a
safety
perspective (2)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Product that
can be self-
administered
by the
participant or a
caregiver (3)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Product
requiring direct
oversight by a
healthcare
provider (such
as an infusion)
(4)
▢ ▢ ▢ ▢ ▢ ▢ ▢
Product
requires
specialized
handling, such
as cold chain
management
(5)
▢ ▢ ▢ ▢ ▢ ▢ ▢
End of Block: Attributes of Innovation

174
Start of Block: Detailed Follow-up on Experience with DCT
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q17 Have you discussed the use of a fully decentralized clinical trial or a hybrid
approach to a decentralized clinical trial with the FDA?
o No (1)
o Discussed with a specific review division (2)
o Discussed with multiple review divisions (3)
o Discussed with a central division (4)
o Not sure (5)

175
Display This Question:
If Q17 = Discussed with a specific review division
Or Q17 = Discussed with multiple review divisions
Or Q17 = Discussed with a central division
Q18 Based on the outcome of the discussions with FDA, rate the level to which you
agree with the following statements related to feedback received from FDA on
decentralized approaches to clinical trials.
Disagree (1)
Neither disagree
nor agree (2)
Agree (3) Not applicable (4)
Generally in favor (1)
o o o o
Transparent advice
provided (2)
o o o o
Gave sufficient
information for
decision-making (3)
o o o o
Gave opportunity for
additional follow-
up/discussion (4)
o o o o
Yielded a clear
understanding of
potential impact to
marketing application
and/or labeling claims
(5)
o o o o
Gave sufficient advice
to ensure
acceptability of data
to support a
marketing application
(6)
o o o o

176
Display This Question:
If Q4 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q4 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Actively seeking information, not ready to make a decision, may pilot in the future
Or Q5 = Resources assigned and corporate initiative has started, will pilot in the future
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q19 Have you discussed the use of a fully decentralized clinical trial or hybrid
approaches to a decentralized clinical trial with trial participants and/or their caregivers?
Check all that apply.
▢ No (1)
▢ Obtained feedback/plan to obtain feedback prior to designing clinical trial (2)
▢ Obtained feedback/plan to obtain feedback while designing clinical trial (3)
▢ Obtained feedback/plan to obtain feedback during the conduct of the trial (4)
▢ Obtained feedback/plan to obtain feedback after conduct of the trial (5)
▢ Not sure (6)

177
Display This Question:
If Q19 = Obtained feedback/plan to obtain feedback prior to designing clinical trial
Or Q19 = Obtained feedback/plan to obtain feedback while designing clinical trial
Or Q19 = Obtained feedback/plan to obtain feedback during the conduct of the trial
Or Q19 = Obtained feedback/plan to obtain feedback after conduct of the trial
Q20 Based on the discussions with participants and/or their caregivers, rate the level to
which you agree with the following statements about participant/caregivers opinion
regarding decentralized clinical trial approaches.
Disagree (1)
Neither agree
nor disagree (2)
Agree (3)
Not applicable
(4)
Generally in
favor of the
approach (1)
o o o o
Confirmed
burden of
participation
was/would be
decreased (2)
o o o o
Confirmed
positive impact
on retention (3)
o o o o
Expressed
willingness to
participant in
trial using
decentralized
approach (4)
o o o o
Mobile
technology
was/is easy to
use (5)
o o o o
Training was/is
sufficient (6)
o o o o
Felt/would feel
sufficiently
supported during
the trial (7)
o o o o
End of Block: Detailed Follow-up on Experience with DCT

178
Start of Block: Final Comments
Display This Question:
If Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Or Q5 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q5 = Have implemented processes/procedures formally (does not mean all studies need to
implement a hybrid approach to decentralized trials)
Q26 Describe any positive experiences you have had with using a decentralized approach
to conducting clinical trials.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Display This Question:
If Q4 = Completing pilot, assessing further implementation in a case-by-case manner
Or Q4 = Have implemented processes/procedures formally (does not mean all studies need to
implement a decentralized approach)
Q27 Describe the most challenging aspect of implementing a fully decentralized clinical
trial.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

179
Q28 Is there anything else you would like to comment on related to challenges or benefits
of decentralized clinical trials?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

End of Block: Final Comments

Start of Block: End of Survey

Q29 Thank you for your support of my survey. I appreciate your time and value your
input on this topic. I will be providing a brief summary of the results to those who have
participated in the survey once the analysis of the survey is complete. If you wish to
receive the summary, please provide your email address below. I hope you will find
the information valuable.
________________________________________________________________

End of Block: End of Survey

180
Appendix B. Data Tables
Q21 - Which statement best describes the department or function you represent
within your company?
# Answer % Count
1 Clinical Development 11.1% 8
2 Clinical Operations 40.3% 29
3 Data Management/Statistics/Clinical Programming 4.2% 3
4 Regulatory Affairs 9.7% 7
5 Quality Assurance/Quality Control/Compliance (Clinical/GCP focus) 9.7% 7
6 Project Leadership or Project Management 6.9% 5
7
Digital/Innovation Services within R&D (includes patient-centricity
office within R&D)
6.9% 5
8 Information Systems/Technology 1.4% 1
9 Clinical Supply Chain 1.4% 1
10 Other, specify 8.3% 6
Total 100% 72
Other, specify - Text
Regulatory Legal
My Dept is called Clinical Development Operations (AKA DevOps)
Business Development (former ops person)
Medical Affairs
Business Development
Change management focused on Development Technology to enable efficient clinical trials

181
Q22 - What role would do you play if/when the decision is made to implement
decentralized clinical trials within your company?
# Answer % Count
1 Responsible for making decision 25.0% 17
4 Other, specify: 0.0% 0
3
Not responsible for decisions related to implementation of decentralized
clinical trials
11.8% 8
2 Influences decision, not necessarily final decision maker 63.2% 43
Total 100% 68

Q23 - At what level is your role within your organization?
# Answer % Count
1 C-Suite 5.9% 4
2 Vice President/President 14.7% 10
3 Director/Senior Director/Executive Director 47.1% 32
4 Manager/Senior Manager 25.0% 17
5 Other, specify: 7.4% 5
Total 100% 68
Other, specify: - Text
Coordinator
Sr. Officer to Executive level
Cra
CRA
Principal Medical Writer

182
Q24 - Which statement best describes the size of your organization?
# Answer % Count
1 Fewer than 250 people 34.8% 23
2 251-2000 people 21.2% 14
3 2001-10,000 10.6% 7
4 10,000-25,000 13.6% 9
5 More than 25,000 people 19.7% 13
Total 100% 66

Q25 - Which statement best describes the average number of interventional trials
your company conducts in a year? Note: Conduct is defined as a trial at any stage
between final protocol approval through final database lock. Interventional trials of
medicinal products from phase 1 through phase 4 should be included.
# Answer % Count
1 5 or less interventional clinical trials/year 25.8% 16
2 6-20 interventional clinical trials/year 25.8% 16
3 26-100 interventional clinical trials/year 21.0% 13
4 More than 100 interventional clinical trials/year 22.6% 14
5 I don't know 4.8% 3
Total 100% 62

183
Q2 - Please indicate your level of knowledge about the following approaches as they
related to the conduct of a decentralized clinical trial of an investigational product
in an interventional trial
# Question
No
knowledge
Some
knowledge
Knowledgeable
HAVE NOT
USED
Knowledgeable
HAVE USED
Total
1 eConsent 6.9% 4 12.1% 7 44.8% 26 36.2% 21 58
2 ePRO/eCOA 13.8% 8 3.4% 2 15.5% 9 67.2% 39 58
3
Mobile data
collection of
digital
endpoints
(beyond
ePRO/eCOA)
5.2% 3 19.0% 11 32.8% 19 43.1% 25 58
4 Telemedicine 17.2% 10 25.9% 15 36.2% 21 20.7% 12 58

Mobile
Healthcare
Provider
17.2% 10 29.3% 17 22.4% 13 31.0% 18 58

Local
Healthcare
Provider
8.8% 5 21.1% 12 19.3% 11 50.9% 29 57

Direct shipment
of study drug
and other
materials to
participant
6.9% 4 22.4% 13 29.3% 17 41.4% 24 58

184
Q3 - How useful are the following support mechanisms for referencing or learning
about the use and conduct of fully decentralized clinical trials or hybrid approaches
to decentralized clinical trials?
# Question
Have not
used
Not useful
Modestly
useful
Very
useful
Total
1
Regulations and
guidance documents
from regulatory
authorities
11.8% 6 9.8% 5 51.0% 26 27.5% 14 51
2
Discussion/meeting
with a regulatory
authority
17.6% 9 3.9% 2 29.4% 15 49.0% 25 51
3
Recommendations from
industry collaborations,
such as CTTI
12.0% 6 4.0% 2 38.0% 19 46.0% 23 50
4
Discussion with
representatives from
industry consortiums
9.8% 5 0.0% 0 62.7% 32 27.5% 14 51

Representatives from
CRO or other vendor
3.9% 2 13.7% 7 58.8% 30 23.5% 12 51

Consultant group (e.g.,
Accenture, PWC,
Deloitte)
19.6% 10 29.4% 15 43.1% 22 7.8% 4 51

Direct contact with
industry peers with
known practical
experience
3.9% 2 2.0% 1 35.3% 18 58.8% 30 51

Patients, caregivers or
patient advocate groups
17.6% 9 2.0% 1 54.9% 28 25.5% 13 51
Seminars/conferences 9.8% 5 5.9% 3 64.7% 33 19.6% 10 51

Literature, publications,
news articles,
magazines
5.9% 3 5.9% 3 62.7% 32 25.5% 13 51
Other, specify: 76.9% 10 7.7% 1 7.7% 1 7.7% 1 13
Other, specify: - Text
I have never been involved with the conduct of a fully decentralized clinical trial; therefore, my
responses are assumptions.

185
Q4 - Which statement best describes the implementation stage for fully
decentralized clinical trials (fully virtual trial) at your company?
# Answer % Count
1 Not considering at this time 31.4% 16
2 Exploring (have a basic understanding, have not actively pursued) 27.5% 14
3
Actively seeking information, not ready to make a decision, may pilot in
the future
7.8% 4
4
Resources assigned and corporate initiative has started, will pilot in the
future
3.9% 2
5
Completing pilot, assessing further implementation in a case-by-case
manner
9.8% 5
6
Have implemented processes/procedures formally (does not mean all
studies need to implement a decentralized approach)
13.7% 7
7 I am not sure 5.9% 3
Total 100% 51

Q5 - Which statement best describes the implementation stage for a hybrid
approach to decentralized clinical trials at your company? For example, portions of
a study may be conducted virtually.
# Answer % Count
1 Not considering at this time 12.2% 6
2 Exploring (have a basic understanding, have not actively pursued) 24.5% 12
3
Actively seeking information, not ready to make a decision, may pilot in
the future
14.3% 7
4
Resources assigned and corporate initiative has started, will pilot in the
future
8.2% 4
5
Completing pilot, assessing further implementation in a case-by-case
manner
6.1% 3
6
Have implemented processes/procedures formally (does not mean all
studies need to implement a hybrid approach to decentralized trials)
26.5% 13
7 I am not sure 8.2% 4
Total 100% 49

186
Q6 - Which statement best describes the decentralized approaches for an
interventional study that you have used or may consider using at your company?
Note: the choices listed below with an asterisk (*) are meant to be options that may
be used outside of a fully decentralized/virtual clinical trial.
# Question Not sure
Will not
use
Considering
using
Piloting Have used Total
1
Fully
decentralized/virtual
clinical trial
19.2% 5 19.2% 5 26.9% 7 11.5% 3 23.1% 6 26
2
Virtual site plus
traditional sites
19.2% 5 0.0% 0 53.8% 14 11.5% 3 15.4% 4 26
3 Telemedicine* 20.0% 5 0.0% 0 44.0% 11 12.0% 3 24.0% 6 25
4
Mobile healthcare
provider*
15.4% 4 0.0% 0 50.0% 13 11.5% 3 23.1% 6 26
5
Local healthcare
provider*
24.0% 6 0.0% 0 32.0% 8 8.0% 2 36.0% 9 25

Direct shipment of
study drug/materials
to participant*
3.8% 1 3.8% 1 46.2% 12 3.8% 1 42.3% 11 26

187
Q7 - Approximately when was/will the first fully decentralized clinical trial (fully
virtual) conducted/be conducted at your company?
# Answer % Count
1 Was conducted more than 5 years ago 0.0% 0
2 Was conducted within the last 3-5 years 21.4% 3
3 Was conducted within the last 2 years 21.4% 3
4 Will be conducted within the next 2 years 50.0% 7
5 Will be conducted within the next 3 or more years 7.1% 1
Total 100% 14

Q8 - Approximately when was/will the first clinical trial conducted/be conducted
utilizing a hybrid approach to decentralized clinical trials at your company?
# Answer % Count
1 Was conducted more than 5 years ago 4.0% 1
2 Was conducted within the last 3-5 years 12.0% 3
3 Was conducted within the last 2 years 32.0% 8
4 Will be conducted within the next 2 years 36.0% 9
5 Will be conducted within the next 3 or more years 16.0% 4
Total 100% 25

188
Q30 - Rank the following approaches to decentralized clinical trials in order of
implementation priority, where #1 would be considered the highest priority in your
company. To rank, drag and drop each priority to sort #1 priority at the top of the
list and the lowest priority at the bottom. Note: the choices listed below with an
asterisk (*) are meant to be options that may be used outside of a fully
decentralized/virtual clinical trial.
# Question 1 2 3 4 5 6
Tota
l
1
Fully
decentralized/virt
ual clinical trial
8.7% 2 4.3% 1
13.0
%
3 8.7% 2 0.0% 0
65.2
%
1
5
23
2
Virtual trial site
plus traditional
sites
26.1
%
6
21.7
%
5
17.4
%
4
13.0
%
3
17.4
%
4 4.3% 1 23
3 Telemedicine*
30.4
%
7 8.7% 2
17.4
%
4
21.7
%
5
17.4
%
4 4.3% 1 23
4
Mobile healthcare
provider*
0.0% 0
26.1
%
6
39.1
%
9
21.7
%
5
13.0
%
3 0.0% 0 23
5
Local healthcare
provider*
4.3% 1
26.1
%
6 4.3% 1
26.1
%
6
26.1
%
6
13.0
%
3 23
6
Direct shipment
of study
drug/materials to
participant*
30.4
%
7
13.0
%
3 8.7% 2 8.7% 2
26.1
%
6
13.0
%
3 23

189
Q9 - Rank the following organizational challenges/barriers that limit the
implementation of decentralized clinical trial approaches for interventional trials in
your company. To rank, drag and drop each challenge to sort with the #1 challenge
moved to the top of the list and the least challenging at the bottom of the list.
# Question 1 2 3 4 5 6 7
To
tal
1
Unclear Regulatory
requirements/guidan
ce/compliance
expectations
36.
4%
1
6
22.
7%
1
0
18.
2%
8
13.
6%
6
6.8
%
3
2.3
%
1
0.0
%
0 44
2
Insufficient
organizational
readiness (i.e.,
know-how,
processes,
templates, etc)
27.
3%
1
2
13.
6%
6
27.
3%
1
2
22.
7%
1
0
4.5
%
2
4.5
%
2
0.0
%
0 44
3
Unclear value
proposition (i.e.,
reduction in time,
positive return on
investment)
11.
4%
5
4.5
%
2
13.
6%
6
20.
5%
9
29.
5%
1
3
9.1
%
4
11.
4%
5 44
4
Concern about data
privacy/security
4.5
%
2
6.8
%
3
13.
6%
6
11.
4%
5
27.
3%
1
2
13.
6%
6
22.
7%
1
0
44
5
Lack of company
support/authority to
implement
2.3
%
1
11.
4%
5
6.8
%
3
15.
9%
7
15.
9%
7
31.
8%
1
4
15.
9%
7 44
6
Risk averse
company
mindset/culture
4.5
%
2
11.
4%
5
13.
6%
6
6.8
%
3
11.
4%
5
22.
7%
1
0
29.
5%
1
3
44
7
Concern about
regulatory
acceptability of
data/study results
13.
6%
6
29.
5%
1
3
6.8
%
3
9.1
%
4
4.5
%
2
15.
9%
7
20.
5%
9 44

190
Q10 - Describe how influential the following feasibility factors have been or would
be in the decision to implement any decentralized clinical trial approaches in your
company.
# Question
No
influence
Some
influence
A lot of
influence
Not sure Total
1
Ability to identify studies where
endpoints can be captured outside
of a clinic
9.8% 4 17.1% 7 70.7% 29 2.4% 1 41
2
Ability to validate mobile device
collection for regulatory acceptance
4.9% 2 26.8% 11 63.4% 26 4.9% 2 41
3
Enough lead time is available to
ensure digital endpoints can be
justified and validated for use in a
pivotal trial
2.5% 1 37.5% 15 57.5% 23 2.5% 1 40
4
Procedures requiring specialized
equipment or assessments, such as
imaging or biopsies
4.9% 2 34.1% 14 53.7% 22 7.3% 3 41

Characteristics of the
investigational product requiring
specialized handling or
administration
7.3% 3 26.8% 11 65.9% 27 0.0% 0 41

Route of administration of
investigational product
14.6% 6 34.1% 14 48.8% 20 2.4% 1 41

191
Q11 - The following organizational factors have been considered to contribute to the
decision to implement decentralized clinical trials (DCT) or hybrid approaches to
DCT. Rate the importance of each factor in influencing the decision to implement a
DCT or hybrid approach to DCT at your company.
# Question
Not
Important
Somewhat
not
important
Neutral
Somewhat
important
Important Total
1
Corporate
strategy/culture
supporting
innovative
approaches
0.0% 0 7.3% 3 14.6% 6 34.1% 14 43.9% 18 41
2
Leadership
supportive of
innovative
approaches
0.0% 0 2.4% 1 4.9% 2 22.0% 9 70.7% 29 41
3
Effort/cost to
develop tools /
processes
0.0% 0 7.3% 3 9.8% 4 36.6% 15 46.3% 19 41
4
New skill sets
needed
2.4% 1 4.9% 2 19.5% 8 51.2% 21 22.0% 9 41
5
Potential to impact
current
organizational
structure
4.9% 2 17.1% 7 36.6% 15 26.8% 11 14.6% 6 41

Potential for a
long-term return
on investment
2.4% 1 4.9% 2 7.3% 3 39.0% 16 46.3% 19 41

Potential for
competitive
advantage
0.0% 0 4.9% 2 7.3% 3 22.0% 9 65.9% 27 41

192
Q12 - How important are the following external factors in influencing the decision
to adopt decentralized clinical trials or hybrid approaches of a decentralized clinical
trial at your company?
# Question
Not
important
Somewhat
not
important
Neutral
Somewhat
important
Important Total
1
FDA support of
approach
0.0% 0 0.0% 0 0.0% 0 15.0% 6 85.0% 34 40
2
Regulatory authority
support outside the
US
0.0% 0 2.5% 1 2.5% 1 27.5% 11 67.5% 27 40
3
Availability of
specific
regulation/guidance
on decentralized
approaches
0.0% 0 5.0% 2 5.0% 2 47.5% 19 42.5% 17 40
4
Ability to maintain
relationship with key
opinion
leaders/investigators
5.0% 2 5.0% 2 15.0% 6 35.0% 14 40.0% 16 40
5
Ability to maintain
relationship with
traditional study sites
5.0% 2 5.0% 2 12.5% 5 45.0% 18 32.5% 13 40

Positive experience
for participants/care
givers
0.0% 0 0.0% 0 5.1% 2 23.1% 9 71.8% 28 39

Security and/or
privacy of data
2.5% 1 0.0% 0 12.5% 5 7.5% 3 77.5% 31 40

Higher retention rate
of trial participants
0.0% 0 0.0% 0 7.5% 3 25.0% 10 67.5% 27 40

Faster trial enrollment
rate
0.0% 0 2.5% 1 5.0% 2 20.0% 8 72.5% 29 40

Increase in diversity
of participants
2.5% 1 2.5% 1 10.0% 4 32.5% 13 52.5% 21 40

193
Q13 - Choose which clinical trial approach your company would generally consider
using for each of the following types of interventional clinical studies. Check all that
might apply for each type of study, understanding that decisions at an individual
study level may depend on other factors as well. Note: the choices listed below with
an asterisk (*) are meant to be options that may be used outside of a fully
decentralized/virtual clinical trial.
#
Questi
on
Fully
decentraliz
ed/ virtual
clinical
trial
Virtual
site plus
tradition
al sites
Telemedici
ne*
Mobile
HCP*
Local
HCP*
Direct
shipment
of study
drug/
materials
to
participa
nt*
Traditio
nal trial
conduct
Tot
al
7
Post-
market
study
14.7% 16
15.6
%
1
7
15.6% 17
14.7
%
1
6
15.6
%
1
7
14.7
%
1
6
9.2%
1
0
109
6
Long-
term
safety
study
13.5% 14
15.4
%
1
6
15.4% 16
14.4
%
1
5
16.3
%
1
7
15.4
%
1
6
9.6%
1
0
104
5
Pivotal
study
for a
market
ed drug
7.7% 7
17.6
%
1
6
15.4% 14
14.3
%
1
3
16.5
%
1
5
14.3
%
1
3
14.3
%
1
3
91

Pragma
tic
study
16.1% 14
14.9
%
1
3
16.1% 14
13.8
%
1
2
13.8
%
1
2
13.8
%
1
2
11.5
%
1
0
87
1
Healthy
volunte
er
study
10.6% 9
15.3
%
1
3
14.1% 12
15.3
%
1
3
10.6
%
9
11.8
%
1
0
22.4
%
1
9
85
4
Pivotal
study
for a
non-
market
ed drug
1.4% 1
17.1
%
1
2
14.3% 10
14.3
%
1
0
15.7
%
1
1
11.4
%
8
25.7
%
1
8
70
3
Proof
of
concept
study
or
dose-
finding
study
3.6% 2
9.1
%
5 9.1% 5
14.5
%
8
18.2
%
1
0
10.9
%
6
34.5
%
1
9
55
2
First-
in-
human
patient
study
2.9% 1
5.9
%
2 8.8% 3
8.8
%
3
8.8
%
3 5.9% 2
58.8
%
2
0
34

194
Q14 - Choose which clinical trial approach your company would generally consider
using for each of the following location of conduct or procedural requirements of an
interventional clinical study. Check all that might apply for each location type and
procedural requirement, understanding that decisions at an individual study level
may depend on other factors as well. Note: the choices listed below with an asterisk
(*) are meant to be options that may be used outside of a fully decentralized/virtual
clinical trial.
#
Questi
on
Fully
decentrali
zed/
virtual
clinical
trial
Virtual
site plus
tradition
al sites
Telemedic
ine*
Mobile
HCP*
Local
HCP*
Direct
shipmen
t of
study
drug/
material
s to
participa
nt*
Traditio
nal trial
conduct
Tot
al
5
Requir
es
biopsy
or
invasiv
e
proced
eure
20.0
%
4
50.0
%
1
0
50.0
%
10
50.
0%
1
0
55.
0%
1
1
50.0
%
1
0
100.
0%
2
0
20
2
Only
outside
US
21.1
%
4
42.1
%
8
57.9
%
11
42.
1%
8
47.
4%
9
47.4
%
9
89.5
%
1
7
19
4
Requir
es
imagin
g
25.0
%
5
60.0
%
1
2
65.0
%
13
55.
0%
1
1
70.
0%
1
4
55.0
%
1
1
85.0
%
1
7
20
1
US
only
60.0
%
12
95.0
%
1
9
65.0
%
13
65.
0%
1
3
70.
0%
1
4
70.0
%
1
4
80.0
%
1
6
20
3
Global
study
with
US
sites
30.0
%
6
100.
0%
2
0
65.0
%
13
55.
0%
1
1
65.
0%
1
3
55.0
%
1
1
75.0
%
1
5
20

195
Q15 - Choose which clinical trial approach your company would generally consider
using for each of the following population types included in an interventional
clinical study. Check all approaches that might apply for each population type,
understanding that decisions at an individual study level may depend on other
factors as well. Note: the choices listed below with an asterisk (*) are meant to be
options that may be used outside of a fully decentralized/virtual clinical trial.
#
Questi
on
Fully
decentrali
zed/
virtual
clinical
trial
Virtual
site plus
traditio
nal sites
Telemedic
ine*
Mobile
HCP*
Local
HCP*
Direct
shipment
of study
drug /
material
s to
participa
nt*
Traditio
nal trial
conduct
Tot
al
3
Depend
ent
upon
caregiv
ers
45.0
%
9
95.0
%
1
9
75.0
%
15
80.0
%
1
6
90.0
%
1
8
75.0
%
1
5
70.0
%
1
4
20
4
Relativ
ely
healthy
with
low
risk
disease
68.4
%
13
89.5
%
1
7
84.2
%
16
73.7
%
1
4
78.9
%
1
5
84.2
%
1
6
57.9
%
1
1
19
6
Mobile
health
platfor
ms
commo
nly
used
with
disease
42.1
%
8
78.9
%
1
5
78.9
%
15
73.7
%
1
4
78.9
%
1
5
63.2
%
1
2
63.2
%
1
2
19
1
Rare
disease
60.0
%
12
85.0
%
1
7
60.0
%
12
70.0
%
1
4
75.0
%
1
5
70.0
%
1
4
80.0
%
1
6
20
2
Low
mobilit
y
capabil
ities
50.0
%
10
90.0
%
1
8
75.0
%
15
75.0
%
1
5
75.0
%
1
5
80.0
%
1
6
80.0
%
1
6
20
5
Modera
te risk
disease
requiri
ng
regular
check-
ups
15.0
%
3
75.0
%
1
5
75.0
%
15
70.0
%
1
4
75.0
%
1
5
60.0
%
1
2
90.0
%
1
8
20

196
Q16 - Choose which decentralized clinical trial approach your company would
generally consider using for each of the following characteristics of a product
evaluated in an interventional clinical study. Check all approaches that might apply
for each characteristic, understanding that decisions at an individual study level
may depend on other factors as well. Note: the choices listed below with an
asterisk (*) are meant to be options that may be used outside of a fully
decentralized/virtual clinical trial.
# Question
Fully
decentrali
zed/
virtual
clinical
trial
Virtual
site plus
tradition
al sites
Telemedici
ne*
Mobile
HCP*
Local
HCP*
Direct
shipment
of study
drug/
materials
to
participa
nt*
Tradition
al trial
conduct
Tot
al
4
Product
requiring
direct
oversight
by a
healthcare
provider
(such as an
infusion)
5.3% 1
36.8
%
7
36.8
%
7
57.9
%
1
1
68.4
%
1
3
36.8
%
7
100.
0%
1
9
19
5
Product
requires
specialized
handling,
such as
cold chain
manageme
nt
17.6
%
3
35.3
%
6
35.3
%
6
35.3
%
6
47.1
%
8
17.6
%
3
100.
0%
1
7
17
2
Product
that is
moderate/h
igher risk
from a
safety
perspective
15.8
%
3
42.1
%
8
47.4
%
9
52.6
%
1
0
63.2
%
1
2
26.3
%
5
94.7
%
1
8
19
1
Product
that is low
risk from a
safety
perspective
78.9
%
15
89.5
%
1
7
84.2
%
16
78.9
%
1
5
84.2
%
1
6
84.2
%
1
6
68.4
%
1
3
19
3
Product
that can be
self-
administere
d by the
participant
or a
caregiver
68.4
%
13
84.2
%
1
6
78.9
%
15
68.4
%
1
3
78.9
%
1
5
89.5
%
1
7
57.9
%
1
1
19

197
Q17 - Have you discussed the use of a fully decentralized clinical trial or a hybrid
approach to a decentralized clinical trial with the FDA?
# Answer % Count
1 No 65.0% 13
2 Discussed with a specific review division 5.0% 1
3 Discussed with multiple review divisions 0.0% 0
4 Discussed with a central division 15.0% 3
5 Not sure 15.0% 3
Total 100% 20

Q18 - Based on the outcome of the discussions with FDA, rate the level to which you
agree with the following statements related to feedback received from FDA on
decentralized approaches to clinical trials.
# Question Disagree
Neither
disagree
nor agree
Agree
Not
applicable
Total
1 Generally in favor 0.0% 0 25.0% 1 75.0% 3 0.0% 0 4
2
Transparent advice
provided
0.0% 0 50.0% 2 50.0% 2 0.0% 0 4
3
Gave sufficient
information for
decision-making
0.0% 0 75.0% 3 25.0% 1 0.0% 0 4
4
Gave opportunity for
additional follow-
up/discussion
0.0% 0 50.0% 2 50.0% 2 0.0% 0 4

Yielded a clear
understanding of
potential impact to
marketing application
and/or labeling claims
0.0% 0 50.0% 2 50.0% 2 0.0% 0 4

Gave sufficient advice
to ensure acceptability
of data to support a
marketing application
0.0% 0 50.0% 2 50.0% 2 0.0% 0 4

198
Q19 - Have you discussed the use of a fully decentralized clinical trial or hybrid
approaches to a decentralized clinical trial with trial participants and/or their
caregivers? Check all that apply.
#
Have you discussed the use of a fully decentralized clinical trial or hybrid
approaches to a decentralized clinical trial with trial participants and/or their
caregivers? Check all that apply.
Count
1
Have you discussed the use of a fully decentralized clinical trial or hybrid
approaches to a decentralized clinical trial with trial participants and/or their
caregivers? Check all that apply.
20.0
# Answer % Count
1 No 19.4% 6
2
Obtained feedback/plan to obtain feedback prior to designing clinical
trial
12.9% 4
3
Obtained feedback/plan to obtain feedback while designing clinical
trial
25.8% 8
4
Obtained feedback/plan to obtain feedback during the conduct of the
trial
19.4% 6
5 Obtained feedback/plan to obtain feedback after conduct of the trial 9.7% 3
6 Not sure 12.9% 4
Total 100% 31
Q20 - Based on the discussions with participants and/or their caregivers, rate the
level to which you agree with the following statements about participant/caregivers
opinion regarding decentralized clinical trial approaches.
# Question Disagree
Neither
agree nor
disagree
Agree
Not
applicable
Total
1
Generally in favor of the
approach
0.0% 0 30.0% 3 70.0% 7 0.0% 0 10
2
Confirmed burden of
participation was/would
be decreased
0.0% 0 10.0% 1 90.0% 9 0.0% 0 10
3
Confirmed positive
impact on retention
0.0% 0 30.0% 3 70.0% 7 0.0% 0 10
4
Expressed willingness to
participant in trial using
decentralized approach
0.0% 0 10.0% 1 90.0% 9 0.0% 0 10

Mobile technology
was/is easy to use
30.0% 3 20.0% 2 50.0% 5 0.0% 0 10

Training was/is
sufficient
0.0% 0 50.0% 5 40.0% 4 10.0% 1 10

Felt/would feel
sufficiently supported
during the trial
0.0% 0 10.0% 1 90.0% 9 0.0% 0 10

199

Q26 - Describe any positive experiences you have had with using a decentralized
approach to conducting clinical trials.
Describe any positive experiences you have had with using a decentralized approach to
conducting clinical trials.
Ease of enrollment.
we are in the middle of conducting one fully virtual and starting 3 hybrid studies. It is
exciting and the organization is gearing up quickly. it's tough to keep up with the
technology demands. the use of RWD to find patients has been really positive and the
colelction of data is going well via actigraphy.
EPRO is easy to use and fully validated
A hybrid approach is both patient and site-centric - allowing technology to complement
the process while maintain the human element important to patients first and foremost.
They provide patient accessible and can be ran with less resources than traditional
trials. They are convenient for the patient.

Q27 - Describe the most challenging aspect of implementing a fully decentralized
clinical trial.
Describe the most challenging aspect of implementing a fully decentralized clinical
trial.
Leadership and sponsor buy in
legal hurdles internally
-many of our trials are global thus having an approach that can be implemented
globally -lack of internal procedures/position to support -lack of operational guidance
from regulatory authorities globally (e.g. guidance to maintain PI oversight but how is
that done in practice when trial is decentralized)
Any trial that is invasive or requires much equipment would be hard. It also may be
hard for a blinded trial.

200
Q28 - Is there anything else you would like to comment on related to challenges or
benefits of decentralized clinical trials?
Is there anything else you would like to comment on related to challenges or benefits of
decentralized clinical trials?
I believe this is ripe for "fast followers", but it will take a few Big Dogs to run
successful studies, and most importantly, demonstrate a clear advantage (e.g. subject
retention, ease of enrolling in especially tough patient populations, overall speed to
filing) to get people to move. Large companies are rigid and avoid dramatic change.
They'll need bait.
n
Should utilized as much as possible to more closely simulate real world usage
Regulatory acceptability of data is paramount and GCP concordance documentation
Need more information at this time.
Education and awareness of the logistics and the pros/cons is lacking.
Nothing to add
Regulations

201
Appendix C. Rank Order Calculations
Appendix C Table 1: Rank of Organizational Challenges/Barriers (Q9), Overall
and By Size of Company (Q24)
Q9 - Rank the following organizational challenges/barriers that limit the implementation
of decentralized clinical trial approaches for interventional trials in your company. To
rank, drag and drop each challenge to sort with the #1 challenge moved to the top of the
list and the least challenging at the bottom of the list.
OVERALL RESULTS
Question 1 2 3 4 5 6 7 Total
Unclear Regulatory
requirements/guidance/compliance
expectations
16 10 8 6 3 1 0 44
Insufficient organizational readiness
(i.e., know-how, processes,
templates, etc)
12 6 12 10 2 2 0 44
Concern about regulatory
acceptability of data/study results
6 13 3 4 2 7 9 44
Unclear value proposition (i.e.,
reduction in time, positive return on
investment)
5 2 6 9 13 4 5 44
Concern about data privacy/security 2 3 6 5 12 6 10 44
Lack of company support/authority
to implement
1 5 3 7 7 14 7 44
Risk averse company
mindset/culture
2 5 6 3 5 10 13 44

Organizational Challenges/Barriers Rank Score Ranking
Unclear Regulatory requirements/guidance/compliance
expectations
247 1
Insufficient organizational readiness (i.e., know-how,
processes, templates, etc)
230 2
Concern about regulatory acceptability of data/study
results
180 3
Unclear value proposition (i.e., reduction in time, positive
return on investment)
165 4
Concern about data privacy/security 140 5
Lack of company support/authority to implement 136 6
Risk averse company mindset/culture 134 7

BY SIZE OF COMPANY
SMALL COMPANY

202
Organizational
Challenges/Barriers
1 2 3 4 5 6 7 Total Rank
Score
Ranking
Unclear Regulatory
requirements/guidance/compliance
expectations
6 4 2 2 2 0 0 16 90 1
Insufficient organizational readiness
(i.e., know-how, processes,
templates, etc)
5 2 5 3 1 0 0 16 87 2
Unclear value proposition (i.e.,
reduction in time, positive return on
investment)
3 0 3 5 3 2 0 16 69 3
Concern about data privacy/security 1 0 2 2 3 4 4 16 46 7
Lack of company support/authority
to implement
0 1 2 2 4 5 2 16 48 6
Risk averse company
mindset/culture
1 3 1 0 2 4 5 16 49 5
Concern about regulatory
acceptability of data/study results
0 6 1 2 1 1 5 16 59 4

MID-SIZED COMPANY
Organizational
Challenges/Barriers
1 2 3 4 5 6 7 Total Rank
Score
Ranking
Unclear Regulatory
requirements/guidance/compliance
expectations
7 3 1 2 1 0 0 14 83 1
Insufficient organizational readiness
(i.e., know-how, processes,
templates, etc)
5 1 4 2 1 1 0 14 74 2
Unclear value proposition (i.e.,
reduction in time, positive return on
investment)
1 0 0 4 3 1 5 14 39 7
Concern about data privacy/security 0 1 3 2 5 1 2 14 48 4
Lack of company support/authority
to implement
0 4 0 1 2 4 3 14 45 5
Risk averse company
mindset/culture
0 0 4 1 2 4 3 14 41 6
Concern about regulatory
acceptability of data/study results
1 5 2 2 0 3 1 14 62 3

LARGE COMPANY
Organizational
Challenges/Barriers
1 2 3 4 5 6 7 Total Rank
Score
Ranking
Unclear Regulatory
requirements/guidance/compliance
expectations
3 3 5 2 0 1 0 14 74 1

203
Organizational
Challenges/Barriers
1 2 3 4 5 6 7 Total Rank
Score
Ranking
Insufficient organizational readiness
(i.e., know-how, processes,
templates, etc)
2 3 3 5 0 1 0 14 69 2
Unclear value proposition (i.e.,
reduction in time, positive return on
investment)
1 2 3 0 7 1 0 14 57 4
Concern about data privacy/security 1 2 1 1 4 1 4 14 46 5
Lack of company support/authority
to implement
1 0 1 4 1 5 2 14 43 7
Risk averse company
mindset/culture
1 2 1 2 1 2 5 14 44 6
Concern about regulatory
acceptability of data/study results
5 2 0 0 1 3 3 14 59 3

204
Appendix C Table 2: Rank of Implementation Priority for Decentralized
Approaches (Q30), Overall and By Size of Company (Q24)
Q30 - Rank the following approaches to decentralized clinical trials in order of
implementation priority, where #1 would be considered the highest priority in your
company. To rank, drag and drop each priority to sort #1 priority at the top of the list
and the lowest priority at the bottom. Note: the choices listed below with an asterisk (*)
are meant to be options that may be used outside of a fully decentralized/virtual clinical
trial.
OVERALL RESULTS
Question 1 2 3 4 5 6 Tota
l
Fully decentralized/virtual clinical trial 2 1 3 2 0 15 23
Virtual trial site plus traditional sites 6 5 4 3 4 1 23
Telemedicine* 7 2 4 5 4 1 23
Mobile healthcare provider* 0 6 9 5 3 0 23
Local healthcare provider* 1 6 1 6 6 3 23
Direct shipment of study drug/materials
to participant*
7 3 2 2 6 3 23

Approach Rank Score Ranking
Fully decentralized/virtual clinical trial 50 6
Virtual trial site plus traditional sites 95 1
Telemedicine* 92 2
Mobile healthcare provider* 87 3
Local healthcare provider* 73 5
Direct shipment of study drug/materials to
participant*
86 4

205
BY SIZE OF COMPANY
Small Company 1 2 3 4 5 6 Total Rank
Score
Ranking
Fully decentralized/virtual
clinical trial
0 0 0 0 0 4 4 4 6
Virtual trial site plus
traditional sites
2 0 1 1 0 0 4 19 1
Telemedicine* 2 1 0 0 1 0 4 19 1
Mobile healthcare provider* 0 1 2 1 0 0 4 16 3
Local healthcare provider* 0 1 1 1 1 0 4 14 4
Direct shipment of study
drug/materials to participant*
0 1 0 1 2 0 4 12 5
Mid-Sized Company 1 2 3 4 5 6 Total Rank
Score
Ranking
Fully decentralized/virtual
clinical trial
0 0 1 2 0 7 10 17 6
Virtual trial site plus
traditional sites
1 4 1 1 3 0 10 39 3
Telemedicine* 3 0 3 2 2 0 10 40 2
Mobile healthcare provider* 0 3 5 2 0 0 10 41 1
Local healthcare provider* 1 3 0 3 2 1 10 35 5
Direct shipment of study
drug/materials to participant*
5 0 0 0 3 2 10 38 4
Large Company 1 2 3 4 5 6 Total Rank
Score
Ranking
Fully decentralized/virtual
clinical trial
2 1 2 0 0 4 9 29 5
Virtual trial site plus
traditional sites
3 1 2 1 1 1 9 37 1
Telemedicine* 2 1 1 3 1 1 9 33 3
Mobile healthcare provider* 0 2 2 2 3 0 9 30 4
Local healthcare provider* 0 2 0 2 3 2 9 24 6
Direct shipment of study
drug/materials to participant*
2 2 2 1 1 1 9 36 2

206
Appendix D. Cross-tabulations
Appendix D Table 1: Cross-Tabulation of Implementation Stage of
Decentralized Clinical Trial (Q4 and Q5) by Size of
Company (Q24)

Q24: Which statement best
describes the size of your
organization?
Total Small Mid-
sized
Large
Q4: Which
statement best
describes the
implementation
stage for fully
decentralized
clinical trials
(fully virtual
trial) at your
company?
Actively seeking information, not
ready to make a decision, may pilot in
the future
4 0 1 3
Completing pilot, assessing further
implementation in a case-by-case
manner
5 0 3 2
Exploring (have a basic understanding,
have not actively pursued)
14 5 3 6
Have implemented
processes/procedures formally (does
not mean all studies need to implement
a decentralized approach)
7 1 2 4
I am not sure 3 2 0 1
Not considering at this time 16 9 6 1
Resources assigned and corporate
initiative has started, will pilot in the
future
2 0 0 2
Actively seeking information, not
ready to make a decision, may pilot in
the future
8% 0% 7% 16%
Completing pilot, assessing further
implementation in a case-by-case
manner
10% 0% 20% 11%
Exploring (have a basic understanding,
have not actively pursued)
27% 29% 20% 32%
Have implemented
processes/procedures formally (does
not mean all studies need to implement
a decentralized approach)
14% 6% 13% 21%
I am not sure 6% 12% 0% 5%
Not considering at this time 31% 53% 40% 5%
Resources assigned and corporate
initiative has started, will pilot in the
future
4% 0% 0% 11%

207

Q24: Which statement best
describes the size of your
organization?
Total Small Mid-
sized
Large
Q5: Which statement best
describes the
implementation stage for
a hybrid approach to
decentralized clinical
trials at your company?
For example, portions of
a study may be conducted
virtually.
Actively seeking information,
not ready to make a decision,
may pilot in the future
7 3 2 2
Completing pilot, assessing
further implementation in a
case-by-case manner
3 0 2 1
Exploring (have a basic
understanding, have not
actively pursued)
12 5 3 4
Have implemented
processes/procedures formally
(does not mean all studies
need to implement a hybrid
approach to decentralized
trials)
13 2 6 5
I am not sure 4 2 0 2
Not considering at this time 6 5 1 0
Resources assigned and
corporate initiative has started,
will pilot in the future
4 0 1 3

Actively seeking information,
not ready to make a decision,
may pilot in the future
14% 18% 13% 12%
Completing pilot, assessing
further implementation in a
case-by-case manner
6% 0% 13% 6%
Exploring (have a basic
understanding, have not
actively pursued)
24% 29% 20% 24%
Have implemented
processes/procedures formally
(does not mean all studies
need to implement a hybrid
approach to decentralized
trials)
27% 12% 40% 29%
I am not sure 8% 12% 0% 12%
Not considering at this time 12% 29% 7% 0%
Resources assigned and
corporate initiative has started,
will pilot in the future
8% 0% 7% 18%

208
Appendix D Table 2: Cross-Tabulation of Decentralized Approaches (Q6) by
Size of Company (Q24)
Q6 - Which statement best describes the decentralized approaches for an interventional study that
you have used or may consider using at your company? Note: the choices listed below with an
asterisk (*) are meant to be options that may be used outside of a fully decentralized/virtual
clinical trial.

Q24: Which statement best describes
the size of your organization?

Total Small
Mid-
sized Large
Fully decentralized/virtual
clinical trial
Total Count 26 5 10 11
Considering using 7 1 2 4
Have used 6 1 1 4
Not sure 5 0 2 3
Piloting 3 0 3 0
Will not use 5 3 2 0
Considering using 27% 20% 20% 36%
Have used 23% 20% 10% 36%
Not sure 19% 0% 20% 27%
Piloting 12% 0% 30% 0%
Will not use 19% 60% 20% 0%

Virtual site plus
traditional sites
Total Count 26 5 10 11
Considering using 14 4 3 7
Have used 4 1 1 2
Not sure 5 0 4 1
Piloting 3 0 2 1
Will not use 0 0 0 0
Considering using 54% 80% 30% 64%
Have used 15% 20% 10% 18%
Not sure 19% 0% 40% 9%
Piloting 12% 0% 20% 9%
Will not use 0% 0% 0% 0%

209

Q24: Which statement best describes
the size of your organization?

Total Small
Mid-
sized Large
Telemedicine*
Total Count 25 5 9 11
Considering using 11 2 4 5
Have used 6 2 0 4
Not sure 5 1 2 2
Piloting 3 0 3 0
Will not use 0 0 0 0
Considering using 44% 40% 44% 45%
Have used 24% 40% 0% 36%
Not sure 20% 20% 22% 18%
Piloting 12% 0% 33% 0%
Will not use 0% 0% 0% 0%

Mobile healthcare
provider*
Total Count 26 5 10 11
Considering using 13 3 6 4
Have used 6 2 1 3
Not sure 4 0 1 3
Piloting 3 0 2 1
Will not use 0 0 0 0
Considering using 50% 60% 60% 36%
Have used 23% 40% 10% 27%
Not sure 15% 0% 10% 27%
Piloting 12% 0% 20% 9%
Will not use 0% 0% 0% 0%

Local healthcare
provider*
Total Count 25 5 10 10
Considering using 8 1 4 3
Have used 9 4 2 3
Not sure 6 0 2 4
Piloting 2 0 2 0
Will not use 0 0 0 0
Considering using 32% 20% 40% 30%
Have used 36% 80% 20% 30%
Not sure 24% 0% 20% 40%
Piloting 8% 0% 20% 0%
Will not use 0% 0% 0% 0%

210

Q24: Which statement best describes
the size of your organization?

Total Small
Mid-
sized Large
Direct shipment of study
drug/materials to
participant*
Total Count 26 5 10 11
Considering using 12 3 6 3
Have used 11 2 4 5
Not sure 1 0 0 1
Piloting 1 0 0 1
Will not use 1 0 0 1
Considering using 46% 60% 60% 27%
Have used 42% 40% 40% 45%
Not sure 4% 0% 0% 9%
Piloting 4% 0% 0% 9%
Will not use 4% 0% 0% 9%

211
Appendix D Table 3: Cross-Tabulation of Knowledge of Decentralized
Approaches (Q2) by Size of Company (Q24)

Q24: Which statement best describes the size of your
organization?

Total Small Mid-sized Large
eConsent
21 6 4 11
32% 26% 19% 50%

ePRO/eCOA
39 11 12 16
59% 48% 57% 73%

Mobile data collection of digital
endpoints (beyond ePRO/eCOA)
25 6 7 12
38% 26% 33% 55%

Direct shipment of study drug
and other materials to participant
24 7 9 8
36% 30% 43% 36%

Local Healthcare Provider
29 9 10 10
44% 39% 48% 45%

Telemedicine
12 3 2 7
18% 13% 10% 32%

Mobile Healthcare Provider
18 6 6 6
27% 26% 29% 27%

Abstract (if available)

Abstract Decentralized clinical trials offer great potential to reduce the cost and time that it takes to obtain marketing authorization of a new drug. However, it is unclear how industry stakeholders perceive opportunities and barriers associated with the use of decentralized trials. This study evaluated how, why and at what rate decentralized clinical trials are being adopted by industry using a survey-based approach based on the diffusion of innovation framework. A total of 72 respondents with backgrounds in clinical development from a range of small and large pharmaceutical companies completed at least one question and 50% of respondents completed all questions. Half identified that their companies had decided to implement fully decentralized clinical trials and two-thirds to implement hybrid approaches. The primary barriers to implementation were lack of clear regulatory guidance and insufficient organizational readiness. Priorities for implementation included the use of virtual trial sites in additional to traditional trial sites, telemedicine, mobile healthcare providers and direct shipment of study drug or materials to the participant

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Asset Metadata

Creator Lau, Wendi Marie (author)

Core Title A survey of US industry views on implementation of decentralized clinical trials

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 07/12/2020

Defense Date 05/14/2020

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

Tag decentralized clinical trials,OAI-PMH Harvest,patient centric clinical trials,virtual clinical trials

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Pire-Smerkanich, Nancy (committee chair), Armstrong, April (committee member), Church, Terry David (committee member), Richmond, Frances (committee member)

Creator Email wendilau@sbcglobal.net,wendilau@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-327013

Unique identifier UC11665986

Identifier etd-LauWendiMa-8654.pdf (filename),usctheses-c89-327013 (legacy record id)

Legacy Identifier etd-LauWendiMa-8654.pdf

Dmrecord 327013

Document Type Dissertation

Rights Lau, Wendi Marie

Type texts

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

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

Repository Name University of Southern California Digital Library

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