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Sharing the results of clinical trials: industry views on disclosure of data from industry-sponsored clinical research

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Sharing the results of clinical trials: industry views on disclosure of data from industry-sponsored clinical research

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SHARING THE RESULTS OF CLINICAL TRIALS:
INDUSTRY VIEWS ON DISCLOSURE OF DATA FROM INDUSTRY-SPONSORED
CLINICAL RESEARCH
by
Grant S Griffin

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 2017

Copyright 2017 Grant S Griffin
2
DEDICA TION...
I wish to honor my wife, Sarena Monique Griffin, and my parents, Gary Lee Griffin and
Kristin Alexis Griffin, for their unconditional support and demonstration of the ideals of
education, work ethic, and resolve that have driven this dissertation forward.

3
ACKNOWLEDGMENTS
First, I wish to acknowledge my committee members, including Drs. Nancy Pire-
Smerkanich, Mary Ellen Cosenza, Daryl Davies, and Michael Jamieson for their
invaluable questions, comments, and assistance with my survey. Second, I wish to
acknowledge fellow DRSc students, including members of my focus group, for providing
insights on stakeholders, frameworks, references, prospective respondents, and overall
support. On transparency in particular, the work of Dr. Martin Solberg, DRSc, paved the
way for my own contribution. Third, I wish to thank Dr. Randa Issa and the rest of the
terrific regulatory science staff that rendered the logistics of this work possible. Fourth, I
wish to call attention to the participation provided by the 77 industry professionals who
so generously completed my survey and thereby rendered me eligible to conduct my
research. Finally, and most importantly, I wish to acknowledge my advisor, Dr. Frances
Richmond, for her tremendous knowledge and keen insights, and ongoing guidance,
patience, and support. I will be forever grateful for her masterful direction of, and
unrelenting dedication to, her students.
4
TABLE OF CONTENTS
Dedication... ........................................................................................................................ 2
Acknowledgments............................................................................................................... 3
List of Tables ...................................................................................................................... 8
List of Figures ................................................................................................................... 10
Abstract…. ........................................................................................................................ 13
CHAPTER 1: Overview ............................................................................................ 14
1.1 Introduction .................................................................................................. 14
1.2 Statement of the Problem ............................................................................. 17
1.3 Purpose of the Study .................................................................................... 18
1.4 Importance of the Study ............................................................................... 19
1.5 Limitation, Delimitations, Assumptions ...................................................... 20
1.6 Organization of Thesis ................................................................................. 21
1.7 Definitions .................................................................................................... 22
CHAPTER 2: Literature Review .............................................................................. 26
2.1 Background to the Literature Review .......................................................... 26
2.2 Protecting Patient Rights .............................................................................. 27
2.2.1 Evolution of Patient Protection in Clinical Trials ........................... 27
2.2.2 Clinical Trial Regulation in the United States, 1938-1962 ............. 28
2.2.3 Emerging Considerations of Patient Privacy, 1970-2000 ............... 31
2.2.4 Privacy and Transparency in Europe .............................................. 34
5
2.2.5 Rebalancing the Privacy-Transparency Equation ........................... 35
2.2.5.1 The US Experience ............................................................ 35
2.2.5.2 The European Experience .................................................. 40
2.2.6 Increasing Pressure for Disclosure ................................................. 41
2.2.6.1 Events in the US ................................................................ 42
2.2.6.2 Events in the EU ................................................................ 45
2.2.7 A Comparison of the FDA and EMA Policies ............................... 57
2.3 Framing the Study of Clinical Trial Results Disclosure .............................. 64
2.3.1 Key Stakeholders ............................................................................ 65
2.3.1.1 Clinical Trial Participants and Patient Advocacy
Organizations ..................................................................... 68
2.3.1.2 Secondary Researchers, Legal Analysts and Associated
Advocacy Organizations .................................................... 70
2.3.1.3 Universities and Research Institutions ............................... 71
2.3.1.4 Sponsors............................................................................. 73
2.3.2 Framing the Study of Industry Views and Actions ......................... 79
2.3.3 Implementation Framework Applied to Industry Clinical
Transparency .................................................................................. 82
CHAPTER 3: Methodology ...................................................................................... 83
3.1 Stakeholder Analysis and Respondent Selection ......................................... 83
3.2 Survey Development .................................................................................... 83
6
3.3 Focus Group ................................................................................................. 84
3.4 Respondent Characteristics .......................................................................... 86
3.5 Survey Delivery ........................................................................................... 87
3.6 Survey Analysis ........................................................................................... 88
CHAPTER 4: Results................................................................................................ 89
4.1 Survey Distribution Analysis ....................................................................... 89
4.2 Profiles of Respondents ............................................................................... 90
4.3 Clinical Disclosure Implementation Practices ............................................. 98
4.4 Pharmaceutical Industry Clinical Disclosure Views .................................. 116
CHAPTER 5: Discussion ........................................................................................ 126
5.1 Clinical Data Disclosure and Implementation by Industry ........................ 126
5.2 Methodological Considerations ................................................................. 127
5.2.1 Delimitations ................................................................................ 127
5.2.2 Limitations .................................................................................... 130
5.2.2.1 Respondent Sampling and Response Rates ..................... 130
5.2.2.2 Development of the Survey Instrument ........................... 134
5.3 Maturity in Clinical Data Sharing Programs .............................................. 135
5.4 Practices and Views in Clinical Data Sharing Programs ........................... 138
5.5 Call for a Global Harmonization of Requirements .................................... 140
5.6 Disclosure of Clinical Data from Products in Development or
Abandoned ................................................................................................. 144
7
REFERENCES ............................................................................................................... 148
APPENDIX A: Final Version of Survey ........................................................................ 158
APPENDIX B: Survey Results Report ........................................................................... 172
APPENDIX C: Additional Tables and Cross Tabulations ............................................. 206

8
LIST OF TABLES
Table 1: Privacy Rule Acceptable Use or Disclosure of PHI ................................. 34
Table 2: Summary of ClinicalTrials.gov Results Database Modules ..................... 38
Table 3: The Path to EMA Data, Per the Nordic Cochrane Centre ........................ 49
Table 4: Roche Justifications for Not Disclosing Data ........................................... 51
Table 5: Focus Group Participants .......................................................................... 84
Table 6: Prospective Respondent Reasons for Not Starting and/or
Completing the Survey ............................................................................. 90
Table 7: Other Company Titles of Respondents ..................................................... 91
Table 8: Other Company Functional Roles of Respondents ................................... 93
Table 9: Other Company Functional Areas Responsible for Clinical
Disclosure ................................................................................................. 94
Table 10: Cross Tabulation of Company Size and Clinical Disclosure
Function .................................................................................................... 96
Table 11: Cross Tabulation of Additional Resources and Company Size .............. 100
Table 12: Other Company Mechanisms for Evaluating the Effectiveness of
Internal Clinical Data Sharing Programs ................................................ 102
Table 13: Other Clinical Data Sharing Frameworks Recognized by
Respondents ............................................................................................ 104
Table 14: Other Documents Required to Obtain Company Clinical Data .............. 108
Table 15: Other Types of Redacted Clinical Documents on Approved
Products Available for Company Disclosure .......................................... 112
9
Table 16: Cross Tabulation of Redaction Type and Company Size ....................... 113
Table 17: Other Company Clinical Data Sharing Platforms ................................... 115
Table 18: Cross Tabulation of Geographic Region and Clinical Disclosure
Experience............................................................................................... 206
Table 19: Cross Tabulation of Geographic Region and Familiarity with
EMA Policy ............................................................................................ 207
Table 20: Cross Tabulation of Geographic Region and Familiarity with FDA
Policy ...................................................................................................... 208
Table 21: Cross Tabulation of Geographic Region and Redaction Practices ......... 209
Table 22: Cross Tabulation of Company Title and Allocation of Resources ......... 210
Table 23: Cross Tabulation of Company Title and Medical Products
Experience............................................................................................... 211
Table 24: Cross Tabulation of Company Title and Clinical Disclosure
Experience............................................................................................... 212
Table 25: Cross Tabulation of In-Development/Abandoned Products and
Granularity of US FDA CSRs................................................................. 213
Table 26: Cross Tabulation of In-Development/Abandoned Products and
Granularity of EU MAA CSRs ............................................................... 214

10
LIST OF FIGURES
Figure 1: Potential Benefits of Sharing Clinical Trial Data ..................................... 63
Figure 2: Four Possible Models for Expanded Access to Participant-Level
Data ........................................................................................................... 64
Figure 3: Clinical Trial Data Sharing Stakeholders ................................................. 66
Figure 4: Comments by Stakeholder on EMA Policy 0070 ..................................... 67
Figure 5: MRCT Data Sharing Benchmarks ............................................................ 78
Figure 6: A Conceptual Framework for Implementation of Defined
Practices and Programs ............................................................................. 80
Figure 7: Stages of Implementation ......................................................................... 81
Figure 8: Company Titles of Respondents ............................................................... 91
Figure 9: Years of Experience of Respondents in the Medical Products
Industry ..................................................................................................... 92
Figure 10: Company Functional Roles of Respondents ............................................. 92
Figure 11: Company Functional Area Responsible for Clinical Disclosure .............. 94
Figure 12: Clinical Disclosure Experience of Respondents ....................................... 95
Figure 13: Size of Company by Employees ............................................................... 95
Figure 14: Size of Company Product Portfolio .......................................................... 97
Figure 15: Geographic Region(s) of Responsibility ................................................... 97
Figure 16: Familiarity with EMA and FDA Data Sharing Policies ........................... 98
Figure 17: Additional Resources for Clinical Disclosure ......................................... 100
11
Figure 18: Current Stage of Company in Fulfilling EMA and FDA
Requirements .......................................................................................... 101
Figure 19: Company Mechanism for Evaluating the Effectiveness of Internal
Clinical Data Sharing Program ............................................................... 102
Figure 20: Challenges to Company Implementation of Clinical Data Sharing
Programs ................................................................................................. 103
Figure 21: Familiarity of Respondents with Clinical Data Sharing
Frameworks............................................................................................. 104
Figure 22: Eligibility Requirements to Obtain Company Clinical Data .................. 105
Figure 23: Requesters of Company Clinical Data .................................................... 107
Figure 24: Documents Required to Obtain Company Clinical Data ........................ 108
Figure 25: Level of Documentation Required to Obtain Company Clinical
Data ......................................................................................................... 109
Figure 26: Company Reviewers of Requests for Clinical Data ............................... 110
Figure 27: Company Reviews Required to Disclose Clinical Data ......................... 110
Figure 28: Types of Redacted Clinical Documents on Approved Products
Available for Company Disclosure ......................................................... 111
Figure 29: Company Redaction Practices ................................................................ 113
Figure 30: Implemented Changes to Company CSR Templates to Reduce
Burden of Redacting CCI and IPD ......................................................... 114
Figure 31: Company Clinical Data Sharing Platforms ............................................. 115
Figure 32: Formats of Disclosed Company Clinical Data........................................ 116
12
Figure 33: EMA and FDA Requirements Have Changed Level of Detail
Included in Clinical Overviews, Clinical Summaries, and Clinical
Study Reports .......................................................................................... 117
Figure 34: Impact Clinical Data Transparency Rankings (Legal Compliance
and/or Ethical Conduct by Company and/or Drug) on Data
Sharing .................................................................................................... 118
Figure 35: Respondent Views on Whether Industry Should Support User
Fees to Help Fund Clinical Disclosure in Exchange for Benefits .......... 120
Figure 36: Respondents on Whether Clinical Data from Products in
Development or Abandoned (Unapproved) Should be Disclosed .......... 120
Figure 37: Respondents on Whether Preclinical Data from Products in
Development or Abandoned (Unapproved) Should be Disclosed .......... 121
Figure 38: Respondents for Penalizing Companies for Non-Compliance with
Clinical Disclosure Requirements ........................................................... 122
Figure 39: Respondent Comments on Improving Clinical Data Sharing ................. 124

13
ABSTRACT….
Prior to the 21
st
century, health authorities held the view that pharmaceutical regulatory
submissions for new marketing applications contain commercially confidential
information not to be disseminated to the public. In the new millennium, however,
secondary researchers and other stakeholders have compelled regulators to change those
policies to allow access and even to publish proactively clinical data that was previously
kept private. This research evaluated the way in which industry approaches and manages
the publication of clinical trial results to meet the new disclosure requirements. Drawing
on the information obtained by the literature review, a survey instrument was developed
to target pharmaceutical employees and contractors working in clinical disclosure.
Seventy seven of 98 respondents working in the clinical disclosure function who
expressed interest completed the survey. The results indicated that most pharmaceutical
companies, and by extension, clinical disclosure professionals, have accepted and even
advocated for the value of releasing clinical information to maximize data utility and
benefit stakeholders. While industry is acting diligently to retain influence over access to,
and use of, company clinical data, many respondents in this study also appeared receptive
to the further uses of clinical and even preclinical data to improve patient health and
safety. Further research could help to ascertain whether other pharmaceutical company
functions, including executive management, recognize clinical transparency as an
important business investment that has provided tangible benefits to patients and
shareholders.

14

CHAPTER 1: OVERVIEW
1.1 Introduction
[G]overnmental decisions, particularly regulatory decisions, should be
based on publicly available information… [P]eople affected by
governmental decisions have a right to know the basis on which they are
made. Anyone who questions the wisdom of a regulatory decision should
be able to examine the factual foundation of the decision. FDA
Commissioner Donald Kennedy, 1978 (FDA, 2010)
It is the common mission of health authorities globally to protect the public by evaluating
potentially risky healthcare products such as drugs, biologics, and medical devices prior
to their commercialization. During this premarket review, the regulatory authority must
judge the benefits and risks of a marketing application from the data with which it is
provided from the sponsoring company. Traditionally, it attempts to assure transparency
in its activities by having mechanisms to inform a diversity of stakeholders, including
other regulatory agencies, academia, industry, healthcare practitioners and patient
advocacy organizations, about the outcome and rationale for its approval decision.
Transparency is a means of “allowing others to see the truth, without trying to hide or
shade the meaning, or altering the facts to put things in a better light” (Oliver, 2004) and
supports “the availability and accessibility of relevant information about the functioning
of the polity” (Gerring & Thacker, 2004). Its end goal is directed toward “creating a
culture of candor, where we are really talking about the free flow of information within
an organization and between the organization and its many stakeholders, including the
public” (Bennis, Goleman, & O'Toole, 2008). It refers to “policies that are easily
15
understood, where information about the policy is available, where accountability is
clear, and where citizens know what role that they play in policy implementation”
(Finkelstein, 2000). In other words, transparency goes beyond the presence of laws,
regulations, or guidelines to illuminate their practice. Such openness engenders a sense of
trust in, and positive reputation for, the health authority amongst stakeholders. At the
same time, however, other important aspects of the regulator-industry relationship,
including protection of proprietary materials and adherence to patient privacy policies,
may place limits on the degree or scope of transparency. Accordingly, even in developed,
wealthy, and stable nations, it can be impossible to achieve full transparency without
disclosing information that damages or threatens commercial or patient interests to some
degree (Solberg, 2010).
Over the past decade, a major shift has been apparent in the level of transparency that
governments and society in the Western world appear to view as desirable for the
management of information about pharmaceutical products. Until the new millennium,
regulators had the policy that pharmaceutical regulatory submissions for new marketing
applications are confidential company information not to be released to the public. More
recently, however, regulators have changed those policies to allow access to clinical data
from submissions, which transcends the results that are publicly available. The driving
source for that change appears to derive, at least in part, from concerns that those
submissions may contain data that could illuminate safety or efficacy issues that
companies have either not detected by their analytical methods or have concealed.
Secondary analytical groups, such as members of the non-governmental organization
16
(NGO) Cochrane Collaboration, who use the data of others to perform additional
analyses or meta-analyses, were notable agents of change. Such researchers persistently
requested access to the clinical data contained in marketing submissions and became
vocal in publicizing their failed attempts to obtain clinical data. The tipping point
occurred in 2007 when the Nordic Cochrane Centre requested that the European
Medicines Agency (EMA) provide clinical study reports and related clinical study
protocols on two specific drugs so that it could conduct secondary research, a request
denied by EMA until the European Ombudsman intervened. The Ombudsman
challenged EMA either to provide access to the requested data or to provide a rationale
for withholding that access. After a contentious set of exchanges, in August 2010, EMA
capitulated to the demands of the Nordic Cochrane Center and identified that it would
provide access to the documents. In February 2011 the Nordic Cochrane Centre received
the information that it had requested (European Ombudsman, 2010). The experience,
however, encouraged EMA to reposition its view on data release by developing Policy
0070, which called for the proactive publication of clinical study reports (CSRs) (Peter C.
Gøtzsche, 2011).
Meanwhile, the US Food and Drug Administration (FDA) followed a somewhat different
approach in its efforts to further clinical transparency. Section 113 of the omnibus Food
and Drug Modernization Act of 1997 ("Food and Drug Administration Modernization
Act of 1997," 1997) required the registration of clinical trials for drugs intended to treat
serious or life-threatening medical conditions in a publicly accessible database, which
was operationalized by ClinicalTrials.gov in February 2000. Then, in 2004,
17
GlaxoSmithKline (GSK) settled a lawsuit from the New York Attorney General, who had
alleged it had kept safety data from the public. GSK agreed to publicly register its clinical
trials and disclose summary results (Miller, 2013). In 2007, the Food and Drug
Administration Amendments Act (FDAAA) expanded its clinical disclosure requirements
(Tse, Williams, & Zarin, 2009). Eventually, in 2013, the FDA requested public comments
on its own new transparency policy, which proposed to make de-identified preclinical
and clinical data from medical product submissions available to experts outside of the
Agency for review. Both the FDA and the EMA shared concerns with regard to
commercially confidential information. Both regulatory agencies were concerned about
the level of data release that they viewed as important down to the level of individual
study data, but grappled with the ways to maintain patient confidentiality through
painstaking and resource-intensive redaction. In the end, the regulatory agencies handed
that responsibility largely to the companies submitting the data, with certain requirements
to prevent over redaction or noncompliance. The details of these requirements are
presented below. What is clear, however, is that the new rules have transferred
significant new requirements for data release, as well as the resources required to ensure
compliance.
1.2 Statement of the Problem
It is clear that pharmaceutical firms have been placed in a position very different than that
even a decade ago with respect to how they manage their clinical trial data. Going
forward, it will be necessary for these companies to provide clinical study reports and
even individual de-identified patient data that will be subject to public and competitor
18
scrutiny. Different stakeholders could, in theory, use that data for many purposes.
Companies could use it to gain intelligence on developments of competitors or potential
acquisitions. Secondary researchers may tackle additional meta-analyses and hire
additional personnel to manage the increased workload. Personal injury attorneys may
have a more accessible means of obtaining information useful in medical product
litigation. Thus, sponsors may have to scrutinize their regulatory submissions to assure
that the data is provided in a way that establishes sufficient protections for private and
proprietary information, and yet contains the information regulators need for decision
making.
We have limited insight into the ways in which the pharmaceutical industry views and
manages the new rules related to clinical trial data transparency. Anecdotal information
or reports of the experiences of single companies comprise the vast majority of the
information that is currently available. However, to date there appears to be no study that
has attempted a more comprehensive assessment of those views. Further, little is known
about the strategies and methods used by companies to share clinical trial data with others
beyond the company. A thorough review of current industry disclosure practices provides
information that could be leveraged for the lawmaking, policymaking, and best practices
in the future.
1.3 Purpose of the Study
This research study assessed the way in which industry views and manages the
publication of clinical trial results to meet the new requirements related to transparency
and disclosure. A survey instrument was developed on the basis of findings in the
19
literature review. It was organized with reference to the implementation framework of
Fixsen and colleagues (Fixsen, Naoom, Blase, Friedman, & Wallace, 2005b). A focus
group of industry and academic experts familiar with this area of study were impaneled to
critique the survey and improve its clarity and validity. The finalized survey was
disseminated to approximately 98 pharmaceutical industry respondents in order to
capture information on the way that their companies are responding to the challenge and
to understand their views on the advantages and problems introduced by new
transparency rules.
1.4 Importance of the Study
This research attempted to support three significant outcomes. First, it provided a
systematic instrument that could be used to compare data from a range of organizations.
This data, in turn, may fuel ongoing conversations amongst stakeholders regarding
current rules and future directions for clinical trial data disclosure.
Second, this study provided a benchmark from which pharmaceutical sponsors may build
or revise company-specific practices, resulting in greater effectiveness, efficiency and
harmonization in clinical transparency measures. In addition, this research on current
practices attempted to call attention to particularly difficult aspects of clinical trial
disclosure. It also attempted to reveal whether current practices may be easily applied to
smaller pharmaceutical sponsors and academic centers, or whether different approaches
may better suit institutions that do not have the same level of funding in human resources
or financial capital.
20
Third, this study was intended to contribute to more effective and efficient laws,
regulations, and guidelines in the area of clinical transparency in the future. Lawmakers
and regulators trying to achieve certain central goals of clinical trial data disclosure may
bring especially valuable amendments in specific areas that are highlighted to have
problems under current rules. In addition, further research may use this study as a
baseline for the evaluation of future advances in the area.
1.5 Limitation, Delimitations, Assumptions
This study delimited the scope of study to pharmaceutical sponsors. However, the
research did not delimit its geographical focus. The US is the largest pharmaceutical
market in the world, and it can be advantageous to understand the specific views of this
constituency. However, the issue of clinical data disclosure is substantially driven by
policies set forth by the European Medicines Agency (EMA) and it is actively under
debate by other stakeholders in the European Union (EU). It is anticipated that
individuals in a highly multinational enterprise such as the typical pharmaceutical
company will be sensitive to both the requirements in the US and the EU. The survey
limited its examination to clinical trial disclosure and not to other forms of disclosure,
such as disclosure of relationships with healthcare professionals, which are also subject to
changing rules. Finally, although clinical trial registration disclosure is a prominent
element of clinical transparency, it was not the focal point of this study. Rather the study
focused on the new policies that address clinical data disclosure.
Several limitations were faced in this study. It was challenging to locate a fully
representative group of experts experienced in the relatively novel area of clinical trial
21
data disclosure. Judging strictly from the formal organizational hierarchy of many
companies, it is not as easy to identify thought leaders in this area. Such individuals work
in a variety of functional areas. Further, encouraging the participation of a sufficient
sample of individuals was difficult. Busy professionals must dedicate time and effort for
the benefit of the research, despite routine high-priority competing commitments. It is
plausible that some respondents attempted to answer survey questions on specific subject
matter for which they had little or no expertise, which may dilute the value of the data
that is obtained. The usefulness of the survey instrument to reflect appropriately the
important aspects of study is always of concern. The use of a focus group to critique the
survey helped to assure that the survey measured meaningful aspects of the problem.
Still, this study may be limited in its design or execution by the skill of the investigator
and the contributions of the focus group (McCracken, 1988). It is plausible to introduce
bias into the survey tool based on views developed from knowledge of current anecdotal
information or strongly held views of individuals close to the investigator or part of the
focus group. If the group is not sufficiently representative and knowledgeable, the value
of the resulting information about current industry tactical and strategic data disclosure
activities and a future transparency index or other tools may be limited (Solberg, 2010).
1.6 Organization of Thesis
The dissertation was organized into five chapters. Chapter 1 provides an introduction to
the research, statement of the problem, the purpose and importance of the research, and
the limitations, delimitations, and assumptions that should be taken into consideration in
evaluating the research. Chapter 2 presents a literature review that synthesizes the current
22
state of knowledge. Chapter 3 describes the research methodology devised for the study,
and Chapter 4 reports the results. Chapter 5 discusses the results, author opinions
emanating from the results, and recommendations for additional research.
1.7 Definitions
AAMC Association of American Medical Colleges
ACRP Association of Clinical Research Professionals
API Application Programming Interface
BI Bioethics International
BMJ British Medical Journal
CCI Commercially Confidential Information
CRF Case Report Form
CRO Contract Research Organization
CSR Clinical Study Report
CTTC Clinical Trial Transparency Certification
DFOI Division of Freedom of Information
DIA Drug Information Association
EASL European Association for the Study of the Liver
EC Ethics Committee
EFPIA European Federation of Pharmaceutical Industries and Associations
23
EMA European Medicines Agency
EPAR European Public Assessment Report
EU European Union
FDA Food and Drug Administration
FDAAA Food and Drug Administration Amendments Act
FDAMA Food and Drug Administration Modernization Act
FDASIA Food and Drug Administration Safety and Innovation Act of 2012
FDCA Food, Drug, and Cosmetic Act
FOIA Freedom of Information Act
FY Fiscal Year
GCP Good Clinical Practice
GSK GlaxoSmithKline
GTP Good Transparency Practice
HHS Department of Health and Human Services
HIPAA Health Insurance Portability and Accountability Act
HTA Health Technology Assessment
IAPO International Alliance of Patients’ Organizations
ICH International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
24
ID Identification
IND Investigational New Drug Application
IOM Institute of Medicine
IPD Individual Patient Data
IRB Institutional Review Board
MAA Marketing Authorisation Application
MAH Marketing Authorisation Holder
MHRA Medicines and Healthcare Products Regulatory Agency
MMR Measles, Mumps, and Rubella
MRCT Multi-Regional Clinical Trials Center at Harvard
NCA National Competent Authority
NEJM New England Journal of Medicine
NIH National Institutes of Health
NGO Non-Governmental Organization
NPRM Notice of Proposed Rulemaking
PHI Protected Health Information
PhRMA Pharmaceutical Research and Manufacturers of America
PLOS Public Library of Science
25
PMC Post Marketing Commitment
PMR Post Marketing Requirement
PPTA Plasma Protein Therapeutics Association
PRSM Program for Regulatory Science and Medicine
RAPS Regulatory Affairs Professionals Society
ROW Rest of World
SAP Statistical Analysis Plan
ToU Terms of Use
US United States
YODA Yale Open Data Access
26
CHAPTER 2: LITERATURE REVIEW
2.1 Background to the Literature Review
It is essential to systematically review the materials that are publicly available in order to
establish the state of the literature on clinical disclosure. The online USC library was
used to conduct a literature search of journal articles, books, and online references. Key
words were clinical transparency, clinical disclosure, clinical trial transparency,
clinical trial disclosure, clinical trial data transparency, and clinical trial data
disclosure. Any publications concerning transparency in general, the history of clinical
trial regulations, and patient privacy were also included. In addition, Google and the
same key words were used to conduct a literature search to obtain references. For the
purposes of this initial literature review, citations concerning clinical trial registration, as
opposed to clinical data disclosure, were retained but not summarized in the below
review. Publications that were not in English were excluded.
Initially, more than 800,000 citations were identified based on the key words above. The
following literature review is based on a survey of several hundred sources that included
the original citations, as well as works cited in the original citations. The list was
ultimately narrowed to approximately 100 bibliographic references. Of all materials,
Sharing Clinical Data: Maximizing Benefits, Minimizing Risk by the Institute of
Medicine and Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients
by Ben Goldacre provided comprehensive overviews of clinical disclosure stakeholders
and issues at hand. The FDA and EMA websites provided guidance documents and the
current thinking of the leading health authorities, while the Decision of the European
27
Ombudsman Closing His Inquiry Into Complaint 2560/2007/BEH Against the European
Medicines Agency provided a comprehensive overview of the case that shifted the
clinical disclosure landscape.
2.2 Protecting Patient Rights
2.2.1 Evolution of Patient Protection in Clinical Trials
Clinical trials have evolved considerably to the state that we see today, where highly
developed laws, regulations, and guidelines define their design and conduct in order to
protect the rights and information about patients. The principles and practices that are
characteristic of the modern clinical trial were introduced over the course of thousands of
years. In the western world, a number of early records show the beginnings of such trials.
For example, the Old Testament of the Bible refers to a trial in which King
Nebuchadnezzar compared a diet of meat and wine to a diet of legumes and water for ten
days (Daniel 1:12 English Standard Version). Around the 10
th
century, Ibn Sina authored
Al-Quanun fi al-Tibb, or the Canon of Medicine, which integrated current medical
knowledge and set forth seven principles for conducting drug trials in humans, addressing
drug quality, controlled design, drug mechanism of action, onset of action, dose
escalation, study reproducibility, and the limitations of animal models in predicting
human disease outcomes (Nasser, Tibi, & Savage-Smith, 2009). In 1863, Austin Flint
then appeared to be the first to conduct a study that prospectively compared the use of an
active treatment against placebo while examining prisoners with rheumatic fever (Bhatt,
2010). In 1926, J. Burns Amberson applied randomization procedures in a medical trial
28
by flipping a coin to assign sanatorium patients to either active treatment or
control(Neuhauser & Diaz, 2004).
In the 20
th
century, research on humans began to be seen as not only important for
advancing health knowledge but also dangerous if not properly managed. Concerns
about the potential dangers of clinical trials were brought into sharp focus by the
atrocities exercised against clinical trial subjects in the Second World War. In response,
the Nuremburg Code in 1947 (Tribunals, 1949) and later the Declaration of Helsinki in
1964 (World Medical Association, 1964) attempted to establish international principles
for the ethical conduct of trials. In turn, these doctrines encouraged nations to establish
laws and regulations to protect human subjects that could be enforced through their
respective judicial systems. Thus, individual national governments began to assume
responsibility for the regulatory oversight of clinical trials, often with somewhat different
approaches.
2.2.2 Clinical Trial Regulation in the United States, 1938-1962
A formalized beginning to clinical trial oversight in the US can be recognized in 1938
when the federal Food, Drug, and Cosmetic Act (FDCA) granted the Food and Drug
Administration the authority to write the regulations that would subsequently govern
industry-sponsored clinical trials (Carpenter, 2010). Among other provisions, FDCA
mandated that drugs demonstrate safety prior to marketing. It also encouraged the more
extensive use of animal and clinical trials to establish product safety, but the rules
governing those trials were poorly developed at that time. Thus, companies did not find it
difficult to meet the safety requirements, and the FDA medical officers, who had much
29
autonomy in making safety decisions, appeared to make those decisions on the basis of
relatively little evidence. In fact, rejecting a new drug was much more difficult than
approving it because the evidence needed to make a negative decision appeared to place
the burden of proof on the FDA rather than on the pharmaceutical sponsor. A rejection
demanded the agreement of the assigned medical officer, chief medical director,
attorneys, drug branch chief, and the commissioner himself. Further, once a drug was
approved, the FDA commissioner had the burden of proof to establish that a drug posed a
serious hazard to human health in order to remove it from the market (Hilts, 2003).
The relatively lax rules governing trial conduct went largely unexamined until the 1960s,
when a major public-health tragedy focused attention on clinical trials regulation. The
sequence of events related to a drug called thalidomide began in the 1950, when the
German company Chemie Grünenthal began to promote thalidomide as a sedative
comparably effective but safer than a barbiturate. The company provided the drug to
German doctors in 1955 to test its effects in humans. Rather than conducting controlled,
blinded investigations, the physicians experimented with varying doses and
administration frequencies, using uncontrolled methods of scientific recordkeeping. In
1957, the drug was introduced into Germany and then England as an over-the-counter
antiemetic drug for “morning sickness” so common in women during the first trimester of
pregnancy. By 1960 thalidomide was marketed in 48 countries and generated revenues
comparable to those of aspirin. However, soon after its introduction, emerging reports
began to identify birth defects in the babies of women who had taken the drug. In
December 1958, Frankfurt doctor Dr. Gustav Smaltz notified the company that some
30
patients taking thalidomide were experiencing neurological problems. Additionally, and
of particular concern, was the appearance of a rare defect called phocomelia, in which the
limbs of babies were greatly shortened. These defects appeared to suggest that the drug
was teratogenic. After a German newspaper reported that 161 babies had phocomelia,
the manufacturer halted production, and most countries banned the drug by March 1962.
As a consequence of its earlier market availability in European countries, it was in
Europe where most of the birth defects occurred (Hilts, 2003).
The tragic consequences of thalidomide administration spurred considerable debate
regarding the adequacy of the regulations governing drug safety and, by extension,
clinical trials. Although the drug had not been given marketing approval in the US by the
time that the birth defects in Europe became well recognized, some of the drug had
already entered the US. The drug was administered as part of poorly controlled clinical
trials, often called “seeding trials,” carried out to encourage familiarity and early adoption
of the drug by clinical thought leaders prior to the FDA approval (Goldacre, 2013). In
fact, 1,267 physicians distributed greater than 2.5 million tablets to roughly twenty
thousand US patients (Hilts, 2003), including 207 pregnant women (Fintel, 2009). All of
these problems led legislators to revisit the FDCA in order to remedy the conditions that
allowed poor oversight of clinical trials with unscientific clinical design.
Subsequent to the discovery of the link between thalidomide and birth defects, the
immediate corrective action was to remove the drug from the market, but a number of
other policy initiatives related to clinical trials then ensued. The Kefauver-Harris Drug
Amendments Act passed in 1962 required manufacturers to demonstrate drug safety and
31
efficacy prior to marketing and led to greatly strengthened requirements for clinical trial
approval prior to drug administration. The law was responsible for the introduction of
regulatory requirements that all drug trials be approved by the FDA through the review of
an Investigational New Drug Application (IND) to be submitted by a sponsoring
company or clinical investigator (Fintel, 2009). In 1974 the Common Rule was developed
to guide human research, regardless of whether investigators were evaluating medical
products or whether the data were used as a basis for marketing authorization ("Code of
Federal Regulations," 1974).
2.2.3 Emerging Considerations of Patient Privacy, 1970-2000
The new attention that was paid to clinical trial conduct naturally raised a number of
issues related to ethics and human rights. In 1932 the Public Health Service had
collaborated with the Tuskegee Institute to study the natural history of syphilis in 600
black men, which included 399 with and 201 without the disease. The researchers did not
provide informed consent or offer penicillin when it became the standard of care in 1947.
Finally, in 1972 the Assistant Secretary for Health and Scientific Affairs convened an ad
hoc advisory panel to review the trial, and the study ended. In 1973 Congress held
hearings, and in 1974 a $10 million settlement was awarded to the participants and their
families. In 1978 the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research issued a particularly influential report, called the
Belmont Report. It outlined three ethical principles, respect for persons or autonomy,
beneficence, and justice, that the Commission felt were important foundations for clinical
research. The third principle, justice, referred to the equal distribution of the benefits and
32
burdens of research, contrary to the conduct of the Tuskegee study, which targeted
disadvantaged black men. The other principles, autonomy and beneficence, had direct
relevance to considerations of transparency and a related principle, patient privacy.
According to the principle of autonomy, each individual possesses a right to keep his or
her personal information confidential. According to the principle of beneficence, those
conducting clinical trials should protect patients by maximizing potential benefits and
minimizing potential harms. Such harms could extend to the psychological, social, or
legal harms that could ensue as a result of unintended disclosure (National Commission
for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979).
The period between 1990 and 2000 was a particularly active decade for the development
of regulations regarding clinical trials and, more specifically, patient privacy. In 1996, the
release of the International Conference for Harmonization (ICH) Guidance for Industry:
E6 Good Clinical Practice (GCP): Consolidated Guidance recommended that, according
to local regulations, institutions should safeguard the confidentiality of records that could
identify patients and compromise individual privacy (ICH, 1996). Also in 1996, the US
Congress passed the Health Insurance Portability and Accountability Act (HIPAA). An
important part of this omnibus legislation strengthened the protection of confidential
patient information protection in electronic medical records by specifying the manner in
which electronic data could be managed and transmitted ("Health Insurance Portability
and Accountability Act," 1996). It also restricted the types of individuals who could have
access to patient information as part of clinical trials and established strong penalties for
noncompliance with data-disclosure restrictions.
33
As a first step to operationalize HIPAA, in November 1999 the US Department of Health
and Human Services (HHS) released a draft policy for public comment that set out
proposed regulations to protect individually identifiable health information. After
reviewing more than 52,000 comments on this draft, HHS published the final Privacy
Rule in December 2000. In March 2002, it published additional proposed changes,
received more than 11,000 comments, and published an updated Privacy Rule in August
2002 ("Code of Federal Regulations," 2002). HHS enunciated what has continued to
become a key issue in establishing privacy boundaries in clinical trials:
A major goal of the Privacy Rule is to assure that individuals’ health
information is properly protected while allowing the flow of health
information needed to provide and promote high quality care and to
protect the public’s health and well-being. The Rule strikes a balance that
permits important uses of information, while protecting the privacy of
people who seek care and healing. Given that the health care marketplace
is diverse, the Rule is designed to be flexible and comprehensive to cover
the variety of uses and disclosures that need to be addressed (Health and
Human Services, 2014).
By regulation, the Privacy Rule restricts the way in which covered entities, such as health
care providers, can use or disclose “individually identifiable health information,” called
Protected Health Information (PHI), for research. Use or disclosure is only permitted, as
shown in Table 1, in specific circumstances, with written authorization by individual
subjects. Historically, HHS has typically interpreted such authorizations to apply only to
specific current and not future research. If future research takes place, investigators must
obtain new subject authorizations or Institutional Review Board (IRB) waivers, a process
viewed as onerous, according to the Institute of Medicine (IOM) and other stakeholders
(Institute of Medicine, 2015). As a result of such criticism, in 2013 HHS established that
34
it had loosened its interpretation of authorizations to include future unspecified research
(Health and Human Services, 2013).
Table 1: Privacy Rule Acceptable Use or Disclosure of PHI
Modified From: ("Code of Federal Regulations," 2002)
1. The subjects sign a written authorization; or

2. A Privacy Rule-compliant IRB either waives the current or approves a modified
written authorization; or

3. The investigator establishes to the covered entity that PHI will be used only for
research purposes, not shared outside the covered entity, and that the lack of the PHI
would undermine the research; or

4. The investigator establishes to the covered entity that the research is only on the PHI of
deceased persons and that the lack of PHI would undermine the research; or

5. The covered entity discloses for limited purposes, per a data use agreement with the
investigator, a limited data set of PHI without specific direct identifying information.

2.2.4 Privacy and Transparency in Europe
As in the US, the 1990s in Europe were marked by increasingly stringent rules regarding
the protection of patient privacy. Because the EU is a union of several countries, it has a
more complicated system of regulations in which many of the rules are made at the EU
level by the European parliament in order to attain specific transnational goals.
Meanwhile, other rules remain under the purview of the individual countries themselves.
Some actions take the form of regulations, which are compulsory legislative actions
35
passed by the European parliament. These regulations are applied in full to each member
state and come into effect immediately according to the conditions prescribed by the
European Parliament. However, more commonly, the legislative items have been framed
as directives that allow member states a certain degree of autonomy to implement or
change their national laws in ways that will achieve the intended goals more
flexibly(Leonard, 2010).
Particularly important in the context of patient privacy was the Data Protection Directive
95/46/EC issued in October 1995, which attempted to protect individuals with regard to
the processing and transport of personal data, and at the same time balance strong
protection of personal privacy with less restrictive communication of personal data.
However, since each Member State executed the legislation on its own, it was necessary
to consider reform to address the resulting administrative costs and legal challenges that
such an approach incurred. In December 2015, the European Commission announced that
the Parliament and Council had agreed on its proposal to reform these data protection
rules. The changes included an updated General Data Protection Regulation 2012/0011
(COD) judged to be more aligned with the latest technology challenges faced in the
digital age. In April 2016 the European Parliament and European Council adopted the
Regulation, and it will become effective in May 2018 (European Commission, 2016).
2.2.5 Rebalancing the Privacy-Transparency Equation
2.2.5.1 The US Experience
For the last half of the twentieth century, all regulatory initiatives appeared to be directed
at strengthening the protections regarding patient privacy. However, toward the end of
36
the millennium, some began to contend that rules to protect privacy had gone too far.
They argued that the rules were, in fact, serving as an excuse for preventing the
potentially useful sharing of clinical trial data. The first evidence of this change in the US
could perhaps be recognized in a seemingly innocuous requirement documented in
Section 113 of the omnibus Food and Drug Modernization Act of 1997 ("Food and Drug
Administration Modernization Act of 1997," 1997). This section mandated the
registration of clinical trials for drugs intended to treat serious or life-threatening medical
conditions in a publicly accessible database. Accordingly, in order to provide the public
with access to such clinical trial information, the National Institutes of Health (NIH)
finalized rules governing a clinical trials database, called ClinicalTrials.gov, in February
2000. To support this initiative, Maine and fifteen other state legislatures initiated or
passed bills in 2005, generally mandating disclosure with the respective Department of
Health and/or federally on ClinicalTrials.gov (Scheineson & Sykes, 2005). In 2007, a
further step toward transparency was taken when FDAAA expanded requirements for
disclosure to all interventional clinical trials of drugs, biologics, and medical devices
under the FDA regulation, excluding studies of Phase I drugs, , drugs approved before
2007, and unapproved drugs . In addition, FDAAA mandated that sponsors report
summary results of post-marketing trials, as well as pivotal trials that form the primary
basis for efficacy claims. Importantly, FDAAA did not require individual patient data
(IPD) or more granular results. Rather, it called for scientific information, shown in
Table 2, and administrative information or a point of contact that could provide further
assistance regarding the reported results (Tse et al., 2009). In 2012, legislators put
37
forward the Trial and Experimental Studies (TEST) Act in an attempt to require
disclosure, regardless of study phase or product approval status. However, some
provisions of the bill dissuaded sufficient support for it to be enacted (Choi, 2015). Even
while it was still in congressional committee review, it was estimated to have a 1%
probability of becoming law (Logvinov, 2014). Per Section 907 of the Food and Drug
Administration Safety and Innovation Act of 2012 (FDASIA), FDA issued the FDA
Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data,
which included a priority to increase data transparency (FDA, 2014a).

38
Table 2: Summary of ClinicalTrials.gov Results Database Modules
Modified From: (Tse et al., 2009)
Summary Description of the ClinicalTrials.gov Results Database Modules
Basic Results Module Summary Description Overview of Minimum
Required Information
Participant flow Description of the No. of
research participants starting
and completing the study,
including exclusions and
dropouts, for each arm or
comparison group (frequently
reported as a CONSORT
diagram in a journal article)
No. of participants who
entered study, and No. of
participants who completed
study
Baseline characteristics Demographic and baseline
data for the study population
and each arm or comparison
group (frequently reported as
“Table 1” in a journal article)
Overall No. of participants
analyzed; gender, for all other
measures reported; name (and
description); unit of
measurement; and summary
data, total and by arm
Outcome measures and
statistical analyses
Table of outcome measure
values for each
arm/comparison group,
including appropriate
statistical analyses
For all prespecified primary
and secondary outcome
measures: name and
description; unit of
measurement; time frame;
analysis population; and
summary data, total and by
arm
Adverse events (optional prior
to September 2009)
Number and frequency of all
serious adverse events and
other adverse events exceeding
a specified frequency
threshold in each arm/group,
grouped by organ system
For all adverse events
reported: adverse event term;
organ system; type of
assessment (spontaneous vs
systematic); and No. of
participants affected, No. of
participants at risk, and total
No. affected, by arm

Generally, the information in ClinicalTrials.gov was seen to improve transparency
without affecting patient privacy because the information on the website was primarily
directed at recruiting and informing patients about trials, and thus provided only
39
summary materials related to the protocol and results of the trial. Nevertheless, some
contended that, within datasets for studies on rare diseases, it would be challenging to
protect the identity of patients with unique profiles (Rabesandratana, 2013). At the same
time, a more direct and potentially problematic challenge to patient privacy originated
from another source, the 1997 amendment to the 1967 Freedom of Information Act
(FOIA). The original FOIA attempted to increase governmental transparency by
categorizing federal records to which the public would have access ("Freedom of
Information Act," 1966). However, while the original law introduced the concept of
transparent information, it lacked the ability to ensure the compliance of federal agencies.
Accordingly, in 1976 the House of Representatives and Senate overrode a veto by
President Gerald Ford to amend FOIA to add penalties for withholding information,
which was followed by subsequent amendments in 1976 and 1986 that elaborated on the
terms and applicable exemptions of the Act (AllTrials, 2016). Subsequent presidential
administrations would utilize executive power to either enhance or dilute the
transparency permitted by FOIA. In 1982, President Ronald Reagan created new
classification rules via Executive Order 12356 that made it easier for the government to
protect sensitive information. Conversely, in 1997, President Bill Clinton signed the
Electronic Freedom of Information Act amendments. The amendment simplified the
cumbersome nature of obtaining information by providing US federal agencies such as
the FDA with a means to publish online the most commonly requested information
proactively. The 1997 amendment thereby eliminated some of the challenges associated
with responding to specific inquiries from stakeholders (AllTrials, 2016). More recently,
40
however, it appears that some of the gains in transparency have been lost. Despite
intentions to be “the most transparent administration in history,” (Obama, 2009) the
Obama administration has reportedly utilized more exemptions and classified more
documents than the George W. Bush administration, and in 2012, 19 of 20 agencies
failed to respond in time, per the law, to a single FOIA request that was submitted as a
test of its progress (Electronic Frontier Foundation, 2016).
2.2.5.2 The European Experience
A shift in thinking regarding the need to balance privacy with transparency also occurred
in the EU after the turn of the century. Perhaps the most visible evidence was that
provided in 2003, when EMA described a multiyear initiative to elevate transparency
generally (EMA, 2003). As part of this initiative and in parallel with the actions of the
US, the EU implemented EudraCT as a European clinical trials database that would
facilitate data sharing among its member states (Secretary's Advisory Committee on
Human Research Protections, 2013). However, unlike ClinicalTrials.gov, EudraCT was
devised as a confidential database, per Article 11 of Directive 2001/20/EC, and was only
available for use by National Competent Authorities (NCAs). As a result, EudraCT only
provided results that could be used by national regulators. However, soon thereafter,
Article 57 of Regulation (EC) No 726/2004 ("Regulation (EC) No 726/2004," 2004) and
Article 41 of Paediatric Regulation (EC) No 1901/2006 ("Paediatric Regulation (EC) No
1901/2006," 2006) required public disclosure of the adult and pediatric clinical trial
information held in EudraCT. Accordingly, in March 2011, EMA launched the EU
Clinical Trials Register to provide public access to a database of Phase 2, 3, and 4 trials
41
in adult and all phases of trials in pediatric populations, much like that of
ClinicalTrials.gov in the US (EMA, 2011). However, some stakeholders criticized the
registry due to its limited functionality (Wieseler, McGauran, & Kaiser, 2011). This
sentiment may have been in part responsible for the repeal of Directive 2001/20/EC soon
thereafter, substituted by Regulation EU No 536/2014 of the European Parliament. The
new regulation was to harmonize the conduct of clinical trials among Member States and
improve efficiency, decrease administrative costs, and otherwise improve the
attractiveness of the European Union for sponsors and other stakeholders (Debaut, 2015).
Effective June 2014, European officials launched a new initiative to replace EudraCT and
the EU Clinical Trials Register with a streamlined single entry system, the EU Portal and
Database, which is to utilize two tiers of access and be completed in 2018 (EMA, 2016b).
Both systems currently exist at the time of writing, and both the EU Portal and Database
or EudraCT can accept clinical trial results (Patton, 2015) until October 2018 (EMA,
2015).
2.2.6 Increasing Pressure for Disclosure
The transparency initiatives identified above addressed issues largely specific to clinical
trials registries, but did not directly address a growing sentiment that government should
be more transparent in a broader range of activities. Thus in both the US and EU, more
substantive initiatives and events showcased transparency more generally, and this had
eventual repercussions for clinical data sharing. In both the US and the EU, specific
events led to changes in the way that disclosure was regarded. In the US it was to a large
extent driven by the backlash to problematic drug-related data uncovered in the
42
postmarket period, such as the late identification of adverse events associated with the
drug Vioxx. Similar negative publicity occurred in the EU as a result of missing data on
Paxil and Tamiflu. However, the EU also had an additional driver, related specifically the
repeated requests for data disclosure from a research organization that wanted the clinical
data for post hoc evaluations of trials as part of their research activities.
2.2.6.1 Events in the US
In the US, the period between 2000 and 2010 saw considerable change in the way that
disclosure of clinical trial data was viewed. Part of this change was in reaction to
concerns that industry sponsors and others might be able to influence the scientific
process and regulatory decision-making by reporting study results selectively and thus
biasing a review or journal article in favor of a drug product. Such bias might not be
unexpected, given that companies trying to market a drug are potentially incentivized to
showcase the positive results from their clinical trials. These concerns became
particularly relevant in the case of Merck’s handling of data related to adverse events
associated with their drug, Vioxx. In January 1999, Merck initiated the Gastrointestinal
Outcomes Research Study (VIGOR) of rofecoxib (Vioxx) in order to evaluate whether
this nonsteroidal anti-inflammatory drug could alleviate pain with fewer gastrointestinal
side effects. In May 2000, it submitted its results to the New England Journal of
Medicine (NEJM) but included only 17 of the 20 heart attacks as adverse drug outcomes,
arguing that the other three heart attacks occurred beyond the “prespecified cutoff date”
of the study. It had, however, provided information to FDA on those additional three
heart attacks in October 2000. In December 2005, NEJM editors requested the missing
43
data and a correction to the original article, but in March 2006, study authors responded
by refusing to provide those changes (Prakash, 2007). In May 2006, Dr. Steven E. Nissen
and Dr. Bruce M. Psaty independently reviewed Vioxx APPROVe study data and
indicated that cardiovascular risks extend from time of first dosing (Prakash, 2006a) to
one year after last exposure to the drug (Prakash, 2006b). In June 2006, research
published in Lancet estimated that 38,000 Americans had died as a result of heart attacks
from rofecoxib. By November 2007, Merck declared that it would pay a record $4.85
billion in a class-action case to settle thousands of lawsuits related to potential Vioxx side
effects (Prakash, 2007).
Concerns about the opacity in governmental activities in this and other areas led to calls
for more transparency in government that had direct effects on FDA policy. In June 2009,
the Obama administration created the FDA Transparency Task Force, which was to
obtain suggestions for providing helpful, clear, and accessible information on FDA
decisions (Sebelius, 2009). The work of the task force was divided into three phases (Tai,
2013), which consisted of launching the online FDA Basics for the public, providing
recommendations to the Commissioner on transparency with the public, and providing
recommendations to the Commissioner on transparency with regulated industry (FDA,
2014b).
One particular area in which this work has specific applicability is the way in which data
associated with marketing submissions should be handled. Historically, regulations
published in 1974 (Halperin, 1979) had allowed the FDA to publicly disclose all of its
records, other than those needed for law enforcement, internal or external
44
communications with other federal agencies, personally confidential information, and
commercially confidential information. However, FDA generally did not disclose data for
medical products in development, manufacturing processes, commercial data, or
statistical data that were submitted voluntarily (Scheineson & Sykes, 2005). By some
accounts, the costs of maintaining such secrecy were high. An observer remarked that
the US government spent $7.2 billion in 2004 alone on classifying and maintaining
classified documents. However, government initiatives to encourage transparency were
not without opposition. Industry in particular was reluctant to support expanded
disclosure of data in their marketing submissions. Instead, it preferred that FDA
illuminate its rationale in arriving at decisions and encourage greater awareness of
forthcoming guidance documents (Tai, 2013).
In June 2014, FDA introduced OpenFDA, a beta platform for sharing its available health
datasets to the public (Kass-Hout, 2014) via Application Programming Interfaces (APIs),
and in December 2015 it added the ability to directly download the same datasets for
offline access (FDA, 2015b). Aside from its Transparency Initiative, a separate initiative
by FDA was directed at improving its processing of Freedom of Information Act (FOIA)
requests. Such a revision was much needed. As of the end of fiscal year (FY) 1998,
13,819 requests were pending (Schulman, 1998). In 2007, a new Director of the Division
of Freedom of Information (DFOI) helped to standardize processing and provide
additional training and funding for the organization (Tai, 2013), and pending requests
decreased from 17,458 in FY 2007 (Sadler, 2007) to 6,568 in FY 2008 (Sadler, 2008). By
the end of FY 2014, in comparison, 2,617 requests were pending at FDA (FDA, 2014b).
45
Currently, FDA provides the public with instructions for completing FOIA requests on its
website, as well as the ability to complete requests online. The FDA utilizes a
decentralized process, meaning that most records are retrieved by the applicable Agency
component rather than the Division of Freedom of Information (DFOI) (FDA, 2015a).
2.2.6.2 Events in the EU
Meanwhile, developments in the EU also helped to fuel a shift in thinking about
transparency. Just as Vioxx helped to drive the conversation in the US, early
conversations regarding transparency in Europe appeared to be associated with a drug
issue, in this instance with the drug, paroxetine (Paxil). Specifically, in February 2003,
GlaxoSmithKline (GSK) provided the Medicines and Healthcare Products Regulatory
Agency (MHRA) with data demonstrating that use of paroxetine did not increase suicide
rate. However, the analysis on which that conclusion was based had combined the data in
children with that of a much higher number of adults and thereby obscured the increase in
suicide rate seen in children. Soon thereafter, the MHRA hosted a meeting with
GlaxoSmithKline (GSK) to discuss paroxetine. At the end of the meeting, GSK
representatives provided a briefing document reporting that children treated with the
paroxetine were more likely to commit suicide than those treated with a placebo. MHRA
decided to investigate further and less than one month later, doctors received letters
advising against the prescription of the drug in patients under eighteen years old. The
critical issue that complicated the case was that GSK had not been legally required to
disseminate the safety information because paroxetine was not approved for treating
children and was only prescribed “off-label” by those physicians (Goldacre, 2013).
46
Nevertheless, in 2004 GSK settled a lawsuit from the New York Attorney General that
alleged it had withheld safety data. As a condition of the settlement, GSK agreed to
publicly register its clinical trials and disclose summary results (Miller, 2013).
The drug-associated concerns that led to discussions of secrecy and bias with respect to
clinical trials data were important to influencing public sentiment. Yet, perhaps the most
specific and influential single sequence of events to shape policy change was initiated by
a less public event, when researchers from the Nordic Cochrane Centre, an affiliate of the
Cochrane Collaboration, requested that the European Medicines Agency, the European
regulatory agency for drugs, provide clinical study reports and related clinical study
protocols on two specific anti-obesity drugs, orlistat (Xenical™/Alli™) and rimonabant
(Acomplia™) in order that they could extend their third-party studies.
At the time that the Nordic Cochrane Centre made its request on June 29, 2007, EMA
generally did not disclose information related to a marketing application (Goldacre,
2013), other than publishing its justification for granting or denying marketing
authorisation within European Public Assessment Reports (EPARs) (Papathanasiou et al.,
2016). Historically, EMA, like FDA, had a policy of restricting the disclosure of certain
types of materials submitted to it by pharmaceutical companies because they contained
proprietary information important for drug development and commercialization. At issue
in this particular case was the request of the Nordic Cochrane Centre for patient-level
data from clinical trials submitted as part of a regulatory dossier. Clinical data such as
that requested by the Nordic group is a central component of the marketing authorization
of a new chemical entity. The data tabulations of clinical trials derive from raw data
47
collected during clinical trials by investigators who assume responsibility for completing
subject-specific case report forms (CRFs) for individual patients. The identities of these
patients are masked, but their demographic information, test results, and other
measurements are given as line items in summary tables (Lietzan, 2014).
Further, each clinical trial in the marketing application is reported in a clinical study
report (CSR) (European Commission, 2008) that elaborates the clinical protocol and the
associated outcomes of the study. In so doing, a considerable amount of information
about the trial itself, that is, its administrative structure, objectives, investigational plan,
subject attributes and results, and evaluations of efficacy and safety, are all shared. The
combined document, with its synopsis, body, subject narratives, statistical tables, and
numerous appendices, can include tens of thousands of pages (ICH, 1995). In addition, a
sponsor may provide their views on the weighting of key information and data on which
it will base its product claims of safety and efficacy. Its discussions may include
information about previous regulatory submissions, meetings and communications with
regulators, and changes in regulatory strategy as a result of those submissions and
interactions. Thus, it is argued that the CSRs, along with the clinical summaries of safety
and efficacy data, can together be used to understand the overarching clinical
development program of the company.
Given the extensive and sensitive nature of the clinical dataset in a marketing application,
it is perhaps unsurprising that the EMA was not initially cooperative with the request.
However, the persistence of the requests by the Nordic Cochrane Centre stimulated a
48
cascade of interactions and arguments that became pivotal in shaping the way that
clinical trial data is now handled.
The receipt of the request from the Cochrane Centre was, on its face, seemingly
straightforward. It was handled initially in same way that the regulators typically
responded to such a request, with a refusal, citing Article 3(2)(a) of the Rules for the
Implementation of Regulation (EC) No 1049/2001 on Access to EMEA Documents
(Rules). In that article, the EMA Management Board had instructed the EMA to refuse
access to information in order to protect commercial interests, provided that no
predominant public interests were present. On August 24, 2007, the researchers repeated
the request, arguing that disclosing the requested clinical study reports would be unlikely
to threaten commercial viability. On September 17, 2007, the EMA reiterated its
decision, noting that, according to Article 3(2)(a), it did not disclose original data
submitted in order to obtain marketing approval (European Ombudsman, 2010).
After several rounds of opinions, observations, replies, proposals, and requests, the
researchers appealed to European Ombudsman, Nikiforos Diamandouros, whose office
inspected the nature of the records that were under consideration. The EMA files on
orlistat and rimonabant were noted to consist of core CSRs and appendices that included
the associated clinical study protocols, submitted in a manner consistent with standard
practice, as dictated by the Note for Guidance on Structure and Content of Clinical Study
Reports (CPMP/ICH/137/95). After some opportunity for further discussion, the
Ombudsman recommended to EMA that it should either grant access to Nordic Cochrane
Centre or convincingly establish the rationale for withholding the documents (European
49
Ombudsman, 2010). According to the researchers, Table 3 chronicles the correspondence
that occurred prior to that point (Peter C. Gøtzsche, 2011).
Table 3: The Path to EMA Data, Per the Nordic Cochrane Centre
Modified From: (Peter C Gøtzsche & Jørgensen, 2011)
The delays on our part amounted to 130 days (11% of the time); we awaited replies for 1028
days.
June 29, 2007 We asked the EMA to provide access to the clinical study reports and their
corresponding protocols on rimonabant and sibutramine.
August 20, 2007 The EMA replied that the documents could not be released because they
came under the exception of commercial interests.
August 24, 2007 We explained that the EMA’s lack of transparency violated basic principles
in the EU treaty and that it leads to suboptimal treatment of patients.
September 17,
2007
With no comment on our arguments, the EMA referred again to commercial
interests and noted we could institute court proceedings against the EMA or
complain to the European ombudsman.
October 8, 2007 We appealed to the ombudsman, noting that the published literature on
drugs is flawed and arguing that protocols and study reports did not disclose
anything that could undermine commercial interests.
January 30, 2008 The EMA replied to two letters from the ombudsman, referred to protection
of commercial interests and mentioned that it could not identify any over-
riding public interest that could justify disclosure of the requested
documents.
February 26,
2008
We told the ombudsman that the EMA had failed to explain why
commercial interests would be undermined.
April 28, 2008 The EMA replied to the ombudsman that it needed to protect the data
against unfair commercial use; that evaluating the balance between benefits
and risks of medicines is the EMA’s job; and that redaction of personal data
would cause disproportionate effort.
June 17, 2008 In our reply to the ombudsman, we argued against this and noted that if
commercial success depends on withholding data that are import for
rational decision making by doctors and patients, there is something
fundamentally wrong with our priorities in healthcare.

50
Table 3: The Path to EMA Data, Per the Nordic Cochrane Centre (Continued)
Modified From: (Peter C Gøtzsche & Jørgensen, 2011)
January 22, 2009 The ombudsman proposes a friendly solution to the EMA and asks it to
grant us access to the documents or provide a convincing explanation why
such access cannot be granted.
February 26,
2009
The EMA restates the commercial interests; claims that we have not given
evidence of an over-riding public interest; and refers to the workload
involved in redacting the documents.
March 10, 2009 The ombudsman again proposed a friendly solution to the EMA and asks it
to clarify its reasoning.
April 7, 2009 The EMA repeats its previous arguments.
May 19, 2009 We again counter the EMA’s arguments: the EMA has provided no
evidence that the documents are commercially sensitive; many patients had
been harmed by selective publication of trial data on COX 2 inhibitors; and
redacting the documents should be quick and easy.
August 31, 2009 We tell the ombudsman that we have received trial data from the Danish
Medical Agency on a third anti-obesity drug, sibutramine.
October 6, 2009 The ombudsman goes to the EMA to inspect the documents we had
requested.
May 19, 2010 The ombudsman issues a draft recommendation that the EMA should grant
us access to the documents or provide a convincing explanation as to why
not.
June 7, 2010 In a press release, the ombudsman accuses the EMA of maladministration
because of its refusal to grant access.
August 31, 2010 The EMA informs the ombudsman that it will provide access.
February 1, 2011 We receive the data.

On August 31, 2010, EMA, in detailed comments, stated that it would provide the data
that the researchers had requested more than three years earlier. Additionally, on
November 24, 2010, the European Ombudsman reported that the EMA had changed its
stance on the basis of General Court case law and agreed to act on his recommendation
for access to the requested documents.
Meanwhile, reviewers from the Cochrane Collaboration recounted other struggles in
obtaining clinical trial data. Reminiscent of the issues described above for the NEJM for
51
Vioxx and the MHRA for Paxil, they described in 2012 their experiences in obtaining
data on oseltamivir (Tamiflu) from its manufacturer, Roche Pharmaceuticals. In 2010,
Cochrane obtained some sections of CSRs for the ten trials detailed in a 2003 meta-
analysis and other sections through a FOI request to EMA, but the authors noted that
other clinical information on Tamiflu is still undisclosed. Table 4 provides the rationale
of the manufacturer and associated Cochrane responses as the latter attempted to obtain
additional data (Doshi, Jefferson, & Del Mar, 2012).
Table 4: Roche Justifications for Not Disclosing Data
Modified From: (Doshi et al., 2012)
Roche’s Reasons for Not Sharing its Clinical Study Reports, and the Authors’ Response
(for 10 trials in Kaiser meta-analysis)
Roche’s Basis for Reluctance or Refusal to
Share Data
Response
“Unfortunately we are unable to send you the
data as a similar meta analysis is currently
commencing with which there are concerns
your request may conflict. We have been
approached by an independent expert influenza
group and as part of their meta analysis we
have provided access to Roche’s study
reports.” (October 8, 2009)
It is unclear why another group of independent
researchers would prevent Roche from sharing
the same data with our group.
Cochrane reviewers were “unwilling to enter
into the [confidentiality] agreement with
Roche.” (December 8, 2009)
The terms of Roche’s proposed contract were
unacceptable to us. We declined to sign for two
reasons: 1) all data disclosed under the contract
were to be regarded as confidential; and 2)
signing the contract would also require us ‘‘not
to disclose … the existence and terms of this
Agreement’’. We judged that the requirement
to keep all data, and the confidentiality
agreement itself, secret would interfere with
our explicit aim of openly and transparently
systematically reviewing the trial data and
accounting for their provenance.

52
Table 4: Roche Justifications for Not Disclosing Data (Continued)
Modified From: (Doshi et al., 2012)
Roche’s Reasons for Not Sharing its Clinical Study Reports, and the Authors’ Response
(for 10 trials in Kaiser meta-analysis)
Roche’s Basis for Reluctance or Refusal to
Share Data
Response
Roche says that it was ‘‘under the impression
that you [Cochrane] were also satisfied with its
provision based on our correspondence earlier
this year (March 2010).’’ (June 1, 2010)
We did not immediately realize that what
Roche had provided was incomplete.
Irrespective of whether we had at one point
seemed ‘‘satisfied,’’ Roche had not delivered
what it publicly promised in the BMJ on Dec.
8, 2009: ‘‘full study reports will also be made
available on a password-protected site within
the coming days to physicians and scientists
undertaking legitimate analyses.’’
‘‘… around 3,200 pages of information have
already been provided by Roche for review by
your group and the scientific community.’’
(August 20, 2010)
What is important is completeness, and 3,200
pages is a fraction of the full study reports for
the ten Kaiser trials Roche promised to make
available.
‘‘Roche undertook this action [release of 3,200
pages] to demonstrate our complete confidence
in the data and our commitment to
transparency to the degree to which patient
confidentiality, data exclusivity and the
protection of intellectual property allow.’’
(August 20, 2010)
This implies that release of the promised-but-
never-released data would impinge on
‘‘patient confidentiality, data exclusivity and
the protection of intellectual property’’. This
does not seem to apply to many elements of
clinical study reports (e.g., the trial protocol
and reporting analysis plan), and it is unclear
why personal data could not be anonymized.
‘‘The amount of data already made accessible
to the scientific community through our actions
extends beyond what is generally provided to
any third party in the absence of a
confidentiality agreement.’’ (Aug. 20, 2010)
It is irrelevant what is ‘‘generally provided’’.
What is relevant is what was promised and the
need for public disclosure of clinical study
reports.

53
Table 4: Roche Justifications for Not Disclosing Data (Continued)
Modified From: (Doshi et al., 2012)
Roche’s Reasons for Not Sharing its Clinical Study Reports, and the Authors’ Response
(for 10 trials in Kaiser meta-analysis)
Roche’s Basis for Reluctance or Refusal to
Share Data
Response
‘‘Over the last few months, we have witnessed
a number of developments which raise
concerns that certain members of Cochrane
Group involved
with the review of the neuraminidase inhibitors
are unlikely to approach the review with the
independence that is both necessary and
justified. Amongst others, this includes
incorrect statements concerning Roche/Tamiflu
made during a recent official enquiry into the
response to last year’s pandemic by a member
of this Cochrane Review Group. Roche intends
to follow up separately to clarify this issue. We
also note with concern that certain
investigators, who the Cochrane Group is
proposing will carry out the planned review,
have previously published articles covering
Tamiflu
which we believe lack the appropriate
scientific rigor and objectivity.’’ (August 20,
2010)
Despite Roche’s promise and our request for
specifics, Roche never responded directly.
‘‘We noted in our correspondence to the BMJ
in December of last year our concern that the
first requests for data to assist in your review
did not come from the Cochrane Group, but
from the media apparently trying to obtain data
following discussions with the Cochrane
Review Group. This raised serious questions
regarding the motivation for the review from
the outset. We note that in subsequent
correspondence regarding your next planned
review you have copied a number of journalists
when responding to emails sent by Roche
staff.’’ (August 20, 2010)
Our view is that Tamiflu is a global public
health drug and the media have a legitimate
reason for helping independent reviewers
obtain data, which includes being informed of
our efforts to do so.

54
Table 4: Roche Justifications for Not Disclosing Data (Continued)
Modified From: (Doshi et al., 2012)
Roche’s Reasons for Not Sharing its Clinical Study Reports, and the Authors’ Response
(for 10 trials in Kaiser meta-analysis)
Roche’s Basis for Reluctance or Refusal to
Share Data
Response
Cochrane reviewers have been provided with
‘‘all the trial data [they]
require …’’ (January 14, 2011)
We disagree. First, it is up to us to decide what
we require. Second, we now know that what
was provided was not enough. For example,
Roche did not provide us with the trial
protocols and full amendment history.
‘‘You have all the detail you need to undertake
a review and so we have decided not to supply
any more detailed information. We do not
believe the requested detail to be necessary for
the purposes of a review of neuraminidase
inhibitors.’’ (April 26, 2011)
We have still not received what was promised
in December 2009, and we know that what we
have received is deficient.
‘‘It is the role of Global Regulatory Authorities
to review detailed information of medicines
when assessing benefit/risk. This has occurred,
and continues to occur with Tamiflu, as with
all other medicines, through regular license
updates.’’ (April 26, 2011)
Independent researchers such as the Cochrane
Collaboration share the goal of assessing
benefit/risk, and require all details necessary to
competently perform this function.
‘‘Roche has made full clinical study data
available to health authorities around the world
for their review as part of the licensing
process.’’ (January 20, 2012)
Roche may have made full clinical study data
‘‘available’’ but that does not mean they
‘‘provided’’ all regulators with full clinical
study data. For at least 15 Tamiflu trials, Roche
did not provide the European regulator (EMA)
with full study reports, apparently because
EMA did not expressly request the complete
clinical study reports. (Correspondence with
EMA, May 24 and July 20, 2011)

55
Overall, EMA also identified a need to develop a public position on the extent to which it
would redact commercially and personally confidential information in the future
(European Ombudsman, 2010). This aim spurred a debate regarding the appropriate
balance between openness and confidentiality. In question were the ways to determine
the right amount and best methods for the disclosure of such data (Lietzan, 2014). On
November 22, 2012, the EMA convened a transparency workshop specific to the release
of clinical trial data so that it could obtain the perspectives of a variety of stakeholders
before disseminating a policy. Five advisory groups that addressed patient confidentiality,
clinical data formatting, rules of engagement, good analysis practice, and legal positions,
respectively, were convened by teleconference between January 2013 and April 2013 and
consisted of an assortment of stakeholder volunteers (EMA, 2013). On June 24, 2013,
EMA released Publication and Access to Clinical-Trial Data, a draft of EMA
Policy 0070. In response, more than 150 individuals and institutions provided more than
1,100 comments (Allchurch, 2014b). Stakeholders submitting comments included the
pharmaceutical industry, academia, healthcare providers, patient advocates, regulatory
agencies, and health technology assessment (HTA) entities. The EMA noted that many
individual citizens conveyed general support for its movement toward greater
transparency (EMA, 2014).
On December 12, 2013, the EMA Management Board put forth a set of principles by
which the draft policy might be finalized. First, the Board outlined that the EMA needed
an operational, sequential set of instructions for implementing the policy on redacted
clinical study reports. Second, it needed an approach for de-identifying patients, and
56
third, a template for clinical trial data submission. In addition, its evaluations suggested
the need for policies that would prevent unfair commercial use of data that might be
consequential to widespread dissemination of study data and reports. All of these
concerns were subsequently deliberated at the March 2014 meeting of the Management
Board and by private consultations with various stakeholders (EMA, 2016a). The EMA
released a second draft policy in May 2014 that clarified that the data would only be
viewable on a screen and not subject to download or printing for analysis.
The discussions however, had not ended. Protests from transparency advocates soon led
the EMA to change its course; EMA identified that researchers without commercial intent
would be able to download, save, or print data (Abbott, 2014). In June 2014, the Board
decided that it would be able to accept the final policy by the middle of July and
implement it in October. Nevertheless, in July 2014, the EMA Management Board
postponed formal adoption of that transparency policy until its October meeting (EMA,
2016a). It expressed ongoing support for the policy but noted that EMA would need more
time to consider the exact text of the document (AllTrials, 2014). Finally, in October
2014, the Board did unanimously adopt the policy, which became effective for new
Marketing Authorisation Applications (MAAs) received on or after January 1, 2015, and
for new indication or line extension applications received on or after July 1, 2015, under
the centralized procedure. In effect, Policy 0070 utilizes two Terms of Use (ToU) for two
levels of access to CSRs, respectively. Access to information viewable on screen only for
non-research purposes will require only a user identification (ID) and password, whereas
expanded access giving the ability to download data for research purposes will require
57
detailed registration, including a user ID, password, name, date of birth, and passport or
ID card number. It remains unclear whether the additional information, namely name,
date of birth, and passport or ID card number, will impact the manner in which the
accessed clinical data is ultimately used. In the first phase of implementation of
Policy 0070, EMA will publish on its website only CSR information, including the
clinical overview, clinical summary, CSRs, protocol and protocol amendments, sample
CRFs, and statistical methods documentation. In the second phase, it will consult with
stakeholders to discuss the best way to provide access to individual patient data (IPD) in
accordance with law (EMA 2015). In March 2016 EMA issued External guidance on the
implementation of the European Medicines Agency policy on the publication of clinical
data for medicinal products for human use, which included guidance for the
administrative, anonymization, and commercially confidential information (CCI)
redaction procedures instrumental for stakeholders to effectively implement Policy 0070.
It essentially reallocated the task of assuring the redaction, a time-consuming and
expensive undertaking, to the affected companies, although it retained the right to
challenge the redactions should they be too extensive and unjustified. Thus, companies
would need to determine the way that they would allocate human, capital, and time
resources to redaction and the associated EMA consultation process (EMA, 2016c).
2.2.7 A Comparison of the FDA and EMA Policies
With the EMA well underway in its efforts to develop an implementation scheme for
transparency through its new policies relating to clinical trial data, the U.S. FDA on
June 3, 2013, requested public comments on its own proposal, 78 FR 33421, which stated
58
that FDA would provide de-identified and masked data from medical product
applications to experts outside the Agency for review. Notably, that information would
include preclinical and clinical data:
The development of new knowledge and insights from clinical and
preclinical study data is an important regulatory science opportunity.
These data have a tremendous potential to help address critical challenges
and provide new opportunities for innovation in medical product
development, including for human drugs, medical devices, and biological
products. Safety and effectiveness data from multiple studies have been
used in the past to address key hurdles in drug development. Analysis of
data from multiple clinical and preclinical studies has been used to
identify potentially valid endpoints for clinical trials, understand the
predictive value of preclinical models, clarify how medical products work
in different diseases, and inform development of novel clinical designs and
endpoints to the benefit of patients (2014).

The FDA request for comments, 78 FR 33421, and draft the EMA Policy 0070, suggest
different approaches toward improving transparency of clinical trial data. Both the FDA
and the EMA address commercially confidential information, but the FDA calls greater
attention to trade secrets and more often identifies data as CCI. In contrast, the EMA
policy permits wider disclosure by connecting data to corresponding product applications
and releasing some of the data to the public. Of note, while EMA has issued its final
Policy 0070 and related implementation guidance, FDA has not publicized any additional
progress in its data transparency efforts. Overall, the ongoing progress of EMA may
reflect the greater pressure exerted by secondary researchers and stakeholders in the EU
relative to in the US.
59
Perhaps it is not surprising that the US and the EU approach transparency initiatives in
different ways. The FDA and EMA are fundamentally different as organizations. The
FDA is a centralized institution with substantial legal authority in a single country that
directs medical product development and conducts independent analyses per established
data standards from sponsor raw and analysis datasets. In contrast, the EMA is a
coordinating body that reviews sponsor data listings and manages some of the processes
and assessments shared by the corresponding national member states (Kreatsoulas, 2009).
On the basis of that difference alone, the EMA intrinsically has an additional layer of
complexity, which can complicate its ability to fulfill its mission. For the implementation
of clinical trial data transparency, the relationship between the EMA and the National
Competent Authorities is an additional issue to address as third parties submit data
requests and expect a clear channel of communication. And beyond organizational
structures, the FDA and the EMA have been viewed as pursuing clinical transparency
efforts as a means of different stated goals. The FDA identifies that it is driven to
enhance the speed and impact of medical product development and advance regulatory
science (2014), whereas the EMA seeks to discourage selective reporting, encourage
study replication, and allow for secondary analyses for the benefit of patients (EMA,
2014).
Given the finite nature of capital and human resources at regulatory agencies, regulators
may be motivated to attain common ground on at least some issues, particularly those
related to the way that documentation is organized and redacted. Similarly, Guido Rasi,
current EMA Executive Director, remarked that, similar to the way that the FDA is not in
60
the publishing business, “the EMA is not in the redaction business” (Rasi, 2014). In fact,
in its explanation to the European Ombudsman earlier in 2007, the EMA had initially
cited the disproportionate burden of time and effort that would be required in order to
fulfill the data requests submitted by the Nordic Cochrane Center. It had argued that the
documentation for only one of the drugs spanned approximately 500 volumes, and each
volume consisted of roughly 300 to 400 pages. However, since the EMA could not
substantiate the way in which disclosure would precisely and exactly damage commercial
interests, redaction of commercially confidential information was irrelevant in the view
of the Ombudsman. Further, the EMA had not provided evidence that individual patients
could be identified retroactively, per the information available in the requested
documents. Accordingly, the Ombudsman had held that the redaction of personal data
could be limited to information on the clinical trial authors and principal investigators. In
other words, the Ombudsman considered the redaction as limited, straightforward, and to
constitute a reasonable use of the EMA resources (European Ombudsman, 2010).
Meanwhile, redaction procedures have also been prescribed for FDA. According to the
2007 amendments to the FOIA, FDA is required to indicate the quantity of removed
information on the released part of a record, and the exemption that is the basis for the
removal. In a 2014 cross-sectional study, researchers from the Nordic Cochrane Centre
and the University of California, San Francisco concluded that FDA provided detailed
information on harms in 25 of 27 CSRs, while EMA provided information on harms in
7 of 27 CSRs on the same drugs. While the redacted information from FDA was more
61
difficult to navigate, the authors found that FDA did provide more data (Schroll, Abdel-
Sattar, & Bero, 2015).
If the industry submitting the marketing materials in both Europe and the United States
find ways of utilizing singular approaches in implementing disclosure to both the US and
EU, harmonization could occur organically. Such approaches would have to be designed
to fulfill the needs of both agencies while providing what they view as essential
protections of proprietary information. Some evidence suggests that numerous
multinational pharmaceutical manufacturers are seeking better models for data
presentation that meet the needs of multiple regulators. Initially, in July 2013 the
Pharmaceutical Research and Manufacturers of America (PhRMA) and the European
Federation of Pharmaceutical Industries and Associations (EFPIA) issued a joint
statement, announcing commitments to protect patient privacy, safeguard the assessment
roles of health authorities, and retain incentives to invest in pharmaceutical research. In
response to an October 2012 workshop, Sharing Clinical Research Data (Institute of
Medicine, 2012), in October 2013, the Institute of Medicine (IOM) of the National
Academies held the first workshop of The Committee on Strategies for Responsible
Sharing of Clinical Trial Data (Institute of Medicine, 2013). In January 2014 the
Committee issued an interim report that proposed four models on which preference
studies could be conducted. The first, a fully open access model, could provide clinical
trial data to scientists and the public. Second, a more limited open model could provide
data only to defined consortia or partnerships. Third and fourth choices were controlled
access models that could provide either pooled data from multiple entities or data from a
62
single entity, respectively, following a formal data request (Zeliadt & Khamsi, 2014). Via
a survey administered prior to a clinical transparency conference held in March 2015,
90% of participants indicated a general preference for a model under private control.
Although various groups have made suggestions about what industry should do to share
clinical trial data, what industry is actually doing is not nearly so clear. A comprehensive
understanding of current practices for data sharing could assist industry, regulators, and
other stakeholders in recognizing current problems and in making more progress toward
best practices that could support benchmarking activities. Chevron defined best practices
as “any practice, knowledge, know-how, or experience that has been proven to be
valuable or effective in one organization that may have applicability to other
organizations.” Benchmarking, in turn, is the “process of identifying, understanding, and
adapting outstanding practices from organizations” (O'Dell & Grayson, 1998).
A comprehensive analysis of current trends is not available, but case studies can provide
a starting point for understanding how industry is sharing clinical data. In October 2013,
Mello, Francer et al. not only summarized the possible benefits of data sharing, as shown
in Figure 1, but the authors also described four models for sharing individual patient data
(IPD), as shown in Figure 2. First, an open access model could provide extensive
transparency but without controls to ensure that the provided data is useful. Second, a
database query model could address the questions posed by secondary researchers
internally, but such an approach would place an extraordinary burden on the sponsor
without providing visibility to requesters. Third, a sponsor review model could reduce the
relative workload of the sponsor and allow it to retain control over data but would at the
63
same time sacrifice a greater advance in transparency. Fourth, a learned intermediary
model, such as the Yale Open Data Access (YODA) Project, could grant access control to
an independent committee (Mello et al., 2013). In 2014, Johnson & Johnson contracted
with Yale and provided it with the authority to independently grant responsible access to
researchers (Krumholz & Waldstreicher, 2016).
Figure 1: Potential Benefits of Sharing Clinical Trial Data
Modified From: (Mello et al., 2013)
Benefit Primary Beneficiaries
Public
or
Patients
Research
Participants
Scientific
Community
Regulators Trial
Sponsors
Encourage characterization of the
benefits and risks of drugs in
research reports, improving public
confidence in clinical research and
pharmaceuticals
X X X X
Improve surveillance of drug safety
and effectiveness
X X X
Facilitate secondary analyses of
clinical trial data to explore new
scientific questions
X X X
Speed innovation X X X
Enable patients and advocacy
groups to learn more about their
specific medical problem
X
Ensure that research participants are
not exposed to unnecessary risk
X X
Ensure that research subjects’
participation advances science
X X
Achieve operational efficiencies in
conducting clinical trials
X X
Inform strategic decisions about
potential avenues of research and
development
X X

64
Figure 2: Four Possible Models for Expanded Access to Participant-Level Data
Source: (Mello et al., 2013)
Variable Open Access Database Query Sponsor Review
Learned
Intermediary
Decision maker None Independent review board
or trial sponsor
Trial sponsor Independent
review board
Process Trial sponsor
routinely posts
data and
supporting
documentation
when trial results
are publicly
reported or
submitted
regulatory
agency;
researchers
download the
material
Requester submits a
research query to the data
holder, who then runs the
query and returns the
results, not the data
Trial sponsor
reviews request,
decides, and
publicly
documents
rationale for the
decision, which
may be appealed
to an independent
board, whose
decision is final
Board reviews
request, collects
input from trial
sponsor,
decides, and
publicly
documents
rationale for
decision
Criteria for
releasing data
Responsible-use
attestation:
Full access as
long as requester
attests that data
will not be used
inappropriately
(e.g., to
reidentify
research
participants)
Sound science: Is there a
reasonable scientific
hypothesis, sound
analytical plan, and
adequate plan to
disseminate findings?

Benefit-risk balancing:
Do the potential public
health benefits of
answering the proposed
questions outweigh the
probable adverse effects
on the trial sponsor (e.g.,
intellectual-property
interests, competitive
concerns, technical-
support burden) and the
potential risks to research
participants?
Same criteria for
sound science and
benefit-risk
balancing as in
database-query
model

Expertise: Does
the research team
have expertise
sufficient to carry
out the proposed
analyses?
Same criteria as
in sponsor-
review model

2.3 Framing the Study of Clinical Trial Results Disclosure
As one example of an industry approach, employees of Roche explained their extensive
clinical trial data-sharing program in the April 2014 issue of Regulatory Rapporteur, so
65
that other sponsors could use the approach as a template for proactive implementation of
regulations and guidelines. In lessons learned, the authors emphasized the need to
promote responsible use, such as incorporating data sharing agreements and allowing
users on-screen access rather than provide downloadable data. They also stressed that
regulators ought to receive first access and that all stakeholders should be held to the
same standards in an environment that encourages transparency. However, it is not clear
whether such approaches are typical of other larger companies. It is also unclear whether
the complex model proposed by Roche would be useful or financially sustainable for
smaller pharmaceutical firms, biotechnology companies, medical device companies,
academic institutions, or other clinical trial data stakeholders (Atzor et al., 2014).
2.3.1 Key Stakeholders
A key concern in all of the transparency initiatives so far has been the need to balance the
interests of the multiple stakeholders involved in seeing and using clinical data. In
January 2015, the IOM Committee in the US disseminated its final report, Sharing
Clinical Trial Data: Maximizing Benefit, Minimizing Risk. It recommended cultivating a
stakeholder culture in which data sharing is expected; specific types of data are shared
within outlined timeframes; data use agreements are implemented; independent review
panels include the lay public; the access to data is transparent; and a global, diverse,
multi-stakeholder entity is established to help solve ongoing, multidisciplinary challenges
in sharing data. It also identified the array of stakeholders that they considered to be
integral to the data sharing landscape, as shown in Figure 3. In their words,
66
These parties have differing perspectives on the benefits, risks, and
challenges associated with sharing clinical trial data. Further, all
stakeholders have a role and responsibility in helping to maximize the
benefits and minimize the risks of data sharing for others, as well as
themselves (Institute of Medicine, 2015; Medicine, 2015)
Figure 3: Clinical Trial Data Sharing Stakeholders
Source: (Institute of Medicine, 2015; Medicine, 2015)

The diversity and level of concern of stakeholders interested in clinical trial data sharing
are also clear from the responses that both EMA and FDA have received in response to
67
its proposed initiatives. For example, in 2013 FDA received comments from 38 different
stakeholders on its Availability of Masked and De-identified Non-Summary Safety and
Efficacy Data. Also in 2013, EMA received 1,138 comments on Policy 0070 on
Publication and Access to Clinical-Trial Data from 169 stakeholders, as shown in
Figure 4. EMA reported that many of the comments it received were provided by
individuals indicating general support for its initiative (EMA, 2014). However, it is
important in any policy setting or evaluation exercise to understand the specialized needs
and particular views of key sets of stakeholders in more detail.
Figure 4: Comments by Stakeholder on EMA Policy 0070
Source: (EMA, 2014)

68
2.3.1.1 Clinical Trial Participants and Patient Advocacy Organizations
Patient populations compose one of the principal stakeholder groups that have become
more visible and vocal. This heterogeneous group spans a full range of income levels,
demographics, cultures and geographies, so that a representative picture of the “patient
voice” is difficult to achieve. Nonetheless, some insights into the patient perspective may
derive from statements and position papers of certain patient advocacy organizations that
are quite clear about the importance of including the voice of the patient in considerations
of clinical transparency. Typically, these groups advocate for better access to clinical
trial data. For example, in response to EMA Policy 0070, the European Consumers
Organization (BEUC) described a subcategory of 21
st
century patients, called “expert
patients,” who know as much as their physicians about disease processes and
pharmaceutical products. These patients are likely to seek out sophisticated medical
information and be able to interpret it. Nevertheless, BEUC expressed the view of its
members that information should not be restricted only to more knowledgeable groups of
patients. Rather they felt that all patients, regardless of knowledge level, should have a
fundamental right to clinical trial data, and that Policy 0070 should apply retroactively to
all authorized products. As stated by the International Alliance of Patients’ Organizations
(IAPO),
Indeed, patients are the only stakeholders with no hidden agenda and no
overriding interest; we are the ultimate beneficiaries or victims in a
clinical trial.
Nevertheless, in the past, many have advanced the view that scientific experts should
shield patients and the lay public from the types of technical and interpretive discussions
69
that can ensue as a result of clinical transparency (Institute of Medicine, 2015). In a
recent survey of US adults and physicians, 52% of physicians expressed the belief that
the general public should be informed about a medication safety issue only after the issue
has been investigated and proven to be associated with the medicine; in contrast, 75% of
the general adult population believed that they should be informed before such an
investigation (Lofstedt, Bouder, & Chakraborty, 2013). Other research found that 77% of
clinical trial participants never received results but that 72% believed that it is “very
important” to confront the issue ("Compliance with results reporting at
ClinicalTrials.gov," 2015). To that end, stakeholder members of the Harvard Multi-
Regional Clinical Trials (MRCT) Center published a guidance document for delivering
lay summaries to clinical trial participants (The Multi-Regional Clinical Trials Center of
Brigham and Women's Hospital and Harvard, 2015). Patient-related groups have largely
expressed widespread support of the FDA and EMA proposals for clinical trial
transparency. Still, some patient representatives have expressed concern about the degree
to which the release of clinical data release might compromise privacy. The International
Alliance of Patients’ Organizations (IAPO) recommended that EMA prioritize subject
privacy over clinical transparency in cases requiring a potential preferential decision. In
addition, Public Citizen’s Health Research Group recommended that subjects should be
informed fully about possible third party data use at the time when they were introduced
to a trial as part of the informed consent process and that they should be re-consented
should conditions of disclosure change (Public Citizen's Health Research Group, 2013).
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2.3.1.2 Secondary Researchers, Legal Analysts and Associated Advocacy
Organizations
Secondary researchers are a growing sector of research specialists who use the data
available from clinical studies to conduct further academic or sponsored research. The
Cochrane Collaboration and other such researchers reevaluate the conclusions of studies
or combine the data with that from other studies using statistical methods or meta-
analyses. The work of such individuals depends heavily on their ability to access the data
that they need to conduct research; it affects their ability to submit successful grant
applications or conduct research for others, which in turn, affects the stature of these
individuals in the research community. It is not surprising, then, that they have been
amongst the strongest advocates of disclosure. Attorneys and law firms, too, are
incentivized to gain access to such data that might strengthen their ability to litigate
against companies on behalf of patients who appear to have been injured by a drug or
device. Secondary researchers and attorneys were also responsible for the majority of
“access to documents” requests to EMA for clinical data, per Policy 0043, or European
Medicines Agency policy on access to documents (related to medicinal products for
human and veterinary use) (Allchurch, 2014a).
Particularly strong expressions of support typically originate from secondary research
groups. For example, in January 2013, Bad Science, British Medical Journal (BMJ),
Centre for Evidence-Based Medicine, Cochrane Collaboration, James Lind Initiative,
Public Library of Science (PLOS), and Sense About Science, together initiated the
AllTrials campaign for the registration and results reporting of all clinical trials. The
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campaign has since garnered support from 88,079 individuals and 654 organizations and
in its comments expressed extensive support and alignment with EMA Policy 0070 as
originally drafted (AllTrials, 2016). In fact, secondary researchers and transparency
advocacy organizations in some instances suggested that the EMA policy was not
extensive enough. For example, in a separate comment, PLOS suggested that EMA
should apply the disclosure policy retroactively in order to include all past clinical trial
data (Public Library of Science, 2013). Transparency advocates, as well as other
stakeholders generally, reasoned that that, as originally drafted, the EMA transparency
requirements would not apply to the many standard-of-care treatments that were
authorized prior to the effective date of the policy (Goldacre, 2013). However, if the
policy were extended retroactively to 2000, for example, its disclosure requirements
would apply to about 80 percent of the drugs currently approved in the EU (European
Association for the Study of the Liver, 2013), and would require a very large amount of
additional work to be done by companies and regulators.
2.3.1.3 Universities and Research Institutions
In response to the FDA’s notice and request, university and academic researchers added
many comments that focused less on the “rights and wrongs” of disclosure but rather on
the management of the disclosure process. Many of their comments centered on
governance, with a particular focus on the entities allowed to gain access to the data and
the terms under which such sharing should occur. They also expressed concern about the
ability to manage the data without disclosing private information or proprietary materials.
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Respondents from the Georgetown University Program for Regulatory Science &
Medicine (PRSM) characterized the overall tone of university remarks:
Making available subject-level data poses challenges that can best be met
by heeding the overarching principal of primum non nocere - 'first, do no
harm' - neither to data generators nor research participants (Shoulson,
Wilhelm, & Christopher, 2013).
In its remarks, the Harvard University Regional Clinical Trial (MRCT) Center stated that
controlled access could provide greater data utility and privacy protections (The Multi-
Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard, 2013).
The Association of Medical Colleges (AAMC) contended that secondary researchers
could distract university researchers. They might conduct inappropriate or biased
research that does not contribute to a better totality of research overall, without the
requirement, in turn, to share their own data (American Association of Medical Colleges,
2013). Employees at Duke Clinical Research Institute questioned whether FDA would
disclose the identities of secondary researchers, and would expand this disclosure to
identify the intentions of those third parties when using the data. Further, they questioned
whether FDA would evaluate possible conflicts of interest, such as former employees or
current competitors requesting access to data on a specific product, and whether
secondary researchers would be compelled to use the data according to their expressed
intents. In extreme cases, individuals or entities with unscientific personal or political
agendas could inflict public harm, as occurred when Andrew Wakefield proposed a link
between the measles, mumps, and rubella (MMR) vaccine and the onset of autism from
flawed data analysis (Belton et al., 2013).
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Some university and academic stakeholders suggested that FDA utilize a staged data
sharing program and initiate pilot studies as a first step in the transition to greater
transparency, perhaps prioritizing orphan diseases, unmet medical need, or diseases with
poor prognoses as initial models (Shoulson et al., 2013). Others however, were more
enthusiastic for a rapid change in policy. In the EU, university faculty and students
expressed more general widespread support for all of the provisions of EMA Policy 0070,
even suggesting that it apply retroactively to medicines regardless of authorization date
(Jones, 2013).
It has been argued that instituting mandatory disclosure will not address the underlying
conflict of interest retained by sponsors as long as those companies conduct or have
control over clinical trials. One proposal is the potential development of an independent
scientific testing agency funded by the larger industry players that could conduct clinical
trials in an arms-length fashion. From more of an arm’s length, universities may play
such a role. Such approaches have also been suggested as a way to streamline and lower
clinical development costs, render prescription medicines less expensive, provide for a
secondary market for abandoned or denied products, and reward qualified scientists
(Reichman, 2009).
2.3.1.4 Sponsors
2.3.1.4.1 Comments on FDA and EMA Data Sharing Proposals
Medical product sponsors constitute a particularly important stakeholder. On one hand,
they are in the unique position of generating most of the clinical trial data subject to the
new clinical disclosure rules. On the other, they will be able to take advantage of the new
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rules to gain insight into the status of competitive molecules under development by
competitors or into trial designs and clinical outcomes of related molecules to guide their
own development strategies. Thus, their stated positions on disclosure are somewhat
complex. With regard to issues of patient privacy, the majority of comments to FDA and
EMA either from individual medical product companies or industry trade organizations
appear similar to those provided by patient-related groups. However, with regard to the
potential for loss of proprietary data, companies and industry organizations were greatly
concerned. To some extent, this concern was justified by the nature of some of the initial
proposals by EMA that, for example, suggested that there would be wider release of data,
even from animal trials or manufacturing. Further, some concern surrounded the
possibility that regulators might expect the release of data from development programs
that have already concluded. For example, the Plasma Protein Therapeutics Association
(PPTA) advocated against retroactive disclosure of data. Its other recommendations
responded to concerns also expressed by academics, as described above. They suggested
that EMA provide in-house hearings to mitigate disagreements over commercial conflict
of interest and recommended that EMA hold secondary researchers to the same level of
scrutiny as that directed toward the data generators themselves. PPTA advised EMA to
exclude orphan products from its policy, and asked for further information on the way
that EMA intended to treat and enforce data sharing agreements (Plasma Protein
Therapeutics Association, 2013).
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2.3.1.4.2 Publically Accessible Company Policies
Of particular interest in this dissertation is not only how companies view the specifics of
data disclosure requirements but also how they are preparing themselves for compliance.
In July 2014, Krumholz et al. tabulated the data-sharing practices of the largest twelve
pharmaceutical companies, estimated according to their own research on market
capitalization in 2013. They analyzed the types of data explicitly defined as shared and
not shared by the company, the availability of Case Report Forms, data access fees, data
application requirements of interest, and the overall data request process. Krumholz and
colleagues contended that industry has embarked on transformative changes in its level of
clinical transparency. Still, they judged that company attitudes and actions are only
starting to adjust, and will be tested going forward (Krumholz et al., 2014).
The regulatory initiatives that have occurred are new, but it may be significant that some
companies began the discussions about data sharing well before governmental initiatives
started. For example, in October 1998, Chairman Richard Sykes wrote in BMJ that
GlaxoWellcome would publish all clinical protocols on a website,
science.glaxowellcome.com. Going forward, the company would register completed
phase 2 and 3 studies near the time of regulatory approval and update the information on
large phase 3b and 4 studies each year. He also committed GlaxoWellcome to a policy of
providing each clinical trial with a unique identifier to enable secondary researchers to
study efficacy more effectively using approaches such as meta-analysis (Sykes, 1998).
More recently a number of large pharmaceutical companies have also announced changes
in their approaches to clinical trial disclosure. For example, in May 2014, Boehringer
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Ingelheim announced that it also would post clinical data on its website, trials.boehringer-
ingelheim.com/trial_results.html, and would assure a dedicated staff to facilitate requests
for CSRs, de-identified patient-level data, and other clinical information generated
retrospectively as far back as 1998. At the same time, however, the company identified
that it will use an independent review panel to assure that the data is given only to
appropriate researchers under a data sharing agreement. Proactively, Boehringer
Ingelheim committed to publishing clinical results for all studies, regardless of outcome
in peer-reviewed journals and at scientific meetings. It also stated that it would register
protocols for studies beginning as early as 1998 on ClinicalTrials.gov. Beginning with
trials whose end-dates were in 2014, the companies also committed to posting on
ClinicalTrials.gov the results of products with ex-US approvals or for which development
was discontinued (Boehringer Ingelheim, 2014).
In a similar move in March 2015, AstraZeneca announced that it would utilize an
independent Scientific Review Board to evaluate requests for clinical trial data submitted
via its Data Transparency Portal. It announced that it would share interventional study
data collected in 2009 or later for submitted, approved, or discontinued indications in the
US, Japan, and/or Europe. The company committed to providing the results of all trials to
public websites, to developing lay language summaries for all participating research
subjects, and to posting Clinical Overviews, Clinical Summaries, CSRs, study protocols,
sample CRFs, and Statistical Analysis Plans (SAPs) to their website at
astrazenecaclinicaltrials.com. Further, it gave the Board the authority to assist researchers
in re-submitting requests for successful approval (AstraZeneca, 2015). In April 2014,
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PatientsLikeMe announced a five-year global agreement to provide Genentech with
access to its patient database to inform the company’s pharmaceutical development
(PatientsLikeMe, 2014). PatientsLikeMe is an online patient network intended to help
patients improve research and patient outcomes, and the announcement marked the first
broad research collaboration using individual patient data (IPD).
2.3.1.4.3 Challenges of Gatekeeping and Logistical Management
The work required to organize and respond to requests and to redact proprietary material
appropriately is one of the largest acknowledged challenges of managing clinical data
disclosure. The Multi-Regional Clinical Trials Center (MRCT) of Brigham and Women’s
Hospital at Harvard devised a framework that establishes and categorizes chronological
stages of clinical trial data governance according to the number and rigor of gatekeeping
requirements. However, these staging methods do not in themselves answer questions
about how companies are managing the processes and requests. It is not clear how many
companies are structuring or are intending to structure their clinical data sharing
programs. For example, it is unclear whether this is done within existing departments or
by new, separate entities, either within the company itself or at arm’s length. Further, it
is unclear what kinds of individuals, such as employees, consultants or contractors are
employed in these activities, and whether they are organized into separate groups dealing
with strategy as opposed to operations. Additional questions, such as the interactions
between these operations and those of other groups and departments, such as clinical
trials management and regulatory intelligence, have not been made clear. It is not even
clear whether all companies are well advanced in implementation or whether some are
78
still at early stages. Finally, it is not clear to what extent the companies have encountered
problems of implementation and how those problems have been managed.
Figure 5: MRCT Data Sharing Benchmarks
Source: (The Multi-Regional Clinical Trials Center of Brigham and Women's Hospital
and Harvard, 2015)

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In addition, data sharing is not a static process. Given that clinical trials are changing on
account of novel trial design, mobile medical applications, electronic medical records,
and other innovations, it follows that data sharing will also be an evolutionary process.
With that knowledge, stakeholders have an opportunity to proactively devise learning
data sharing systems that facilitate the review and ongoing modification of Good
Transparency Practices (IOM 2015). This study will provide an indication of current data
sharing practices and views that can be reevaluated in time.
2.3.2 Framing the Study of Industry Views and Actions
In order to explore comprehensively the way that industry has approached the challenge
of clinical trial data disclosure, it would be useful to consider possible frameworks that
could systematize the research. In this study, we are interested in the way that companies
are implementing data disclosure. Thus, we propose to create a survey instrument based
on an established implementation framework. Fixsen and his coworkers developed on
reputable framework that models implementation as an activity with certain actors and
linkages (Fixsen et al., 2005b). The framework is comprised of a source, destination,
communication link, feedback mechanism, and influence, as shown in Figure 6. In this
model, the source is the practice to be implemented, which, in the case of data
transparency, would be the requirements to implement applicable FDA and EMA
regulations and guidances. The destination is the organization that must ensure the
implementation, or, in this case the industry sponsor. The communication link is the
entity dedicated to implementation, which in this case would be the groups in the
company that assume some degree of responsibility for implementation. The feedback
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mechanism is the channel that provides information on the effectiveness of the
implementation. Influence factors are external factors that impact the implementation
process, such as the regulators, public groups, or other stakeholders who have reasons to
want to affect the way that the process is occurring.
Figure 6: A Conceptual Framework for Implementation of Defined Practices
and Programs
Source: (Fixsen, Naoom, Blase, Friedman, & Wallace, 2005a)

An implementation program is further characterized to take place in several phases,
specifically identified as exploration, installation, initial implementation, full
implementation, and sustainability stages, as defined by Fixsen and colleagues (Fixsen et
al., 2005b) in Figure 7.
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Figure 7: Stages of Implementation
Source: (Fixsen et al., 2005b)

In exploration, the communication link devises an implementation strategy. During
installation, staffing changes, additional funding, and other operations are assigned to
enable the tactical execution of the strategy. During initial implementation, the changes
begin but the challenge of accomplishing all aspects of the plan may produce an awkward
period of adjustment that can test the organizational faith in the change. In full
implementation, the new program gains acceptance. Finally in sustainability, the
implemented program is evaluated and, if necessary, modified over time in response to
changes in staffing, funding, and the underlying regulatory landscape.
In order to utilize such a stepwise approach, Fixsen (Fixsen et al., 2005b) placed
particular emphasis on core elements associated with the individuals comprising the
communication link. These “most essential and indispensable components of an
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implementation practice or program” are staff selection, pre-service and in-service
training, ongoing consultation and coaching, staff and program evaluation, facilitative
and administrative support, and systems interventions. Together, the components can
define culture and staff behavior.
2.3.3 Implementation Framework Applied to Industry Clinical Transparency
The present study will use the conceptual framework of Fixsen and his colleagues
(Fixsen et al., 2005b) to examine how industry is responding to new requirements related
to data transparency. As part of this examination, the research will explore the
compliance strategies available to the companies, and the degree to which the companies
have already implemented new processes. Given the complexity of the process, a
particular focus will be placed on the communication link. At each stage, questions will
be asked to assess at which stage company activities are concentrated. Further, at each
stage we anticipate the companies have encountered challenges and have learned lessons
that would be valuable to collect and document in order to understand stresses on their
systems.

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CHAPTER 3: METHODOLOGY
3.1 Stakeholder Analysis and Respondent Selection
A stakeholder analysis, as described in Chapter 2, identified that the principal group now
responsible for the implementation of the new clinical data sharing requirements are the
pharmaceutical companies providing the information to the regulators. We presume that
the individuals most knowledgeable about these arrangements will be those responsible
for preparing submissions to the regulatory agencies or authoring or redacting the clinical
sections of the submission. In order to provide a set of results with sufficient focus, we
limited the search for qualified respondents to those employed by pharmaceutical rather
than all medical product professionals. Effort was made to assure that respondents were
sought from companies of all sizes, with the specific intent of including smaller and less
frequently profiled companies.
3.2 Survey Development
This study employed a multistep mixed methodology to study pharmaceutical industry
views and management of clinical disclosure. First, a survey tool was drafted on the basis
of the literature review, comments from the doctoral thesis committee at the USC
International Center for Regulatory Science, and collaboration with the Drug Information
Association (DIA). A preliminary pilot and then a final survey were developed and
managed using Qualtrics web-based survey software. The survey included approximately
30 questions in various multiple-choice, matrix, open text-entry, scaled, ranked-order,
and yes-no formats. The clarity, appropriateness, and content of the questions were
reviewed by a focus group.
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3.3 Focus Group
On September 21, 2016, a small focus group (n=9) convened at the USC International
Center for Regulatory Science to evaluate the content, structure, and clarity of the survey
instrument. I served as moderator and briefly summarized the intended focus of the
survey before guiding a discussion of the individual questions. Video recording and
WebEx captured feedback from the focus group.
Table 5: Focus Group Participants
Name Title
Frances J.R. Richmond, BNSc, MSc, PhD Director, International Center for Regulatory
Science, USC
Director, Regulatory Science Programs,
Professor of Clinical Pharmacy, USC
Nancy Pire-Smerkanich, DRSc, MS Assistant Professor, School of Pharmacy, USC
Michael W. Jamieson, DRSc Associate Director, International Center for
Regulatory Science, USC
Assistant Professor, Clinical Pharmacy, USC
Mary Ellen Cosenza, PhD, DABT, ATS, RAC Consultant, NDA Partners LLC
President, MEC Regulatory & Toxicology
Consulting LLC
Daryl L. Davies, PhD Professor of Clinical Pharmacy, USC
Director, Management of Drug Development
Master’s Program, USC
Neal Storm, DRSc, MS, MBA, RAC Director, Global Regulatory Affairs, Amgen
Cesar Medina, DRSc, MBA, RAC Senior Manager, Regulatory Affairs CMC,
Amgen
Ali Reza Rejaei, MS, MBA, MSc Director, Clinical Development, POM
Wonderful
Erik Lakes, MSc Associate Director, Global Clinical Study
Disclosures, Takeda Pharmaceuticals

85
Focusing on non-demographics questions, some focus group participants first suggested
redefining the numerical cutoffs in one question that defined small, medium, and large
companies by numbers of employees. One suggestion was to reduce the maximum
number of employees for small companies, and another was to reduce the minimum
number of employees for large companies. However, another participant mentioned that
more narrowly defining small companies by an even smaller number of employees may
make it difficult to obtain sufficient responses in that category. For larger companies, I
clarified that preliminary research suggested that more than ten pharmaceutical
companies have more than 50,000 employees.
In another case, a participant suggested that asking respondents to estimate the way in
which their work activities are distributed may not be particularly insightful. Several
members alluded to the merits of recruiting respondents from small companies at
different points during the overall discussion. Some stated that it would be interesting to
see whether developing companies are concerned more than others with the impact of
clinical disclosure rules on their ability to compete and be successful within the industry.
One member commented positively on the value of a question concerning Contract
Research Organizations (CROs), remarking that it would be important to understand the
use of third parties within industry clinical disclosure programs. For other survey
questions in general, one member advised that it would be helpful to add “I do not know”
as a possible response in several cases in which it could be appropriate. One participant
reminded that it will be important to utilize questions that inform and align with the
selected implementation framework. A number of participants pointed to the merits of
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utilizing short, simple, straightforward questions, particularly to encourage respondents to
complete the survey in its entirety. Overall, one participant pointed to the insights that
could be provided by asking respondents to specify their experiences by region. On
several occasions members recommended that specific questions could be improved
merely by changing the general structure of those questions. At other times, questions
were recognized as interesting but not necessarily in alignment with the survey focus or
framework.
3.4 Respondent Characteristics
A pool of potential respondents was developed by soliciting individuals categorized as
clinical disclosure professionals with some measure of experience. Individuals targeted
were those with roles in the management of clinical data sharing activities and who were
receptive to completing a survey on those practices. Prospective survey respondents were
sought from an assortment of departments within pharmaceutical companies, including
regulatory affairs, clinical development, legal, medical writing, and clinical disclosure. In
order to be eligible, a prospective survey respondent had to be employed by a
pharmaceutical company, contract agency, or consultancy in which he or she is assigned
responsibility for at least one activity in clinical disclosure strategy and/or operations.
Participants were contacted as a result of professional networking, recommendations
from committee members and DRSc regulatory science program alumni and current
students, and other sources such as meeting lists that identified individuals with an
appropriate knowledge of clinical disclosure. By evaluating professional titles,
presentations, and publications, I identified more than 350 individuals as prospective
87
respondents. On a smaller scale, respondents were asked to refer other colleagues who
also have a strong knowledge of clinical disclosure practices.
3.5 Survey Delivery
According to the advice provided by the focus group, the survey tool was revised and
reformatted and was then disseminated electronically to a small group of administrative
reviewers who checked that it transmitted faithfully and that the results would be
compiled properly by the software.
After validation, the survey was distributed to the survey respondents who were
previously contacted by telephone and/or email and had expressed interest in
participating. Eligible and interested professionals received the electronic survey via
web-based link in an email. Additional referrals were provided by DRSc alumni and
current students in order to increase the number of participating respondents. The survey
was distributed via the Qualtrics Mailer function that delivers unique links to individual
respondents. The email included an introductory message, an opt-out link to prevent
email security software from identifying the email as SPAM, and the invitation-only
survey. Separate from the list of official contacts populated in Qualtrics, a spreadsheet
captured the names and email addresses of possible participants based on LinkedIn
clinical disclosure or clinical transparency job titles, LinkedIn clinical data disclosure
group affiliations, and DIA Clinical Trial Data Disclosure Community participation. The
spreadsheet also captured ongoing comments as to whether each individual proved to be
qualified after further investigation, and whether he or she was invited, confirmed interest
in participating, and officially completed the survey.
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No emails were returned as undeliverable. To encourage completion, prospective
respondents received email reminders in instances in which the survey was not returned
after a period of time, in accordance with well-established marketing techniques. A
prospective respondent was considered lost to follow up after multiple failed attempts to
obtain a completed survey. Each respondent who completed the survey was anonymized
and received a note of appreciation and a promise to receive a copy of the published
dissertation.
3.6 Survey Analysis
Once the survey period ended, continuous data from respondents was analyzed
graphically and statistically, as applicable. Open-ended responses were evaluated
qualitatively by evaluating themes and opinions in relevant categories. Each question was
reviewed on the basis of responses received. Non-respondents were not included in the
analysis.

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CHAPTER 4: RESULTS
4.1 Survey Distribution Analysis
On November 12, 2016, the survey was launched via Qualtrics emails to 29 prospective
respondents who had expressed previous interest in participating in the survey, and
whose interest was established by USC email and/or LinkedIn invitation. Subsequent
individuals who were approached and expressed interest received a Qualtrics email, and
recruitment status information was captured both in Qualtrics and in a separate
spreadsheet. Of 358 prospective respondents targeted at the outset, 210 (59%, 210/358)
were vetted as meeting the study inclusion requirements, and 98 (47%, 98/210) of those
eligible confirmed interest in completing the survey. The survey remained open until
February 9, 2017, at which time 79/98 (81%) prospective respondents invited by
Qualtrics email started and 77/98 (79%) completed the survey. In addition, two
individuals inadvertently completed a preview version of the survey instead of the official
survey itself. The preview responses were deleted and not included in the official survey
results.
Some of those who started but did not complete the survey provided unsolicited further
explanations, usually by email, as shown in Table 6. Two indicated that they could not
answer many questions that were outside of their professional competence. A third stated
by email that she was currently employed by a separate consulting company and not
directly by a pharmaceutical company. Two more believed that they had completed the
survey, but Qualtrics reports indicated that the responses were incomplete. In one case,
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the discrepancy appeared to relate to issues related to the security systems of the
employer. Six additional participants started but did not complete the survey.
Table 6: Prospective Respondent Reasons for Not Starting and/or Completing
the Survey
(n=6)
Questions surpassed knowledge and responsibilities and sought additional expertise
Judged it appropriate to complete a response, given currently employment by a separate
consulting company and not directly by a pharmaceutical company
Not fully qualified to respond to the questions
Stated that survey was completed, while Qualtrics indicated an incomplete response
Received an employer security error message but stated that survey was completed,
although Qualtrics showed an incomplete response
Refusal to engage with solicitation

4.2 Profiles of Respondents
As shown in Figure 8, the majority of respondents were either Director/Senior Directors
(26%, 20/77), Manager/Senior Managers (25%, 19/77), or Associate/Senior Associates
(23%, 18/77). The remaining respondents self-identified as Vice President (4%, 3/77),
Consultant/Senior Consultant (9%, 7/77), or Other (13%, 10/77). Seven of the ten
“Other” responses entered as text are shown in Table 7 and included medical writers and
specialists. No description was provided for the remaining three “Other” responses.
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Figure 8: Company Titles of Respondents
Q1 - What title best describes your role within your company? (n=77)

Table 7: Other Company Titles of Respondents
Principal/Senior Medical Writer (2)
Managing Partner
Specialist (2)
Strategy Officer
Senior Expert

Respondents with less than 3 years of experience (6%, 5/77) were outnumbered by those
with 3-5 years (18%, 14/77), 6-10 years (18%, 14/77), 11-15 years (26%, 20/77), and 16
or greater years (31%, 24/77) (Figure 9).
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Figure 9: Years of Experience of Respondents in the Medical Products Industry
Q2 - How many years have you worked in the medical products industry? (n=77)

As illustrated in Figure 10, the majority of respondents identified that their primary
functional roles were in Clinical Disclosure (56%, 43/77). Other functional areas
included Other (19%, 15/77), Medical Writing (10%, 8/77), Clinical Operations (8%,
6/77), and Regulatory Affairs (6%, 5/77). Thirteen of the 15 “Other” responses further
defined by text entries are shown in Table 8. No description was provided for the
remaining three “Other” responses.
Figure 10: Company Functional Roles of Respondents
Q3 - Which of the following best represents the area of your company in which you
work? (n=77)

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Table 8: Other Company Functional Roles of Respondents
(n=13)
Biometrics
GCP Quality Control
Medical writing especially clinical trial disclosure and regulatory writing.
Quality Assurance
business consulting
Strategy, business operations, internal consultancy and data disclosure
Medical Affairs
Real World Evidence and Commercial Excellence
Software for disclosure
Pharmaceutical research and development
Consultancy
Product Management
Clinical Trial Transparency

Respondents were asked to select one or more company areas in which clinical disclosure
activities occur, and the most identified Clinical Disclosure (44%, 41/93), as represented
in Figure 11. Medical Writing (22%, 20/93) was another common area, followed by
Clinical Operations (12%, 11/93), Other (10%, 9/93), Regulatory Affairs (4%, 4/93),
Regulatory Writing (3%, 3/93), Outsourced (2%, 2/93), Clinical Safety (1%, 1/93), Legal
(1%, 1/93), and Regulatory Operations (1%, 1/93). All nine “Other” responses entered a
text explanation, many of which identified vendors or consulting companies (Table 9).
The two respondents who identified that work was outsourced clarified this response in
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one instance by indicating the use of a CRO to enter information into public registries,
and in the other to redact and anonymize documentation.
Figure 11: Company Functional Area Responsible for Clinical Disclosure
Q4 - Which functional area(s) of your company is/are primarily responsible for clinical
disclosure? (n=93)

Table 9: Other Company Functional Areas Responsible for Clinical Disclosure
(n=9)
Software company (3)
None
Disclosure strategy consulting company (3)
Clinical Research Development and Medical Affairs
Clinical Trial Transparency
Figure 12 illustrates that most participants possessed significant experience in clinical
disclosure. Of 75 respondents who answered this question, approximately one third of
respondents worked in clinical disclosure for 6-10 years (35%, 26/75), one third for
3-5 years (35%, 26/75), and fifteen for 1-2 years (20%, 15/75). Only eight (11%, 8/75)
had less than one year of experience in clinical disclosure.
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Figure 12: Clinical Disclosure Experience of Respondents
Q5 - How many years have you worked in clinical data disclosure? (n=75)

As shown in Figure 13, more than half of respondents (56%, 43/77) reported working for
medium-sized companies, defined as 500 to 49,999. Almost one third (32%, 25/77)
worked for small companies with 500 to 49,999 employees, while only 12% (12%, 9/77)
worked for large companies with 50,000 and greater employees.
Figure 13: Size of Company by Employees
Q6 - How many employees work at your company? (n=77)

Further, in Table 10, responses identifying company size were cross tabulated with
responses identifying functional area(s) primarily responsible for clinical disclosure
activities. Company size was directly correlated with the likelihood that the company had
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a dedicated clinical disclosure group or department, instead of incorporating such
activities under the umbrella of other functional areas. More than one third of responses
from respondents (35%, 8/23) of the smallest companies indicated that they had a
separate clinical disclosure group, whereas more than half of medium-sized companies
(60%, 25/42) and all of the largest companies (100%, 8/8) did so.
Table 10: Cross Tabulation of Company Size and Clinical Disclosure Function
(n=73)

How many employees work at your
company?

1-499 500-49,999 50,000+ Total
Clinical Disclosure (as a separate
group or department)
8 25 8 41
Clinical Operations 3 7 1 11
Clinical Safety 1 0 0 1
Medical Writing 5 13 2 20
Legal 0 1 0 1
Regulatory Affairs 0 3 1 4
Regulatory Operations 1 0 0 1
Regulatory Writing 1 1 1 3
Outsourced (Please describe) 0 1 1 2
Other 8 1 0 9
Total 23 42 8 73

Most respondents were in companies with numerous marketed products in their
portfolios, either 21 or more (26%, 19/74) or 6-20 (27%, 20/74). Four respondents (5%,
4/74) worked for companies with 1-5 approved products, and fifteen (20%, 15/74) had no
products (Figure 14).
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Figure 14: Size of Company Product Portfolio
Q7 - What best estimates the current number of approved products across your company's
portfolio? (n=74)

When asked to select one or more responses, most participants (59%, 59/100) reported
having global responsibilities at their respective companies; the others reported US (21%,
21/100), EU (18%, 18/100), or other regional (2%, 2/100) responsibilities (Figure 15).
Both responses representing “Other Regions” were entered as text, one being global
besides the US, and the other being Asia.
Figure 15: Geographic Region(s) of Responsibility
Q8 - For which geographical region(s) are you responsible at your company? Please
select all that apply and specify, as appropriate. (n=100)

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Respondents were familiar with various policies and guidance documents related to
clinical disclosure to different degrees. More respondents were extremely familiar (29%,
22/77) or very familiar (40%, 31/77) with EMA Policy 0070 on Publication and Access
to Clinical-Trial Data than were extremely familiar (14%, 11/76) or very familiar (26%,
20/76) with, FDA’s Availability of Masked and De-Identified Non-Summary Safety and
Efficacy Data. This is reflected also amongst respondents with lower levels of familiarity.
Only a small number were moderately familiar (21%, 16/77), slightly familiar (5%, 4/77),
or not familiar at all (5%, 4/77) with EMA Policy 0070, but a majority were either
moderately familiar (28%, 21/76), slightly familiar (20%, 15/76), or not familiar at all
(12%, 9/76) with FDA’s notice.
Figure 16: Familiarity with EMA and FDA Data Sharing Policies
Q9 - How familiar are you with EMA and FDA policies on data sharing? (n=77 and
n=76)

4.3 Clinical Disclosure Implementation Practices
On a company level, Figure 17 indicates that, of those who answered the question, most
respondents reported working for companies that had received (56%, 43/73) or were
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expecting to receive (7%, 5/73) additional staff, funding, and other resources earmarked
for clinical disclosure. Only twelve (16%, 12/73) reported that the clinical disclosure
function had not received and did not expect additional resources and thirteen (18%,
13/73) were not aware of the resourcing plans of their companies.
In Table 11, responses identifying whether companies had received or expected to
receive additional resources were cross tabulated with responses identifying company
size. Company size was correlated with the likelihood that more resources would be
provided for clinical disclosure activities. Less than half of respondents (39%, 9/23) from
small companies had received additional resources whereas nearly two thirds of
respondents (64%, 27/42) from medium companies and nearly all of the respondents
(88%, 7/8) from large companies had received more resources. Nearly one third of
respondents (30%, 7/23) from small companies answered that no additional resources
were received or expected going forward whereas such responses were less frequently
given by respondents (12%, 5/42) from medium-sized companies and no such responses
were given by respondents (0%, 0/8) from large companies.
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Figure 17: Additional Resources for Clinical Disclosure
Q10 - Have additional resources, such as additional staff and funding, been allocated for
clinical disclosure at your company? (n=73)

Table 11: Cross Tabulation of Additional Resources and Company Size

How many employees work at your
company?
1-499 500-49,999 50,000+ Total
Yes 9 27 7 43
No, but my company plans to do so 0 5 0 5
No, and my company does not plan to
do so 7 5 0 12
Do not know 7 5 1 13
Total 23 42 8 73

Most respondents were affiliated with companies that had implemented programs to meet
EMA disclosure requirements (Figure 18). Twenty respondents (27%, 20/74) categorized
their companies as having a program in place, sixteen (22%, 16/74) described their
companies as maintaining their current programs, and seventeen (23%, 17/74) stated that
their companies are exploring and developing strategy. Ten respondents (14%, 10/74)
reported their companies to be in the piloting process, and three (4%, 3/74) described
their companies as adding staff and funding.
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When asked about their progress in implementing FDA requirements, 25 respondents
(34%, 25/73) categorized their companies as maintaining current programs, fifteen (21%,
15/73) described their companies as having a program in place, and fourteen respondents
(19%, 14/73) stated that their companies were exploring and developing strategy. An
additional five respondents (7%, 5/73) described their companies as adding staff and
funding, and three (4%, 3/73) reported their companies as in the piloting process.
Figure 18: Current Stage of Company in Fulfilling EMA and FDA Requirements
Q11 - How would you best describe the current status of your company in adjusting to
fulfill EMA and FDA clinical data disclosure requirements? (n=74 and n=73)

Respondents were given three choices to describe the mechanisms used by their
companies to monitor the effectiveness of their data-sharing programs. More than one
choice could be made, which resulted in 72 respondents making 111 selections. As
shown in Figure 19, participants (38%, 42/111) most commonly reported that their
employers use internal company metrics. Less frequently, they used indexes (20%,
22/111) and/or staff performance reviews (18%, 20/111). Some respondents (10%,
11/111) indicated that other methods were used. Nine of eleven “Other” responses
provided a text explanation, such as the use of either user or market surveys (Table 12).
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Three of the nine indicated N/A. Finally, sixteen respondents (14%, 16/111) did not know
what metrics were used.
Figure 19: Company Mechanism for Evaluating the Effectiveness of Internal
Clinical Data Sharing Program
Q12 - How does your company evaluate the effectiveness of its clinical data sharing
program? Please select all that apply. (n=111)

Table 12: Other Company Mechanisms for Evaluating the Effectiveness of
Internal Clinical Data Sharing Programs
Nothing yet
Have own internal clinical trial data transparency program for outside researchers
interview and survey users of our data sharing system
Completed reports and publications
Client reviews and satisfaction/retention
Market surveys, customer feedback, customer KPIs

On a scale of 1 to 10, where 1 represents the greatest challenge, respondents on average
judged that the most challenging obstacle to implementing a successful data sharing
program was the absence of harmonized clinical disclosure requirements (3.92)
(Figure 20). Other factors weighted above the halfway value of 5 included significant
changes to work processes (4.63), lack of an adequate clinical data sharing framework
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(4.66), lack of manpower (4.81), and lack of knowledge (4.84). Least challenging
obstacles included cultural resistance (5.94), lack of senior management support (5.84),
significant staff training (5.52), and lack of financial resources (5.11). One respondent
used a text box to indicate that the greatest challenge related to the ongoing, changing
requirements and associated timelines of rules, such as Policy 0070. One participant
stated that the question was not applicable to his/her situation.
Figure 20: Challenges to Company Implementation of Clinical Data Sharing
Programs
Q13 - Successful implementation of a company clinical data sharing program may be
impeded by certain barriers. Please rank, according to the degree of challenge presented
the challenges of implementing clinical data sharing. (1 = Most difficult challenge, 10 =
Least difficult challenge)

When asked about their levels of familiarity with certain data sharing models or services,
only ClinicalStudyDataRequest.com was identified as familiar to more than half of the
respondents (65%, 48/74). Less than half of the respondents were familiar with the
MRCT (46%, 34/74) and the YODA Project (47%, 35/74). Other clinical data sharing
options, entered in textboxes are shown in Table 13.
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Figure 21: Familiarity of Respondents with Clinical Data Sharing Frameworks
Q14 - With which clinical data sharing models are you familiar? (n=74, n=74, n=74, n=9)

Table 13: Other Clinical Data Sharing Frameworks Recognized by Respondents
Company website
FDAAA 801 requirements
PharmaCM
several others, most notably Project Data Sphere
Alltrials
OpenTrials
ideaPoint/ClinicalStudyDataRequest.com (2)

Respondents were asked to indicate the types of requirements in place to allow access to
data requesters. As shown in Figure 22, most reported that their companies require that
clinical data requesters possess technical expertise, such as a scientific degree and expert
qualifications (37%, 37/99). Fewer respondents indicated only general requirements, such
as a specific degree (22%, 22/99), or no requirements and access for the general public
(22%, 22/99). Eighteen (18%, 18/99) reported that they do not know the eligibility
requirements established by their respective companies for those requesting data.
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Figure 22: Eligibility Requirements to Obtain Company Clinical Data
Q15 - Who is eligible to obtain clinical data from your company? Please select all that
apply. (n=99)

Respondents queried about the nature of individuals and groups requesting clinical data
identified that, industry and industry organizations, clinical trial participants and patient
advocacy organizations, universities and research organizations, secondary researchers,
legal analysts and associated advocacy organizations all request company data
(Figure 23). In the US, most participants (24%, 31/128) identified that universities and
research organizations most commonly requested clinical data, but industry and industry
organizations (23%, 30/128), clinical trial participants and patient advocacy organizations
(19%, 24/128), and secondary researchers, legal analysts and associated advocacy
organizations (18%, 23/128) were also commonly identified. In addition, two (2%, 2/128)
selected other groups.
For the EU, respondents most commonly selected industry and industry organizations
(24%, 28/119), but universities and research organizations (23%, 27/119) were also
identified in similar numbers. Clinical trial participants and patient advocacy
organizations (18%, 22/119), and secondary researchers, legal analysts and associated
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advocacy organizations (18%, 21/119) were identified as requestors at somewhat lower
rates. As seen in responses regarding the source of requestor sources in the US, two
selected other (2%, 2/119) groups.
When the same question was asked regarding the rest of the world, nearly one-quarter of
respondents selected universities and research organizations (24%, 18/75), followed by
industry and industry organizations (19%, 14/75), secondary researchers, legal analysts
and associated advocacy organizations (16%, 12/75), and clinical trial participants and
patient advocacy organizations (13%, 10/75). For the rest of the world, 2 selected other
(3%, 2/75) groups.
In addition, eighteen respondents (14%, 18/128) reported that they did not know who
request clinical data from the US, nineteen (16%, 19/119) reported that they did not know
with respect to the EU, and nineteen (25%, 19/75) reported that they did not know with
respect to the rest of the world. Across regions, additional responses were entered into
textboxes. Several responses clarified that the respondents were consultants who are not
employed by the companies that had clinical data to release. One participant reminded
that, “through [EMA P]olicy [00]43 and other F[O]I requests[,] anyone can get access” to
clinical data.

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Figure 23: Requesters of Company Clinical Data
Q16 - Who requests clinical data from your company? Please select all that apply.
(n=128, n=119, n=75)
US EU
Rest of
World
Total
Industry/Industry Organizations 30 28 14 72
Clinical Trial Participants/Patient
Advocacy Organizations
24 22 10 56
Universities/Research
Organizations
31 27 18 76
Secondary Researchers/Legal
Analysts/Associated Advocacy
Organizations
23 21 12 56
Other (Please specify) 2 2 2 6
Do not know 18 19 19 56
Total 128 119 75

When asked about specific documents that are required to gain access to a company’s
clinical data, a signed data sharing agreement (24%, 38/156) was the most common
prerequisite (Figure 24). Other documents required from requesters included a research
proposal (22%, 35/156), Statistical Analysis Plan (SAP), (17%, 27/156), Institutional
Review Board/Ethics Committee (IRB/EC) approval (11%, 17/156), and a lay protocol
summary (10%, 15/156). A small number of respondents (9%, 14/156) did not know the
required documents, indicated “Other” documents, or indicated that none (1%, 1/156) are
required. Seven of nine of the “Other” responses, shown in Table 14, were entered as
text. One participant indicated that his or her company requires CVs from requesters,
while another indicated that requesters are required to show evidence of a qualified
statistician or equivalent team member.
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Figure 24: Documents Required to Obtain Company Clinical Data
Q17 - What specific documents are required to obtain clinical data from your company?
Please select all that apply. (n=156)

Table 14: Other Documents Required to Obtain Company Clinical Data
NA, we're a CRO
To the best of my knowledge
evidence of a qualified statistician (or equivalent) on team
Again, we provide disclosure services to sponsors/clients but any document requests would go to
our sponsors/clients, not to us.
Protocol and clinical study report
We are a solutions provider. Customers use our platform to disclose data
CV of researcher

As part of request packages, the greatest number of respondents (48%, 31/65) reported
that their companies expect to receive technical documentation such as a protocol, SAP,
and IRB/EC approval in order to gain access to clinical data as shown in Figure 25.
Significantly fewer (11%, 7/65) reported that a non-technical package, such as a lay
protocol summary, would be sufficient, and only one (2%, 1/65) indicated that no level of
documentation would be needed. Significantly, a large proportion of the respondents
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(40%, 26/65) stated that they did not know the level of documentation required on the
part of clinical data requesters.
Figure 25: Level of Documentation Required to Obtain Company Clinical Data
Q18 - What level of documentation is required to obtain clinical data from your
company? Please select all that apply. (n=65)

Different methods were used to qualify the requestors, as shown in Figure 26. Most
respondents (48%, 39/81) identified that their companies had reviewers internal to the
company, although a third of respondents (33%, 27/81) reported the use of external, non-
company reviewers. Fifteen (19%, 15/81) stated that they did not know who reviews
requests for company clinical data, and none (0%, 0/81) indicated that their companies do
not use reviewers at all.
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Figure 26: Company Reviewers of Requests for Clinical Data
Q19 - Who reviews requests to obtain clinical data from your company? Please select all
that apply. (n=81)

However, in Figure 27, it was identified that most company reviewers rely on either
discretionary, scientific merit reviews (39%, 33/84) or administrative reviews that require
requests to meet specific criteria to gain approval (36%, 30/84). Meanwhile, two
respondents (2%, 2/84) suggested that their companies utilize automated systems.
Nineteen did not know (23%, 19/84) how to classify their company review practices.
Figure 27: Company Reviews Required to Disclose Clinical Data
Q20 - How does your company review clinical data requests? Please select all that apply.
(n=84)

When allowed to select one or more answers to the question, respondents stated that
several types of redacted clinical documents on approved products are eligible for
111
disclosure per company policy once access to clinical documents is granted, as illustrated
in Figure 28. These include full Clinical Study Reports (CSRs) (31%, 40/127), CSR
synopses (26%, 33/127), and individual patient data (IPD) (20%, 26/127). Twelve stated
that they do not know (9%, 12/127), and nine referred to other documents, some of which
were identified in text boxes (7%, 9/127) (Table 15). These included documents as varied
as case report forms (CRFs), SAPs, data dictionaries, and protocols. Five stated that no
redacted documents (4%, 5/127) are eligible for release, and two indicated that the
eligible redacted clinical documents are decided on a case-by-case basis (2%, 2/127). One
of the latter two respondents indicated that redacted CSRs for clinical trials of approved
products, per EFPIA/PhRMA position statement, are eligible for disclosure. Several
respondents reiterated that they were third party software companies or other vendors that
provide redaction services or disclosure support or platforms.
Figure 28: Types of Redacted Clinical Documents on Approved Products
Available for Company Disclosure
Q21 - What types of redacted clinical data on approved products does your company
provide to secondary researchers? Please select all that apply. (n=127)

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Table 15: Other Types of Redacted Clinical Documents on Approved Products
Available for Company Disclosure
I believe it's one of the 2.
Protocol, SAP, data dictionary, CRF (3)
N/A - Software company or vendor performing redaction services or disclosure support or
platform
Varies by proposal

Figure 29 shows that respondents (47%, 30/64) work for companies who most commonly
utilize both manual redaction and redaction software, as opposed to manual redaction
(14%, 9/64) or redaction software (6%, 4/64) alone. Ten (16%, 10/64) indicated that the
redaction process is outsourced, and 11 (17%, 11/64) did not know the company process.
A cross tabulation of responses related to redaction methods against company size
suggested that these activities were more commonly outsourced by large rather than small
companies (Table 16). Nearly half of respondents (43%, 3/7) from large companies
suggested that the activities were outsourced, while less than one fifth of respondents
(18%, 7/39) from medium companies and no respondents (0%, 0/18) from small
companies reported that activities were outsourced. However, companies of various sizes
did not differ so greatly with respect to their preference for a combination of manual
redaction and redaction software [small companies (56%, 10/18), medium-sized
companies (44%, 17/39), large companies (43%, 3/7)].
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Figure 29: Company Redaction Practices
Q22 - How does your company redact clinical trial data? (n=64)

Table 16: Cross Tabulation of Redaction Type and Company Size

How many employees work at your
company?
1-499 500-49,999 50,000+
Total
Manual redaction 2 7 0 9
Redaction software 1 3 0 4
Manual redaction and reaction
software 10 17 3 30
Outsourced 0 7 3 10
Do not know 5 5 1 11
Total 18 39 7 64

One way to reduce the amount of redaction needed by a company is to modify documents
templates to remove fields of proprietary data, including CCI and IPD. As shown in
Figure 30, respondents (41%, 26/64) most commonly reported that their companies had
not yet incorporated changes to CSR templates, but that they are planning to do so. Only
thirteen (20%, 13/64) reported that their companies had already implemented such
changes. A significant number, nineteen (30%, 19/64), stated that they did not know the
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status of changes to CSR templates. Six (9%, 6/64) stated that the company has not
already and does not plan to change internal CSR templates.
Figure 30: Implemented Changes to Company CSR Templates to Reduce
Burden of Redacting CCI and IPD
Q23 - Has your company modified its Clinical Study Report (CSR) template to minimize
the burden the redacting commercially confidential information (CCI) and individual
patient data (IPD)? (n=64)

When asked about the databases used to share clinical data, half of the respondents (50%,
52/103) identified government databases (Figure 31). Single-company databases (23%,
24/103), and multiple-company databases (15%, 15/103), such as
ClinicalStudyRequest.com were used less frequently. Additional respondents did not
know (4%, 4/103), or identified the use of no platform at all (3%, 3/103). Five responses
(5%, 5/103) pointed to the use of other platforms, as specified in Table 17.
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Figure 31: Company Clinical Data Sharing Platforms
Q24 - How does your company provide access to clinical data? Please select all that
apply. (n=103)

Table 17: Other Company Clinical Data Sharing Platforms
Homegrown sharing portal and/or secured data transfers; CSRD in consideration
We also share full documents via an online reading room for enquiries received for
documents-only via CSDR.com Also share of PDS and other stand-alone ad hoc requests
(like IMI or disease-specific initiatives)
n/a software company
dedicated data transfer
Multiple company database IdeaPoint

Finally, respondents described the format by which successful clinical data requesters
receive the requisite information. More than one-quarter (28%, 21/76) reported that they
did not know the format. Others reported that their companies provide exportable data
(30%, 23/76), exportable analysis of data (25%, 19/76), or non-exportable data (17%,
13/76). In a separate email and outside of the survey, one respondent clarified that he had
not understood the question.
116
Figure 32: Formats of Disclosed Company Clinical Data
Q25 - What clinical information does your company provide? Please select all that apply.
(n=76)

4.4 Pharmaceutical Industry Clinical Disclosure Views
Respondents were split in their views of whether EMA and FDA clinical disclosure
requirements have encouraged companies to change the level of detail included in clinical
overviews, clinical summaries, and clinical study reports. For NDAs, marginally more
respondents answered affirmatively (34%, 20/59) or “do not know’ (37%, 22/59) than
stated “no” (29%, 17/59). For MAAs, the most common response was “do not know”
(36%, 21/59), although nearly as many reported “yes” (31%, 18/59) or “no” (34%,
20/59).
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Figure 33: EMA and FDA Requirements Have Changed Level of Detail Included
in Clinical Overviews, Clinical Summaries, and Clinical Study
Reports
Q26 - Have the EMA and FDA requirements generally impacted the level of detail that
you provide in clinical overviews, clinical summaries, and clinical study reports (CSRs)
for marketing applications? Please comment further on these specific impacts. (n=59 and
n=59)

Respondents also varied in their views on the impact of clinical data transparency
rankings that benchmark companies and/or drugs against each other (Figure 34). Their
views were most positive on the effects of assigning such rankings on legal compliance
and ethical conduct to companies. When asked about effects on legal compliance on
companies, 35 respondents (60%, 35/58) expressed the view that rankings incentivize
legal compliance, nine (16%, 9/58) stated that they do not incentivize, and fourteen (24%,
14/58) stated that they do not know. When asked about the effects on ethical conduct,
33 respondents (56%, 33/59) stated that rankings incentivize, eleven (19%, 11/59) stated
that rankings do not incentivize and fifteen (25%, 15/59) stated that they do not know.
The results were less differentiated for individual drugs. With respect to effects on legal
compliance on drugs, 22 respondents (39%, 22/57) stated that rankings incentivize drug
rankings for legal compliance, 21 (37%, 21/57) stated that they do not know, and
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fourteen (25%, 14/57) stated that rankings do not incentivize. Finally, 24 respondents
(41%, 24/58) stated that rankings incentivize drug rankings for ethical conduct, 21 (36%,
21/58) stated that they do not know, and thirteen (22%, 13/58) stated that rankings do not
incentivize. In addition, one comment was provided via email and outside of the survey
itself:
However, these rankings must be fair and consistent with requirements –
current rankings are not accurate or consistent with requirements –
‘ethical’ is especially subjective… most of these rankings mix
requirements and ethical and this only serves to confuse and disincentivize
– the best approach is to rank based on requirements and sponsor
policies, not arbitrary ethical views of academics.

Figure 34: Impact Clinical Data Transparency Rankings (Legal Compliance
and/or Ethical Conduct by Company and/or Drug) on Data Sharing
Q27 - Some organizations have suggested that a clinical data transparency index, in
which companies or drugs are ranked by legal compliance and/or ethical conduct
regarding clinical data disclosure requirements, could incentivize clinical data sharing.
Do you agree? (n=58, n=59, n=57, n=58)

As illustrated in Figure 35, respondents were asked whether the pharmaceutical industry
ought to support new user fees to help fund clinical disclosure in exchange for specific
benefits. Marginally more “yes” responses were received than “no” or “do not know” for
most of the offered choices for incentives.
119
Specifically, 22 (37%, 22/60) responded “yes”, 18 (30%, 18/60) responded “no,” and 20
(33%, 20/60) responded “do not know” with respect to patent extension; 21 (36%, 21/59)
responded “yes”, 16 (27%, 16/59) responded “no,” and 22 (37%, 22/59) responded “do
not know” with respect to exclusivity; 24 (40%, 24/60) responded “yes”, 13 (22%, 13/60)
responded “no,” and 23 (38%, 23/60) responded “do not know” with respect to increased
health authority transparency; 21 (36%, 21/59) responded “yes”, 16 (27%, 16/59)
responded “no,” and 22 (37%, 22/59) responded “do not know” with respect to additional
health authority reviewers. Some other responses were entered as text. One respondent
commented,
I do not foresee such a quid pro quo (fee + data = some reward)[.]
Industry and sponsor release of data should be sufficient[,] especially if
being tracked by these evolving indexes. This is the more responsible and
controlled way to manage the release of these data which are sensitive in
many ways.
Another participant suggested that disclosing companies ought to receive royalties from
countries where other companies use the information to obtain marketing approval or
otherwise benefit from the information.
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Figure 35: Respondent Views on Whether Industry Should Support User Fees to
Help Fund Clinical Disclosure in Exchange for Benefits
Q28 - Should industry support user fees to help fund clinical disclosure by health
authorities in exchange for specific benefits? (n=60, n=59, n=60, n=59, n=16)

Respondents expressed substantial support for disclosure of clinical data from products in
development or abandoned, unapproved products, as shown in Figure 36. Forty seven
respondents either strongly agreed (37%, 23/62) or somewhat agreed (39%, 24/62),
respectively, two (3%, 2/62) neither agreed nor disagreed, ten (16%, 10/62) somewhat
disagreed, two (3%, 2/62) strongly disagreed, and one (2%, 1/62) did not know.
Figure 36: Respondents on Whether Clinical Data from Products in
Development or Abandoned (Unapproved) Should be Disclosed
Q29 - Do you agree that clinical data for products in development or abandoned
(unapproved) should be disclosed? (n=62)

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In contrast, less alignment was seen among respondents with regard to the disclosure of
preclinical data from products in development or from abandoned, unapproved products.
30 respondents either strongly agreed (19%, 12/62) or somewhat agreed (29%, 18/62),
but nine (15%, 9/62) neither agreed nor disagreed, 12 (19%, 12/62) somewhat disagreed,
9 (15%, 9/62) strongly disagreed, and 2 (3%, 2/62) did not know (Figure 37).
Figure 37: Respondents on Whether Preclinical Data from Products in
Development or Abandoned (Unapproved) Should be Disclosed
Q30 - Do you agree that preclinical data for products in development or abandoned
(unapproved) should be disclosed? (n=62)

Survey respondents (56%, 34/61) most commonly expressed support for penalizing
companies that do not comply with clinical disclosure requirements (Figure 38). Only
about one- quarter (23%, 14/61) indicated that companies should not be penalized, or that
they did not know (22%, 13/61).
122
Figure 38: Respondents for Penalizing Companies for Non-Compliance with
Clinical Disclosure Requirements
Q31 - On September 16, 2016, HHS and FDA updated their rules and policies to require
registration and summary results on ClinicalTrials.gov. However, some have suggested
that the greatest problem in obtaining industry compliance is a failure to enforce the
rules. For example, AllTrials recently estimated that $25 billion has been lost since no
fines have ever been levied for noncompliance. Do you or would you support penalizing
companies that do not comply with clinical disclosure requirements? (n=61)

Finally, as illustrated in Figure 39, respondents were asked to provide thoughts on ways
that clinical data sharing within the pharmaceutical industry could be improved.
First, participants commonly requested harmonized requirements to increase efficiency
and compliance and reduce redundancy and inconsistency, as half of open text responses
either alluded to harmonization or referred to it outright (50%, 8/16). In particular, one
participant requested a single method of registration/results posting, as well as a standard
methodology for measuring compliance. Another participant stressed that the ongoing,
evolving nature of requirements, in combination with stringent timelines, are a heavy
burden. Yet another participant that requirements should be more specific and directed at
all companies in order to limit the relative differences in data ultimately disclosed. On a
related note, another pointed to the difficulty of current data reporting systems.
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Second, multiple respondents addressed privacy and transparency issues. One respondent
expressed support for access to IPD, while another stated that the ability of redaction
software to “un-redact” is a threat to subject participation. One participant requested the
dissemination of more precise instructions for de-identification. Another individual called
for more public information generally to establish clearer disclosure profiles and greater
support for transparency from upper management.
Third, respondents provided comments on compliance and related incentives. On the
subject of benchmarking transparency rankings, one respondent remarked that such
indexes should only reflect compliance with requirements and sponsor policies, and not
arbitrary ethical benchmarks. Another indicated that reports of widespread
noncompliance with clinical disclosure requirements are misrepresentations, which is
supported by the publicized lack of fines imposed on noncompliant companies. Given
such limited impact for noncompliance, another respondent conveyed a limited interest in
fulfilling disclosure requirements. One individual cited the huge costs to implement and
maintain clinical data sharing programs relative to a lack of benefit to the company.
Finally, several respondents had keen opinions on clinical data sharing for in-
development and abandoned products. One participant expressed that development
products and abandoned products should be treated separately, given that disclosure for
development products dis-incentivizes innovation, but disclosure for abandoned products
increases the greater probability of success for the product or related products. Another
suggested that real world evidence (RWE) ought to be integrated with late phase clinical
trial data.
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Figure 39: Respondent Comments on Improving Clinical Data Sharing
Q32 - Please provide any additional information or comments on the ways in which the
current clinical trial data sharing environment has impacted industry. What, if anything,
would improve the current landscape? (n=16)
Harmonization and Ease of Current Systems
Harmonization of requirements--one stop shop for clinical data
There is no true methodology for which compliance is measured, since there are many
requirements to meet. Money should be invested in establishing one method of registration/results
posting and standard methodology for measuring compliance.
Harmonization of global disclosure requirements
ONE SINGLE clinical data sharing/disclosure platform would increase efficiencies, compliance
and reduce redundancy (which is resulting in inconsistencies). This would also ease the search for
trials including their results and documents for patients and the general public!
stringent timelines and new requirements for clinical data sharing has imposed a lot of
burden/pressure on industries.
A unified global regulation/law where a single portal services all requirements and permits
information to be shared in a harmonized and standardized manner to all patients.
One single global registry with uniform requirements would really foster transparency and would
make everyone's live easier
[…]The data sharing requirements should be more specific for all companies so there is not so
much diversity in what data is shared.
Current systems are very onerous to report data effectively
Privacy and Transparency
A request that all clinical trial sponsors provide access to individual patient level data and it not
be only industry would be a welcome change[…]
I believe it is good to share information when a trial is conducted and has completed. The
individual details are what is worrisome especially if it is a small trial where the participant can
be readily identified. This is because just as we have software to redact, there are softwares out as
well, where the data can be reversed. Participants who are worried of that might hesitate to
participate in trials. This is the major issue I see on this.
More precise instructions from regulatory agencies as to acceptable de-identification rules - there
is currently a wide range of interpretation regarding EMA Policy 0070 and related transparency
requirements because the guidelines are vaguely written.
What could improve: More public information to give a unambiguous disclosure profile (i.e.
approval status, approval dates); support for transparency from upper management; global place
for disclosures
Incentives and Compliance
Any indices of compliance must stick strictly to requirements and sponsor policies but not
arbitrary ethical benchmarks
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Huge costs to implement and maintain. Do not see benefit to company.
[…]As for tracking of compliance, the major issue has been and continues to be a
misrepresentation of compliance. In fact, this is a primary reason why no fines have been levied.
The NLM also recently stated that trials that complete (have primary outcome LPV) prior to the
final rule effective date do not need to have results posted which further shows that no money has
been "lost.”
First let me say that I have done my best to answer the survey questions as accurately as possible,
but the services provided by my company have prevented pertinent responses in some cases. My
employer provides outsourcing disclosure services to pharma companies, academic institutions,
etc., so we do not have any products of our own that require data sharing. However, working for
this company has allowed me to perform disclosure service for clients who may represent the
opposite ends of the spectrum (full disclosure versus disclosure of only required
elements/studies). In my opinion, the current data sharing environment is not having enough of
an impact on industry. One of the biggest issues is lack of education. With limited impact for
companies who are non-compliant, there is limited interest in fulfilling disclosure
requirements[…]
In Development/Abandoned Products and Data Utility
People should keep separate trials for drugs in development vs abandoned products. I don't think
companies should be forced to share information on drugs still in development - that
deincentivises development and innovation. They SHOULD be pressured into disclosing results
for abandoned products because someone else might be able to use that data to improve the
product so it WILL work.
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CHAPTER 5: DISCUSSION
5.1 Clinical Data Disclosure and Implementation by Industry
Pharmaceutical companies face challenges posed by recent requirements to provide
clinical study reports and even individual patient data to the public. These rules expose
the data collected by a manufacturer to other groups, including competitors, law firms,
and secondary researchers, which may lead sponsors to reevaluate their approaches to
regulatory submissions. On one hand, companies must provide clinical data in a way that
establishes sufficient protections for commercially confidential and patient information,
but on the other the data must contain the information that regulators will need to support
their decision making. Limited insight beyond anecdotal information is currently
available on the practices and views of the pharmaceutical industry on clinical disclosure.
Therefore, this study attempted to explore such practices and views in a more systematic
way. Specifically, the goal of this research was to support three ultimate objectives: 1) to
provide a systematic instrument to collect and compare information from a broad range
of pharmaceutical companies; 2) to provide a benchmark from which sponsors may
construct or refine company-specific practices, resulting in greater effectiveness,
efficiency and harmonization in clinical transparency measures; and 3) to provide data
that can help to shape more effective and efficient laws, regulations, and guidelines in the
area of clinical transparency in the future.
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5.2 Methodological Considerations
5.2.1 Delimitations
This study had several delimitations important to recognizing the limits to which its
findings can be generalized. First, its scope was narrowed to identifying the views of
individuals working in the pharmaceutical sector. Conceivably, it could have been
extended to practices in other medical products sectors, most notably that of medical
devices. However, medical device regulations differ substantially from those of the
pharmaceutical industry, and the industry professionals who work in those sectors often
have quite different backgrounds and experiences. Although both sectors have some level
of requirement to share data, it is in the pharmaceutical sector where those requirements
are most extensive and contentious. In the pharmaceutical sector, essentially all new
drugs must undergo extensive clinical trials, usually with thousands of subjects.
However, most medical devices do not undergo clinical trial evaluation. Rather, such
trials are limited only to those medical devices receiving higher risk assessments. Even
these typically require a small number of subjects relative to the large populations needed
for drug trials (Faris & Shuren, 2017). As a result, the number of experienced
practitioners is smaller and the likelihood that they have sophisticated data-sharing
systems for those trials is lower. Given these differences, medical device professionals
were excluded to preserve the relative homogeneity of the survey participant pool and
prevent the introduction of confounding factors, or a “mixing of effects”, into the study
(Skelly, Dettori, & Brodt, 2012). Thus, the findings of the present study may not be
representative of the medical device and other sectors. However, the implementation of
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clinical data sharing programs for other types of medical products could be the subject of
future interesting research.
The study carried out here did not delimit its geographical focus to only one country. The
US is the largest pharmaceutical market in the world, so it was considered important to
capture the specific views of this constituency. However, most of these companies have a
multinational reach. Further, the issue of clinical data disclosure is substantially driven
by policies set forth by the European Medicines Agency (EMA), and these are actively
under debate by other stakeholders in the European Union (EU) as well as the US. It was
anticipated that individuals in multinational pharmaceutical companies, which market
products in both the US and Europe, would need to be sensitive to the requirements in
both the US and the EU. It was not surprising, then, to find that respondents most often
reported having global responsibilities at their respective companies. However, the
specific reach of job responsibilities did not seem to affect the views of the respondents
to any great extent. Cross tabulation to compare responses between participants with
global versus regional responsibilities revealed that both groups were comprised of
employees with extensive clinical disclosure experience (Appendix C, Table 18) who
identified themselves as similarly familiar with EMA (Appendix C, Table 19) and FDA
(Appendix C, Table 20) policies on clinical data sharing. However, for most applicable
questions, respondents who self-identified as having regional responsibilities more often
answered “do not know” to some questions, such as how company clinical data is
redacted (Appendix C, Table 21), relative to those with global responsibilities. It is
unclear from the results why these differences were present. However, it is plausible that
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clinical disclosure professionals with specific regional responsibilities are not expected to
have knowledge of policies of regions outside of their regions. Of course, given the small
sample size, only additional research could confirm such speculation.
Certain other restrictions delimited the survey. The survey confined its assessment to
clinical trial disclosure and not to other forms of disclosure, such as disclosure of
relationships with healthcare professionals, which are also subject to changing rules.
Further, although clinical trial registration disclosure is a prominent element of clinical
transparency, it was not the focal point of this study. Rather the study focused on the
policies that address clinical data disclosure. A significant delimitation to a survey that
occurs in the midst of policy development was its restriction in time, to a period between
early November 2016 and early February 2017. During or near that time, new
developments took place that could be important in shaping the views expressed here by
the respondents. The NIH and HHS Clinical Trials Registration and Results Information
Final Rule (Health and Human Services, 2016) issued in September 2016, and the EMA
External guidance on the implementation of the European Medicines Agency policy on
the publication of clinical data for medicinal products for human use (Sue & Ritter,
2012) was updated in December 2016. Apart from this update, no policy announcements
of significance to the study were issued during the actual survey period.
Nonetheless, the rules and requirements during the recent period covered by the survey
are still in transition. For instance, a recent event at EMA illustrates the evolving nature
of this area of policy setting. On February 15, 2017, EMA issued a revised European
Medicines Agency policy on access to documents, or Policy 0043, and requested
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comments by May 16, 2017 (EMA, 2017). Then, on March 1, 2017, the Vice President of
the Court of Justice dismissed the EMA’s September 2016 appeal of the Court’s decision
to grant interim orders to PTC Therapeutics. In May 2014 the company had been granted
a conditional orphan marketing authorization (MA), and in October 2015 EMA received
a third-party access to documents request, to which PTC objected on the basis that the
entire CSR was commercially confidential. In November 2015, EMA instead issued a
decision to disregard the company’s objection, and PTC requested interim orders to
suspend the enforcement of the EMA decision, which were successful (Tizzano, 2017).
On the whole, then, the survey was conducted as EMA was at work expanding its
transparency policies while awaiting underlying clarification from the Court. Thus,
respondents may have expressed viewpoints that might no longer represent their thinking
in the future as the nascent regulations and guidance documents change over time.
5.2.2 Limitations
5.2.2.1 Respondent Sampling and Response Rates
Perhaps the largest potential limitation for any survey of busy professionals is assuring
sufficient numbers of engaged respondents (Galesic & Bosnjak, 2009). This effort is
particularly challenging in the relatively novel and niche area of clinical trial data
disclosure. A multifaceted approach was required to find qualified respondents, by
searching key opinion leaders and practitioners in conference agendas and proceedings,
LinkedIn profiles and groups, DIA communities, and Association of Clinical Research
Professionals (ACRP) and Regulatory Affairs Professionals Society (RAPS) membership
listings. This kind of approach was useful because it ensured that the search was
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wide-ranging across many groups, an advantage that can improve the representativeness,
or external validity, of the results (Sue & Ritter, 2012). However, such an approach
made it more difficult to define and apply consistently any inclusion requirements to the
survey respondent pool. Of note, consultants were deliberately included in the survey to
capture the valuable experiences that they gained by working in the field alongside
industry employees. However, in practice, it is likely that such contractors vary
considerably in their level of engagement in clinical data disclosure, according to the
extent of their work responsibilities beyond clinical disclosure, as well as their exact roles
with respect to disclosure. It is therefore important to ask whether the presence of
respondents with different roles in clinical disclosure would blur the results in some way
(Sue & Ritter, 2012). However, few differences were evident between contractors and
pharmaceutical employees when this question was explored by cross tabulating the titles
of company respondents, which included consultants as a distinct category, with
responses to other key questions, such as appropriation of additional resources to clinical
disclosure (Appendix C, Table 22). Regardless, any differences were too small to
substantiate persuasive statistical comparisons. However, it was remarkable that
employees and consultants responded similarly in most cases, and it suggests they share a
common understanding and sentiment toward the clinical disclosure field exists at this
time of study.
Even when multiple sources for respondents are used, it can be challenging to ensure
participation of a sufficient sample of individuals. A strong rate of response is well
known to be important in assuring study validity (Cook, Heath, & Thompson, 2000).
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However, this requirement places restrictions on what can be done using survey methods.
For example, the length of the survey in this study was limited deliberately to
32 questions, as previous literature has made it clear that long surveys are tiring to
participants, who may then abort the survey or answer questions less carefully. However,
data quality suffers as survey length decreases (Galesic & Bosnjak, 2009). Therefore, it
was encouraging that a majority, 79%, of invited respondents completed the survey. This
response rate is higher than that often published previously for internet-based surveys.
Cook and colleagues (Cook et al., 2000), for example, reported an average response rate
of 34.6% in a meta-analysis of web-based surveys. The high response rate, together with
an often convergent set of views across the diverse job categories represented in this
study, provided some confidence that the selected respondents had knowledge and views
similar to those of the larger population of clinical disclosure professionals.
At the same time, however, a high response rate and a broad representation does not
ensure that all of the respondents have the appropriate background and experience for the
types of questions that were asked. It is possible that some respondents attempted to
answer survey questions on specific subject matter with which they had little or no
expertise. The clinical disclosure rules are relatively new and may not be as familiar to
some respondents. In such circumstances, their efforts to answer all questions would not
be helpful. It was therefore encouraging that respondents appeared to be transparent
when they were unsure of the way in which to answer specific questions. Of note, a small
number of respondents stopped answering questions roughly halfway through the section
of the survey that focused on clinical disclosure practices. The trend continued for the
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duration of the survey. It is speculated that such participants may have lacked the
requisite operational knowledge and abandoned at least some of the remaining questions
once it was clear that a substantial portion of the survey was devoted to such content. In
addition, respondents who identified themselves as Associates or Senior Associates most
often provided “do not know” responses related to company clinical disclosure practices
or individual views. These job functions typically are staffed by individuals with the
least and narrowest work experience, as shown when job titles were cross tabulated with
years of experience overall and in clinical disclosure in particular (Appendix C,
Table 23).
Most of the respondents in this study were found to have at least a general understanding
of clinical data disclosure requirements. Presumably this was, in part, guaranteed by the
selection process that was carried out at the outset of the study. Of course, it is possible
that companies exist that are conducting clinical trials but have such a low profile that
they would not be sampled. Such companies quite possibly have a much lower level of
understanding related to disclosure, or they may not share the views of the more visible
respondents included in this survey. As noted by Sue and Ritter (Sue & Ritter, 2012),
non-respondents are inherently different than respondents.
Establishing an environment of full candor is a concern when dealing with data that
might be proprietary or where views may be contentious. To encourage responses,
prospective participants were encouraged to share their valuable expertise and reminded
at every opportunity that the Qualtrics tool would anonymize their responses. Further, the
survey itself was deliberately kept as simple as possible (Sue & Ritter, 2012), and
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multiple questions provided an option to select “do not know.” Despite all of these
efforts, it is never fully possible to differentiate the views of individuals to those of the
company to which they feel connected.
5.2.2.2 Development of the Survey Instrument
It is critical for a study of this kind that the survey instrument be designed in a way that
captures insights in the areas of interest. The instrument is potentially limited in its
design and/or execution by the skill of the investigator and the effectiveness of the focus
group (McCracken, 1988). The use of a focus group to critique the survey is one way that
has been suggested to help assure that the survey is measuring meaningful aspects of the
problem (Sue & Ritter, 2012). The composition of the focus group for this study was
weighted toward academic members, who had significant experience developing and/or
commenting on the content, structure, and clarity of successful research surveys. Their
contributions certainly assisted in finding areas where questions were confusing or
inappropriate. However, the relatively low number of focus group participants from
industry may have introduced a certain level of bias into the survey tool. Accordingly, the
value of the resulting insights into current industry tactics and strategy related to data
disclosure will always be influenced by the nature of the questions that were posed, as
has been discussed as a limitation elsewhere (Solberg, 2010). On balance, however, the
variety of questions allowed exploration of many viewpoints effectively, within the
constraints of the limitations on survey length.
There were nevertheless questions that in retrospect could have been eliminated or
reworded for greater clarity. In one case, two different questions asked to solicit similar
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information. The question, “What specific clinical documents are required to obtain
clinical data from your company” appeared to be straightforward for respondents, most of
whom answered the question without difficulty. However, a similar question, “What
level of documentation is required to obtain clinical data from your company” appeared
more confusing. In this case, 40% of respondents did not know the general level of
documentation required to obtain company clinical data. Given that the subject matter
was the same for both questions, it is likely that participants were less confused by the
specific question to indicate the required documents, rather than the general question that
referred to “level of documentation”. In retrospect, it would seem that the latter question
could have been removed without affecting the results of the survey. In another instance,
more than one quarter of respondents did not know whether their companies provide
“exportable data”, “exportable analysis of data”, or “no exportable data or analysis”. In
this case, respondents may not have understood the meanings of the jargon-like phrases,
“exportable data” and/or “exportable analysis.” This conclusion is supported by one
comment received via email and outside of the survey, in which a respondent stated “I
was not clear on ‘exportable’ question…”
5.3 Maturity in Clinical Data Sharing Programs
At the outset of this study, it was clear that some form of systematized approach would
aid the research on implementation of clinical trial disclosure. The implementation
framework of Fixsen (Fixsen et al., 2005b) therefore was viewed as potentially helpful in
establishing a structure and vocabulary for the work. Fixsen and colleagues identify
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several stages of implementation maturity against which we can judge the progress made
by companies with regard to their implementation strategies.
The results suggest that many companies are already quite sophisticated in their
approaches. Perhaps the most direct evidence to support this conclusion were the stated
responses of most survey participants who indicated either that they have programs
appropriate for FDA and EMA in place or they are maintaining those programs. It was
also initially surprising to learn that most respondents work for companies with dedicated
clinical disclosure roles, as the mere existence of such positions establishes a certain
degree of maturity that was not anticipated at the outset of the study. Using cross
tabulation, it was interesting to compare the responses of small and large companies. A
greater percentage of large than small companies identified that they had a separate
clinical disclosure department and had already obtained additional resources for clinical
disclosure activities. This may not be unexpected, as the scale of the disclosure work no
doubt increases with the size of the company. Yet, the fact that a subset of all sizes of
companies use such dedicated groups suggests that the industry overall has assigned
some weight to their obligations related to clinical transparency. Of note, some small
companies identified that they were “maintaining” their programs, as might be expected
if they were at a mature point in the implementation cycle, but others were still
“exploring and developing strategy”, the least advanced stage. Acknowledging this split
amongst small enterprises, the Fixsen model would still place most companies in the full
implementation domain.
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That many companies were at or beyond the stage of full implementation was also
suggested by the state of certain key elements that Fixsen’s model has identified to be
essential supports to successful implementation. These included the selection and
training of appropriate staff and the provision of essential resources. More than half of
respondents reported working for companies that had received additional staff, funding,
and other resources earmarked for clinical disclosure. In addition, it is likely not a
coincidence that the least difficult challenges for many respondents included a lack of
manpower, lack of financial resources, significant staff training, lack of senior
management support, and cultural resistance. Further, the fact that many companies were
already using metrics to evaluate the effectiveness of their programs is further evidence
that these activities are highly mature. Going forward, it would be informative to direct
further research to elaborate on the types of metrics employed by companies.
If most companies have implemented clinical disclosure systems, an obvious question is
how the functions associated with that system are embedded into the prevailing hierarchy
within company structure. In most companies, the survey suggests that the function has
been placed in a standalone Clinical Disclosure group. This observation suggests that
considerable thought and resource allocation has been devoted to clinical disclosure. At
the same time, however, in those companies without such a group, the widespread
distribution of the practitioners across different functional areas of companies suggests a
more diffuse approach. In some of these companies, it would be interesting to explore
the relative visibility of these activities to senior management. An absence of a dedicated
group could make the decentralized system more vulnerable to failures of disclosure.
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Interestingly, however, no meaningful differences could be discerned in the practices or
views of participants with standalone company departments when their results were
compared with those where clinical disclosure was a responsibility of another part of the
company, so whether one system is better than another remains an interesting question
for future exploration.
5.4 Practices and Views in Clinical Data Sharing Programs
Given that most companies have relatively mature clinical disclosure policies and
procedures, it was possible to explore some of the ways in which these operations
function. As has been reported anecdotally by some companies in trade journals (Atzor
et al., 2014), most companies seem to be employing ways to filter information requests so
that clinical data is not provided without review. Respondents most commonly indicated
their companies expected the requestors to have some level of scientific or technical
expertise before certain data are released to them. They also identified that data requests
originated from a variety of geographic locations and a variety of sources, including
industry, patients, universities, and secondary researchers. This response was surprising
because it suggests that the community of users may be widening to encompass a broader
audience. A recently as 2014, EMA had stated that secondary researchers and attorneys
had been responsible for the majority of “access to documents” requests to EMA for
clinical data, per “reactive” Policy 0043, or European Medicines Agency policy on access
to documents (related to medicinal products for human and veterinary use) (Allchurch,
2014a). The results of the currently survey, therefore, suggest that a variety of
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stakeholders are now aware of the channels through which they can obtain company
clinical data, and are taking advantage of that access.
By asking questions about both policy-related and operational approaches, it became
clear that many respondents were uncertain about the level of documentation required to
obtain data, the way that requests are reviewed, the clinical information released, and
whether EMA and FDA policies have impacted the level of detail in company clinical
documents. The fact that this observation could be generalized to respondents with global
as well as regional responsibilities was interesting. One might anticipate that global
clinical disclosure professionals, who typically are more experienced, would have a better
understanding of the clinical disclosure system. It is possible that companies with such
groups deal with a larger volume of work and have a more subdivided distribution of
work responsibilities to handle that larger load. In more differentiated workgroups,
information about all aspects of the disclosure system may not be communicated
effectively to all group members. These results may also reflect the difficulty in keeping
abreast of the regional stakeholder groups who request data, particularly for respondents
with global assignments that encompass only a particular global region. As another
possibility, the results may signify the distinctiveness of policy knowledge and
operational compliance, and the difficulty for professionals to be proficient in both areas.
More fundamentally, the findings may show that some personnel require further
education about the clinical disclosure strategies and activities even in their own
companies.
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Although requirements for releasing clinical data varied, the most common document
required of eligible requesters was a signed data sharing agreement. This finding may
suggest that such agreements are becoming an industry standard. Model templates for
agreements such as ClinicalStudyDataRequest.com (ClinicalStudyDataRequest.com,
2015) and MRCT (Multi-Regional Clinical Trials Center at Harvard, 2015) are
undoubtedly useful in bringing some degree of harmonization to that process. In
addition, nearly half of respondents worked for companies that require some level of
technical documentation, including a protocol, Statistical Analysis Plan (SAP), and
Ethics Committee (EC) approval; many have internal reviewers to evaluate requests.
More than one third of respondents reported that such requests undergo a discretionary or
scientific merit review. Taken together, these results convey the impression that many
companies have significant measures in place to control access to, and use of, their
clinical data.
5.5 Call for a Global Harmonization of Requirements
At the end of the survey, participants were instructed to describe in open text the ways in
which the current clinical data sharing environment have impacted industry and what, if
anything, could be done to improve the current landscape. One area of particular interest
was the common focus of respondents on a global harmonization of clinical disclosure
requirements, identifying variously its poor efficiency, insufficient compliance metrics,
redundant and evolving requirements, stringent timelines, and inconsistent data
requirements. Tackling harmonization might help to improve compliance and reduce the
costs of compliance, so it could be a particularly attractive issue to address. However,
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because most requirements are developed nationally, it is also a difficult problem to
solve, because it must be handled at a supranational level.
The potential for dissonance increased every time a national government adds a new law
or policy. A case in point that illustrates some of the national changes that have global
potential for dissonance is that of the recently published rules regarding the provision of
results to the website, Clinicaltrials.gov. In this final rule, published by HHS, on
September 16, 2016, reporting requirements for results were expanded to require that
sponsors provide the full protocol and SAP of the trial at the time of results submission.
The rule also added the requirement to provide results for applicable clinical trials of
unapproved products. The protocol and SAP are intended to facilitate an appropriate
interpretation of the study, and results for unapproved products can provide important
benefit-risk information. In a complementary policy, NIH will publish received records,
and will note with a disclaimer regarding those that do not meet certain quality control
criteria. Given that records with quality control issues were not disclosed previously, the
new NIH policy is a means of providing all records to the public with greater
transparency (Zarin, Tse, Williams, & Carr, 2016). In this case, the level of data
disclosure is greater than that required in the EU system. At the same time however,
FDA seems disinclined to release other types of data, and in particular, the CSRs that it
receives in submissions, despite the fact that the EU is moving in that direction. This
difference in policy has been highlighted by Davis and Miller, who questioned whether
FDA would continue to be regarded as the “gold standard” regulatory agency (Davis &
Miller, 2017)
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However, EMA and FDA are not the only regulatory agencies with stated positions
regarding the disclosure of CSRs, a fact that can create additional momentum toward a
more global policy if most countries appear to be converging on a common practice. For
example, on March 10, 2017, Health Canada released a white paper, Public Release of
Clinical Information in Drug Submissions and Medical Device Applications (Health
Canada, 2017b), and guidance document, Disclosure of Confidential Business
Information under Paragraph 21.1.(3)(c) of the Food and Drugs Act (Health Canada,
2017a), proposing the release of clinical data in drug and medical device applications
subsequent to regulatory decision-making. Shortly thereafter, on April 25, 2017, a
number of stakeholders including industry representatives convened to develop a
Blueprint for Transparency at FDA. As one of five major principles, the blueprint stated
that FDA should disclose scientific data. Specifically, it called for FDA to disclose CSRs
included in marketing applications, release final reports applicable to post-marketing
requirements (PMRs) and post-marketing commitments (PMCs) once FDA judges that
they are fulfilled, and allow access to repositories holding clinical data, including patient-
level data, with attention to de-identification practices. Interestingly, FDA contributed
technical comments to this exercise (Sharfstein & Stebbins, 2017). Its willingness to
become involved leaves open the possibility that movement on national fronts may
position health authorities in greater alignment with one another in the future.
Beyond the regulatory agencies are other players with the ability to affect and perhaps
improve the current state of disharmony. Given a clear call to action, perhaps WHO, an
organization that already imports regional trial records into its International Clinical
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Trials Registry Platform, could bring together regulatory agencies in a multilateral effort
to establish a single user-friendly portal by which clinical data may be directly submitted
to all jurisdictions. Such an approach is not without precedent. ICH demonstrated the
value of multilateral action on issues of regulatory inconsistency when it developed the
Common Technical Document for drug submissions. This submission format has been
considered a major accomplishment that has been of enormous value to industry in all
countries (Gelman, 2006). Given its achievements, ICH could be a preferred organization
to take on such an initiative for multinational clinical trial disclosure.
However, any effort to improve and harmonize disclosure rules internationally will be
difficult. Such activities involve many stakeholders with multiple points of view.
Further, the highly charged nature of some aspects of that work can open the organization
to uncomfortable scrutiny and criticism. For example, MoreTrials, a public campaign
launched on January 1, 2016, to advocate for improved clinical trials, has been critical of
the approaches used by ICH. At the same time as it has called for revisions of the E6
Guideline for “Good Clinical Practice” it has asked that ICH become more open and
transparent in its practices:
Our criticism of ICH is in no way directed at the people who work there,
like most people they’re just trying to do a half-decent job. It sometimes
feels to us though that ICH are holed up in a bunker in Switzerland so
maybe it would be good for them to get out more (MoreTrials, 2016).
Of course, like other organizations, the capacity of ICH is only as extensive as its finite
resources and volunteer-based experts. Yet, regardless of the exact nature of its
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challenges, these types of concerns underline just how difficult it might be to work on
thorny issues such as clinical data disclosure at a global level.
5.6 Disclosure of Clinical Data from Products in Development or Abandoned
It seems clear from the results obtained in this work that companies have come to terms
with clinical disclosure requirements for approved products. But what are their views
regarding the disclosure of other sorts of data, such as that gathered during the testing of
unapproved products? The release of data associated with such products has become a
contentious issue since a final rule issued by HHS in September 16, 2016, that expanded
requirements set forth by FDAAA. Starting on January 18, 2017, the regulation requires
that sponsors provide results for applicable clinical trials of unapproved products, which
were viewed as a useful source of benefit-risk information (Health and Human Services,
2016). Prior to this rule, HHS had received almost 900 comments from industry and other
stakeholders in response to the preceding November 2014 Notice of Proposed
Rulemaking (NPRM) (Zarin et al., 2016). Much of this discussion centered around
protecting incentives for pharmaceutical investment as set forth by PhRMA and EFPIA
years earlier in July 2013 and thus were not enthusiastic about the change (PhRMA,
2013). Moreover, more recent anecdotal discussions reinforced the sensitivity of industry
to the disclosure of clinical data for unapproved products without careful consideration of
the potential repercussions, such as the unintended disclosure of trade secrets (Barlas,
2015). It is not surprising, then, that nearly all survey participants, including those who
did not know how to answer other questions, such as whether FDA (Appendix C,
Table 25) and EMA (Appendix C, Table 26) policies have impacted the granularity of
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company CSRs, had opinions on the release of clinical data for in-development or
abandoned products.
What was surprising, however, were the response patterns suggesting that most
participants favored the release of data for unapproved products, although that support
was more pronounced for clinical than for preclinical data. Perhaps companies are
reluctant to call attention to research in animals, or some other factor can explain why
respondents were relatively less likely to support disclosure of preclinical data. In
retrospect, it may have been advantageous to split the two corresponding survey
questions into four separate questions in order to distinguish in-development and
abandoned drugs. As one respondent suggested in open text, limiting disclosures for in-
development products and encouraging disclosures for abandoned products can each
promote innovation. Of note, four questions were proposed originally, but in-
development and abandoned drugs were combined into two questions to restrict the
length of the overall survey. It is difficult to know whether the predominance of support
expressed by individuals who are close to clinical disclosure are shared by other parts of
the companies, such as R&D or legal departments, who may have a different view of the
implications of such releases.
The results of the present survey suggest that most pharmaceutical companies, and by
extension, clinical disclosure professionals, have accepted the release of clinical
information to maximize data utility and benefit stakeholders. While industry is acting
diligently to retain influence over access to, and use of, company clinical data, at least
some of its personnel are receptive to the further uses of that clinical and even preclinical
146
data to improve patient health and safety. The data also suggest that a minority of
employees and consultants do not share those views.
In many cases, companies seem to be in advanced stages of implementing clinical data
disclosure. However, the fact that companies have publicly supported clinical
transparency and implemented clinical disclosure does not necessarily mean that they
have recognized these efforts as an important business investment. The views collected in
this study, which are more commonly supportive than critical of disclosure, come from a
highly selected group of individuals working directly in pharmaceutical clinical
disclosure. What would be interesting to understand is the degree to which these views
differ from those in other parts of the companies. The small amount of literature that is
currently available suggests that companies continue to have underlying concerns about
the benefits of transparency relative to the costs. For instance, one Vice President of
Clinical and Regulatory Affairs indicated that his small pharmaceutical company would
not voluntarily disclose any more clinical information than necessary, stating, “We
release too much clinical data as it is [to accommodate investors] (Anonymous, 2015).”
However, the lack of more overt critiques of clinical disclosure may underscore current
company efforts to avoid negative publicity in that regard. Further research targeted at
pharmaceutical executives or employees in other departments could shed light on the
degree to which they share the same views as clinical disclosure employees and
contractors. The present study has suggested that even small companies have expended
significant resources to comply with clinical disclosure requirements. Accordingly, it is
not unimaginable that, in the not-distant future, pharmaceutical executives may be more
147
vocal in asking for the tangible benefits produced by these exercises in transparency. But
how would such an assessment be conducted?
Perhaps one possibility would be to “follow the data” and conduct case studies that
review instances in which specific clinical data is disseminated, who obtains it, the
analyses that are conducted, the results and transparency of such analyses, and the
ultimate outcome of the benefits of the disclosure relative to the cost incurred. In the
absence of hard evidence that demonstrates the merits, it is possible that stakeholders will
arrive at another turning point, the precarious position of daring to defy the progress of
transparency amidst a clinical data sharing ecosystem that cannot justify its own cost.
Alternatively, it is possible that, even if additional studies reveal an undercurrent of
internal opposition to specific aspects of clinical disclosure, these findings may be critical
to optimizing the investments in these activities. Understanding any divergent views may
be important in defining the best compromise by which the release of clinical data can be
achieved for all stakeholders.
148
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158
APPENDIX A: FINAL VERSION OF SURVEY
Q1 *This survey is being administered solely to complete a doctorate degree in
regulatory science and is unconnected to any business affiliation. It is not intended to
solicit the disclosure of confidential or non-public information. You may skip individual
questions if you do not wish to answer, although there are "do not know" response
options for some questions.*What title best describes your role within your company?
 Vice President (1)
 Director/Senior Director (2)
 Manager/Senior Manager (3)
 Associate/Senior Associate (4)
 Consultant/Senior Consultant (5)
 Other (6) ____________________

Q2 How many years have you worked in the medical products industry?
 (1)
 3-5 Years (2)
 6-10 Years (3)
 11-15 Years (4)
 16+ Years (5)

Q3 Which of the following best represents the area of your company in which you work?
 Clinical Disclosure (1)
 Clinical Operations (2)
 Clinical Safety (3)
 Medical Writing (4)
 Legal (5)
 Regulatory Affairs (6)
 Regulatory Operations (7)
 Regulatory Writing (8)
 Other (9) ____________________

159
Q4 Which functional area(s) of your company is/are primarily responsible for clinical
disclosure?
 Clinical Disclosure (as a separate group or department) (1)
 Clinical Operations (2)
 Clinical Safety (3)
 Medical Writing (4)
 Legal (5)
 Regulatory Affairs (6)
 Regulatory Operations (7)
 Regulatory Writing (8)
 Outsourced (Please describe.) (9) ____________________
 Other (10) ____________________

Q5 How many years have you worked in clinical data disclosure?
 <1 Year (1)
 1-2 Years (2)
 3-5 Years (3)
 6-10+ Years (4)

Q6 How many employees work at your company?
 1-499 (1)
 500-49,999 (2)
 50,000+ (3)

160
Q7 What best estimates the current number of approved products across your company's
portfolio?
 0 (1)
 1-5 (2)
 6-20 (3)
 21+ (4)
 Do not know (5)

Q8 For which geographical region(s) are you responsible at your company? Please select
all that apply and specify, as appropriate.
 Global (1)
 US (2)
 EU (3)
 Other Region (4) ____________________
 Other Country (5) ____________________

161
Q9 How familiar are you with EMA and FDA policies on data sharing?
Extremely
familiar (3)
Very
familiar (4)
Moderately
familiar (5)
Slightly
familiar (6)
Not familiar
at all (7)
European
Medicines Agency
(EMA)'s Policy
0070 on
Publication and
Access to Clinical-
Trial Data (1)
    
Food and Drug
Administration
(FDA)'s
Availability of
Masked and De-
identified Non-
Summary Safety
and Efficacy Data
(2)
    

Q10 Have additional resources, such as additional staff and funding, been allocated for
clinical disclosure at your company?
 Yes (1)
 No, but my company plans to do so (2)
 No, and my company does not plan to do so (3)
 Do not know (4)

162
Q11 How would you best describe the current status of your company in adjusting to
fulfill EMA and FDA clinical data disclosure requirements?
Exploring
and
developing
strategy (3)
Adding
staff and
funding (4)
Piloting
process (5)
Program in
place (6)
Maintaining
(7)
None (8)
EMA
Requirements
(1)
     
FDA
Requirements
(2)
     

Q12 How does your company evaluate the effectiveness of its clinical data sharing
program? Please select all that apply.
 Company metrics (1)
 Clinical trial data transparency index (Good Pharma Scorecard, etc.) (2)
 Staff performance reviews (3)
 Other (4) ____________________
 Do not know (5)

163
Q13 Successful implementation of a company clinical data sharing program may be
impeded by certain barriers. Please rank, according to the degree of challenge presented
the challenges of implementing clinical data sharing. (1 = Most difficult challenge, 10 =
Least difficult challenge)
______ Lack of manpower (1)
______ Lack of financial resources (2)
______ Lack of knowledge (3)
______ Cultural resistance (4)
______ Significant changes to work processes (5)
______ Significant staff training (6)
______ Lack of senior management support (7)
______ Lack of adequate clinical data sharing framework (8)
______ Lack of harmonized clinical disclosure requirements (9)
______ Other (10)

164
Q14 With which clinical data sharing models are you familiar?
Familiar (1) Not Familiar (2)
The Multi-Regional Clinical Trials
Center (MRCT) of Brigham and
Women's Hospital and Harvard (1)
 
Yale University Open Data Access
(YODA) Project (2)
 
ClinicalStudyDataRequest.com (3)
 
Other (5)
 

Q15 Who is eligible to obtain clinical data from your company? Please select all that
apply.
 General public (1)
 General requirement (Specific degree) (2)
 Technical expertise (Scientific degree and expert qualifications) (3)
 Do not know (4)

165
Q16 Who requests clinical data from your company? Please select all that apply.
US (1) EU (2) Rest of World (3)
Industry/Industry Organizations (1)
  
Clinical Trial Participants/Patient
Advocacy Organizations (2)
  
Universities/Research Organizations
(3)
  
Secondary Researchers/Legal
Analysts/Associated Advocacy
Organizations (4)
  
Other (Please specify.) (5)
  
Do not know (6)
  

Q17 What specific documents are required to obtain clinical data from your company?
Please select all that apply.
 Research Proposal (1)
 Lay Protocol Summary (2)
 Statistical Analysis Plan (SAP) (3)
 Institutional Review Board (IRB)/Ethics Committee (EC) Approval (4)
 Signed Data Sharing Agreement (5)
 None (6)
 Other (7) ____________________
 Do not know (8)

166
Q18 What level of documentation is required to obtain clinical data from your company?
Please select all that apply.
 None (No research question) (1)
 Non-Technical (Lay protocol summary) (2)
 Technical (Protocol, Statistical Analysis Plan (SAP), and Ethics Committee approval)
(3)
 Do not know (4)

Q19 Who reviews requests to obtain clinical data from your company? Please select all
that apply.
 No reviewer (No review) (1)
 Internal reviewer (Company reviewer) (2)
 External reviewer (Non-company reviewer) (3)
 Do not know (4)

Q20 How does your company review clinical data requests? Please select all that apply.
 No review (Automated system) (1)
 Administrative review (Approval by meeting specific criteria) (2)
 Discretionary review (Scientific merit review) (3)
 Do not know (4)

167
Q21 What types of redacted clinical data on approved products does your company
provide to secondary researchers? Please select all that apply.
 Clinical Study Report (CSR) Synopses (1)
 Full Clinical Study Reports (CSRs) (2)
 Individual Patient Data (IPD) (3)
 Varies by product (Please explain.) (4) ____________________
 None (5)
 Other (6) ____________________
 Do not know (7)

Q22 How does your company redact clinical trial data?
 Manual redaction (1)
 Redaction software (2)
 Manual redaction and reaction software (3)
 Outsourced (4)
 Do not know (5)

Q23 Has your company modified its Clinical Study Report (CSR) template to minimize
the burden the redacting commercially confidential information (CCI) and individual
patient data (IPD)?
 Yes (1)
 No, but my company plans to do so (2)
 No, and my company does not plan to do so (3)
 Do not know (4)

168
Q24 How does your company provide access to clinical data? Please select all that apply.
 Government databases (ClinicalTrials.gov, EudraCT/EU Clinical Trials Register (EU
CTR) Portal and Database (1)
 Single-company database (2)
 Multiple-company database (ClinicalStudyDataRequest.com) (3)
 None (4)
 Other (5) ____________________
 Do not know (6)

Q25 What clinical information does your company provide? Please select all that apply.
 Exportable data (1)
 Exportable analysis of data (2)
 Non-exportable data (No exportable data or analysis) (3)
 Do not know (4)

Q26 Have the EMA and FDA requirements generally impacted the level of detail that
you provide in clinical overviews, clinical summaries, and clinical study reports (CSRs)
for marketing applications? Please comment further on these specific impacts.
Yes (3) No (4) Do not know (5)
US New Drug Application (1)
  
EU Marketing Authorisation
Application (2)
  

169
Q27 Some organizations have suggested that a clinical data transparency index, in which
companies or drugs are ranked by legal compliance and/or ethical conduct regarding
clinical data disclosure requirements, could incentivize clinical data sharing. Do you
agree?
Incentivizes (7) Does not incentivize
(6)
Do not know (5)
Company ranking for legal
compliance (1)
  
Company ranking for ethical
conduct (2)
  
Drug ranking for legal
compliance (3)
  
Drug ranking for ethical
conduct (4)
  

Q28 Should industry support user fees to help fund clinical disclosure by health
authorities in exchange for specific benefits?
Yes (5) No (6) Do not know (7)
Patent extension (1)
  
Exclusivity (2)
  
Increased health authority
transparency (3)
  
Additional health authority reviewers
(4)
  
Other (5)
  

170
Q29 Do you agree that clinical data for products in development or abandoned
(unapproved) should be disclosed?
 Strongly agree (1)
 Somewhat agree (2)
 Neither agree nor disagree (3)
 Somewhat disagree (4)
 Strongly disagree (5)
 Do not know (6)

Q30 Do you agree that preclinical data for products in development or abandoned
(unapproved) should be disclosed?
 Strongly agree (1)
 Somewhat agree (2)
 Neither agree nor disagree (3)
 Somewhat disagree (4)
 Strongly disagree (5)
 Do not know (6)

Q31 On September 16, 2016, HHS and FDA updated their rules and policies to require
registration and summary results on ClinicalTrials.gov. However, some have suggested
that the greatest problem in obtaining industry compliance is a failure to enforce the
rules. For example, AllTrials recently estimated that $25 billion has been lost since no
fines have ever been levied for noncompliance.Do you or would you support penalizing
companies that do not comply with clinical disclosure requirements?
 Yes (1)
 No (2)
 Do not know (3)

171
Q32 Please provide any additional information or comments on the ways in which the
current clinical trial data sharing environment has impacted industry. What, if anything,
would improve the current landscape?

172
APPENDIX B: SURVEY RESULTS REPORT
Default Report
Q1 - *This survey is being administered solely to complete a doctorate degree in
regulatory science and is unconnected to any business affiliation. It is not intended
to solicit the disclosure of confidential or non-public information. You may skip
individual questions if you do not wish to answer, although there are "do not know"
response options for some questions.
* What title best describes your role within your company?

Other
Principal Medical Writer
Managing Partner
Specialist
Senior Medical Writer
Specialist
Strategy Officer
Senior Expert
173
Q2 - How many years have you worked in the medical products
industry?

174
Q3 - Which of the following best represents the area of your company in
which you work?

Other
Biometrics
GCP Quality Control
Medical writing especially clinical trial disclosure and regulatory writing.
Quality Assurance
business consulting
Strategy, business operations, internal consultancy and data disclsoure
Medical Affairs
Real World Evidence and Commercial Excellence
Software for disclosure
Pharmaceutical research and development
Consultancy
Product Management
Clinical Trial Transparency

175
Q4 - Which functional area(s) of your company is/are primarily
responsible for clinical disclosure?

Other
We advise companies on disclosure responsibilities and best practices. My answers refer to the
clients we are supporting
N/A - software company
Software development
None
Consulting company which performs all disclosure activities for sponsors.
Clinical Research Development and Medical Affairs
We are a software provider
176
Clinical Trial Transparency
My company provides consulting services related to disclosure strategy and procedures.
Outsourced (Please describe.)
We use one CRO to make the entries into the public registries
Redaction, anonymization

177
Q5 - How many years have you worked in clinical data disclosure?

178
Q6 - How many employees work at your company?

179
Q7 - What best estimates the current number of approved products
across your company's portfolio?

180
Q8 - For which geographical region(s) are you responsible at your
company? Please select all that apply and specify, as appropriate.

Other Region
Asia
Global excluding USA

181
Q9 - How familiar are you with EMA and FDA policies on data
sharing?

182
Q10 - Have additional resources, such as additional staff and funding,
been allocated for clinical disclosure at your company?

183
Q11 - How would you best describe the current status of your company
in adjusting to fulfill EMA and FDA clinical data disclosure
requirements?

184
Q12 - How does your company evaluate the effectiveness of its clinical
data sharing program? Please select all that apply.

Other
Nothing yet
Have own internal clinical trial data transparency program for outside researchers
interview and survey users of our data sharing system
Completed reports and publications
N/A - software company
Not applicable - I am a consultant
Client reviews and satisfaction/retention
Market surveys, customer feedback, customer KPIs
Not applicable

185
Q13 - Successful implementation of a company clinical data sharing
program may be impeded by certain barriers. Please rank, according to
the degree of challenge presented the challenges of implementing
clinical data sharing. (1 = Most difficult challenge, 10 = Least difficult
challenge)

Other
evolving requirements and timelines hamper ability to prepare organization (eg policy 70 is
constantly being adjusted by the agency)
Not applicable
186
Q14 - With which clinical data sharing models are you familiar?

Other
Company website
FDAAA 801 requirements
PharmaCM
Belong to clinicalstudydatarequest
several others, most notably ProjectDataSphee
alltrials
OpenTrials
IdeaPoint

187
Q15 - Who is eligible to obtain clinical data from your company? Please
select all that apply.

188
Q16 - Who requests clinical data from your company? Please select all
that apply.

Answer % Count
Clinical data is not requested from my company, it is requested from the
sponsors that we provide disclosure services to.
25.00% 1
n/a - software company 25.00% 1
through policy 43 and other FoI requests anyone can get access. For data-set
sharing we allow IRB to evaluate researcher credentials
25.00% 1
We are a solution provider, Our customers use out platform for disclosure - not
us
25.00% 1
Total 100% 4
189
Q17 - What specific documents are required to obtain clinical data from
your company? Please select all that apply.

Other
NA, we're a CRO
To the best of my knowledge
evidence of a qualified statistician (or equivalent) on team
Again, we provide disclosure services to sponsors/clients but any document requests would go to
our sponsors/clients, not to us.
Protocol and clinical study report
We are a solutions provider. Customers use our platform to disclose data
CV of researcher

190
Q18 - What level of documentation is required to obtain clinical data
from your company? Please select all that apply.

191
Q19 - Who reviews requests to obtain clinical data from your company?
Please select all that apply.

192
Q20 - How does your company review clinical data requests? Please
select all that apply.

193
Q21 - What types of redacted clinical data on approved products does
your company provide to secondary researchers? Please select all that
apply.

Varies by product (Please explain.)
redacted CSRs for trials of approved products per EFPIA/PhRMA position statement
Other
I believe it's one of the 2.
blank CRF, SAP, data dictionay and other documents (see CSDR for details)
Protocol, SAP, annotated CRF
protocol, crf, sap, data dictionary
N/A - software company
We perform redaction services for our clients.
We are the vendors for various pharma companies providing disclosure support. We do not share
company data with public. Thia is handled by the sponsor themselves
Customers use our platform to disclose data
Varies by proposal

194
Q22 - How does your company redact clinical trial data?

195
Q23 - Has your company modified its Clinical Study Report (CSR)
template to minimize the burden the redacting commercially
confidential information (CCI) and individual patient data (IPD)?

196
Q24 - How does your company provide access to clinical data? Please
select all that apply.

Other
Homegrown sharing portal and/or secured data transfers; CSRD in consideration
We also share full documents via an online reading room for enquiries received for documents-
only via CSDR.com Also share of PDS and other stand-alone ad hoc requests (like IMI or
disease-specific initiatives)
n/a software company
dedicated data transfer
Multiple company database IdeaPoint

197
Q25 - What clinical information does your company provide? Please
select all that apply.

198
Q26 - Have the EMA and FDA requirements generally impacted the
level of detail that you provide in clinical overviews, clinical summaries,
and clinical study reports (CSRs) for marketing applications? Please
comment further on these specific impacts.

199
Q27 - Some organizations have suggested that a clinical data
transparency index, in which companies or drugs are ranked by legal
compliance and/or ethical conduct regarding clinical data disclosure
requirements, could incentivize clinical data sharing. Do you agree?

200
Q28 - Should industry support user fees to help fund clinical disclosure
by health authorities in exchange for specific benefits?

Other
I do not foresee such a quid pro quo (fee + data = some reward) Industry and sponsor release of
data should be sufficient especially if being tracked by these evolving indexes. This is the more
responsible and controlled way to manage the release of these data which are sensitive in many
ways
royalities from countries where other companies use the information as part of their competitive
advantage, i.e. obtain market approval

201
Q29 - Do you agree that clinical data for products in development or
abandoned (unapproved) should be disclosed?

202
Q30 - Do you agree that preclinical data for products in development or
abandoned (unapproved) should be disclosed?

203
Q31 - On September 16, 2016, HHS and FDA updated their rules and
policies to require registration and summary results on
ClinicalTrials.gov. However, some have suggested that the greatest
problem in obtaining industry compliance is a failure to enforce the
rules. For example, AllTrials recently estimated that $25 billion has
been lost since no fines have ever been levied for noncompliance. Do you
or would you support penalizing companies that do not comply with
clinical disclosure requirements?

204
Q32 - Please provide any additional information or comments on the
ways in which the current clinical trial data sharing environment has
impacted industry. What, if anything, would improve the current
landscape?

Please provide any additional information or comments on the ways in which...
Harmonization of requirements--one stop shop for clinical data
There is no true methodology for which compliance is measured, since there are many
requirements to meet. Money should be invested in establishing one method of registration/results
posting and standard methodology for measuring compliance.
I beleve it is good to share information when a trial is conducted and has completed. The
individual details are what is worrisome especially if it is a small trial where the participant can
be readily identified. This is because just as we have software to redact, thee are softwares out as
well, where the data can be reversed. Participants who are worried of that might hesitate to
participate in trials. This is the major issue I see on this.
205
Harmonization of global disclosure requirements
stringent timelines and new requirements for clinical data sharing has imposed a lot of
burden/pressure on industries.
Current systems are very onerous to report data effectively
utilzing real world data and developing methodologies for integrating with clinical trial data for
late phase studies
ONE SINGLE clincial data sharing/disclosure platform would increase efficiencies, compliance
and reduce reduncancy (which is resulting in inconsistencies). This would also ease the search for
for trials including their results and documents for patients and the general public!
Any indices of compliance must stick strictly to requirements and sponsor policies but not
arbitrary ethical benchmarks
Huge costs to implement and maintain. Do not see benefit to company.
A request that all clinical trial sponsors provide access to individual patient level data and it not
be only industry would be a welcome change. As for tracking of compliance, the major issue has
been and continues to be a misrepresentation of compliance. In fact, this is a primary reason why
no fines have been levied. The NLM also recently stated that trials that complete (have primary
outcome LPV) prior to the final rule effective date do not need to have results posted which
further shows that no money has been "lost".
What could improve: More public information to give a unambiguous disclosure profile (i.e.
approval status, approval dates); support for transparency from upper management; global place
for disclosures
More precise instructions from regulatory agencies as to acceptable de-identification rules - there
is currently a wide range of interpretation regarding EMA Policy 0070 and related transparency
requirements because the guidelines are vaguely written.
First let me say that I have done my best to answer the survey questions as accurately as possible,
but the services provided by my company have prevented pertinent responses in some cases. My
employer provides outsourcing disclosure services to pharma companies, academic institutions,
etc., so we do not have any products of our own that require data sharing. However, working for
this company has allowed me to perform disclosure service for clients who may represent the
opposite ends of the spectrum (full disclosure versus disclosure of only required
elements/studies). In my opinion, the current data sharing environment is not having enough of
an impact on industry. One of the biggest issues is lack of education. With limited impact for
companies who are non-compliant, there is limited interest in fulling disclosure requirements.
The data sharing requirements should be more specific for all companies so there is not so much
diversity in what data is shared.
A unified global regulation/law where a single portal services all requirements and permits
information to be shared in a harmonized and standardized manner to all patients.
One single global registry with uniform requirements would really foster transparency and would
make everyone's live easier
People should keep separate trials for drugs in development vs abandoned products. I don't think
companies should be forced to share information on drugs still in development - that
deincentivises development and innovation. They SHOULD be pressured into disclosing results
for abandoned products because someone else might be able to use that data to improve the
product so it WILL work.
206
APPENDIX C: ADDITIONAL TABLES AND CROSS TABULATIONS
Table 18: Cross Tabulation of Geographic Region and Clinical Disclosure
Experience
(n=75)

For which geographical region(s) are you responsible
at your company? Please select all that apply.

Global US EU Other
Region
Other
Country
Total
How many
years have
you worked
in clinical
data
disclosure?
< 1 Year 5 3 2 0 0 8
1-2 Years 12 4 3 0 0 15
3-5 Years 19 5 4 1 0 26
6-10+ Years 21 9 9 1 0 26
Total 57 21 18 2 0 75

207
Table 19: Cross Tabulation of Geographic Region and Familiarity with EMA
Policy
(n=77)
For which geographical region(s) are you
responsible at your company? Please select all
that apply.

Global US EU Other
Region
Other
Country
Total
How familiar are
you with EMA
and FDA policies
on data sharing?
- European
Medicines
Agency (EMA)'s
Policy 0070 on
Publication and
Access to
Clinical-Trial
Data
Extremely
familiar
17 7 7 0 0 22
Very
familiar
27 5 7 2 0 31
Moderately
familiar
11 4 3 0 0 16
Slightly
familiar
3 2 1 0 0 4
Not familiar
at all
1 3 0 0 0 4
Total 59 21 18 2 0 77

208
Table 20: Cross Tabulation of Geographic Region and Familiarity with FDA
Policy
(n=76)
For which geographical region(s) are you
responsible at your company? Please select all
that apply.

Global US EU Other
Region
Other
Country
Total
How familiar are
you with EMA
and FDA policies
on data sharing?
- Food and Drug
Administration
(FDA)'s
Availability of
Masked and De-
identified Non-
Summary Safety
and Efficacy
Data
Extremely
familiar
8 5 5 0 0 11
Very
familiar
17 3 2 1 0 20
Moderately
familiar
16 5 3 1 0 21
Slightly
familiar
11 3 4 0 0 15
Not familiar
at all
6 4 3 0 0 9
Total 58 20 17 2 0 76

209
Table 21: Cross Tabulation of Geographic Region and Redaction Practices
(n=64)

For which geographical region(s) are you
responsible at your company? Please
select all that apply.

Global US EU Other
Region
Other
Country
Total
How does your
company redact
clinical trial data?
Manual
redaction
7 1 3 1 0 9
Redaction
software
3 2 3 0 0 4
Manual
redaction and
reaction
software
23 7 4 1 0 30
Outsourced 9 1 1 0 0 10
Do not know 5 7 4 0 0 11
Total 47 18 15 2 0 64

210
Table 22: Cross Tabulation of Company Title and Allocation of Resources
(n=73)

Have additional resources, such as additional
staff and funding, been allocated for clinical
disclosure at your company?

Yes No, but my
company
plans to do
so
No, and my
company
does not
plan to do
so
Do
not
know
Total
What title
best
describes
your role
within your
company?
Vice President 2 0 1 0 3
Director/Senior
Director
12 1 4 3 20
Manager/Senior
Manager
12 1 3 2 18
Associate/Senior
Associate
9 2 1 5 17
Consultant/Senior
Consultant
5 0 1 0 6
Other 3 1 2 3 9
Total 43 5 12 13 73

211
Table 23: Cross Tabulation of Company Title and Medical Products Experience
(n=77)

How many years have you worked in the
medical products industry?

< 1
Year
3-5
Years
6-10
Years
11-15
Years
16+
Years
Total
What title best
describes your
role within
your company?
Vice President 0 0 0 0 3 3
Director/Senior
Director
0 1 2 7 10 20
Manager/Senior
Manager
0 0 6 7 6 19
Associate/Senior
Associate
4 10 2 1 1 18
Consultant/Senior
Consultant
0 3 2 0 2 7
Other 1 0 2 5 2 10
Total 5 14 14 20 24 77

212
Table 24: Cross Tabulation of Company Title and Clinical Disclosure
Experience
(n=75)

How many years have you worked in
clinical data disclosure?

< 1 Year 1-2
Years
3-5
Years
6-10+
Years
Total
What title
best
describes
your role
within your
company?
Vice President 0 0 1 2 3
Director/Senior
Director
2 4 6 8 20
Manager/Senior
Manager
1 4 4 9 18
Associate/Senior
Associate
3 5 8 2 18
Consultant/Senior
Consultant
0 0 5 1 6
Other 2 2 2 4 10
Total 8 15 26 26 75

213
Table 25: Cross Tabulation of In-Development/Abandoned Products and
Granularity of US FDA CSRs
(n=59 and n=59)
Have the FDA
requirements generally
impacted the level of detail
that you provide in clinical
overviews, clinical
summaries, and clinical
study reports (CSRs) for
[US NDA] marketing
applications?

Yes No Do not know Total
Do you agree that
clinical data for
products in development
or abandoned
(unapproved) should be
disclosed?
Strongly agree 6 11 5 22
Somewhat agree 8 3 13 24
Neither agree nor
disagree
0 1 1 2
Somewhat disagree 5 1 2 8
Strongly disagree 1 0 1 2
Do not know 0 1 0 1
Total 20 17 22 59
Do you agree that
preclinical data for
products in development
or abandoned
(unapproved) should be
disclosed?
Strongly agree 3 6 3 12
Somewhat agree 5 4 9 18
Neither agree nor
disagree
5 2 1 8
Somewhat disagree 5 0 6 11
Strongly disagree 2 3 3 8
Do not know 0 2 0 2
Total 20 17 22 59

214
Table 26: Cross Tabulation of In-Development/Abandoned Products and
Granularity of EU MAA CSRs
(n=59 and n=59)
Have the FDA
requirements generally
impacted the level of detail
that you provide in clinical
overviews, clinical
summaries, and clinical
study reports (CSRs) for
[EU MAA] marketing
applications?

Yes No Do not know Total
Do you agree that
clinical data for
products in development
or abandoned
(unapproved) should be
disclosed?
Strongly agree 5 9 7 21
Somewhat agree 7 7 10 24
Neither agree nor
disagree
0 1 1 2
Somewhat disagree 5 2 2 9
Strongly disagree 1 0 1 2
Do not know 0 1 0 1
Total 18 20 21 59
Do you agree that
preclinical data for
products in development
or abandoned
(unapproved) should be
disclosed?
Strongly agree 3 4 4 11
Somewhat agree 4 7 7 18
Neither agree nor
disagree
4 2 2 8
Somewhat disagree 4 3 5 12
Strongly disagree 3 2 3 8
Do not know 0 2 0 2
Total 18 20 21 59

Abstract (if available)

Abstract Prior to the 21st century, health authorities held the view that pharmaceutical regulatory submissions for new marketing applications contain commercially confidential information not to be disseminated to the public. In the new millennium, however, secondary researchers and other stakeholders have compelled regulators to change those policies to allow access and even to publish proactively clinical data that was previously kept private. This research evaluated the way in which industry approaches and manages the publication of clinical trial results to meet the new disclosure requirements. Drawing on the information obtained by the literature review, a survey instrument was developed to target pharmaceutical employees and contractors working in clinical disclosure. Seventy seven of 98 respondents working in the clinical disclosure function who expressed interest completed the survey. The results indicated that most pharmaceutical companies, and by extension, clinical disclosure professionals, have accepted and even advocated for the value of releasing clinical information to maximize data utility and benefit stakeholders. While industry is acting diligently to retain influence over access to, and use of, company clinical data, many respondents in this study also appeared receptive to the further uses of clinical and even preclinical data to improve patient health and safety. Further research could help to ascertain whether other pharmaceutical company functions, including executive management, recognize clinical transparency as an important business investment that has provided tangible benefits to patients and shareholders.

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Asset Metadata

Creator Griffin, Grant S. (author)

Core Title Sharing the results of clinical trials: industry views on disclosure of data from industry-sponsored clinical research

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 06/19/2017

Defense Date 05/12/2017

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

Tag clinical data disclosure,clinical data transparency,clinical disclosure,clinical transparency,clinical trial data disclosure,clinical trial data transparency,clinical trial disclosure,clinical trial transparency,data transparency,OAI-PMH Harvest,trial disclosure

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances J. (committee chair), Cosenza, Mary Ellen (committee member), Davies, Daryl L. (committee member), Jamieson, Michael W. (committee member), Pire-Smerkanich, Nancy (committee member)

Creator Email gsgriffi@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-387811

Unique identifier UC11259159

Identifier etd-GriffinGra-5426.pdf (filename),usctheses-c40-387811 (legacy record id)

Legacy Identifier etd-GriffinGra-5426.pdf

Dmrecord 387811

Document Type Dissertation

Rights Griffin, Grant S.

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