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Current practices of U.S. investigators in the management of the clinical trial agreement: a survey of knowledge, attitudes, perceptions, and engagement

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Current practices of U.S. investigators in the management of the clinical trial agreement: a survey of knowledge, attitudes, perceptions, and engagement

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CURRENT PRACTICES OF U.S. INVESTIGATORS IN THE MANAGEMENT OF THE CLINICAL
TRIAL AGREEMENT: A SURVEY OF KNOWLEDGE, ATTITUDES, PERCEPTIONS, AND
ENGAGEMENT

by

JoAnn P. Pfeiffer

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

May 2014

Copyright 2014 JoAnn P. Pfeiffer
2

Dedication

Dedicated to my dear husband, Bob Pfeiffer who supported me, acted as a sounding board, and
was my anchor during this long process. And to my mother, Bernice Wille Phillipp, who was a
champion of further education and an astonishing role model.
3

Acknowledgements

Kellie Ann Moore, ESQ, who inspired me in her class and was a catalyst for my undertaking of
this study and special thanks to Frances J. Richmond, Ph.D., who without her unending support
and challenging me in ways that sometimes frustrated but made me a much better researcher,
this dream would not have been realized.
4
Contents
Dedication ............................................................................................................................................ 2
Acknowledgements .............................................................................................................................. 3
List of Tables ......................................................................................................................................... 7
List of Figures ........................................................................................................................................ 8
Abstract .............................................................................................................................................. 11
Chapter 1: Overview of the Study ...................................................................................................... 12
1.1 Introduction ........................................................................................................................... 12
1.2 Statement of the Problem ...................................................................................................... 14
1.4 Importance of the Study ........................................................................................................ 18
1.5 Limitations and Delimitations ................................................................................................ 19
1.6 Organization of the Study ....................................................................................................... 20
1.7 Definitions and Acronyms ...................................................................................................... 20
Chapter 2: Literature Review .............................................................................................................. 24
2.1 Introduction to the Clinical Trial Agreement (CTA) ................................................................ 24
2.2 History and Evolution of the Clinical Trials Paradigm ............................................................. 29
2.3 Clinical Trial Agreements as Contracts ................................................................................... 42
2.4 Essential Components of a Clinical Trial Agreement .............................................................. 46
2.5 Reviewing and Negotiating the Clinical Trial Agreement ........................................................ 53
2.6 Summary of the Background Literature ................................................................................. 55
5
2.7 Direction of This Study ........................................................................................................... 55
Chapter 3: Methodology .................................................................................................................... 60
3.1 Introduction ........................................................................................................................... 60
3.2 Development of Survey .......................................................................................................... 60
3.3 Survey Deployment ................................................................................................................ 61
3.4 Data Analysis .......................................................................................................................... 63
Chapter 4: Results............................................................................................................................... 64
4.1 Focus Group ........................................................................................................................... 64
4.2 Analysis of Survey Respondents ............................................................................................. 64
4.3 Analysis of Organization and Environmental Factors ............................................................. 68
4.4 Respondent Attitudes and Perceptions .................................................................................. 71
4.5 Investigator Engagement in the Clinical Trial Agreement Process .......................................... 78
4.6 Investigator Knowledge .......................................................................................................... 80
4.7 Additional Respondent Comments......................................................................................... 81
4.8 Cross-Tabulations ................................................................................................................... 82
Chapter 5: Discussion ......................................................................................................................... 87
5.1 Considerations of Delimitations and Limitations.................................................................... 87
5.2 Consideration of Results ......................................................................................................... 95
APPENDIX A ...................................................................................................................................... 118
APPENDIX B ...................................................................................................................................... 126
6
APPENDIX C ...................................................................................................................................... 136
APPENDIX D ...................................................................................................................................... 149
APPENDIX E ...................................................................................................................................... 153
APPENDIX F ....................................................................................................................................... 156

7

List of Tables

Table 1: Federal Regulation Governing Human Research .............................................................. 46

Table 2: Roles of other respondents .............................................................................................. 67

Table 3: Other organizations .......................................................................................................... 68

Table 4: Who manages the clinical trial agreement at your organization? .................................... 71

Table 5: Who manages the CTA, identified as ‘other’? .................................................................. 71

Table 6: Professional organization used by investigators to understand the CTA .......................... 77

Table 7: "What do you think is the worst thing that might happen if you let your organization
review and negotiate the clinical trial agreement without your input?" ............................... 79
Table 8: Conflicts with sponsors: conflicts identified as “other” in text box. ................................. 82
8

List of Figures
Figure 1: Indexed Number of Active Substances Entering Each Phase of Development .................. 42
Figure 2: Rising Costs of Research Development ............................................................................ 42
Figure 3: Rules of Offer and Acceptance (based on Brian A. Blum Model) ...................................... 44
Figure 4: Essential Elements of the Social Ecological Model of Bronfenbrenner (Modified by
McLeroy, Steckler, Bibeau, and Glanz, 1988) ......................................................................... 59
Figure 5: Essential Features of the Health Belief Model of Rosenstock, et al. (Modified from Janz
& Becker, 1984) ...................................................................................................................... 60
Figure 6: Types of studies conducted by respondents. ................................................................... 69
Figure 7: Study phases conducted by respondents. ....................................................................... 70
Figure 8: “Please rate your organization/employer on each of the following items”........................ 72
Figure 9: Investigator perceptions regarding the importance of the CTA ....................................... 73
Figure 10: Do you agree or disagree with the following statements? ............................................. 74
Figure 11: Would you feel comfortable reviewing and negotiating a clinical trial agreement? ... 75
Figure 12: Attitudes of colleagues to the CTA ................................................................................ 76
Figure 13: Influences on the investigator’s capabilities with respect to the CTA ............................. 77
Figure 14: Investigator perception of non-inclusion in the CTA Process ......................................... 78
Figure 15: Investigator mood when dealing with CTA .................................................................... 80
Figure 16: Do you sign the clinical trial agreement (n=114)? ............................................................. 81
Figure 17: Have you had a negative experience/conflict with a sponsor in the following areas?
(Multiple answers permitted.) .................................................................................................... 82
Figure 18: Items in CTA identified by investigators ......................................................................... 83
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Figure 19: Type of institution and time to process the CTA. ........................................................... 84

10

Figure 20: Type of institution against availability of resources ....................................................... 85
Figure 21: Type of institution against investigator's belief that organization is capable of
negotiating a fair and balanced contract ................................................................................ 86
Figure 22: Type of institution and includes investigator in the review and negotiation of the CTA.
............................................................................................................................................... 86
Figure 23: Type of organization against investigator comfort level in the review and negotiation
of the CTA ............................................................................................................................... 87
Figure 24: Type of institution against investigator happiness with institution's CTA process ........... 87
Figure 25: Type of institution against investigator signature on the CTA ........................................ 88
Figure 26: Type of Institution against issues with sponsors (n=114) ............................................... 88

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Abstract
The Clinical Trial Agreement (CTA) is one of the many documents that govern the conduct of
investigators doing human research. This exploratory survey study examines the current
practices of investigators in the U.S. in the management of clinical trial agreements. The study
looked at the investigator’s knowledge, attitudes, perceptions, and engagement in the
management of the CTA as well as organizational and environmental factors that impact the
clinical trial agreement process. The study began with a review of the literature to examine
available data regarding the investigator’s role in the review and management of the CTA. This
review suggested that relatively little has been written in comparison to other study documents
such as the study protocol, the investigator’s brochure, the informed consent, and the FDA Form
1572, that governs the investigator’s behavior. Thus in this study, a combination of the Social
Ecological Model of Bronfenbrenner and the Health Belief Model of Rosenstock were used as a
framework to design survey questions that examined the knowledge, attitudes, perceptions and
the environment of the survey participants. Results of this study indicate that both the
investigator and the institution impact the efficiency of the CTA process. The majority of
respondents believed that their involvement in the process was important and reported their
institution encouraged their involvement. In addition to including the investigator in the review
and negotiation of the CTA, respondents who worked in organizations that provided training
and resources reported a higher level of happiness with the organization’s management of the
CTA. Additionally the survey collected demographic data to describe and substratify the
respondent population and the degree to which investigators are engaged in the CTA process.
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Chapter 1: Overview of the Study

1.1 Introduction

Collaboration between industry sponsors and research investigators is essential for the ongoing
development and marketing of medical products. The specifics of the collaboration are outlined
in the Clinical Trial Agreement (CTA), a legal and binding contract that governs the conduct and
defines the responsibilities of the involved parties in the human research study (Webb, 2006).
The CTA is the foundation on which the relationship between the sponsor, the site, and the
investigator is built. The CTA can have a serious impact on both the safety of the human subject
and on the investigator’s ability to conduct research effectively and with scientific integrity.
However, the CTA is one of the least examined of the study-related documents in industry
sponsored clinical trials. Despite its key role in the governance of the study, it is believed that
investigators fail to give adequate attention to the review, negotiation and management of CTAs
(DuVal, 2003). Often the investigator is not a direct party to the contract discussions and does
not thoroughly review the CTA even though its language governs the investigator’s behavior
with respect to performance of the research (Drazen, 2002). Generally the investigator’s
understanding of the CTA is believed to be low, especially in academic settings where the
investigator relies on contracts and grants or another administrative office to review, negotiate
and approve the CTA (Drazen, 2002; Duval, 2003; Goldfarb, 2004). According to Goldfarb, based
on a survey conducted by CenterWatch, many investigators sign the CTA without properly
reviewing the document (Goldfarb, 2004).

If an investigator seeks to learn more about the CTA he/she will find few available resources. A
review of literature and research web sites identified little published information, training
13

sessions, or resources related to CTAs. The registration fees for identified training sessions were
costly, usually $1,600 - $2,000 for full-day sessions that would require travel and time
commitments for the already busy investigator. The United States Food and Drug
Administration (FDA), which has regulations and guidance documents on many aspects of
clinical trial ethics and logistics does not provide guidance as to the content of the CTA. The CTA
therefore remains an unregulated study document. It is, however, critical that the CTA complies
with all current applicable laws and regulations promulgated with respect to the clinical trials
that are typically supervised by the FDA. These include the documents created by the
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of
Pharmaceuticals for Human Use outlining the unified standards for conducting clinical trials
known as Good Clinical Practices (GCPs) and subsequently adopted by the European Union (EU),
Japan and the United States (International Conference on Harmonisation, 1996). The ICH E6
guideline defines the international ethical and scientific quality standards for designing,
conducting, recording, and reporting of clinical studies that involve the participation of human
subjects. Other regulations for human protections are found in the United States Code of
Federal Regulations (CFR) Title 21 sections 11, 50, 54 and 56. These sections of the CFR outline
the regulations for electronic records and electronic signatures (section 11), protection of
human subjects (section 50), financial disclosure by clinical investigators (section 54), and
institutional review boards (section 56). In addition to adhering to the above regulations the
investigator must also comply with the Health Information Portability and Accountability Act
(HIPAA) of 1994 (US Department of Health and Human Services [DHHS]), which was enacted to
protect an individual’s personal health information (PHI).
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The CTA is written to define the industry-investigator relationship and the obligations of each
party. It should in theory spell out how the investigator and the sponsor will deal logistically
with the applicable laws, regulations and guidelines including federal, state and local laws that
apply, but it can and should extend much further. Typically, the most important and often
contentious parts of the CTA have been identified in the anecdotal literature as: 1) publication
rights, 2) how and when results for the trial will be published, 3) who owns the study data and
any intellectual property associated with the study, 4) the confidentiality of documents, and 5)
indemnification of the institution and its staff (Mello, Phil, Clarridge, and Studdert, 2005;
Regulski, 2009).

1.2 Statement of the Problem

Published literature around CTAs is scanty and where present, typically deals with the roles of
the institution and the sponsor in designing and negotiating the CTA. Perhaps the most
systematic study was the Schulman survey study conducted in 2002. In this study, 122 medical
schools that form the membership of the Association of American Medical Colleges (AAMC)
were asked to participate in a survey about their institution’s agreements with industry
sponsors. From this group, 108 institutions participated in the survey, whose questions focused
on the provisions in agreements between the institution and the industry sponsor (Schulman,
Seils, Timbie, Sugarman, Dame, Weinfurt, Mark, and Califf, 2002). The study population included
only academic institution officials who were involved with CTAs and not clinical investigators.
Further, the study primarily focused on whether their agreements described the parties’ roles
in the design and conduct of trials, access to data, and commitment to publications (Schulman
et al., 2002; Mello et al., 2005). A more recent global survey conducted by Salvius Legal in
conjunction with Applied Clinical Trials sought to gain insight on
15

the general experience and understanding of the CTA from the point of view of the clinical
research industry (Rijswijk-Trompert, 2012). This survey resulted in 534 completed responses
mostly from clinical departments ranging from small to very large CROs, pharmaceutical
companies, biotechnology companies and other related organizations both in and outside of the
U.S. This study like the others appeared to be most concerned with the administration of the
CTA by the institution.

Review of the literature found no study that has focused on the investigator’s participation in
the management of the CTA. It is, however, important to understand better the role, experience
and views of the clinical investigator in the process of reviewing and negotiating the CTA. The
ramifications of failing to adhere to the CTA will have a critical impact not only on the institution
but also on the investigator, and potentially the study subject. In an article published in the
NEJM in 2005, Mello et al. stated that:

“Although industry sponsors provide approximately 70 percent of the funding for clinical
drug trials in the United States, little is known about the legal agreements that exist
between industry sponsors and academic investigators.”

Eight years later this appears to remain true. The review of literature and the survey conducted
by CenterWatch of 875 of clinical sites (2003) leads us to believe that not only does this apply to
the academic investigator but also to the non-academic investigator. CTAs are generally
considered low-risk agreements because the parties are operating in a strongly regulated
environment (Rijswijk-Trompert, 2012). However, a poorly drafted CTA can create legal risk and
financial liabilities for the site and the investigator. A review of the literature suggests that a
majority of academic sites (Mello et al., 2005) and non-academic clinical sites (Rijswijk-
Trompert, 2012) do experience problems with the CTA.
16

In preparation for study start, sponsors conduct investigator meetings, typically with sessions on
HIPAA, Good Clinical Practices (GCPs), electronic data capture, expected Adverse Events (AEs),
grading and reporting of AEs and Serious Adverse Events (SAEs), the protocol, and the
investigator’s brochure. Institutions, industry sponsors, Clinical Research Organizations (CROs),
and clinical sites have policies that require successful completion of HIPAA and GCP training for
investigators and study staff. Many of these sessions are available electronically allowing the
investigator to complete them at a time that is convenient for him/her. However, no such
training or policies appear to be offered or required regarding the CTA.

The available research data on this topic is very limited. No systematic examination of the
investigators’ understanding and perceptions of the CTA has been published. A few experts in
the field have suggested that this is a problematic area, but no systematic data related to the
involvement of the investigator is available to substantiate these suggestions. It is therefore not
possible to determine whether the investigator understands the CTA or perceives it to be an
important or even critical part of conducting clinical trials. A number of questions remain to be
answered.
 Does the investigator have the knowledge needed to understand the CTA?
 What are investigator’s perceptions and attitudes with regard to the CTA and its
importance in the study?
 What barriers exist that might impact the investigator’s involvement in the CTA
process?
 Does the institution/organization provide adequate support to educate and
inform the investigator?
 How do environmental factors related to peers, institutional policies and
practices and social structures affect the perceptions, attitudes, and behaviors
of the investigator with regard to the CTA?

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1.3 Purpose of the Study

In this study we examined the knowledge, perceptions and experience of investigators with
respect to the CTA in an attempt to describe current practices. We postulated that investigators
might not be active participants in the process, as suggested by anecdotal literature, and
therefore at least two important aspects would need to be explored. First, is the failure to take
an active role because the investigators see no need to be more involved? Alternatively, do
investigators feel that they should be more involved but find disincentives or barriers related
either to their understanding of the process or to the culture and institutional organization
around them? Such information is critical in assessing whether problems in fact exist, and if
they exist, how best to intervene in future to improve the situation.

This study used survey methods to explore the knowledge, experience, perceptions, attitudes
and behaviors of principal investigators in the United States. More specifically it evaluated: 1)
the investigators’ knowledge of the CTA, 2) their perceptions and attitudes regarding the
importance of the CTA, and 3) their experience in the CTA review process, including barriers that
they may face. The survey was structured around two nested frameworks. First was the
overarching Social Ecological Model of Bronfenbrenner (1979) that encourages a broad
evaluation of the environmental elements that have the capacity to influence the views and
behavior of individuals. These elements include social networks and institutional affiliations, as
well as community elements and public policy elements that affect an individual’s actions.
18

Added to this framework was a more focused consideration of the interpersonal domain of the
Social Ecological Model using the Health Belief Model of Rosenstock (1950s). This model
advances the theory that behaviors are motivated both by perceived threats and outcome
expectations, and encouraged exploration with regard to the way in which behavior with regard
to participation in the CTA process is shaped by perceptions that are specific to the investigator.
The design and questions of the survey tool were evaluated by a focus group of experienced
professionals who had knowledge of clinical trials or had managed CTAs and were able to
discuss the scope, clarity and validity of the survey questions. The survey was then distributed
electronically to Investigators and study staff, using a range of methods employed to identify
potential respondents.

1.4 Importance of the Study

This study contributes to a better understanding of how CTAs are viewed and managed by the
investigator. The data provides a picture of current practices by investigators and their
management and involvement in the CTA process. The collected information may prompt
institutions, organizations, and professional research organizations to reassess the role of the
investigator in the management of the CTA. Concerns identified by the research can be used to
justify more effective inclusion of the investigator in the CTA process. Ideally it will bring more
attention to possible next steps to review the impact of the CTA in the investigator’s conduct of
clinical trials.

The results of this study provide a benchmark of current practices and a possible roadmap for
future research and education in this area. An understanding of the level of knowledge and
engagement by investigators as well as attitudes and perceptions provides an opportunity to
19

assess to what extent the CTA is seen as a critical study document deserving the same degree of
attention by the investigator as other study documents.

1.5 Limitations and Delimitations

This study was delimited to investigators in the US who have at least two years of experience
conducting industry sponsored trials and are currently conducting industry sponsored clinical
studies that are governed by a CTA. Thus the results did not include the views of other
stakeholders in this agreement, such as the contracts and grants offices, or sponsors of the trial.

There are several potential limitations to the approach being taken in this study. An important
challenge to validity inherent in any small study is the difficulty to obtain the cooperation of the
subject population in completing the survey. Participation in surveys of this nature may be a low
priority to busy professionals who may not perceive any benefit in investing the time and effort
to complete the survey. The investigator’s willingness to answer questions fully and honestly
may be affected by the nature of the questions, the time required to complete the survey, and
the interest of the investigator in the topic being studied. This may cause the results to be
skewed towards those who are interested in this topic and see some merit of the research.
Further limitations to the sample size and external validity are imposed by the use of
convenience and snowball sampling methods that were chosen to assure better participation
from individuals who are contacted, but may not be representative of all investigators,
institutions, or geographical locations in the US.

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1.6 Organization of the Study

This study is organized into 5 chapters. Chapter 1 provides a general overview of the problem
and an introduction to the research. Chapter 2 is a review of the current state of the literature
in regard to management of the CTA. Chapter 3 outlines the methods used for this study,
including the construction of the survey instrument. Chapter 4 provides an analysis of the
results. Chapter 5 discusses the implications of the results.

1.7 Definitions and Acronyms
1.7.1 Definitions

For this study the following definitions apply:

Clinical Trial Agreement: A legal and binding contract between a sponsor and a study site which
outlines the conduct and responsibilities of the sponsor, site, and investigator.

Debarment: The denial of access to investigational drugs to clinical researchers who have been
found to be in serious or repeated violation of Investigational New Drug (IND) requirements.

Due Diligence: Thorough review of the contract prior to signing.

Indemnification: The scope and survival obligations of the parties. It is an act of compensation
for actual loss or damage or for trouble and annoyance by the other party to the contract when
it has been breached.

Jurisdiction: The state that governs the agreement.
21

Site: The institution or practice at which the study in conducted.

Negligence: Deviation from the standard of care of a reasonable clinical investigator that could
result in injury to the subject.

Sponsor: The pharmaceutical company directing the overall study, providing the funding, the
protocol, study documents, and materials.

Tenants: The sections/articles included in the agreement.

Tort Litigation: A civil wrong. The behavior of one party that causes another party to suffer loss
or harm.

1.7.2 Acronyms

AAMC = Association of American Medical Colleges
ACRP = Association of Clinical Research Professionals
AE = Adverse Event
CFR = Code of Federal Regulations

CISCRP = Center for Information and Study on Clinical Research Participation
CRF = Case Report Form
CRO = Clinical Research Organization
CTA = Clinical Trial Agreement
22

DHHS = US Department of Health and Human Services
EU = European Union
FDA = U.S. Food and Drug Administration
GCP = Good Clinical Practices
HBM = Health Belief Model

HIPAA = Health Information Portability and Accountability Act

HITECH = Health Information Technology for Economic and Clinical Health

ICH = International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use

IDE = Investigational Device Exemption
IND = Investigational New Drug
IRB = Institutional Review Board

MAGI = Model Agreement Guidelines International
NIH = National Institutes of Health
PHI = Personal Health Information

RAPS = Regulatory Affairs Professional Society
SAE = Serious Adverse Event
SEC = Social Ecological Model
23

SOCRA = Society of Clinical Research Professionals
USC = United States Code
USD = United States Dollar
24

Chapter 2: Literature Review
2.1 Introduction to the Clinical Trial Agreement (CTA)

Successful clinical trials require extensive systems of documentation that are linked to legal and
ethical obligations. For example, written procedures identify the roles and responsibilities of
study personnel, sponsors, and subjects; records memorialize important events for future
reference; and agreements outline the exchange of money and services. A voluminous
literature exists on the management of certain types of documents such as the experimental
protocol and informed consent forms that are required for the conduct of human research
studies. This intensive focus is reflected, for example, in the 57,000 items identified using the
Web search engine, Google Scholar©, when searching with the term “informed consent form”
(June 1, 2012). However, not all trial related documents have been subjected to this same
degree of scrutiny. An important study document that has received much less attention is the
CTA. According to DuVal (2004), CTAs remain largely unregulated, are not always reviewed for
adherence to ethical standards, and rarely ensure adequate protection for their investigators to
publish study data (DuVal, 2004).

The CTA is the legal and binding agreement outlining the roles, responsibilities, and financial
exchanges between the clinical trial site, the investigator and the sponsoring entity. A well
written and balanced CTA is critical to protect the site, the investigator, and the research
participants. It lays the foundation for the relationship between the sponsor and investigator
and defines the many obligations on both sides to ensure that the trial is run in a safe and
disciplined manner that is compliant with regulations governing human subject research. As a
legal and binding contract it should also include legal remedies in the event that one of the
25

signatory parties does not fulfill the stated obligations. Despite the importance of a CTA in a
clinical trial, much less guidance is available about its proper design, content, and
implementation than is generally associated with other documents. Another Google Scholar©
search on the term “clinical trial agreement” yielded only 251 results (June 28, 2012). The
majority were articles that dealt with the management of the CTA by academic institutions.
Most focused on the routing of a CTA through the academic system, with attention paid to items
such as identifying the appropriate offices to review and approve the CTA (e.g., Office of
Sponsored Research, Office of Clinical Trials), identifying the department heads who must sign
the CTA, and describing the affiliated forms needed for this routing or negotiation process (e.g.,
review request form, internal budget, study letter).

Other articles discussed the challenges that a university may face when negotiating the CTA with
the sponsor. An often-discussed challenge is the need to define publication rights that meet the
university’s mission of disseminating knowledge and are acceptable to the sponsor who may
want to limit what is published (Davidoff, DeAngelis, Drazen, Hoey, Højgaard, Horton, and
Krotzin, 2001; Gotzche, 2006). Another challenge is agreement on the nature of documents and
data that should be kept confidential. An academic institution would prefer to have a narrow
definition of what constitutes confidential documents and data, so that investigators are free to
give presentations and to publish, whereas the sponsor may have a broader definition that
allows the sponsor to exercise judgment over the data that it is willing to share, and to restrict
or even withhold data that it does not want to be disseminated in articles that are submitted for
publication (University-Industry Demonstration Project [UIDP], 2012). Other challenges faced by
the two parties are the terms of ownership of patents or intellectual property, indemnification,
26

and notice and access to study data. There was no information found in the published literature
that examined non-academic investigators and their challenges with the CTA.

A much smaller number of articles dealt with the required content and best practices when
composing a CTA. These articles were typically authored by members of the professional
organization, by Model Agreement Guidelines International (MAGI), or by attorneys at
academic institutions. The modest size of the body of searchable literature reinforces a view
that has been occasionally expressed in the trade literature that the potential importance of the
CTA is often underestimated (Drazen, 2002; Goldfarb, 2004). Further and more specifically, its
importance for the clinical investigator, who is one of the parties to the agreement, has not
been an area of emphasis despite the potential negative consequences of entering into such an
agreement without a full understanding of its significance.

Investigators accept legal and ethical accountability for the conduct of human subject research
that occurs under their supervision. This acceptance is formally acknowledged in two types of
contracts. The first is the Investigational New Drug (IND) or Investigational Device (IDE)
exemption, which is essentially a “contract” with the government for those drug and device
clinical trials that are subject to FDA oversight. For example, the IND for pharmaceutical
products is prefaced by the FDA Form 1572 that clearly defines investigator responsibilities
related to the conduct of the trial under GCPs (21 CFR Part 312). This form spells out investigator
obligations and is relatively easy to read and understand. Investigators and co-investigators are
required to sign this form to signify their acceptance of the requisite responsibilities and
obligations prior to conducting investigational drug research. The second contract, the CTA, is
bidirectional in that it sets out not only responsibilities of the investigator to the sponsor but
27

also of the sponsor to the investigator. This much longer document, with legal language that is
often more sophisticated than the FDA Form 1572, is not as easy to read or understand.

A well-written CTA frames the boundaries for acceptable conduct of the investigator during his
or her participation in the sponsored clinical trial. However, investigators involved with the
multiple tasks of setting up a clinical trial might not pay much attention to the specific terms of
the CTA which can only be understood well by investing significant time to read and question its
terms (Goldfarb, 2006). In 2003, a survey of U.S. clinical trial sites by CenterWatch, a
professional association of clinical research organizations, reported that approximately two-
thirds of community-based sites sign the CTA without reading it. Further they do not always
have the knowledge to understand the investigator’s role, and may not take the time to review
the investigator responsibilities in the CTA adequately (Goldfarb, 2004). In an editorial in the
Journal of the American Medical Association (JAMA) in 2002, Drazen contends that investigators
often are not party to the development and review of the contract with an academic institution.
In addition, some university administrators deemed it acceptable to keep the terms of the
agreement secret (Mello et al., 2005). No further data could be found regarding the review of
the CTA by academic investigators or non-academic investigators.

The CTAs between sponsors and academic institutions appear from a scattering of reports to be
most often managed at the administrative level by the institution (Schulman et al., 2002; Mello
et al., 2005). Schulman and colleagues conducted a structured mail survey of medical research
administrators at 122 academic institutions across the United States, from November 2001 to
January 2002. Of the 108 institutions that participated in the survey 48% of respondents worked
in the office of grants and contracts, 40 percent in research administration offices, 7% in
28

industry-liaison offices, and 5% in legal affairs. Findings from the survey indicated that
institutions do not always address important elements of the CTA such as rules for access to all
study data or authorship of publications for multi-center trials.

Insights from the survey study of Schulman and colleagues were published in several articles in
the New England Journal of Medicine between 2002 and 2005. In an article titled Academic
Medical Centers’ Standards for Clinical-Trial Agreements with Industry published in May 2005,
Mello and colleagues reported that amongst the 108 institutions, 85% identified that they had
faced issues related to publication. These issues included situations in which the sponsor was
allowed to revise manuscripts and the investigator was not allowed to examine the data
independently. In another article in the same issue, titled Gag Clauses in Clinical-Trial
Agreements, Steinbrook (2005) reported situations where industry sponsors attempted to
suppress negative or unfavorable results by incorporating gag clauses in the CTA or requiring the
consent of the sponsor prior to publication. Fifty-six percent of the respondents to the Schulman
survey reported that multi-center trials were the most difficult to negotiate. They identified a
number of issues that included ownership of inventions and intellectual property, authorship of
manuscripts, and access to the data from the entire study. Of those surveyed 82% reported
having a least one dispute with an industry sponsor in the previous five years. The most
common disputes reported were related to payments, ownership of intellectual property,
control or access to data, content of publications, and the confidentiality of research results. The
survey also found that 69% of those surveyed felt pressure to compromise the language of the
CTA (Mello et al., 2005).
29

Three additional articles addressing important aspects of industry-site CTAs appeared in peer
reviewed journals after 2005. In the New England Journal of Medicine, Mello, Phil, and Joffe
(2007) studied the Abney v Amgen case to highlight the complexity of the relationships of all
parties to the contract and discussed the critical importance of communicating the obligation of
the sponsor to the subject in the CTA. The Abney v Amgen case raised serious concerns about
the relationships between the sponsor, investigator, and institute that ultimately resulted in
legal action including tort litigation and civil law suits. Regulski (2009) searched the language in
actual CTAs, and from those reviewed was able to extract what she considered to be 12
publication loopholes. Regulski then suggested appropriate language for the CTA that she
adapted from MAGI’s Model Clinical Trial Agreement. An article reporting the findings of a
survey of global clinical trial departments related to experience and understanding of the CTA by
Rijswijk-Trompert appeared in Applied Clinical Trials in June 2012. No articles related to the
management of CTAs by investigators were found.

2.2 History and Evolution of the Clinical Trials Paradigm

Understanding the role and the importance of the CTA may be enhanced by understanding the
history and the recent evolution of the clinical trial process. For much of its history, clinical
research at academic institutions was carried out by investigators who framed their own
research questions and designed their own studies with little oversight from other entities. Such
studies had little need for legal agreements because they typically were self-funded or were
financed by a public, federal or nonprofit institution that held little long-term commercial
interest in the data that resulted. Perhaps the clearest example of this divestiture is illustrated
by the actions of the US government, one of the largest funding sources of clinical research, that
30

assigned its rights to the results of federally funded research to the university under the terms
of the Bayh-Dole Act of 1980 (http://www.gpo.gov).

In the last 30 - 40 years, multiple shifts have occurred in the approaches, regulations, and
funding for clinical trials. An increasing reliance on biotechnology, the entry of other players
such as Clinical Research Organizations (CROs), decreased public funding, stricter regulatory
oversight, and the need for larger-scale clinical trials have all increased the challenges, especially
those facing the academic investigator. A brief discussion of the trends and challenges that have
impacted clinical trial research over the past forty years are described below, because each
exemplifies the need for and importance of the CTA.

2.2.1 Economic Shifts in Funding

Flattening growth in the U.S. economy combined with strong year-by-year increases in the
national debt has put pressure on government agencies to reduce spending, and more
specifically, to reduce research grants to academic institutions. In the past, academic centers
have been able to rely on funding from governments or non-profit organizations for much of
their research. For example, in 1991, 80% of clinical trials were funded by the federal
government or philanthropic organizations (Gilbert, 2008). However, in the past 10 years, the
number of applications for grants to the National Institutes of Health (NIH) has almost doubled
while budget constraints have not kept pace. In 1998, approximately 32% of grant applications
were funded by the NIH. In 2000 that level dropped to 21% and in 2012 only the top 10% of
grant proposals to NIH were funded (NIH Policy Forum, 2008; Rehman, 2012). As public funding
decreased, industry assumed a larger share of the support for clinical research. From the 1970s
to the mid -1990s, the pharmaceutical industry showed a pattern of increased involvement with
31

academic institutions for much of their research (Bodenheimer, 2000). The predominance of this
support was graphically illustrated in a 2006 report by The Center for Information & Study on
Clinical Research Participation (CISCRP). In its study of 2,405 volunteers participating in clinical
trials, 775 were enrolled in government funded clinical trials, 880 in Phase I - III industry-funded
trials, and 750 in Phase IV industry-funded trials.

Initially, the pharmaceutical industry relied on academic institutions to perform drug trials for
three reasons: 1) the companies did not have the in-house expertise to design trials, 2) academic
medical centers provided a large pool of patients as subjects for clinical trials, and 3) companies
needed the prestige of academic publications to market their product (Bodenheimer, 2000).
This gave the academic investigator significant power in the university-industry partnership.
Non-academic investigators did not share in this power.

However, academic power began to erode as companies began to employ highly experienced
and specialized research teams to design and analyze their own drug trials, and to recruit
patients from many different centers and different parts of the world. In-house expertise
reduced the need to collaborate with academic researchers in the design phase of clinical trials.
Further, as companies hired well-qualified investigators with sound scientific reputations, as
clinical research directors, the prestige provided by the university was no longer as critical to the
industry (Bodenheimer, 2000). This changed the dynamic from one in which industry relied on
academia to one in which academia now relied on industry for many of its research activities.

Industry has now become the major source of funding for clinical trials in the United States. By
2005 industry funded an estimated 70% of U.S. clinical trials (Moran, 2005). To continue to
32

work with industry, academic investigators have had to adjust to industry goals that are typically
driven by the ability to bring drugs to market in a timely manner (UIDP, 2012). Thus, instead of
discovering drugs and designing research, academic investigators have had to adopt the role of
“testers” in industry sponsored trials. The role of “tester” implies a service function that relies
on scrupulous adherence to a preset protocol and following stringent regulations, and the
careful collection of data in order to satisfy the needs of the sponsor and the FDA.

In comparison non-academic organizations did not experience these challenges to the same
extent. These organizations had always relied on industry to financially support the majority of
their research and were familiar with the challenges of industry sponsored trials.

2.2.2 Cultural Changes

The social views of academic-industry partnerships have also changed in the past four decades.
In the 1970s and into the 1980s, investigators and academic organizations involved in industry-
sponsored research were often viewed by colleagues as lacking scientific rigor and interested
only in financial gains (Stossel, 2005). Media reports of misconduct, injury, and death in industry
sponsored trials added to the sense that industry sponsored trials were not “real” research and
might not be entirely ethical or safe.

The view that industry-sponsored trials had problems was not without substance. In the late
1990s and early 2000s sensationalized media reports of misconduct damaged the reputations of
a number of elite institutions. The behaviors of some investigators were clearly in breach of the
CTA with serious legal and ethical ramifications on the institution and the investigator. Some of
these incidents, listed below, have become landmark cases for clinical trial ethics.
33

 In 1988, a Harvard-affiliated hospital was accused of misconduct in corporate sponsored
research related to the investigator’s financial ties with the sponsor. In this particular
case, findings provoked the medical school into tightening its standards and placing
financial restrictions on investigators who worked with industry sponsors (Stossel,
2005). This led not only to universities requiring financial disclosure and conflict of
interest forms from all investigators, but also the industry.
 In 1999, the tragic death of a young adult, Jesse Gelsinger, who was a participant in a
gene therapy study at the University of Pennsylvania, focused intense publicity on the
university and on clinical trials in general. The subsequent investigation into that death
by both the FDA and the university brought to light questionable practices such as the
presence of financial ties between the investigator and the company sponsoring the
research. Procedural issues, such as inadequate oversight and inadequate informed
consent of subjects were also criticized (Kimmelman, 2008). Stricter enforcement of
procedures and policies as well as increased transparency at the site, industry, and
federal government levels resulted from the investigation of this case.
 An investigator at the University of Alabama-Birmingham, conducting an industry
sponsored lymphoma study in 2002, was convicted of falsifying data. An investigator at
the Cleveland Clinic in Ohio was similarly accused of falsifying records (Nguyen, 2007).
These investigators clearly breached the protocol, the CTA and the FDA Form 1572.
 An investigator at Wake Forest University was forced to resign in 2005 after it was
discovered that he created ghost subjects putting the entire study results in question.
(Nguyen, 2007).
34

 An investigator at the University of Wisconsin failed to fully disclose that he received
ongoing royalties from a sponsor of his clinical trials as required and this may have
resulted in study bias (Nguyen, 2007).

The non-academic investigator was not immune to issues and negative publications. Many
private clinical research sites also experienced investigator misconduct and legal and ethical
problems.

It is possible that prior to the last decade, many of the cases of fraud and abuse in clinical trials
could be hidden or downplayed. However, with the internet changing the way we
communicate, information can be disseminated more rapidly and to a larger audience.
Advanced media technologies have also increased the visibility and transparency of clinical
trials. Popular U.S. publications such as Time and Newsweek Magazine, as well as major, local,
and national newspapers such as U.S.A Today, the LA Times, Washington Post, and New York
Times, regularly publish stories and articles on clinical research. Although many of these articles
describe the benefits of new drugs and data reported from successful clinical trials, others
highlight the faults and disasters resulting from clinical research. A flavor of such articles is
reflected in their titles: Clinical trials: professional guinea pigs (Time, 2010), Clinical trial
dilemma: save lives now-or-later (Szalavitz, 2010), The seroqual scandal (Szalavitz, 2011), Some
pharmaceutical clinical trial results are buried (Begley, 2010), Smackdown! Why we need more
head-to-head drug trials (Carmichael, 2010), Lilly discontinues schizophrenia trials (Norqvist,
2012), Heartless science (Boyle, 2011), and Germans apologize for thalidomide (LA Times, 2012).
It is possible that this type of negative publicity may cause potential participants to reconsider
35

their participation in research studies, thus decreasing the subject pool and increasing recruiting
challenges.

In response to the allegations and investigations of misconduct, federal agencies have increased
their oversight of human subject research. The DHHS established the Office for Human Research
Protection in 2000. In 2001, the Office for Good Clinical Practices was created and in 2004 the
DHHS issued guidance on disclosing and managing financial relationships between an
investigator and sponsor. The FDA and NIH have also pushed for more transparency in clinical
trials. As part of this effort, in 1997, Congress passed a law requiring registration of all human
clinical research studies conducted in the U.S. (FDAAA801) (FDA, 2007). As a result of this law
NIH was tasked with creating a public registry for publicly and privately funded clinical studies.
Sponsors are mandated to register all clinical trials conducted in the US that require human
subjects on clinicaltrials.gov. Failure to adhere to these requirements could have serious
negative repercussions. CTAs should include this as part of the sponsor’s responsibilities.

2.2.3 The Biotechnology Revolution

Research on biological products has a number of challenges not so typical of small-molecule
development including the need for researchers with special expertise in the characterization
and testing of complex molecules and the often-unpredictable clinical performance of highly
targeted and immunogenic compounds (Cortright and Mayer, 2000). Industry was forced to
vary their standard approaches to clinical trials by outsourcing some its early stage research to
specialized laboratories in universities that appeared better able to carry out translational
research related to pharmacodynamics and immunology, in ways that often demanded unusual
animal models or patient sub-stratification according to genetic or biomarker information.
36

Thus, many prominent academic researchers founded or became involved in the first
biotechnology companies. These new relationships between industry and key opinion leaders in
science also assisted in revising traditional views that academic researchers who partnered with
industry were compromising their integrity only for the sake of financial gain, so that working
with industry appears recently to have become more acceptable and even fashionable (Stossel,
2005).

The rapid growth of biotechnology has also had an impact on university-industry relationships.
Cortright and Mayer (2000) define biotechnology as “the application of biological knowledge
and techniques pertaining to molecular, cellular, and genetic processes to develop products and
services”. Biotechnology depends on highly trained researchers, many of who reside in
universities and medical colleges and most of whom depend on the support of NIH for their
research. Federal support for biotechnological research has steadily increased in the previous
two decades from $2.4 billion USD in 1985 to $7.6 billion USD in 2000. The largest share of this
funding has gone to universities and medical colleges for specialized research to expand the
biotechnological horizon (Cortright and Mayer, 2000).

However, from its beginnings, commercial entities have also been involved in biotechnology
research. Some trace the early roots of the biotechnology industry to an academic-industry
partnership at the University of California, San Francisco in the 1970s that produced the first
biotechnology firm, Genentech (UCSF, 2012). In 1976, Genentech reported its development of
the first artificially created protein strand and in 1978 Genentech produced the first
commercially available biological product, human insulin (Rhodes, 2012).
37

Currently the two largest biotechnology firms in the U.S. are Amgen and Genentech, of which
the latter merged with the Roche Group in 2009 (www.gene.com). These two companies are
together staffed by 34,500 individuals world-wide and have sales exceeding $15 billion USD
(Genentech, 2008; Amgen, 2011). However, applications of biotechnology have also produced
and continue to produce hundreds of small biotechnology companies (Rhodes, 2012) and over
150 FDA approved biologics (www.fda.gov). The majority of these smaller biotechnology
research firms rely on their ties to academic institutions where researchers are able to produce
large libraries of new molecules with medicinal properties (Stossel, 2005). Academic
institutions generally do not have the financial resources needed to scale up to produce
biologics. Industry typically is better positioned to scale up the production and testing of these
molecules. These complementary capabilities have forced the two sets of players into more
frequent and varied partnership agreements.

2.2.4 Emergence of Clinical Research Organizations

Increased federal oversight, tighter regulations, and more stringent requirements for data to
support safety and efficacy have all been factors leading to the need for trials with scrupulous
attention to integrity and quality. At the same time, the size and complexity of trials has
increased because pharmaceutical firms often must demonstrate the efficacy, safety, and value
of their investigational products statistically by comparing them to others in the same drug class,
in order to justify approval and reimbursement in an increasingly crowded marketplace. Large
scale trials have become critical for the commercialization of pharmaceutical products (Tufts
Center for the Study of Drug Development, 2012). It is impossible for a single site to recruit the
thousands of subjects required for these large trials. Thus, trial designs must include
38

mechanisms to integrate activities of different investigators at multiple sites. These factors have
increased the cost of bringing a new drug to market.

Universities can be expensive and often difficult places to conduct clinical trials. Indirect costs to
underwrite the facilities and services at the university can be a significant part of the budget. A
review of university policies shows that academic institutions typically charge 25 – 27% indirect
costs on clinical trials that are industry-funded (Google® search, December 15, 2012). Further,
universities have often proved to be slow with regard to IRB and contract approvals. Delays in
drug approval cost the pharmaceutical company an average of $1.3 million USD for each day lost
(Goldfarb, 2004). Evidence indicates that pharmaceutical sponsors have become frustrated with
the delays of obtaining approval and starting clinical trials at academic institutions
(Bodenheimer, 2000). In efforts to expedite and reduce the costs related to unnecessary delays
in trial conduct, pharmaceutical firms began to explore the availability of using clinical sites
outside of universities (Bodenheimer, 2000). A growing option has been to partner with CROs. A
CRO is an organization that provides research services to pharmaceutical and biotechnology
companies (e.g., conducting clinical trials, site selection and monitoring, data management,
recruitment, and provision of central lab services). The number of these organizations has
grown rapidly in the last decade. In 2000 there were an estimated 800 CROs operating in the
U.S. By the end of 2011 this number increased to more than 3,100 (Getz, 2012).

CROs offer many advantages to industry. Many CROs employ their own investigators and have
facilities, laboratories and practice-based sites identified to conduct clinical trials with little or no
need for academic medical centers (Bodenheimer, 2000). CROs have become more specialized
in the past decade in order to provide industry with easier and quicker ways to manage various
39

aspects of drug research at lower costs. CROs are able to begin clinical trials and recruitment
much faster than academic institutions. It takes a sponsor an average of 35 days to negotiate a
CTA with a CRO and 96 days with an academic center (Goldfarb, 2004). On average it takes a
sponsor 133 days to start of clinical trials at an academic site versus 40 days for non-academic
sites (Goldfarb, 2006). In addition to taking longer to start studies universities often over
promise and under deliver (Bodenheimer, 2000).

In addition a partnership with a CRO can help the pharmaceutical firm transfer some of the risk
involved in bringing a new drug entity to market as the CRO accepts higher levels of risk in the
operation of the trial (Getz, 2012). This is illustrated in the following scenario. A CRO contracts
with a pharmaceutical firm to conduct a clinical trial for a specified sum of money. That sum is
estimated according to the nature of the trial and the previous experience of the CRO with
similar studies. When the clinical trial does not proceed as projections would have indicated,
and for example, has unusually slow recruitment, the additional costs inherent in a longer trial
are borne by the CRO, thus decreasing the financial risk of the study to the sponsor.

Additionally, the CRO is responsible for selecting qualified investigators and sites to ensure that
the site staff is adequately trained and adequately supported with resources to conduct the
study safely. When subject injury or a death occurs in the trial, the CRO is a key party to any
subsequent legal actions, thus to some extent indemnifying the pharmaceutical company.

As industry outsourced more research and development services to CROs over the last decade,
the academic setting has been displaced as the only option for many types of clinical trials. This
trend has impacted the ability of academic investigators to attract industry funding
40

(Bodenheimer, 2000). In the mid-1990s approximately 70 percent of industry dollars for
research and development went to academic institutions (Moran, 2005). By 2006, CROs were
receiving the major share of pharmaceutical outsourcing dollars. The academic market share
declined from about 80% in 1991 to 26% by 2006 (Goldfarb, 2006). Twenty-seven percent of
large pharmaceutical companies and 47 percent of small companies outsourced at least part of
their research and development to CROs in 2010 (Silverman, 2011). CROs now play the major
role in providing the pharmaceutical industry with a wide variety of services and solutions to
achieve greater efficiency, productivity, and reduced costs (Azoulay, Repenning, and Zuckerman,
2010) and often do not use academic institutions as sites for their trials.

2.2.5 Pharmaceutical Pipeline

Pharmaceutical products are becoming more difficult and expensive to develop, and much has
been written about the impact that these forces have had on the number of new products in the
pipeline. One effect is that pharmaceutical companies have moved away from having a large
number of back-up drug candidates in the pipeline to focusing on fewer candidates that show
promise (Arrowsmith, 2012). This has resulted in fewer clinical trials. With fewer drugs entering
Phase I trials the number that enter Phase II and III are also reduced. This trend is shown in
Figure 1. This reduction of drug candidates may limit the number of available trials, especially in
later phases.
41

Figure 1: Indexed Number of Active Substances Entering Each Phase of Development

Reprinted with permission (Arrowsmith, 2012)

In addition to the challenge of fewer trials the cost of developing a new drug has increased
significantly over the past two decades as shown in Figure 2.

Figure 2: Rising Costs of Research Development

Reprinted with permission (Munos, 2009)
42

Pharmaceutical corporations and financial analysts estimated the cost of developing a new drug
in 2001 at $800 - 900 million USD. By 2011 the cost was calculated at close to $2 billion USD
(Collier, 2009; Munos, 2009). While some might argue with the validity of the numbers in
absolute terms the trends are nevertheless quite clear. Clinical trials are known to account for a
substantial part of the cost of drug development, and these costs continue to grow as more
sophisticated and expensive approaches are required to assess and prove efficacy and safety per
regulations (Munos, 2009). The level of complexity of clinical trials, which often have as many as
100 interventions, also adds to the increasing cost of conducting clinical trials (Bodenheimer,
2000). Industry is now spending more money to develop fewer drugs. Competition for the
reduced funding has impacted both the academic and non-academic investigator.

2.3 Clinical Trial Agreements as Contracts

As the preceding section suggests, investigators have many challenges when pursuing research
funding that may not be true for the non-academic investigator. Federal research funds are
decreasing and more difficult to obtain and industry-funded trials are often outsourced to CROs
and non-academic sites rather than academic institutions. As more players vie for industry
dollars, the expectations of industry can increase in ways that put pressure on investigators and
institutions to provide support and services in a faster and more professional way than might
have been tolerated previously. Greater attention may be needed with respect to the CTA which
forms the legal basis of the relationship between the institution and the industry sponsor. In
such a challenging environment it is important for investigators to negotiate contracts that are
fair to all parties, and that outline clearly the responsibilities of the investigator. As importantly,
the transactional aspects of the negotiation and signing must be carried out as efficiently as
possible to be competitive in obtaining clinical research.
43

All contracts, including the CTA, are governed by contract law. A contract is a legally enforceable
agreement that contains a promise to act or to refrain from acting at some time in the future
(Karambelas, 2007). No party may be bound in contract without that party’s assent (Emanuel,
2006). This does not mean that a party must agree totally with the contract, but each party must
feel that the contract is reasonable and fair. After a negotiation process involving offers and
counter offers, both parties typically sign the contract to document that indicates that an
agreement has been reached (Blum, 2004; Emanuel, 2006).

Figure 3: Rules of Offer and Acceptance (based on Brian A. Blum Model)

Offer

Acceptance Rejection
Counter

Contract terms of offer No Contract

Offer Accepted Rejected New Counter Offer

Throughout history, courts have been responsible for deciding what constitutes an offer and
what constitutes acceptance to make the contract legally binding. Contract rules that are the
basis for current law were mostly developed in the 19
th
century, and have since been shaped by
many court cases that have established contract law precedence. One of the earliest and most
well-known cases on what forms a contract in the medical products industry is Carlill v Carbolic
Smoke Ball Company (Carlill v. Carbolic Smoke Ball Co. [1893] Q.B. 256 C.A.). In this 1893 case,
44

Carbolic Company advertised a new "wonder drug", a smoke ball, that they claimed would
prevent users from catching influenza. Their advertisements promised that the individual would
receive £100 from the Carbolic Smoke Ball Company if the smoke ball did not prevent influenza.
In addition the company indicated that it had set aside funds in an escrow account to cover
payouts. Mrs. Louisa Elizabeth Carlill purchased the smoke ball and subsequently contracted
influenza. The Carbolic Smoke Ball Company refused to give Carlill the £100, arguing that the
advertisement was not to be taken seriously and that it was merely a gimmick to sell the
product. The initial court that heard the case and the court of appeals both disagreed with the
argument of the company and ruled that a reasonable man would take the advertisement
seriously (Babatunde, 2010; Heffey, 2010). In this case, the Carbolic Smoke Ball Company made
an offer and the purchaser accepted that offer, affirming this contract by purchasing the
product (Macken, 2012).

The CTA, like any other contract, legally enforces the roles and responsibilities of the sponsor,
site and investigator. One of the fundamentals of contract law is that a party should be held
accountable in some way for their promises (Emanuel, 2006). Failure to be accountable can
result is serious legal action.

In the United States, contracts fall under the jurisdiction of state law. This means that 50 judicial
bodies oversee contract law in the U.S. Although similarities exist among the laws of different
states, each body of contract law also includes nuances applicable only in that state. Federal
contract laws also exist, but these laws are limited to federal concerns such as the regulation of
interstate commerce (Emanuel, 2006). Thus, when a contract promise is broken, the power of
legal enforcement enables the disappointed party to sue the other party in a state court of law.
45

The remedy is generally not to compel the party breaching the contract to perform but to award
compensatory damages to the party affected by the breach.

Even though contracts are governed by state law, CTAs because of their specialized relationship
to human subject research must take into consideration a number of federal laws that regulate
the conduct of that research. The applicable regulations must be considered and addressed in
the CTA so that, at the very least inconsistencies are not present in the contract (FDA, 2008).
Examples of clauses in Federal regulations applicable to human study research are described in
Table 1.

Table 1: Federal Regulation Governing Human Research

Regulation Description
21 CFR Part 50 This section of the CFR applies to all clinical investigations regulated by the
FDA and the protection of the research subject. An investigator may not
involve a human being in a research study without first obtaining a legally
effective consent. Section 50.20 outlines the process for obtaining the consent
and requires that the informed consent not contain language through which a
subject is made to waive or appears to waive any of their legal rights. Not only
is the investigator responsible for obtaining a proper and legal consent it is
critical that appropriate portions of the consent be reflected in the CTA.
21 CFR Part 54 The FDA requires that each investigator conducting an FDA regulated study
disclose any financial arrangements with the sponsor and the nature of those
arrangements or certify they have no financial conflicts. It is the responsibility of
the sponsor to collect a financial disclosure form from each investigator. The
CTA should contain language that defines the process for completing this form,
when it is due, and how the sponsor will collect the information.
21 CFR Part 312.62 This regulation, as well as Good Clinical Practices (GCPs), requires that the
investigator maintain accurate records of the disposition of the drug and to
retain these records for a period of two years after the FDA approves marketing
of the drug or the study is terminated. The sponsor should define in the CTA
how the records are to be stored and after approval of the drug or termination
of the study their expectations for retaining records and how and when records
may be destroyed.
21 CFR Part 56 The responsibilities of the Institutional Review Board (IRB), functions and
operations, the board make-up, and criteria for protocol approval are
addressed in this section of the CFR. The IRB, like the investigator, is tasked
with the protection of the subject and ensuring that risks to the subject are
minimized as much as possible. The IRB requirements and the party
responsible for the requirement (e.g., obtaining approval of the protocol and/or
consent, reporting adverse events, and submitting continuing reviews) must be
included in the CTA.
The Health Insurance Portability
and Accountability Act (HIPAA)
This rule protects the privacy of individually identifiable health information.
It also requires that the patient be informed of uses and disclosures of their
medical information for research purposes, and their right to access
46

information about them (45 CFR Parts 164.501, 164.508, and 164.512(i)). The
CTA must contain language that the sponsor, the organization, and the
investigative staff will comply with HIPAA.
21 CFR Part 312.68 The investigator upon the request of the FDA must allow authorized access to
copy and verify all records and reports of the investigator. In the CTA the
sponsor outlines their expectations of what the investigator should do when
the FDA notifies them of an upcoming inspection. The CTA will cover when and
how to notify the sponsor and how the sponsor will assist the site in preparing
for an FDA inspection.
21 CFR 11 This regulation sets out the requirements for the use of electronic records to
collect subject data and electronic signatures. The CTA should define how the
data will be collected, verification of the investigator’s signature, and the
training on the electronic data capture system that will be provided to the
investigator and study staff.
FDA Form 1572: Statement of the
Investigator
Describes the investigators duties (U.S. Dept. of HHS) and agreement to comply
with all requirements regarding the obligations of clinical investigators and all
other pertinent requirements in 21 CFR 312. The investigator cannot begin a
study prior to signing this statement. The CTA must correspond with the
responsibilities and duties defined on this form
18 USC Sec. 1001 This United States Code (USC) defines crimes and criminal procedures for any
investigator or a member of the study team who knowingly commits fraud or
provides false statements during the conduct of the research study. This should
be spelled out clearly in the CTA.
The Medical Kickback Law This statute prohibits companies paying or providing incentives to physicians to
induce referrals. The CTA should include language related to physician
incentives and state that the investigator cannot use incentives to induce
physicians to refer patients to the study.
No Charge Study subjects cannot be charged for the investigational drug or procedures
related to the study. This information should be included not only in the CTA
but also the informed consent form.
Fair Market Value Compensation of the investigator and the site must be reasonable and based
on work. When negotiating the CTA and budget, the site/investigator and the
sponsor must take into account what is reasonable compensation based on
comparable services in the geographical area where the study is being
conducted.
Debarment Investigators who have been found to have engaged in ‘deliberate or repeated’
violations of IND requirements may be debarred by the FDA resulting in the
FDA denying them access to investigational drugs. The sponsor, the
organization, and the investigator must certify that no individual involved in
any aspect of the study has been debarred. The contract needs to contain
language that all parties will exercise appropriate actions to ensure that a
debarred investigator is not involved in the trial in any capacity.
Physician Payment Act/Sunshine
Act
Beginning in January 2013, under the Affordable Care Act, pharmaceutical
companies must report to the Centers for Medicare & Medical Services
payments of more than $10 made to physicians. This ACT is an effort to bring
transparency to company-physician relationships. Under this Act the company
must report aggregate information pertaining to individual healthcare
professionals. This should also be included in CTAs signed after January 3013.

2.4 Essential Components of a Clinical Trial Agreement

In addition to state and federal laws, universities and other research organizations have strict
47

policies governing many of the activities and relationships that must take place in a typical
clinical trial. These include, for example, policies covering financial conflict of interest, the
informed consent process, subject safety, subject confidentiality, management of electronic
data, training and qualifications of the study staff, and the submission of documents to the
Institutional Review Board (IRB). Many of these policies are driven by legal and regulatory
requirements to protect the institution, the subjects that it serves, and the personnel in its
employ.

Offices of research, grants and contracts offices, and legal departments in universities are
generally responsible for the CTA because technically it is executed between the sponsor and
the university that employs the investigator. Many universities now have staff in these
departments who understand issues important for the conduct of clinical trials and associated
contracts (Schulman et al., 2002; Mello et al., 2005). Still, often overlooked as part of the terms
of the contract are the specific roles and responsibilities of the parties with respect to satisfying
FDA regulations and the expectations with respect to specific aspects of protocol execution. No
data could be found that identified the party responsible for contract review and negotiation at
non-academic sites.

The failure to pay close attention to the details of the responsibilities assigned to an investigator
can cause problems later in the study. These problems are not always legal in nature. However,
a clear appreciation of elements that should appear in a CTA can provide the parties to the
contract with a structure for its content and a framework for negotiation and discussion. There
are certain elements that almost certainly would be expected to appear in a CTA and are linked
to the responsibilities of the investigative team. For example a good CTA would require that the
parties to the contract comply with all applicable regulations, such as those in Title 21 Code of
48

Federal Regulations Parts 11, 50, and 54. Similarly, regulations governing the protection of PHI
under HIPAA require parties to the contract be compliant with this Act. However neither of these
regulatory agencies has provided guidance on how to address their respective obligations in a
CTA. An inexperienced team might find it difficult to know how to address these issues.
Reaching a fair and balanced agreement that protects both the institution and the investigator
and includes the applicable regulations requires due diligence not only on the part of the
organization but also the investigator (MAGI, 2012).

A CTA deals not only with elements that are regulated, such as procedures for informed consent
and adverse event reporting, but also with elements relating to logistical issues, such as how
money is paid for various services and what the parties might expect in terms of milestones,
audits, timelines and penalties. Thus, institutions and investigators should not only understand
the regulations that govern human subject research but also understand the additional content
and obligations under the contract to insure full compliance with its terms. Given this
complexity, it seems important to have information on best practices with regard to the content
of the CTA.

The best source of information for constructing a CTA seems to be that provided by MAGI, an
organization that has invested significant time and effort to create a standard working model of
the CTA. This model shows what they believe to constitute a complete CTA. In this model are
many sections beyond the scope of the thesis here that are shown in Appendix A. However,
because the focus of this thesis relates to the understanding of the investigator with respect to
the CTA, it may be useful to identify in more detail the key sections that might affect the
investigator. Presented below is a brief overview of these key sections.
49

2.4.1 Scope of Work

The scope of work defines in broad terms the duties and deliverables of the clinical site and the
investigator. Tasks assigned to the investigator are defined in a number of areas including
his/her role with respect to the supervision of the study, obtaining informed consents,
delegation of duties to members of the study team, management of protocol amendments,
recruitment and enrollment, and handling of human materials if applicable (MAGI, 2012).

2.4.2 Records, Reporting, and Audits

The contract should clearly define the responsibilities of the investigator and the institution with
respect to the management of study records. It should clarify who should be permitted access to
the study documents, what level of access should be given to different team members (e.g.,
study coordinator, monitor, data manager), and how documents should be secured and
archived. The methods for collecting, analyzing, checking and releasing patient data should be
defined. Also to be addressed would be the management of regulatory audits, including the
sponsor’s expectations and requirements of the investigator to provide records in the event of
an FDA inspection. The contract should also spell out the nature of assistance that might be
expected from the sponsor in preparing for the inspection.

Ownership of data and records must be defined. The CTA should identify who has the assigned
rights to the completed case report forms, electronic databases created as part of the study,
source documents, study reports, and analyzed data. It should describe clearly the ownership of
intellectual property relating not only to the data itself, but in some cases even to the form of its
display (MAGI, 2012).
50

2.4.3 Sponsor Obligations

It is in this section that the relationship between the sponsor and the participant should be
established in accordance with the content of the informed consent. The CTA should also spell
out the nature of any goods and services, such as study equipment, documents, drugs/devices,
lab supplies, and miscellaneous study supplies to be supplied by the sponsor. The sponsor’s
payment plan and arrangements to register the study on clinicaltrials.gov or other additional
registries should be reflected under the sponsor’s obligations. Often absent from the CTA are
considerations of the relationship between the sponsor and the research subject (Mello, Phil,
and Joffe, 2007). The sponsor’s obligations should detail the fiduciary relationship between the
parties. This fiduciary relationship creates two legal duties: a duty of care and a duty of loyalty.
The duty of care is addressed in the informed consent process. Any promises made in the
consent should be incorporated in the CTA. A duty of loyalty infers that the sponsor will act in
the best interest of the subjects (MAGI, 2012). This may extend to the provision of treatment
for adverse events that occur during the trial or continued access to treatment beyond the term
of the trial.

2.4.4 Confidentiality

Defined in this section of the agreement should be the obligations of the parties related to
confidentiality. It should include for example: 1) Exceptions, such as information that is or
becomes publicly known, 2) Permitted disclosure of information to study staff (e.g., only
information needed in connection with their role in the study will be disclosed) and, 3)
Disclosure of data in source documents. The period of confidentiality for specified materials
should be clearly defined. Written and oral materials that must be considered confidential must
51

be explicitly defined in the CTA. Documents and data that are confidential can then be clearly
marked and designated for the eyes of only specified individuals (MAGI, 2012).

2.4.5 Publication

The terms under which the data from a clinical trial are published can often be a point of
contention between the sponsor and the academic site (Mello et al., 2005). CTAs should also
include authorship in multi-site publications and order of authorship for these publications. The
sponsor’s timeline for publishing study data should be clearly defined. Sponsors often seek
control over what is published (Baer, Feiler, Regulski, and Switzer, 2004). However, rights over
publication are important to academic investigators because their careers may depend on their
publication patterns. The contract should not interfere with the timely publication and
presentation of results by academic investigators in professionally recognized scientific forum or
peer reviewed publications. The sponsor should have a defined time period (e.g. 60 days) to
review the information prior to publication to ensure that no confidential information is
disclosed.

2.4.6 Indemnities and Insurance

The CTA should include language that ensures that the institution is able to recover costs
associated with lawsuits filed in connection with the trial. Indemnification covers damages and
expenses that might arise from the proper conduct of the clinical trial and related procedures
(Baer et al., 2004). The sponsor should indemnify the investigator, study staff, institution, its
officers and directors, provided that the study is conducted according to protocol, GCPs, medical
standards of care, and applicable laws and regulations. On the other hand, it should also include
the disclaimer that the sponsor will have no such obligation if the institution or any of its
representatives are negligent or involved in willful misconduct (MAGI, 2012).
52

2.4.7 Representations and Covenants

The parties responsible for maintaining the different regulatory approvals during the term of the
contract should be identified. The sponsor may require proof that staff members have the
training and experience needed to perform assigned activities (MAGI, 2012). Several federal
regulations must be addressed here including compensation to the site and investigator for
activities performed in the conduct of the study, policies on physician referrals, methods of
handling conflicts of interest, completing and submitting the FDA Form 1572, and submission of
required documents such as medical licenses and curriculum vitae (MAGI, 2012).

The party accepting the contract should be aware of the state of jurisdiction of the CTA as one
state may favor one party over the other. If a contract dispute arises it is important for each
party to ensure that the governing law does not unduly favor one or another party (Fox, 2008;
West and Lewis, 2008-2009; MAGI, 2012).

2.4.8 Term and Termination

The CTA should define the term of the agreement by identifying the date that the agreement
goes into effect and the day that the contract ends. It should also define the rules by which the
sponsor or the institution can terminate the agreement and the legal process to be followed if
either party breaches the contract. Additionally the CTA should detail the procedures to be
followed if the contract must be terminated before its specified termination date (MAGI, 2012).

The conditions and covenants of a contract can be confusing and the contract can easily contain
terms that favor one party over the other. Literature points to several concerns often
encountered in industry-academic CTAs. These should be carefully considered and addressed by
53

the academic site and the investigator when entering into a CTA with the sponsor. Three
important concerns that recur with particular frequency include publication rights; ownership of
data, intellectual property, and patents; and indemnification of institution, investigator, and
study staff.

2.5 Reviewing and Negotiating the Clinical Trial Agreement

The research sponsor, institution, and investigator each have interests in the conduct of the
research and will seek contractual terms to protect their interests (DuVal, 2003). Negotiation of
the CTA should be a process of inspection and rework by all parties accepting the offer to
identify and correct deficiencies in the initial draft and to reach an agreement that is fair to all
parties (Goldfarb, 2006). The rights and responsibilities of the investigator that are addressed in
the CTA can be best managed if the investigator understands the conditions and terms of the
contract. Conversely the investigator who does not understand the CTA can be out of
compliance with its terms by the performance of a simple act exposing them to litigation (MAGI,
2012). Yet anecdotal literature leads us to believe that investigators rarely have the legal
background or knowledge that would enable them to review and negotiate the CTA effectively.

It is difficult for an investigator to identify or correct deficiencies with little or no understanding
of the document, because terms may not be clear and omissions may not be apparent.
Resources to obtain this knowledge are difficult to find. An internet search conducted between
June 10 - 12, 2012, querying “research staff training and requirements” uncovered an array of
required and recommended training sessions for investigators. For example, all academic
institutions, pharmaceutical companies, and CROs that were searched require training in the
protection of human subjects, informed consent, the Health Insurance and Portability and
54

Accountability Act (HIPAA) which protects the privacy of personal health information, and good
clinical practices (GCPs). In addition many required or strongly recommended training in
research ethics, reporting of adverse events, proper documentation, and managing records.
However, it was difficult to find specific training in the management and negotiation of the CTA
for investigators.

Where do investigators obtain sufficient knowledge and training that will prepare them to be
actively involved in the contract process? How do they learn to negotiate a fair and compliant
contract? The review of the above-mentioned training requirements identified in the internet
search did not reveal any required training regarding the review and/or negotiation of the CTA,
especially pertaining to the role of the investigator. Multiple academic institutions do provide
CTA templates. Other than institution template the search identified only two possible academic
resources including a Cornell University Power Point on CTAs that was last updated in
September 2006 and a training session titled “Fundamentals of Clinical Trial Contracting” at the
University of North Carolina. In addition, three professional opportunities were identified
through the literature search. These opportunities included: (1) “Masterclass CTAs” which was
sponsored by the Association of European Science and Technology (AEST), (2) “Clinical Trials
Research Administration,” included as a small portion of a conference sponsored by the Society
of Research Administrators (SRA), and (3) the MAGI 2012 Conference West that included 10
sessions related to CTAs (www.magi.org). The lack of literature on CTAs would lead us to believe
that investigators do not have CTA training that is comparable to GCP, CFR and HIPAA training
and do not have access to this type of training. No articles were found relating to the
investigator’s understanding of the CTA or their involvement in the review and negotiation
process.
55

2.6 Summary of the Background Literature

Literature tells us that the pharmaceutical industry has a long history with academic
organizations and other private/public institutions that has not always been positive. Academic
medical centers can help bridge the gap between discovery and clinical development in ways
that are not available to non-academic research organizations. For academics to be able to
compete with non-academic sites they must help pharmaceutical companies to find new ways
to work with academia. These collaborations require a CTA. Recent evidence exists to suggest
that academic administrators are becoming more adept at reviewing and negotiating the CTA
(Mello et al., 2005), but it is unclear to what extent the academic investigator has participated in
the process. No such research data was found to demonstrate the non-academic investigator’s
role in the review and negotiation of CTAs.

It seems wise for investigators to have sufficient knowledge and the ability to play a key role in
the review and negotiation of documents that directly govern their conduct. A lack of knowledge
may cause misunderstandings related to intellectual property ownership, research publication,
sharing of data, management of subject safety and payment, and decision-making in
implementing the protocol. Legal consequences to such misunderstandings can include lawsuits
related to breach of contract, subject injury, liability, negligence, and failure to perform.

2.7 Direction of This Study

Because so little data is currently available about the investigator’s general understanding and
experience with the CTA we have elected to approach this problem using an exploratory
approach based on survey methodology. A structured survey was designed and distributed to
probe the investigators’ basic knowledge of the CTA and the degree to which they are involved
56

in its review and negotiation. Questions will also explore their perceptions about its role in the
conduct of clinical trials and the challenges that they have faced related to CTA. The use of a
survey will allow input from a broader sector of the study population than would interviews at
this early stage.

To allow us to pose appropriate questions systematically, several social and cognitive theory
frameworks were examined to identify if they could provide a useful framework for this survey.
One such model, the Social Ecological Model introduced by Bronfenbrenner in the 1970s, was
formulated as a theory in the 1980s, and progressively revised until his death in 2005. This
theory has been employed in a variety of contexts to understand what drives behavior in a social
environment. Its basic tenets are illustrated in Figure 4. It contends that behaviors are affected
and developed through our interactions with the environments around us (Bronfenbrenner,
1979). Multiple factors related to the individual, the environment and culture around him or her
impact behavior. Factors include elements that are particular to the individual, such as
knowledge, beliefs, and perceptions, but also include elements that have the capacity to
influence that individual, including their social networks and institutional affiliations, as well as
community elements and public policy elements. This theory appears particularly useful in the
context of the current study because it guides us to examine not only the knowledge and
motivation of the individual, but also the potential ways that these are affected by institutions
and social structures with which the individual must deal.
57

Figure 4: Essential Elements of the Social Ecological Model of Bronfenbrenner (Modified by
McLeroy, Steckler, Bibeau, and Glanz, 1988)

However, to some extent, the Social Ecological model which emphasizes the external influences
on the person may lack depth relating to motivations of the individual. I wish to capture these
intrinsic factors as fully as possible. Thus, a second model, the Health Belief Model (Rosentock,
Strecher, and Becker, 1988) has been considered to provide value and can perhaps also be used
to guide the research further.

The Health Belief Model (HBM) attempts to explain and predict health behaviors by focusing
specifically on the attitudes and beliefs of individuals. The HBM was developed by the social
psychologists, Hochbaum and Rosenstock in the 1950s and extended by Kirscht and Becker in
1974 (Glanz, Rimer, and Viswanath, 2008). The HBM is a psychological model that attempts to
explain and predict behavior. The model contains four constructs: 1) perceived susceptibility, 2)
58

perceived severity, 3) perceived benefits, and 4) perceived barriers. According to this model a
person’s belief in the perceived threat and the perceived benefits associated with an action,
along with their confidence in their ability to achieve the behavior, determines the action the
person will take (Rosenstock et al., 1988). The HBM model’s essential features are illustrated in
Figure 5.

Figure 5: Essential Features of the Health Belief Model of Rosenstock, et al. (Modified from Janz
& Becker, 1984)

Since the introduction of the Health Belief Model it has been adapted to explore how various
forces affect an individual’s behavior in a variety of situations. We would propose that the main
tenet of this model; that behaviors are motivated both by perceived threats and outcome
expectations could fit readily as an expansion of the “Interpersonal” domain in the Social
Ecological Model. By using these models in the present study we will explore the beliefs that
investigators have about the CTA, and further attempt to understand the range of factors that
may affect their beliefs and behaviors. By using such a systematic approach, we anticipate that
59

the data reported here might be useful to identify not only the extent to which some
investigators understand and read the CTA, but also why those particular behaviors are in
evidence.

Data related to the investigators' knowledge, experience and perception of the CTA will lay the
foundation from which to understand if investigators are participating in the development and
review of the CTA. We postulate that such participation is relatively underdeveloped and that
barriers may exist both within the attitudes of the investigators and in the way that they are
influenced by the institutional culture and policies around them. Such insights might help to
identify barriers that prevent the inclusion of American academic investigators in the CTA review
and negotiation process and may suggest ways in which these barriers can be reduced where
appropriate.

60

Chapter 3: Methodology

3.1 Introduction

The purpose of this study is to explore current practice on investigators related to the CTA,
including: 1) to explore the attitudes and knowledge of investigators with regard to the CTA, and
2) to collect information on the extent of their involvement in the review and negotiation of the
CTA. We will in the course of this work also explore any disincentives and barriers that in the
view of the investigators prevent them from being a key party in the management and approval
of the CTA.

3.2 Development of Survey

Questions were developed based on the information gleaned from the literature review,
discussions with academic professionals, and the elements of the frameworks chosen to
improve comprehensiveness of the survey. The survey tool consisted of 30 questions in a variety
of formats including single answer, multiple-choice, Likert scale, yes/no, and open- ended text
questions. The survey was constructed to facilitate participation and enable completion in a
reasonable amount of time (15 – 20 minutes).

Section 1 included demographic and background questions that characterized the responding
investigator and his/her institution. Questions in section 2 explored the culture of the
environment, the nature of affiliations, and the perceptions of the investigator with regard to
the forces that provided external barriers if any, during the development and negotiation of the
CTA. Bodenheimer’s (1979 ) Social Ecological Model framework was used to assist in structuring
questions in section 2. Questions in section 3 were concerned with the knowledge and attitudes
of the investigator. The Health Belief Model developed by Rosenstock, et al., (1988) was
61

referenced to frame these questions. The final section of the survey explored the level of
involvement of the investigator with respect to the process of reviewing, negotiating, and
signing the CTA.

A focus group of ten experts was convened to assist the researcher by providing feedback on the
design of the investigator survey and the formatting of questions to maximize the effectiveness
of the survey and the response rate. The focus group consisted of qualified experts with an in-
depth knowledge of human subject research and the CTA process and/or the construction of
survey instruments. The focus group was held on May 14, 2013, at the University of Southern
California, health science campus. With the exception of one member, who joined via the
interactive electronic platform, WebEx (webex.com) all focus group members attended in
person. Group members were composed of both academic and non-academic professionals
including regulatory science professors, regulatory administrators, research management
organization professionals, human subject protection executives, and a contracts attorney.

3.3 Survey Deployment

The survey was delivered using Qualtrics (http://qualtrics.com), a web-based platform that can
both send the survey to respondents and assist in the collation and analysis of responses. Web-
based distribution allowed us to improve the speed with which we were able to recruit a broad
sampling of the study population, geographically dispersed across the continental US.

The survey was checked for its integrity and usability by sending it to a group of individuals who
were associated with the administration of the University of Southern California Regulatory
Science doctoral program. It was then disseminated to potential respondents in three phases.
62

Initially, the survey was sent to colleagues identified by the members of the focus group and the
researcher. The second phase of the survey distribution was to investigators at the 63 academic
institutions that received Clinical and Translational Science Awards (CTSA) from theNIH,
investigators identified through professional societies such as the CenterWatch, the Association
of Clinical Research Professionals (ACRP) and the Regulatory Affairs Professional Society (RAPS).
The third phase included investigators identified through the clinicaltrials.gov website. As part
of the survey we requested that respondents identify colleagues who they whom they know.
These additional individuals (n=7) were emailed the survey in the second and third phases of
dissemination.

The survey was open for responses from June 1 – July 26, 2013. The target population was
investigators with experience conducting industry-sponsored trials requiring a CTA. To be
included in the survey, respondents were required to have at least two years of experience in
conducting industry sponsored trials and to be currently conducting industry sponsored studies.
Some respondents were selected using the snowball technique, where respondents were asked
to recommend others. This technique helped to increase the diversity of the participant
population. Individuals were contacted by email requesting their assistance and willingness to
complete the survey or to pass the survey on to investigators they know. The electronic link for
the survey was included in the email request. The first question of the survey asked the
respondent if they conduct or have conducted industry-sponsored clinical trials. If the
respondent answered no, the program took the respondent to the end of the survey and
thanked them for their time. The second question identifying years conducting industry -
sponsored studies also routed those with less than two years of experience to the end of the
survey. Individuals were assured of anonymity if they participated.
63

Follow-up reminders were sent to the various panels of respondents reminding them that if they
had not responded to please consider responding. At least one follow-up reminder was sent to
each member on each panel.

In addition messages and blogs were posted on multiple professional group forum sites from
which no responses were received. Surveys requests were sent to investigators, research
directors/managers, and study coordinators. Non-investigators were asked to forward the
survey to investigators.

3.4 Data Analysis

After data were captured, survey responses from individuals who answered fewer than 70% of
the questions were removed. Questions that had continuous data such as those from Likert
scales were inspected for normalcy. The Qualtrics software system automatically calculates
statistical data such as percentages, counts, minimums, maximums, standard deviation, variance
and means. Many questions such as those with yes/no answers could not be collated with
statistical methods and were reported graphically.

Where data is presented in a Table or Figure, shading of the most common answer(s) is used to
direct the reader.
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Chapter 4: Results

4.1 Focus Group

The 90-minute meeting of the focus group had two phases. In the first phase, I presented an
overview of the research study and then introduced the study survey. The discussion during this
phase focused on the nature of the study population to which the survey would be
administered. The committee recommended that the survey be expanded beyond the initial
target group that was limited to academic investigators, to include non-academic investigators
such as those working in practice-based, non-academic hospitals, and clinical research
organizations.

In the second phase, the committee considered the format and wording of questions in the
survey. Focus group members recommended changes to the wording of multiple questions to
improve clarity and to make the questions more suitable for a respondent group that included
both academic and non-academic respondents. Members suggested additional questions that
they believed would enhance the depth of information collected regarding the clinical trial
agreement process. Finally, the committee discussed the avenues for the distribution of the
survey that might improve its response rate. The survey was then revised to incorporate the
useful suggestions. The initial and final survey, reflecting the changes, can be found in Appendix
B and Appendix C.

4.2 Analysis of Survey Respondents

The survey was sent to 783 individuals throughout the U.S. Respondents to the survey were
asked to provide names of investigators who they thought might complete the survey. However
65

in this study very few respondents provided the names of colleagues, so that such referrals
accounted for only about 5% of the surveys sent. Responses were received from 167
individuals, yielding a response rate of 21%. Surveys of respondents who did not meet the
inclusion criteria, respondents who did not answer any of the questions, and respondents who
only answered the background questions were removed from this group, so that the analysis
reported here was based on complete or near-complete submissions from 127 respondents.
Respondents who only answered the background questions and were eliminated from analysis
had similar backgrounds to respondents who completed the survey. Of the qualifying
respondents, the majority (72%) had more than ten years of experience conducting trials. The
remaining 28% had 2 – 10 years of experience. Seventy percent of the respondents were
investigators and the remaining 30% stated that they had other roles such as research
directors/managers, contract office personnel, and study coordinators (Table 2).

Table 2: Roles of other respondents

Manager (9) Study Coordinator (8)
Director (11) Operations
Site PI President
Sub-Investigator (2) Site
Business (2) CEO of site
Both, Chair of Executive and Steering
Committee, DSMC member

Respondents were employed by a variety of academic or non-academic organizations; 34% were
from academic institutions (universities and university affiliated hospitals) and 66% from non-
academic institutions, including practice-based organizations, clinical research organizations and
others described in the text box below (Table 3).
66

Table 3: Other organizations

Community Hospital
Research department of hospital
Private Research Center
Dedicated Research Site with 3 private practices for 3 PI's to use
department in multi-specialty group practice
independent research facility
SMO working with practice based physicians
Private Research Organization
Dedicated Research Facility
I work as an admin leader in a university system that includes hospital and practice
Dedicated Research Site
Free standing research sites with affiliated physicians practices
DEDICATED RESEARCH FACILITY
private research center
Private specialty hospital
free standing clinical research site
privately owned research site
Dedicated Research Facility

Respondents were asked to identify the types and phases of clinical study in which they were
involved. Almost all of the respondents (96%) conducted drug/biologic studies and 58%
conducted device studies. Vaccine and non-therapeutic/diagnostic studies were conducted by
31% and 29% respectively (Figure 6). Other types of studies conducted by respondents included
naturalistic/observational, chart review, health and patient outcomes, cosmetic, and
mechanistic studies.
67

Figure 6: Types of studies conducted by respondents.

Respondents could identify more than one category so that totals exceed the number of
respondents (n=127).

Drug/Biologic (96%)

Device (57%)

Vaccine (30%)

Non-Therapeutic/Diagnostic (29%)

Gene Therapy (8%)

Other (5%)

Stem Cell/Human Tissue (6%)

0 20 40 60 80 100 120 140

Most respondents conducted multi-center studies. More than half conducted early stage and
post-marketing studies and nearly half conducted investigator-initiated studies (Figure 7). The
distribution of responses suggested that many respondents had participated in more than one
phase of study. This pattern was also apparent in text responses in which respondents
identified that they were involved in multiple types of studies.
68

Figure 7: Study phases conducted by respondents.

Respondents could self-identify in more than one category (n=126).

Multi-Center Trials (84%)

Early Stage/Feasibility (59%)

Post-Marketing (59%)

Investigator-Initiated (47%)

Multi-phases (6%)

Animal Studies (2%)

0 20 40 60 80 100 120

Almost 50% (n=114) of the respondents reported belonging to a professional organization that
had held a session on CTAs in the last five years. Fifty-five percent (n=113) of the respondents
reported that they would attend a session on CTAs if one were offered at a professional
meeting.

4.3 Analysis of Organization and Environmental Factors

The majority of the respondents identified either the research director/manager (40%) or the
contracts office (27%) as the entity that manages the CTA process at their site (Table 4, shaded
cells). Only 9% of the investigator respondents reported that they were responsible for the
management of the CTA. A small number (11%) selected “other” as a response option and
these responses are found in Table 5.
69

Table 4: Who manages the clinical trial agreement at your organization?

Response Number Percent
Director/Manager of Research 52 40%
Contracts Office 35 27%
Other 14 11%
Investigator 11 9%
Study Coordinator 9 7%
Legal Office 3 3%
Central Administration 3 3%
Total 127 100%

Table 5: Who manages the CTA, identified as ‘other’?

Division and CTO
Director
Site Manager
Budget/Contracts Manager on site
Financial Coordinator
Clinical Research Organization (this is changing though)
Our entire team reviews, with the director having final say.
Both investigator and staff
Chief Operations Officer
Our Medical Director is the PI on most studies
Various stages are reviewed by different entities, then discussed and then legal comes into play
At my institution it is carried out by a combination of the investigator, manager of clinical research activities and
research administrator
CEO

Most of the respondents reported that their organization was able to review, negotiate and sign
the CTA within three months. Almost 60% (n=115) of this subset completed the process within
one month and an additional 25% completed the process within 2 -3 months.
70

Respondents were asked to rate their organizations by identifying the degree of agreement or
disagreement with certain statements about their organization. Respondents generally
indicated a high degree of support and capability with respect to the ability of the
organization/employer to deal with CTAs. Almost 90% felt that their organization was capable
of negotiating a fair and balanced CTA. Fifty-six percent reported that their organization
provided training and resources to help them understand the CTA. Over 60% reported that their
organization involved them in the review and negotiation of the CTA. A majority (77%) also
believed that the organization addressed potential issues in the CTA, and 80% felt their
organization was able to deal effectively with issues when they arose. Sixty-five percent agreed
that their organization is able to complete the review, negotiation, and signing of the CTA in a
timely manner (Figure 8).

Figure 8: “Please rate your organization/employer on each of the following items”.

Note that the numbers rather than percentages are listed in each category of answer.

Question
Strongly
Agree
Agree
Neither
Agree or
Disagree
Disagree
Strongly
Disagree
Do not
know
Total
Can complete the review/
negotiation of a CTA in a
timely manner that does
not delay study.
51 23 12 9 18 1 114

51 24 12 9 18 1 115
Can review/ negotiate a fair
and balanced CTA.
48 56 4 3 5 0 116
Deals effectively with
contract issues when they
arise.
44 49 10 4 7 2 116
Anticipates and addresses
potential CTA issues
41 49 13 7 6 0 116
Includes the investigator in
review/ negotiation of the
CTA.
36 36 14 16 14 0 116
Provides investigators with
resources and training to
understand the CTA.
36 29 18 21 10 1 115

71

When responding to the question, “Are you happy with the process for the review and
negotiation of the clinical trial agreement at your institution/organization?” the majority of
respondents (68%; n=114) reported that they were happy with how their organization managed
the CTA. Twenty-one percent reported they were not happy and 11% were not sure.

4.4 Respondent Attitudes and Perceptions

Survey questions probed respondent attitudes and perceptions about the importance of the
CTA in their conduct of clinical trials. Survey participants were asked about the importance and
ownership of responsibility for the CTA. Almost 70% of the respondents thought the CTA was
as important as the informed consent document (69.8%) and the study protocol (67%); 92%
believed the CTA was important for the resolution of conflicts with sponsors (Figure 9).
Responsibility for the CTA was considered by most to be the responsibility of their
organization/employer.

Figure 9: Investigator perceptions regarding the importance of the CTA

Neither
Agree
nor
Disagree

Question Strongly Agree

Disagree
Strongly
Disagree
Total Responses
Agree
As important to the study
as the informed consent.
42 39 16 16 3 116
As important to the study
as the study protocol.
33 44 14 19 5 115
The responsibility of my
organization/employer.
38 45 19 7 5 114
Important to resolve
issues and conflicts.
50 55 7 2 0 114

Respondents were also asked to rank statements related to their role in the management of the
CTA at their organization. Almost 80% reported that it was important for them to be involved in
the review and negotiation of the CTA and that their involvement might prevent or reduce
72

contract issues. The majority (60%) reported that their organization encourages their
involvement in the negotiation of the contract and almost 55% reported that they are allowed
to edit the CTA. Almost 80% respondents felt confident in their institution’s ability to negotiate
CTAs (Figure 10).

Figure 10: Do you agree or disagree with the following statements?

Question
Strongly
Agree

Agree
Neither
Agree nor
Disagree

Disagree
Strongly
Disagree

Total
In my role it is important for me
to be actively involved in the
review and negotiation of the
CTA.

56

35

14

8

2

115
My involvement in the CTA
process may prevent or reduce
contract issues.

47

40

15

11

2

115

My organization actively
encourages me to be involved in
the negotiation of the contract.

44

25

22

14

10

115
I feel empowered by my
institution to edit the clinical trial
agreement.

34 28 27 16 9 114
I feel confident in my institution’s
ability to negotiate the CTA.

54 35 14 8 3 114

When probing whether the investigator was comfortable reviewing and negotiating a CTA, 44%
responded they definitely would be comfortable and an additional 20% thought they probably
would be comfortable. Twenty-five percent reported that they probably or definitely would not
feel comfortable reviewing and negotiating the CTA (Figure 11).
73

Figure 11: Would you feel comfortable reviewing and negotiating a clinical trial agreement?

Type of Institution

Academic Non-Academic Total
Would you feel comfortable
reviewing and negotiating a
CTA?
Definitely Would 8 43 51
Probably Would 8 15 23
Maybe Would/Maybe Not 6 7 13
Probably Would Not 11 6 17
Definitely Would Not 5 5 10
Total 38 76 114

To evaluate current practices several questions asked respondents about the degree of
participation and perceptions of the CTA by colleagues. Most respondents (67%; n=70) believed
that their colleagues were actively involved in the CTA process at their organizations.
Respondents were given the choice of four items that might describe their colleagues’ attitudes
when dealing with a CTA. A little over one-third believed their colleagues to consider their
involvement in the CTA as an important and useful process. Almost 40% believed that their
colleagues felt that dealing with the CTA was a necessary but unsatisfying activity. Relatively few
(5%) thought that their colleagues regarded the CTA as a negative experience. Almost one-
fourth thought that their colleagues trusted the management of the CTA to their organization
(Figure 12).
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Figure 12: Attitudes of colleagues to the CTA

“In your best judgment, which choice below best describes the most common attitudes of your
colleagues with respect to their personal involvement in the review and negotiation of the
Clinical Trial Agreement?”
Answer Response %
An important and useful activity 39 35%
A necessary but unsatisfying activity 43 38%
A negative experience that they would prefer to avoid 5 5%
An exercise that they trust to their organization to
manage

25

22%
Total 112 100%

Survey respondents were asked to rank individuals/groups based on the degree to which the
individual/group influenced the investigator’s understanding or management of the CTA. The
organization/employer was ranked as the primary influence by almost 42% of the respondents.
The contracts office was ranked the primary influence by 18% and the research office by 16% of
the respondents (Figure 13).
75

Figure 13: Influences on the investigator’s capabilities with respect to the CTA

“Please rank the following individuals/groups according to the influence that they have had on
your understanding or management of the clinical trial agreement.”
Answer 1 2 3 4 5 6 7
Total
Responses
Organization/Employer 44 23 21 12 5 2 0 107
Professional
Organization
4 16 14 20 28 23 2 107
Legal Entity 14 13 24 22 20 11 3 107
Research Office 18 20 16 26 17 10 0 107
Contracts
Office/Individual
19 23 18 17 18 11 1 107
Peers 6 11 13 10 19 46 2 107
Other 2 1 1 0 0 4 99 107
Total 107 107 107 107 107 107 107 107

Respondents were also requested to provide information on the professional organizations or
other entities that served as the most common resource for their understanding of the CTA
(Table 6). Of the respondents, Society of Clinical Research Sites (SCRS), Association of Clinical
Research Professionals (ACRP), American Society of Clinical Oncology (ASCO), and Model
Agreement and Guideline International (MAGI) were common answers, but no one organization
was viewed as the most important resource by a majority of respondents to this question.

Table 6: Professional organization used by investigators to understand the CTA

MAGI (Model Agreements & Guidelines
International) (2)
ASCO (American Society of Clinical Oncology) (2)
SCRS (Society of Clinical Research Sites) (5) DIA (Drug Institute of America), ACRP, SOCRA
Took a contracts course at Notre Dame SOCRA (Society of Clinical Research Associates)
ACRP (Assn. of Clinical Research Professionals) (5) Radiant Research SMO
American College of Neuropyschopharmacology My own research
NCCN (National Comprehensive Cancer Network) Cancer Center
Study team training We do not use any of the above groups
None of them

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One-third of the respondents felt that it would not be a serious problem if others negotiated the
CTA without their input. However, 43% believed that it would be problematic to let others
manage the CTA without their input (Figure 14).

Figure 14: Investigator perception of non-inclusion in the CTA Process

"How problematic do you think it is to let others negotiate and manage the clinical trial
agreement without your input?”
Answer Response %
Not Serious 12 10%
Somewhat Serious 21 18%
Neutral 32 28%
Serious 28 24%
Very Serious 22 19%
Total 115 100%

Survey participants were asked what they thought was the worst thing that might happen if they
let the organization/employer negotiate the clinical trial agreement without their input. Eighty-
eight survey participants responded to this open-ended question. An analysis of trends in
respondent answers identified the top five issues shown in Table 7. Full responses to the
question are shown in Appendix D.
77

Table 7: Responses Grouped by Principle Issue

"What do you think is the worst thing that might happen if you let your organization review and
negotiate the clinical trial agreement without your input?"
Response
Budget Issues/Funding: Person(s) negotiating the contract may not be familiar with the study procedures, fees for
procedures, nature of the research, and thus may not negotiate a budget that covers all study costs.
The person(s) negotiating the contract does not read the protocol and may not cover everything needed; he/she
may promise deliverables that are not reasonable or achievable.
Person(s) negotiating the contract does not know which procedures should be charged to standard of care and
which to research, creating legal problems if incorrectly charged or double-billed.
Negotiator takes too long, or queries too many details.
Negotiator cannot know the nuances of clinical research, what clinical research entails, and the many different kinds
of research and is not able to address all the components of clinical trials.

Eighty-four respondents provided comments to the open-ended question, “What do you think is
the best thing that might happen if you let your organization/employer negotiate the clinical
trial agreement without your input?” The most frequent responses suggested that the process
might be quicker and that the people handling the contract might be more effective because of
their greater familiarity with contract issues. Some respondents suggested that it might
decrease the amount of time and/or work or paper work for the respondent. (Full responses are
collated in Appendix E)

Respondents were asked about their mood when dealing with a typical CTA. A little over one-
third (n=113) described their mood as being confident when dealing with clinical trial agreement
activities. About an additional one-third reported that they felt satisfied and 14% reported their
mood as being confused. Twelve percent reported that they do not deal with the CTA (Figure
15). Additional comments included: confident, but stressed; frustrated; frustrated with the lack
of infrastructure support; and placid.
78

Figure 15: Investigator mood when dealing with CTA

“When I participate in activities related to the review and negotiation of the clinical trial
agreement my best description of my mood is”: (n=113).

Confident (34%)

Satisfied (32%)

Confused (14%)

Upset (3%)

I do not deal with the CTA (12%)

Other (5%)

0 5 10 15 20 25 30 35 40 45

4.5 Investigator Engagement in the Clinical Trial Agreement Process

The majority of the respondents reported that they review the clinical trial agreement before it
is finalized. Thirty-one percent sign the CTA as a party to the agreement and, 45% sign the CTA
to acknowledge their responsibilities as the investigator (Figure 16).
79

Figure 16: Do you sign the clinical trial agreement (n=114)?

As a Party to Agreement (31%)

Investigator Acknowledging Responsibilities (45%)

Do Not Sign (24%)

0 10 20 30 40 50 60

Respondents were provided the following nine options (Figure 17) and asked if they had
experienced a problem or conflict with any of the items when working with a sponsor:

About 80% of the respondents reported having at least one problem with the sponsor. Over 50%
reported problems with either funding/study payment or budget negotiations. Almost 20%
reported a problem with patient injury language (Figure 17). Ten percent listed other problems
including indemnification, conflict of interest, adverse/serious adverse event reporting, and
indirect rates (Table 8).
80

Figure 17: Have you had a negative experience/conflict with a sponsor in the following areas?
(Multiple answers permitted.)

Publication (7%)
Confidentiality (2%)
Access to Data (6%)
Funding/Payment (50%)
Intellectual Propertu (6%)
Patient Injury Language (19%)
Budget Negotiations (54%)
None (28%)
Other (9%)

Number 0 10 20 30 40 50 60 70

Table 8: Conflicts with sponsors: conflicts identified as “other” in text box.

Indemnification
Conflict of interest issues
Indemnifications
Indemnification agreement wording
All of the above Indemnity issues between sponsor and institution
Indemnification Indirect rate
AE/SAE reporting/assigning causation
Indirect rate

4.6 Investigator Knowledge

To evaluate the investigator’s knowledge of the CTA, respondents were asked to check all items
that they would find in a CTA from a list of 15 options (multiple answers permitted). All of the
listed items were identified to belong in a CTA by a majority of respondents with the exception
of the investigator brochure. Only about one-third (35%) of the respondents believed that the
investigator brochure should be included. Nevertheless 35% selected all of the given options
(Figure 18). Two respondents checked “other” and added indemnification, audit terms,
archiving, and intellectual property rights to the list of included elements.
81

Figure 18: Items in CTA identified by investigators

“As you reflect back, to the best of your knowledge clinical trial agreements for your studies
addressed the following items”:
Response Number Percent
FDA Code of Federal Regulations 69 61%
Subject Safety 72 63%
HIPAA 75 66%
Informed Consent 63 55%
Contract Jurisdiction 77 68%
Payments and Financial Arrangements 94 82%
Liability 90 79%
Insurance 79 69%
Materials/Information to be Kept Confidential 82 72%
Publication 82 72%
Investigator's Brochure 39 34%
Deliverables 63 55%
All of the Above 39 34%
Other 2 2%
I Do Not Know 3 3%

4.7 Additional Respondent Comments

Forty two participants responded to the open-ended question, “Do you have comments about
the way that your institution manages clinical trial agreements?” The most common comments
included (Table 9):

Table 9: Additional comments about the CTA process at institution

Process is slow, inefficient
CTAs protect the institution, not always the investigator
Managed poorly, incompetently
There are too many layers
Extremely time consuming

(See Appendix F for all comments.)
82

Type of Institution

Academic Non-Academic Total
How long does it take for your
organization to review,
negotiate, and sign the clinical
trial agreement?
Within 1 mo. 4 64 68
2 - 3 months 20 8 28
4 - 6 months 10 0 10
> 6 months 7 0 7
I don't know 0 1 1

Other 0 1 1

Total 41 74 115

4.8 Cross-Tabulations

The pool of survey respondents was sub-stratified into two categories so that the responses of
academic versus non-academic investigators could be compared. Academic institutions included
academic/university and university affiliated hospitals. Non-academic institutions included
practice-based, private research centers, CROs, and community and private hospitals. A series of
cross-tabulations were performed to identify differences in their experiences and perceptions.

The first comparison concerned length of time taken to review, negotiate, and sign the CTA.
Results showed that non-academic institutions were generally able to process the CTA in a much
shorter time than their academic counterparts. Less than 10% of academic respondents
reported that their institution was able to complete the CTA process within one month whereas
86% of non-academic institutions appeared able to complete the process within one month.
Close to fifty percent of academic institutions were able to complete the review and negotiation
within 2 – 3 months (Figure 19). Notably, nearly one quarter of academic respondents
suggested that the negotiation took more than 6 months.

Figure 19: Type of institution and time to process the CTA.
The most common answer is indicated by the shaded cell.
83

The degree to which the institution provided training and resources with regard to the CTA
suggested that both academic and nonacademic organizations commonly but not universally
provided resources and training. Most commonly the non-academic respondents “strongly”
agreed, whereas the most common answer for academic respondents was “agree” (Figure 20).

Figure 20: Type of institution against availability of resources

Type of Institution

Academic Non-Academic Total
Organization provides the
investigator with resources
and training to understand
the clinical trial agreement.
Strongly Agree 3 33 36
Agree 16 13 29
Neither Agree nor
Disagree

6

12

18
Disagree 11 10 21
Strongly Disagree 5 5 10

Total 41 72 114

Investigators in non-academic settings rated their organization’s ability to negotiate a fair and
balanced CTA as higher than academic respondents. Of the non-academic respondents 56%
strongly agreed and almost 40% agreed that their organization was capable of negotiating a fair
and balanced CTA. Of the academic respondents 17% and 66% strongly agreed or agreed,
respectively, that their organization was capable of negotiating a fair and balanced contract.
Only 4% of non-academic respondents disagreed that their organization was capable of
negotiating a fair and balanced contract compared to 12% of their academic counterparts
(Figure 21).
84

Figure 21: Type of institution against investigator's belief that organization is capable of
negotiating a fair and balanced contract

Type of Institution

Academic Non-Academic Total
Rate your organization on
their ability to review and
negotiate a fair and
balanced clinical trial
agreement.
Strongly Agree 7 41 48
Agree 27 28 55
Neither Agree nor
Disagree

2

2

4
Disagree 3 0 3
Strongly Disagree 2 3 5

Total 41 74 115

Over 50% of the academic respondents and over 60% of the non-academic respondents
reported that they were included in the review and negotiation of the CTA by their institution.
Nevertheless, only about 10% of the academic respondents strongly agreed that their institution
involved them in the review and negotiation of the CTA, whereas 44% of non-academic
respondents strongly agreed (Figure 22).

Figure 22: Type of institution and includes investigator in the review and negotiation of the CTA.

Type of Institution

Academic Non-Academic Total
Rate your organization on
including the investigator in
the review and negotiation
of the clinical trial
agreement.
Strongly Agree 4 32 36
Agree 21 15 36
Neither Agree nor
Disagree

7

7

14
Disagree 4 11 15
Strongly Disagree 5 9 14

Total 41 73 115

Non-academic investigators (79%) were almost twice as likely to report that they felt
comfortable with the review and negotiation of the CTA compared to academic investigators
(40%), (Figure 23). The most common answer for the academic investigator indicated that the
respondent probably would not feel comfortable.
85

Figure 23: Type of organization against investigator comfort level in the review and negotiation
of the CTA

Type of Institution

Academic Non-Academic Total
Would you feel comfortable
reviewing and negotiating a
CTA?
Definitely Would 8 42 50
Probably Would 8 15 23
Maybe Would/Maybe
Not

7

5

23
Probably Would Not 11 6 17
Definitely Would Not 6 4 10

Total 40 72 112

The majority of non-academic respondents were happy with the handling of the CTA process by
their institution. On the other hand, academic investigators were divided with a higher number
reporting that they were not happy with the way their institution managed their CTAs (Figure
24).

Figure 24: Type of institution against investigator happiness with institution's CTA process

Type of Institution

Academic Non-Academic Total
Are you happy with the
process for the review and
negotiation of CTAs at your
organization?
Yes 17 60 77
No 19 5 24
Not Sure 5 6 11
Total 41 71 112

The majority of both academic (85%) and non-academic respondents (70%) signed the CTA.
Investigators at non-academic institutions signed the CTA as a party to the agreement
approximately 40% of the time whereas only about 20% of academic investigators signed as a
party to the agreement. Instead, 65% of academic investigators signed the CTA as the
investigator acknowledging their responsibilities compared to 33% of non-academic
investigators. Only 15% of academic respondents reported that they did not sign the CTA while
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twice that number (30%) of their non-academic counterparts reported not signing the CTA
(Figure 25).

Figure 25: Type of institution against investigator signature on the CTA

Type of Institution

Academic Non-Academic Total
Do you sign the clinical
trial agreement?
As a Party to the Agreement 8 27 35
As the Investigator
Acknowledging Responsibilities

26

24

50
I Do Not Sign the CTA 6 22 28

Total 40 72 113

About 80% of academic respondents and 86% of non-academic respondents reported that they
had experienced some type of problem with a sponsor related to the CTA. The majority of issues
experienced by both groups concerned funding and budget problems. Reports of other issues such
as patient injury language and access to study data were also similar between the two groups
(Figure 26).

Figure 26: Type of Institution against issues with sponsors (n=114)

Type of Institution
Academic Non-Academic Total
Have you had a negative
experience or issue with
a sponsor in the
following areas? Check
all that apply.
Publication Issues 4 4 8
Confidentiality 1 1 2
Access to Study Data 4 3 7
Funding/Study Payment 10 47 57
Intellectual Property/Patent 6 1 7
Patient Injury Language 8 14 22
Budget Negotiations 20 42 62
None 14 18 32
Other 4 7 10
87

Chapter 5: Discussion

The CTA is a legally binding agreement between a study site and a sponsor that lays out the
foundation of their relationship by defining the roles and responsibilities of the sponsor, site and
investigator. It is one of several important documents that govern the investigator’s conduct of
the study. To date little systematic study has been directed at the nature of the investigator’s
involvement, understanding and perceptions of the CTA. Previous reports have suggested that
the management of the clinical trial agreement rests primarily with the contract or other
research administrative office of an academic medical institution (Schulman et al., 2002; Mello
et al., 2005). In addition some investigators have suggested that clinical trial investigators
underestimate the importance of the CTA (Drazen, 2002), may fail to give adequate attention to
issues that impact subject safety, and the integrity of the research (DuVal, 2003).

To my knowledge, this study offers the first systematic examination of current practices
amongst U.S. investigators in the management of the CTA. The survey data collected here
suggests that some areas of concern exist but the level of engagement by the investigator in the
CTA process is higher than previously suggested in literature. Respondents’ answers to survey
questions also indicate that their level of understanding may be higher than previously reported.

5.1 Considerations of Delimitations and Limitations

The present study was delimited to investigators in the US. It is important to acknowledge this
delimitation because the way that clinical trials are managed from country to country will differ.
Much effort in the past two decades has been directed at reducing these differences through
harmonized ethical, logistical and technical guidelines for safety, quality, and efficacy, largely
88

through the efforts of ICH (ICH, 2013). These efforts have been particularly successful with
regard to the implementation of harmonized Good Clinical Practices and the adoption of
common medical terminologies across various constituencies (ICH - MedDRA, 2013). However,
what often is not harmonized is the way in which authority is structured, personnel are assigned
tasks, and trial agreements are written.

A country that serves to illustrate some of the differences that can exist is Japan. Japanese trials
are typically headed by the medical director of the institution, who bears the burden of the
responsibility for the investigation, according to the Ministerial Ordinance of Good Clinical
Practices for Drugs (2012). Amongst other obligations, the head of the medical institution is
responsible for gaining trial approvals, reporting deviations and adverse events to the sponsor,
IRB and other governing authorities, overseeing the quality and maintenance of records and
related SOPs, and ensuring confidentiality of subjects (Japan Ministry of Health and Welfare,
2012). The study investigator reports to the head of the medical institution. Article 13 of the
Ministerial Ordinance specifies the 17 items that must be included in the clinical trial contract
and what information is required for each item. Thus, in Japan, an investigator does not have
the autonomy that investigators in other countries may have, and this might potentially shape
their views on the questions posed in this survey.

Another country that differs in its logistical organization and oversight of clinical trials is China.
The Drug Administrative Law of the Peoples’ Republic of China (2001) requires that clinical trials
be conducted in qualified hospitals that have been accredited by the China Food and Drug
Administration (http://www/eng.cfda.cn). The majority of accredited institutions are
sophisticated university hospitals located in the densely populated cities of Beijing, Shanghai
89

and Guangzhou. Thus, their investigators are under stronger scrutiny and follow more
homogeneous rules than do investigators in the US, where trials are conducted in a range of
environments both inside and outside of hospitals, and with a range of investigators who have
different levels of experience and oversight.

Because of these local differences, it seemed important to limit this early-stage study
concerning the use of clinical trial agreements to investigators in the U.S. The country-wide
approach was considered to be appropriate because the US clinical trial system is under federal
oversight, so the rules by which it functions tend to be reasonably homogeneous across
different states. However, it is possible that some differences may exist from state to state that
would not be recognized in this survey.

An initial intent of the research described here was to delimit the study to academic
investigators. However, the members of both the dissertation committee and focus group
suggested that a better understanding of US practices might be gained if the survey was
distributed to two subgroups of investigators, those who worked in academic institutions and
those who worked in non-academic environments. By acting on this suggestion, it was possible
to compare the responses of the two groups, who indeed appeared to differ in their answers to
certain questions. Of the 127 respondents, 34% represented academic institutions and 66%
non-academic organizations. We might question whether this distribution is representative of
the distribution of the population of US investigators conducting industry-sponsored studies as a
whole. The proportion of industry funding awarded to academic institutions has been reported
to be as high as 40% (Bodenheimer, 2000; Davidoff et al., 2001) and as low as 26% (Goldfarb,
2006). The 34% response rate for academic investigators falls in between the previously
90

reported percentages leading us to believe this sampling distribution may be fairly
representative of the two groups.

A limitation of any study using survey methods is that of reaching the right respondent
population. The type of survey used and the sampling method to obtain respondents can
introduce selection bias (Atkinson and Flint, 2001; Sadler et al, 2010). “Online surveying has
become very popular with the advent of Survey Monkey™, Zoomerang™, and other survey
software. This software allows for the quick and easy creation and administration of online
surveys…” (US Geological Survey, 2013). Email surveys also have the ability to reach a large
pool of participants and to assist in the subsequent data analysis (Atkinson and Flint, 2001;
Hulley et al., 2001; Sadler et al., 2010; Heckathorn, 2011). A disadvantage is that of potential
selection bias and challenges of external validity - the ability to generalize from the studied
subpopulation to the study population (Atkinson and Flint, 2001). Generalization may be
problematic, for example, if only certain respondents have an email address, access to the
internet, and technical proficiency on the computer (USGS, 2013). However, the growth of
electronic communications and access to the internet over the last decade has continued to
increase the use and acceptability of electronic surveys (Reitz and Anderson, 2013). Such issues
appear to be of greater concern when surveying the general population than a highly educated
and specialized subpopulation such as that composed of physicians. Medical doctors who
conduct clinical trials typically have a high level of technical proficiency not only in research but
also in the use of electronic medical records, computerized medical procedures, and day-to-day
electronic communication. Thus, it seems unlikely that individuals in this profession do not
possess the tools or skills required to complete an email survey.
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Email surveys also have other limitations. For example, a disadvantage that was experienced in
this survey was the use of spam filters by many email systems. This limitation had been identified
in previous studies so that care had been taken in the wording for the subject line of the email to
minimize the chance that the email would be identified as spam by the computer. Nevertheless,
when following up with investigators who had not responded to the survey request, several
indicated that the survey was found in their spam box. Another concern was the possibility that
individuals could have multiple email addresses and might receive the survey more than once.
Due to the anonymity of the survey it would be difficult to identify a respondent who submits
more than one response to the survey. Nevertheless, the email address chosen to distribute the
survey was the investigator’s listed professional address and the survey was sent only to this
email address, to minimize the chance that an individual would complete the survey multiple
times. Given the challenges of obtaining a response even once from many investigators, and
that the biggest challenge of email surveys is the ability to assure a good response rate (USGS,
2013), it seems unlikely that an investigator would expend the added effort to respond to this
survey more than once.

In any survey study, it is anticipated that responses will not be supplied by all of the applicants
who are polled. It is a particular challenge to identify and secure the assistance of health care
professionals who are typically busy and hard to reach (Bhattacherjee, 2012). Thus a variety of
strategies as discussed above were selected in order to reach investigators throughout the U.S.
and provide a representative sample of the study population. Snowball sampling techniques
were used to identify potential respondents who met the criteria, by gaining the assistance and
recommendations of professional colleagues, respondents who had already completed the
survey, members of the dissertation committee and participants in the focus group. The
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snowball method is useful to identify respondents who might otherwise be hard to reach.
Further it was hoped that recommendations from known associates might encourage the
participation of these respondents and thus would help to increase the response rate.

Snowball methods have already been acknowledged widely to have the advantages of
efficiency, low cost, ability to identify individuals with the desired traits, and ability to access
hard-to-reach populations (Sadler, Lee, Lim, and Fullerton, 2010; Heckathorn, 2011). However,
snowball methods have also been criticized because they challenge to ability to draw a sample
randomly from the target population. The sample depends on the subjective choices of those
first contacted who then provide additional respondents who are related to one another in ways
that might lead to more similar views on the questions in the survey (Atkinson and Flint, 2001)
and over-represent individuals with the same characteristics (Sadler et al., 2010). It may slant
the survey toward investigators who are more active in the field, more interested in the topic,
and perhaps more knowledgeable about clinical trials and their associated logistical activities.
This problem might be especially significant if many respondents recruited members of their
immediate peer group to the study. It is not possible to guarantee that the respondents polled
here are truly representative of principal investigators overall. However in this study very few
respondents provided the names of colleagues, so that such referrals accounted for only about
5% of the surveys sent. Based on the low numbers of such referrals, it is unlikely that they
introduced a major bias into the study. Further analysis of the geographical and backgrounds of
the respondents showed that they spanned across the US and worked in a variety of research
organizations. This is considered important to assure some level of generalizability to the overall
study population. Nevertheless the possibility cannot be discounted that, individuals who
believe that the issue is relevant or important might be more likely to respond (Bhattacherjee,
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2012). These respondents might be more knowledgeable about the CTA than might other
investigators who declined participation. The breadth of responses regarding knowledge and
attitudes did not appear to support the presumption that the respondents were all exceptionally
knowledgeable or that they were unusually experienced in the field, but it was not possible to
explore this potential bias in depth.

Another approach that was used to make the selection process more random was to recruit
some respondents through other channels. The identification of additional potential
respondents was aided by websites such as clinicaltrials.gov which provides information on all
studies conducted in the U.S., and CenterWatch which provides information on studies
conducted by clinical sites of its members. Over 500 potential respondents were identified
using these types of networks. In addition, messages summarizing the study and requesting
help in identifying appropriate investigators were posted on discussion forums of professional
organizations such as the ACRP, the RAPS, and appropriate LinkedIn groups. These methods
however did not produce additional respondents. It seemed clear at least for this population of
respondents that more personalized messages and recruitment based on references from
colleagues were central in gaining the trust and time of these difficult to reach individuals.

Short surveys are known to elicit higher response rates (Bhattacherjee, 2012). It generally took
respondents to this survey less than 10 minutes to complete and this may have also ensured that
few participants failed to complete the survey once it had been opened. In addition non-
respondents were sent a follow-up request in an effort to increase response rates. Although the
anticipated target population for this research was expected to be investigators, links to the
electronic survey were also sent to research managers/directors, coordinators and individuals
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listed as a study contact in an effort to reach additional investigators. It was anticipated that
these individuals would refer the survey to the principal investigator. Thus it was surprising that
30% of the respondents to the survey identified that they played roles other than that of an
investigator but appeared to feel capable of answering the survey questions. The roles of these
individuals included CEO, research director/manager, and study coordinator. It is not unusual in
the US for significant responsibilities in a study to be delegated to additional team members.
These respondents are typically involved actively in the conduct of the study and are familiar
with the CTA process. The teams that conduct clinical trials are usually quite small, and
communicate extensively, so the assumption was made that these individuals were capable of
providing answers not greatly different from those of the principal investigator.

Of the 167 responses received, 127 were deemed acceptable for analysis. The surveys removed
from analysis include those who did not complete at least 70% of the questions or opened the
survey and submitted it without responding to any questions. A review of the respondents who
answered background questions but were eliminated showed that they had similar backgrounds
to those who completed the survey. There is no way to know whether those who did not failed
to complete the survey did so because of the time commitment, lack of interest, or lack of
knowledge.

The fact that the survey was anonymous may have helped in increasing the response rate and
assuring that the respondents felt safe to express their views honestly. An advantage to this
type of survey methodology is that the respondents do not have direct contact with an
interviewer and therefore are less likely to be affected by interviewer bias. However, an email
survey has the disadvantage that the feedback from individual respondents cannot be sought
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using other means to gain more detailed information. If the survey were to be followed up with
a secondary study using interview methods it might be possible to extend the amount and depth
of data reported here, but that might have been too onerous for respondents to provide in
written form using text boxes.

5.2 Consideration of Results

It has been more than a decade since Schulman and colleagues (2002) surveyed the practices
and perceptions of the CTA process by academic institutions engaged in industry-sponsored
clinical trials. That previous survey was directed at a rather different respondent group,
specifically academic contract administrators, whose names were requested by the investigators
by contacting 122 US medical school research offices (Schulman et al., 2002). Respondents to
the survey were asked questions regarding provisions and best practices related to data
collection, monitoring, authorship of publications for multi-center studies, access to data, right
to publish, and confidential rights that might affect publication of results (Schulman et al., 2002).
This survey noted in its discussion that “academic institutions rarely ensure that their
investigators have full participation in the design of the trials, unimpeded access to trial data
and the right to publish their findings”. However, it is silent on the actual role played by the
investigator in the process of drawing up and negotiating the CTA. A reader who inspects this
survey might be led to believe that the principal expert and negotiator is the academic
administrative office. Goldfarb (2004) reinforced this view in a later publication by stating

“In large, sophisticated research centers, the investigator often sees only the signature
page of the agreement. In the small, unsophisticated sites…, investigators generally do
not read the CTA, and do not understand much of what they do read”.
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Significantly, findings from the survey described in this dissertation suggest that investigators
are involved more actively in the review of the CTA and have a better understanding of the CTA
elements and processes than the previous studies might suggest. This survey further suggests
that the administrative environment, including the role played by the investigator, may be quite
different in many facets between the academic and nonacademic site. Of particular interest for
discussion are several areas related to the attitudes, understanding, and role of principal
investigator in the CTA process. These include:

1. Their level of engagement in the review and negotiation of the CTA,

2. Their knowledge and understanding of the CTA,

3. The issues/problems experienced by investigators related to the CTA, and,

4. The environmental factors affecting their involvement in CTA development and
negotiation.

5.2.1 Engagement in the CTA Process

The degree of investigators’ engagement in the CTA process appeared to be perhaps the largest
element of inconsistency with respect to previous literature. A consistent theme in the limited
previous literature available on this topic was the implication that investigators were largely
disengaged during the contracting process. The statement of Goldfarb (2004) quoted above
implied that investigators do not generally play a significant role in the review and negotiation
of the CTA. Drazen (2002) reinforced this view by stating that “the investigator who actually
does the research is not a direct party to the contract”. Further, Goldfarb refers to a
CenterWatch survey (2003) showing that sites typically do not review the CTA before signing
(Goldfarb, 2004). It is tempting to explain these observations as a feature of a different time in
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history from which the clinical trial enterprise has since progressed. However, a recent survey of
industry subscribers to the journal Applied Clinical Trials resulted in 534 completed
questionnaires that together also suggested that CTAs are still mostly managed by internal
administrative staff (Rijswijk-Trompert, 2012). It was therefore surprising that so many
investigators in the present study identified that they did review and sign the CTA before it was
finalized. When queried about their colleagues’ involvement in the CTA process, both academic
and nonacademic respondents believed that their colleagues were also actively involved in the
review and negotiation of the CTA at their institutions and they believed it was important for
them to be involved in the process. Academic respondents reported that they signed the CTA at
a somewhat higher rate (85%) than their nonacademic counterparts (70%). Nonetheless, the
majority of both groups also characterized their active engagement in the process as important,
and expressed the view that this involvement could prevent or reduce contract issues. Results of
the present study suggest that investigators have become much more involved in the CTA
process and are being included more commonly in the review and negotiation of the CTA now
than when most of the papers above were written (Drazen, 2002; Schulman et al., 2002;
Goldfarb, 2004).
Even though the majority of individuals did sign the CTA, a quarter of the respondents reported
that they did not, for reasons that are not yet clear. Upon further review of these respondents,
nonacademic investigators (30%) were twice as likely not to sign compared to academic
investigators (15%). It would be of interest to conduct a follow-up study of investigators who did
not sign contracts to see whether this reflects a specific institutional practice or a lack of interest
in the process on the part of the investigators. It would be interesting to compare the number
and type of issues experienced by sites where the investigators had strong feelings about the
importance of active involvement compared to sites where they are not. In addition, it would
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be helpful to explore in more depth the training received by the administrators and the
investigators in sites where investigators were involved or not involved.

The importance of investigator involvement in the CTA process has recently been
acknowledged. For example, Rijswijk-Trompert (2012) discussed the importance of involving all
of the key players in the CTA process in order to draft a well-balanced and successful
agreement. Based on the survey responses here, it would seem that many academic institutions
have in fact begun to develop a more balanced management structure for the CTA between a
triumvirate of key stakeholders - the sponsor, the investigator and the contracts manager.
Over 60% of both academic and nonacademic respondents agreed that their institution
encouraged their involvement in the review and negotiation of the CTA and over half felt
empowered by their institution to edit the CTA. Nonetheless, practices vary. For example,
University of Florida is specific that:

“The parties to the Agreement should be by and between the University of Florida and the
Sponsor. The Investigator as an employee of the university should not be named as a legal party
to the Agreement. We do allow the Investigators to sign CTA’s as Read and Acknowledged if the
Sponsor insists,” (http://research.ufl.edu).

However, when comparing the two groups nonacademic respondents reported they were
allowed to edit the CTA by their institution much more often than did academic respondents
(70% versus 23%). Why this difference in an environment in which non-academic investigators
often feel more satisfied with the process (see below) is not clear.

Is investigator engagement only explained by the trends on the part of institutions to seek their
input? The investigators themselves may also be influential in making the choice to become
involved, for reasons as yet unexplored. It may be, for example, that an increased investigator
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engagement might be a consequence of the increased emphasis on clinical trial transparency
that has made investigator liability associated with clinical trial problems more visible and
threatening. Since the high profile of deaths in early stage clinical trials in 2000-2001, discussed
in chapter 2, active and often sensational media coverage of clinical trial problems has often
placed investigators in an uncomfortable and defensive spotlight. In the last decade as well, the
FDA and NIH have generated promotional materials to educate potential trial participants
about their rights and the risks associated with clinical trials, as reflected by consumer web
pages such as Learn About Clinical Studies (clinicaltrials.gov), Clinical Research Trials and You
(NIH), Clinical Trials Information (Medline® Plus), and Participating in Clinical Trials (FDA). In
addition is the availability of clinical trial registries that have empowered consumers to take an
active role in clinical trial participation. Thus, investigators may see the CTA as a significant
document that will help to protect them from difficult legal consequences. A well-crafted,
comprehensive CTA makes it clear that the trial is well-organized and properly configured in
advance.

This survey does not deny a central role for contract administrators insofar as respondents
generally agreed that the management of the CTA by their institution was effective and
appropriate. On balance the majority of respondents reported that they were happy with their
institution’s management of the CTA. Several comments from respondents identified that the
administrator may be in a better position to understand the legal language of the CTA because
of their greater experience and familiarity with contracts. Other comments suggest that by
letting the institution manage the CTA the investigator is better able to concentrate on
conducting the clinical trial. However, nonacademic respondents appeared to be much happier
with the system compared to the academic respondents. This impression was reinforced by the
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observations that most comments expressing concerns about the institution’s management of
the CTA came from academic respondents. Some of these respondents felt that the contract
staff did not understand fully the logistics associated with conducting clinical trials, the current
system was inefficient, and the process was suboptimal and slow. One academic respondent
noted that the process was broken at his/her institution. Exploring the management differences
at the academic institution as opposed to nonacademic institutions might provide interesting
and valuable insight for improving the process at academic sites. It would be useful to now
conduct interviews with investigators to explore the relative importance of different factors that
might shape their views about participating in the CTA review and negotiation process. It would
also be interesting to conduct a parallel survey of administrators who manage the CTA, in the
manner that was first conducted by Schulman and colleagues (2002), to understand whether the
administrators hold similar views regarding the investigator’s role in the CTA process at their
institution. This might identify whether the attitudes and roles of the administrators have also
undergone a shift or whether the administrators and investigators see the investigators’ level of
involvement differently.

5.2.2 Investigator Knowledge

A particular goal of this survey was to obtain information about the investigator’s understanding
and knowledge of the CTA. The little data available in the literature had suggested that the
investigator’s knowledge and understanding was relatively modest (Drazen, 2002; Goldfarb,
2004). Further, as chapter 2 has identified, very few resources were found during a review of
educational opportunities and resources that would assist investigators to understand what
elements should be included in a CTA. The most common resources found on academic websites
were organization-specific procedures and CTA templates. For example the University of
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Pittsburg site includes procedures, information, CTA template and FAQs; the University of
Southern California site includes proposal preparation, policies, agreement terms and forms;
Johns Hopkins University includes information, model agreements, and policies; and Indiana
University includes a CTA template and Master Agreements.

The level of knowledge of many investigators appeared to be reasonably good, as reflected by
the fact that most survey respondents correctly identified the multiple items that should and
should not be included in a CTA. Nevertheless there were some deficiencies. Of the 15 items
provided in the question, “As you reflect back, to the best of your knowledge clinical trial
agreements for your studies addressed the following items (please check all that apply):” two
options, “the investigator’s brochure” and “all of the above” were incorrect answers, selected
by one-third of respondents. This finding suggests that there is still work to do in helping some
investigators to understand the components of the CTA. However, this survey was not able to
probe further the level of understanding in depth. Further research would be helpful to
determine not only the extent of their understanding of the components of the CTA, but also
their primary source of education about the CTA.

We might speculate that there will be a relationship between the level of knowledge of the
investigator and his or her degree of comfort with regard to reviewing and negotiating a CTA.
The majority of respondents to this survey reported that they would feel comfortable reviewing
and negotiating the CTA. Upon further analysis of these numbers, less than 50% of the academic
respondents reported feeling comfortable compared to almost 80% of nonacademic
respondents. This is interesting because over 80% of both groups indicated they reviewed the
CTA before it was finalized. Again, further surveys looking at the CTA management by academic
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compared to nonacademic sites might shed some light on the review process and why the
comfort level is significantly different between the two. The finding that one-fourth of the
respondents did not feel comfortable suggests this to be an area worth improving through
training and education. Despite the fact that academic respondents’ level of comfort was lower
than that of nonacademic respondents, academic investigators were twice as likely to sign the
CTA compared to their nonacademic colleagues. This may support, at least for academic
investigators, some previous suggestions that investigators sign without reviewing the CTA.

Individuals who did not feel comfortable reviewing and negotiating the CTA also typically
reported fewer issues with sponsors related to the CTA. Why do individuals who do not review
the CTA and would not feel comfortable doing so report experiencing fewer issues? Is this due
to the fact that many issues are handled without their knowledge at the level of the
administrative office, or do other factors account for fewer reported conflicts? This exploratory
survey did not have the ability to answer such questions definitively.

Future research to understand the extent of the investigator’s knowledge of the CTA would be
valuable to identify deficiencies of knowledge or areas that are less understood. This
information could guide the creation of appropriate education and resources for investigators
related to the management of CTAs. It could also guide policy development. It seems clear from
responses to this survey that a significant proportion of investigators are open to learning more
about the CTA. Further the fact that the investigator’s institution and professional organization
were ranked as the most important resources for understanding the CTA suggests that these
organizations would be appropriate avenues to reach the investigators and to disburse
information on CTAs. It is significant that some professional organizations already have sessions
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at their annual meetings regarding CTA management. For example, the Model Agreement and
Guidelines International (MAGI) 2013 West Conference
(www.magiworld.org/events/2013W/program) included a contracts track with multiple sessions
on CTAs. Similar sessions can also be identified by inspecting the agendas of meetings of the
Association of Clinical Research Professionals (ACRP) (http://acrp2013.org.org/conference-
program).

5.2.3 Contract Issues Experienced by Investigator/Institution

Contract issues between investigators and sponsors are well known to be problematic for clinical
trial sites. In 2005, Mello and colleagues reported that 75% of the respondents to the Schulman
survey experienced at least one problem with an industry sponsor in the previous year. In
concordance with reported data from the Schulman and colleagues survey (2002), disputes
related to payments were the most common conflicts experienced by the respondents to this
survey. Other disputes reported by Mello and colleagues (2005) were related to the ownership
of intellectual property (IP), control of or access to study data, content of publications, and
confidentiality of research results. These were all areas identified as often challenging by
Schulman and others (2002). However the relative incidence with which certain types of
problems were reported appeared to vary from the earlier reports. For example, 16% of
respondents to the Schulman and colleagues survey reported disagreements with sponsors
related to publication, and almost 90% considered sponsor revisions to manuscripts
unacceptable (Mello et al., 2005). However, in the present study, issues related to publication
appeared to be less troublesome, and were flagged by less than 10% of respondents. A few
potential explanations may account for this difference. Since the time of the first survey, much
attention has been given to clarifying best practices regarding the handling of publication rights.
104

Issues surrounding the publication of study results have been discussed extensively
(Bodenheimer, 2000; Davidoff et al., 2001; Baer et al., 2004; Mello et al., 2005). Many academic
sites such as the University of Southern California, Johns Hopkins University, Ohio State
University, Purdue University, and others have developed standard policies and acceptable
language regarding publications and data access in CTAs that meet the ICMJE standards for
publication (personal review of university websites). Further, scientific journals have adopted
publication standards from the International Committee of Medical Journal Editors (ICMJE) for
articles that appear in their publications.

An alternative explanation of the reduced number of concerns regarding publication rights might
be that investigators are unwilling for some reason to identify problems than the administrators
in the Schulman survey (Mello et al., 2005). This explanation appears unlikely in the face of
findings that investigators report greater concerns in other areas compared to the survey data
reported by Schulman (Schulman et al., 2002) and Mello (Mello et al., 2005). For example, an
area of concern identified by the current survey respondents almost three times more often
than publication issues were problems with patient injury language. Multiple articles have been
published in the last several years recommending language for the CTA that would ensure that
the sponsor is liable for injuries or death that is related to the study (Leibowitz and Sheckler,
2006; Goldfarb and Regulski, 2008; King and Longmire, 2010). Subject compensation for harm
related to the trial is also covered in the most recent version of the Declaration of Helsinki
(2103) which states, “Appropriate compensation and treatment for subjects who are harmed as
a result of participating in research must be ensured.” This issue was not previously reported in
the aforementioned literature. The greater attention to this issue could be the result of multiple
factors including increased media attention to clinical research, initiatives by the FDA
105

and the NIH to make research more transparent, educational campaigns to educate the public
about their rights and expectations for clinical trials, and multiple well-publicized lawsuits, as
noted above. Of particular relevance may be the increased visibility and frequency of lawsuits
related to harm to patients during clinical trials. Bodily injury and harm claims represent the
most common type of lawsuit related to human studies (Bradford, 2012). The tragic death of
teenager Jesse Gelsinger during participation in a gene therapy trial at the University of
Pennsylvania spotlighted the risks of participating in clinical trials and resulted in investigations
by the FDA and NIH (Kimmelman, 2008). Although settled out of court, this lawsuit and the
follow-up investigations by the regulatory bodies resulted in major changes to the conduct of
clinical trials and were instrumental in increasing visibility of clinical trial problems (Kimmelman,
2008; Steinbrook, 2008).

5.2.4 Environmental/Institutional Factors Impacting the CTA Process

In the discussion above, the results of the present study were compared to results from surveys
conducted in academia. No similar surveys could be found relating to clinical trial agreements
between sponsors and investigators who were not located in academic institutions, even though
currently most clinical sites are in fact located outside of such settings. Thus it is important to
recognize that differences are present between these two groups that may have a bearing on
how sponsors of clinical trials will allocate resources and choose sites in future. One of the most
compelling observations when comparing the two groups was the finding that it takes academic
institutions much longer to finalize the CTA on average than non-academic sites. This is a major
obstacle for academic institutions because it can impact their ability to obtain sponsor funding.
A sponsor’s goal is to initiate a new study as quickly as possible. It is estimated to cost the
sponsor over $1 million per day of delay of the study start (Goldfarb, 2006). In this survey fewer
106

than 10% of the academic respondents worked in an institution capable of completing the CTA
process within one month; in comparison, almost 90% of non-academics were able to do this.

This study supports previously reported data that time delays are the biggest obstacle impacting
a site’s ability to be competitive in obtaining industry funding (Blumenthal, Causino, Campbell,
and Louis, 1996; Jaffe, 1998; Johnson, 2007; Mikhail and Giddings, 2011). As long as academic
institutions are not able to close this gap, their share of research funding from sponsors will
likely remain low compared to non-academic research sites and perhaps drop even lower. If
academic institutions want to compete with their non-academic counterparts they must find
ways to streamline this process to meet the needs of the industry and still meet the policies and
standards of the institution. One solution may be the use of electronic technology for reviewing,
editing and tracking the CTA. This has been reported to be a much more efficient and effective
process (Rijswijk-Trompert, 2012). The use of master contracting agreements is also being
implemented at a number of research-intensive institutions to reduce the timelines and
negotiations that can place bottlenecks in the way of finalizing a CTA (Melese, Lin, Chang, and
Cohen, 2009).

Less than 10% of the investigator respondents indicated that they managed the CTA at their
organization. This supports the previous reports (Schulman et al., 2002; Mello et al., 2005)
suggesting that most CTAs, at least at academic institutions, are managed by other
administrators. The two subgroups however are quite different in who manages the CTA. In
academic organizations the primary personnel appear to be in a contract or research office
whereas in non-academic organizations, the CTA is managed most commonly by a research
director or manager. This difference may be in some part responsible for longer delays at
107

academic institutions. Review of the CTA by a single staff member (manager/director) as
opposed to an office would likely be completed more quickly. Again, a review of the
administrative process of academic versus non-academic institutions would provide a much
clearer picture of comparative bottlenecks in the systems.

As predicted by using the Social Ecological Theory (Bronfenbrenner, 1979) as one of the
frameworks for this study we were able to identify some environmental factors that impact the
respondents of this study in their role in the CTA process. The present study highlights a few
areas in which improvement of the institutional or organizational research environment of the
institution might benefit the site investigator. One important area is that of training. Results of
this survey suggest that many investigators received training of some kind related to CTAs from
their institution, but over one-fourth of respondents reported that they did not receive training
or resources related to the CTA at their institution. Almost 20% more nonacademic than
academic respondents reported receiving training and resources from their institution. We
might speculate that those with more training are able to complete the CTA process more
efficiently. It would be interesting to collect data from institutions and investigators about their
CTA-related training and resources to determine the extent and content of that training.

The busy investigator may find the review of yet one more document, one that is lengthy and
full of legal language, to be daunting. Comments to this survey by some respondents indicate
that because of time constraints, the investigator would rather rely on others to manage the
CTA. If the institution were to have a standardized checklist of common elements in the CTA,
possible red flags, and specific inclusions depending on the type of trial, the simplifications
might encourage investigator participation, and at the same time improve and shorten the
108

process. It seems that it would be beneficial to implement policies at the institutional level
requiring, at the least, that the investigator review and sign the CTA. There is no guarantee that
the investigator will allocate the necessary time for a rigorous examination of the CTA, but some
form of accountability, coupled with checklists or other supporting materials for the education
of the investigator, would at least provide a more fertile environment to encourage investigator
participation. If the investigator does not sign formally as a party to the contract he or she
should be required to review the CTA and warrant to perform the trial according to the CTA and
with all applicable laws, regulations, and industry guidance and standards (Leibowitz and
Sheckler, 2006). This survey suggests that investigators working in an environment where they
have appropriate resources, training, and a quick turn-around time are more satisfied. Perhaps
academic institutions should look to their nonacademic colleagues to learn more effective ways
to manage the CTA.

Results of this survey tend to support the recent recommendation by Rijswijk-Trompert (2012)
that all study parties must be involved in the management of the CTA and that each party can
make a unique and meaningful contribution to a successful contractual arrangement with
mutually acceptable terms. Further, as the frameworks on which this study were based have
pointed out, factors related to both the inclination of the investigator (Rosenstock et al., 1988)
and the environment in which he/she is located (Bronfenbrenner, 1979) appear to be significant
in affecting the level and likelihood of participation. The investigator is able to identify key
issues of which an administrative staff member may not be aware. An investigator cannot do
this without reviewing and understanding the CTA. While this survey suggests that the majority
of investigators possess at least a limited understanding of the CTA and realize its importance,
109

there is still room for improvement and additional education. Targeting these factors in future
research, training, and policy development would help to improve the overall process.
110

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118

APPENDIX A

SECTIONS OF THE CLINICAL TRIAL AGREEMENT

Based on CTA Model by MAGI

 Parties & Recitals – Formal names, addresses, and official contact information to all
entities of contract; under what State laws; reason for the contract.

 Definitions – a list of legal definitions and abbreviations.

 Study Governance
o Protocol & Amendments – Official and full name and number of the Protocol;
requirement to follow the protocol and how to manage amendments; sponsor
will provide the site with official and approved protocol, future versions, and
amendments.
o Study {Drug/Device/Biologic} and Materials – List of all study materials,
sponsor’s obligations to supply, shipment, ordering, how they will be supplied,
any special handling instructions. Sponsor certifies that all investigational
products have been approved by the FDA.
o Sponsor Monitoring – monitoring plan; how often, who will be at site, time at
site, what will be monitored, monitor reports and site reports
o Sponsor-supplied Equipment – listing of any equipment required by the study
that will be provided by sponsor; when, how, shipping, handling, and
instructions
o CROs – If the study or any part of the study in managed by a CRO – CRO
identification, address, contact(s); services provided, expectations, reporting
o Audits – Expected audits to be performed by sponsor or CRO, type, activities,
schedule, notification, and expectations. Directions for notification to
sponsor/CRO and preparation for FDA audits.
o Inspections – Expected inspections by sponsor and CRO. Directions for site
notification to sponsor and preparation for FDA inspections.
o Other Sponsor Duties – Sponsor obligations and any additional negotiated
sponsor duties. Site and sponsor/CRO will comply with all current applicable
regulations and laws.

 Duties of Site and Investigator – obligations and responsibilities of the site and
investigator.
o Conduct of Study; Protocol – study will be conducted in compliance with Good
119

Clinical Practices and in accordance with the approved study protocol. The
site/investigator may deviate from the protocol for subject safety.
o GCP; Compliance with Laws and Regulations – All parties must comply with all
applicable laws and regulations; federal and state.
o Debarment and Disqualification – certification by the site that they will not use
any investigator or study staff member who has been debarred or disqualified
by the FDA. If during the course of the study an investigator or staff member is
debarred or disqualified they will be immediately removed from the study and
site will immediately notify the sponsor/CRO.
o Financial Disclosure – site and investigators must complete all financial
disclosure forms prior to the start of study and submit to sponsor/CRO.
o Conflict of Interest – investigators must report any conflict of interest prior to
start of study to sponsor/CRO.
o Investigator – name of investigator, investigator responsibilities and duties,
required to complete FDA Form 1572 (Statement of the Investigator) prior to
starting the study. Submission of curriculum vitae, medical license, and other
requested information. Investigator duties and assignment of duties by
investigator.
o Sub-investigators and other Personnel – list all sub-investigators on Form 1572,
each sub-investigator is required to submit a financial disclosure, conflict of
interest, curriculum vitae, medical license, and other listed documentation.
o Delegation of Investigator Duties – statement that the investigator is able to
delegate investigator duties during an absence. Who investigator can delegate
duties to and length of time for absence.
o Facilities – description of site and facilities to be utilized in the study; facility
requirements. The investigator/site will use only facilities listed on the FDA
Form 1572.
o IRB/IEC – Sponsor is responsible for obtaining protocol approval for the overall
study. The site/investigator is responsible for approval for informed consent and
site specific protocol. If site does not use sponsor identified IRB it will notify
sponsor of alternate IRB and receive sponsor approval. Site/investigator will
conduct study only under IRB approved protocol and amendments. Site will
submit the required ongoing approval applications to IRB of record. Site will
submit and obtain any other site approval requirements (e.g. biohazard
committee, radiation committee, etc.)
o Study Documents – description of study documents (protocol, consent, CRFs,
etc.) and who is responsible for providing, how managed, and submission
requirements. Site/investigator is responsible for the completion and accuracy
of all study records.
o Reporting and Meetings – required reports by sponsor/CRO, submission
requirements. Any required meetings for the investigator, coordinator and
other study staff.
o Record Retention & Destruction – must be compliant with FDA regulations. All
study record will be retained, where, length of time, and process for
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destruction.
o Enrollment – any enrollment activities or campaigns provided by sponsor/CRO;
site enrollment quotas, dates of enrollment, process and/or approval for over
enrollment. If the enrollment is competitive – a description.
o Adverse Events – reporting and management of adverse and serious adverse
events including FDA requirements, IRB requirements, and sponsor/CRO
requirements.
o Protocol Violations & Deviations – management, notification and reporting of
any protocol violations and deviations, contact information for notification.
o Informed Consent – consent process will comply with FDA CFR. Description of
the consent process. Site will confirm receipt of subject consent prior to
screening of subject.
o Study {Drug/Device} – name and description of study drug(s) or device(s).
Storage of study device/drug by site; inventory of investigational product;
inventory and return (if required) of unused investigational product. Shipping
and handling of study drug/device. Retention and return of empty containers if
required.
o Specimens; Shipment of Hazardous Materials – list and description of all
specimens to be collected; management and shipping of specimens. Description
and proper handling of hazardous materials to be used in the conduct of the
study.
o Genetic data and specimens – collecting and storage requirements. Sponsor
assumes all liability for use of genetic data and specimens used in the conduct of
the study.
o Electronic Data and Signatures – compliance with 21 CFR 11; requirements and
process for electronic signatures and collection and submission of electronic
data. Site will use electronic data management system provided by
sponsor/CRO and complete any required training.
o Data Clarification Queries – process and time period for handling any
discrepancies or queries identified during monitoring or audit visits by
sponsor/CRO.
o Communication of Results to Subjects – what study information is to be
provided to study subjects, how and when it will be reported. Under what
conditions blinding can be broken.
o Return of Study Materials – at end of study/close-out how the site is to handle
the return of study materials to the sponsor/CRO; what is to be returned and
timeline.
o Disaster Preparedness – site must have a disaster preparedness plan in place
and description of the requirements. Site must have plans to protect study and
subject data, study materials, and investigational product.
o Shipment of Hazardous Materials – shipping and handling of any study related
hazardous materials. Site will ensure that personnel handling hazardous
materials will be certified to handle the materials.

121

 Compensation
o Budget – site and sponsor/CRO agreed upon study budget. Fee schedule.
o Initial Payment – one time up-front payment for study set-up. When payment
will be received by site.
o Advance Payment – description of any agreed upon advance payments and how
these are managed. Generally an agreed upon amount to get the study up and
running once the contract is signed that will be applied to site costs by the
sponsor/CRO.
o IRB/IEC Fees – generally the responsibility of the sponsor/CRO, but may be
included in the study site budget and paid by site. Who is responsible if site
requires approval of local/institute IRB.
o Subject Recruiting – recruitment period, expectations, recruitment materials
provided by sponsor/CRO, and acceptable recruitment practices/examples.
o Payment for Study Visits & Milestones – specifics of payments to study site;
how managed, how often, amount per milestone or visit.
o Screen Failures – how many screen failures the sponsor/CRO will compensate
for and compensation amount.
o Incomplete Subjects – management of subjects who do not complete the study.
Payment for visits/procedures completed.
o Third-party Costs – description of any third party (medical procedures,
additional labs) involved in the study. Unless stated in the contract the
site/investigator is responsible for any third-party payments.
o Hold-back & Final Payment – How final payment will be managed and percent of
budget the sponsor/CRO will hold-back until completion of the study.
o Change Orders & Unanticipated Costs – management and notification of
changes and unanticipated costs by site and sponsor/CRO.
o Payment Schedule – specifics of payment schedule and plan (e.g. monthly,
quarterly milestones, etc.)
o Study Cancellation, Suspension or Early Termination – reasons for study
cancellation, suspension or early termination by sponsor/CRO or site;
notification and management.
o Charges to Third-parties – any study related costs charged to another party in
compliance with Medicare and other regulations.
o Payment Accounting & Discrepancies – description of how payment/accounting
discrepancies will be managed by the site and the sponsor/CRO.
o Overpayment – description of how any overpayment to the site will be managed
by the sponsor/CRO.
o Invoices – type, information required by the sponsor/CRO for payment to the
site.
o Budget Adjustments – how to request budget adjustments during the course of
the study; approval of adjustments, and sponsor/CRO adjustments that might
occur and how these will be managed.
o Contingent Fees – additional fees agreed upon such as bonus fees. How
site/investigator will invoice sponsor/CRO.
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o Payee – official name and address of who the sponsor/CRO will pay.
o Taxes – requirement of federal tax identification numbers, each party to the
contract is responsible for reporting income and other taxes.

 Confidential Information
o Confidential Information – what is considered confidential; how confidential
information will be identified – both written and oral. Does not apply to
information in the public domain.
o Disclosures – define what study information may be disclosed by the
investigator/site. Confidentiality does not apply to information in the public
domain.
o Confidentiality Obligations – obligations by the sponsor/CRO, the site, and the
investigator in the management and reporting of confidential data and/or
materials. Who has access to this information (e.g. investigator, sponsor, IRB,
FDA, etc.) Confidential information may only be used for purposes identified in
the contract. Notification to sponsor of any lost or compromised information
and management of the situation.
o Protected Health Information and Use of Data – the site, investigator and
sponsor will comply with HIPAA.
o Intellectual Property – definition of intellectual property, who owns the IP.
o Separate Property – any property owned prior to the start of the study ensuring
ownership by appropriate party.
o Site Authority – site warrants that it has the right of representation of IP.
o Disclosure – the site will notify the sponsor in a designated amount of time of
any inventions.
o Data Ownership –defines who owns the study data. Study data is confidential
and the property of the sponsor. The site owns all source documents.
o Ownership of Inventions – who has ownership of any inventions created during
the conduct of the study. The sponsor will have ownership of all invention that
are a direct result of the study.
o License - Site grants the sponsor an exclusive option, without fee, exercisable
within 90 calendar days following written notice of an Invention, to obtain an
exclusive or nonexclusive, worldwide, royalty-bearing commercialization license,
to all rights, title and interest that site may have or obtain in that Invention
o Filings – the site will upon request of the sponsor execute all rights to the
invention to the sponsor.
o License to Site - upon the site’s request, once the sponsor has obtained patents
and rights, the sponsor will grant a license to the site to use inventions for
conduct of the study or educational purposes.
o Other Funding – the site will not knowingly provide other funding for the study
that might affect the sponsor’s rights to inventions, patents, or IP.

 Publication – rights to publish study data including specific site data and data for multi-
center studies. Right to review by sponsor for confidential information. Timeline for
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review by sponsor. Description of publication/presentation venues.
o General – who, when, what and where study data can be disbursed.
o Multicenter Articles – description of authorship for articles related to data from
overall study, all sites, or multiple sites.
o Multicenter Data – who owns the data from all centers, who has access to the
data, how to access the data, when the data will be available and disbursed to
sites/investigators. Sponsor will provide de-identified study data to investigator
within a set time after completion of study by all sites.
o Confidentiality – all study staff are required to sign a confidentiality agreement
to not disclose study data.
o Copyright – the investigator/author will own the copyright for materials
submitted for publication or used in presentations.
o Authorship – description of management of authorship for articles and
manuscripts submitted on study data; acknowledgements; limitations; individual
or multi-site. Publications will comply with ICMJE’s current standards for
publication.
o Statement of Support – When submitting/publishing an article or conducting
scientific presentation any required statement of support by sponsor.
o Communication – description of form of communication between the
site/investigator and the sponsor/CRO; any time lines.
o Registry – the sponsor is responsible for registering the study and all study sites
on clinicaltrials.gov.
o Acknowledgement - any acknowledgments of study funding that required by the
sponsor or publication.
o Publications Committee – if there is a publication committee, description,
members, contact information and requirements for submission of data for
publication. Committee will designate who is able to submit the first publication
of study data.

 Subject Injury – describe who is responsible for subject injury related to the study,
management and payment. How and time to notification of an injury. Relationship of
sponsor to the study subject.

 Indemnification
o Indemnification by Sponsor – hold harmless the sponsor/CRO for negligence by
the site or investigator.
o Indemnification by Site – hold harmless the site/investigator for negligence,
injuries, death, lawsuits related to the study not caused by site/investigator
negligence.

 Insurance & Liability
o Site Insurance – sponsor requirements for site and investigator for general
liability insurance limits per occurrence.
o Sponsor Insurance – description of general liability insurance and limits per
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occurrence by sponsor/CRO.
o Limit of Liability – No party has any right to special, indirect, consequential or
punitive damages for breach of contract or tort claim under the contract (except
as identified in other sections).

 Effective Date, Term and Termination
o Effective Date – date the contract becomes effective
o Term – length of the contract.
o Termination – when the contract will be terminated, reasons for termination by
sponsor/CRO or site, notification and management of termination of contract.
o Compensation – management and payment of any fees due the
site/investigator upon termination of the contract.
o Survival – Rights and obligations of the contract will survive remain in full force
and effect following termination or expiration of the agreement.
o Continuing Treatments – if the sponsor terminates the agreement or study,
upon request of the site the sponsor will provide investigational product and
allow site to complete visits and procedures required for safety of the subject.
 Notice – list the various types of notices, time for notification, and how notices are to be
managed (e.g. telephone, fax, email, postal service, certified letter, etc.) Contact name
and information for person to be notified.

 General
o Governing Law & Jurisdiction – state of jurisdiction. If there are contract issues
this identifies what state will govern the contract issues.
o Publicity and Use of Names – approved uses of names and logos of the parties
to the contract.
o Entire Agreement; Modifications – modification of one section or portion of the
contract does not impact the entire contract or other portions of the contract.
All modifications must be made in writing and approved by authorized
representatives of the contract parties.
o Counterparts – the contract may be executed in multiple copies. Each copy must
include the signature of all contract parties.
o Freedom to Contract – parties to the contact freely signed the contract and
have the right to enter into a contract with the other parties.
o Authorized Representatives – names and contact information of representatives
authorized to sign on behalf of the site/investigator and the sponsor/CRO.
o Assignment –the site/investigator may assign rights to the agreement to
another party and must provide notification within a certain time frame to the
sponsor. The sponsor must approve and the assigned party must accepts all
responsibilities and obligations of the contract.
o Delegation – the site/investigator may delegate duties and responsibilities
under the contract to qualified individuals under investigator’s supervision.
o Relationship of the Parties – description of the relationship of the parties
(site/investigator and sponsor/CRO). The site/investigator is an independent
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contractor.
o Third-party Rights – no third party is represented or has rights under the
contract.
o Severability – if a court or legal jurisdiction finds any part of the contract not
legal the remainder of the contract will remain in force.
o Force Majeure - no party will be liable for failure or delay in performing its
obligations under if the failure or delay is beyond reasonable control of the
party.
o Alternative dispute resolution - contract parties will resolve any dispute
pertaining to the contract with Alternative Dispute Resolution (“ADR”) as set
forth in the contract.
126

APPENDIX B

ORIGINAL STUDY SURVEY

1. What is your role in research studies?

 Principal Investigator
 Co-investigator
 Other

2. For how many years have you conducted industry sponsored clinical trials?

 Less than 2 years
 2 - 10 years
 More than 10 years
 I have never conducted industry sponsored trials

If I have never conducted industry trials is selected, then skip to end of survey

3. Please identify your location by U.S. region:

 Northeast
 Southeast
 Midwest
 Southwest
 West

4. In what type of institution do you work? Please choose the most suitable answer if you are in
two settings, or explain in "other"
 Academic/University
 Practice-based
 University Affiliated Hospital
 HMO
 Clinical Research Organization
 Other
127

5. What study phase(s) do you conduct? Please check all that apply.

 Early Stage/ feasibility studies with industry sponsor
 Multi-Center pivotal
 Post-marketing studies for sponsor
 Investigator-Initiated
 Other

6. What type of studies do you conduct? Please check all that apply.

 Drug/Biologic
 Device
 Stem Cell/Human Tissue
 Gene Therapy
 Pharmacovigilence
 Pharmacokinetics
 Other

7. Who manages (reviews & negotiates) the clinical trial agreement at your organization? Please
select the individual that you would consider to take the lead in such activities.

 Investigator
 Director/Manager
 Research Office
 Legal Office
 Other
128

8. Please rate your organization/employer on each of the following items:

Strongly
Agree

Agree

Neither
Agree or
Disagree

Disagree

Strongly
Disagree

Do
not
know

Is capable of reviewing
and negotiating a fair

 

 

 

 

 

 
and balanced Clinical
Trial Agreement.

Provides investigators

with resources and            
training to understand
the Clinical Trial
Agreement.

Includes the study

investigator in the
review and
           
negotiation of the
Clinical Trial
Agreement.

Anticipates and

 

 

 

 

 

 
addresses potential
agreement issues.

Deals effectively with

 

 

 

 

 

 
contract issues when
they arise.

Is able to complete

the review and
negotiation of a            
clinical trial agreement
in a timely manner
that does not delay
the start of the study.
129

9. How long does it take you/your organization to review, negotiate and sign the clinical trial
agreement?

 1 - 6 days
 2 -3 weeks
 4 - 6 weeks
 More than 6 weeks
 I do not know

10. Have you had a negative experience/conflict with a sponsor in the following areas? (Select
all that apply.)

 Publication issues
 Confidentiality
 Access to study data
 Payment
 Intellectual property/patent
 None
 Other

11. Based on your experience how would you rank the value of the following entities that might
be available as resources to assist you in the understanding and management of clinical trial
agreements: (Drag & drop to rank.)

Institution/Employer

Professional Workshops

Professional Organization(s)

Colleagues

Literature Review/Research

Other

130

12. I consider the clinical trial
agreement to be:

Strongly
Agree

Agree

Neither
Agree nor
Disagree

Disagree

Strongly
Disagree

Important in my conduct of the

 

 

 

 

 
study.

As important to the study as the

 

 

 

 

 
informed consent.

As important to the study as the

 

 

 

 

 
study protocol.

The responsibility of the

 

 

 

 

 
organization/employer.

Important to prevent

 

 

 

 

 
issues/conflicts.
131

13. Do you agree or disagree with the following statements?

Strongly
Agree

Agree

Neither
Agree nor
Disagree

Disagree

Strongly
Disagree

In my role it is important for me

 

 

 

 

 
to be actively involved the
review and negotiation.

My involvement in the process

 

 

 

 

 
may prevent or reduce contract
issues with the sponsor.

My lack of understanding of the

 

 

 

 

 
contract may result in legal
implications.

My organization actively

 

 

 

 

 
encourages me to be involved in
the negotiation of the contract.

I rely on the sponsor to write the

 

 

 

 

 
contract.

I feel empowered by my

 

 

 

 

 
institution to change or rewrite
the contract.

I feel confident in my

 

 

 

 

 
institution's ability to manage
the Clinical Trial Agreement.
132

14. My most recent clinical trial agreement addressed the following items (please check all that
apply):

 FDA Code of Federal Regulations
 Subject Safety
 HIPAA
 Informed Consent
 Contract Jurisdiction
 Payments and financial arrangements
 Liability
 Insurance
 Materials/information to be kept confidential
 I am not able to remember
 Other

15. Based on your experience and knowledge would you feel comfortable reviewing and
negotiating a clinical trial agreement with the sponsor?

 Definitely would
 Probably would
 Maybe would/Maybe not
 Probably would not
 Definitely would not

16. Do you review the clinical trial agreement before it is finalized?

 Yes
 No

17. Do you sign the clinical trial agreement?

 Yes
 No
133

18. Have you discussed your clinical trial agreements with colleagues who also conduct clinical
trials?

 Frequently: they have given me useful input
 Occasionally: they have given me useful input
 Occasionally: the input was not very useful
 Not in my memory

19. To your knowledge, do your colleagues participate actively in the management of their
clinical trial agreements?

 No
 Yes

20. In your best judgment, which choice below best describes the most common attitudes of
your colleagues with respect to the exercise of managing a clinical trial agreement?

 An important and useful activity
 A necessary but unsatisfying activity
 A negative experience that they would prefer to avoid
 An exercise that they trust to their organization to manage

21. Do you belong to any professional organization that has held a session on clinical trial
agreements in the last 5 years?

 Yes
 No

22. Would you go to a session on clinical trial agreement management sponsored by a
professional organization if it were free?

 Yes
 No
134

23. Please rank the following individuals/groups according to the influence that they have had
on your understanding or management of the clinical trial agreement. (Drag and drop to rank.)

My Organization/Employer

Professional Organization

Legal Entity

Research Office

Contracts Office/Individual

Peers

Other

24. How problematic do you think it is to let others negotiate and manage the clinical trial
agreement without your input?

 Not Serious
 Somewhat Serious
 Neutral
 Serious
 Very Serious

25. What do you think is the worst thing that might happen if you let your university/employer
negotiate and manage the clinical trial agreement without your input?

26. When I work with the clinical trial agreement my best description of my mood is:

 Confident
 Satisfied
 Confused
 Upset
 Hostile
 I do not deal with the clinical trial agreement
 Other
135

27. Do you have comments about the way that your institution manages clinical trial
agreements?

28. If you wish to obtain a copy of the survey results please provide your email:
136

APPENDIX C

FINAL STUDY SURVEY

Do you currently, or have you in the past conducted industry sponsored studies?

 Yes
 No

For how many years have you been conducting research studies?

 Less than 2 years
 2 - 10 years
 More than 10 years

What is your role in research studies?

 Principal Investigator
 Co-Investigator
 Both
 Other

Please select your state from the drop down menu:

 AL
 AK
 AZ
 AR
 CA
 CO
 CT
 DE
 FL
 GA
 HI
 ID
 IL
 IN
 IA
 KS
137

 KY
 LA
 ME
 MD
 MA
 MI
 MN
 MS
 MO
 MT
 NE
 NV
 NH
 NJ
 NM
 NY
 NC
 ND
 OH
 OK
 OR
 PA
 RI
 SC
 SD
 TN
 TX
 UT
 VT
 VA
 WA
 WV
 WI
 WY
138
In what type of institution do you work? Please choose the most suitable answer if you are in
two settings, or explain in "other"

 Academic/University
 Practice-based
 University Affiliated Hospital
 HMO
 Clinical Research Organization/Site Maintenance Organization
 Non-Academic
 Other

What study phase(s) do you conduct? Please check all that apply.

 Early Stage/ feasibility studies with industry sponsor
 Multi-Center pivotal
 Post-marketing studies for sponsor
 Investigator-Initiated
 Other

What type of studies do you conduct? Please check all that apply.

 Drug/Biologic
 Device
 Stem Cell/Human Tissue
 Gene Therapy
 Vaccine
 Non-therapeutic/Diagnostic
 Other

Who manages (reviews & negotiates) the clinical trial agreement at your organization? Please
select the individual that you would consider to take the lead in such activities.

Investigator

Director/Manager of Research Activities
Contracts Office
Legal Office
139

Central Administration
Study Coordinator
Other _
Do Not Know
140
Please rate your organization/employer on each of the following items:

Strongly
Agree

Agree

Neither
Agree or
Disagree

Disagree

Strongly
Disagree

Do
not
know

Is capable of reviewing
and negotiating a fair

 

 

 

 

 

 
and balanced clinical
trial agreement.

Provides investigators

with resources and            
training to understand
the clinical trial
agreement.

Includes the

investigator in the
review and
           
negotiation of the
clinical trial
agreement.

Anticipates and
addresses potential

 

 

 

 

 

 
clinical trial agreement
issues.

Deals effectively with

 

 

 

 

 

 
contract issues when
they arise.

Is able to complete

the review and
negotiation of a
           
clinical trial agreement
in a timely manner
that does not delay
141

the start of the study.

Generally, how long does it take you/your organization to review, negotiate and sign the clinical
trial agreement?

 Within 1 Month
 2 -3 Months
 4 - 6 Months
 More than 6 months
 I do not know

Have you had a negative experience/conflict with a sponsor in the following areas? (Select all
that apply.)

 Publication Issues
 Confidentiality
 Access to Study Data
 Funding/Study Payment
 Intellectual Property/Patent
 Patient Injury Language
 Budget Negotiations
 None
 Other

Based on your experience how would you rank the value of the following entities that might be
available as resources to assist you in developing and complying with clinical trial agreements:
(Drag & drop to rank.)

Institution/Employer

Professional Workshops

Professional Organization(s)

Colleagues

Literature Review/Research
142
Legal

Insurance Carrier/Broker

Other

I consider the clinical trial agreement to be:

Strongly
Agree

Agree

Neither
Agree nor
Disagree

Disagree

Strongly
Disagree

As important to the

 

 

 

 

 
study as the informed
consent.

As important to the

 

 

 

 

 
study as the study
protocol.

The responsibility of

 

 

 

 

 
my
organization/employer.

Important to resolve

 

 

 

 

 
issues/conflicts.
143
Do you agree or disagree with the following statements?

Strongly
Agree

Agree

Neither
Agree nor
Disagree

Disagree

Strongly
Disagree

In my role it is

 

 

 

 

 
important for
me to be
actively
involved the
review and
negotiation of
the clinical
trial
agreement.

My

involvement
in the clinical
trial
agreement
         
process may
prevent or
reduce
contract
issues.

My

organization
actively
encourages          
me to be
involved in
the
negotiation of
the contract.

I feel

 

 

 

 

 
empowered
by my
144

institution to
edit the
clinical trial
agreement.

I feel
confident in
my
institution's
ability to
negotiate the
clinical trial
agreement.

 

 

 

 

 

As you reflect back, to the best of your knowledge clinical trial agreements for your studies
addressed the following items (please check all that apply):

 FDA Code of Federal Regulations
 Subject Safety
 HIPAA
 Informed Consent
 Contract Jurisdiction
 Payments and Financial Arrangements
 Liability
 Insurance
 Materials/Information to be Kept Confidential
 Publication
 Investigator's Brochure
 Deliverables
 All of the Above
 Other
 I Do Not Know
145
Would you feel comfortable reviewing and negotiating a clinical trial agreement?

 Definitely would
 Probably would
 Maybe would/Maybe not
 Probably would not
 Definitely would not

Do you review the clinical trial agreement BEFORE it is finalized?

 Yes
 No

Do you sign the clinical trial agreement?

 As a Party to the Agreement
 As the Investigator Acknowledging Responsibilities
 I Do Not Sign the Clinical Trial Agreement

Have you discussed your clinical trial agreements with colleagues who also conduct clinical
trials? Please choose the best answer.

 Frequently: they have given me useful input
 Occasionally: they have given me useful input
 Occasionally: the input was not very useful
 Not in my memory

To your knowledge, do your colleagues actively participate in the review and negotiation of their
clinical trial agreements?

 No
 Yes
 I Do Not Know
146
In your best judgment, which choice below best describes the most common attitudes of
your colleagues with respect to their personal involvement in the review and negotiation of
the Clinical Trial Agreement?

 An important and useful activity
 A necessary but unsatisfying activity
 A negative experience that they would prefer to avoid
 An exercise that they trust to their organization to manage

Do you belong to any professional organization that has held a session on clinical trial
agreements in the last 5 years?

 Yes
 No
 I Do Not Know

Would you go to a session on clinical trial agreements sponsored by a professional organization
if it were offered?

 Yes
 No
 I Do Not Know
147
Please rank the following individuals/groups according to the influence that they have had on
your understanding or management of the clinical trial agreement. (Drag and drop to rank.)

My Organization/Employer

Professional Organization

Legal Entity

Research Office

Contracts Office/Individual

Peers

Other

How problematic do you think it is to let others negotiate and manage the clinical trial
agreement without your input?

 Not Serious
 Somewhat Serious
 Neutral
 Serious
 Very Serious

What do you think is the worst thing that might happen if you let your organization/employer
negotiate the clinical trial agreement without your input?

What do you think is the best thing that might happen if you let your organization/employer
negotiate the clinical trial agreement without your input?
148

When I participate in activities related to the review and negotiation of the clinical trial
agreement my best description of my mood is:

 Confident
 Satisfied
 Confused
 Upset
 Hostile
 I do not deal with the clinical trial agreement
 Other

Do you have comments about the way that your institution manages clinical trial agreements?

Are you happy with the process for the review and negotiation of the clinical trial agreement at
your institution/organization?

 Yes
 No
 Not Sure

If you wish to obtain a copy of the survey results please provide your email in the text box
below:

149

APPENDIX D

“WHAT DO YOU THINK IS THE WORST THING THAT MIGHT HAPPEN IF YOU LET YOUR
ORGANIZATION/EMPLOYER NEGOTIATE THE CLINICAL TRIAL AGREEMENT WITHOUT YOUR
INPUT?

Takes forever for them to nitpick irrelevant details.
N/A
Not sure, but it happens all the time and had not really thought about it.
may not see all of the potential risks
make less income
I have a very experienced Director of Finance. Over the years he has become the expert on
clinical trial agreements. I have no concern about him handling every aspect.
Indemnification clauses Budgets not being accurately calculated.
Lost revenue
Not enough Money will paid to my site
Misunderstanding which protocol-required procedures are standard of care
lack of proper indemnification inadequate budget
Would worry about indemnification clause and also flow of monies dealing with how site
would be paid during study
I do not believe there will be a "Worst Thing". The people at my organization who manage this
are very knowledgeable and skilled at what they do.

Would not understand budget as it relates to study procedures/work-load and we may end up
with an inadequate study budget. Frequently need to remind sponsors that we ask for a start-
up fee to cover these expenses - someone not knowledgeable would not know to ask for this.
Seriously underbid due to no knowledge of trial assessments labor time
They won't understand what costs to include when negotiating and might agree to a less
amount per subject than what we usually get
budget could be low or insurance information could be incorrect
Not enough money negotiated for test to be performed.
they do not cover the overhead costs enough to cover payment for doing the study
They have no idea what research is or is about. Therefore they would not be able to know if
the values they are negotiating are fair or reasonable to a study.
rate would not be as high
Often, Budgets and Contracts individuals are not aware of the protocol, percentages of screen
failures anticipated, etc.
Nothing
150

They cannot know the nuances of clinical research in so many diverse areas
They would commit us to something we can't deliver
I always negotiate the clinical trial agreements
Wrong estimation for budget allotment

These agreements are often fairly standard when it comes to terms - the big difference is often
in the budget and indemnification language. The worst that would happen is that I would
disagree with something and require that it be looked at again prior to my signing it.
Anything that could go wrong. I could be asked to do something in the contract that is not
legal or ethical putting me in a catch 22 situation.
lose control
Errors may effect funding
Improper deliverables, inadequate compensation.
Take on a trial we might not be able to run well or would lose money on
it takes a long time and the terms are unreasonable
N/A
Unnecessary demands from our university
Nothing
They may not be aware of the true costs and long term liabilities of the project
Not applicable
poor financial reimbursement
They do not realize what procedures need to have sub-contracts. Do not always read the
protocol
may not cover all issues with the trial
Oversights that were not understood by very experienced contract person. Each year there are
many "strange things" added into contracts.
WE HAVE A SYSTEM OF CHECKS AND BALANCES IN PLACE WITH MULTI PERSON REVIEW
budget issues
N/A
unknown liability
They will not understand what it takes to complete the research and will not negotiate
appropriate terms for time lines, resources, IP (often try to get more than is justified, holding
up progress).
The legal language would likely be okay, but the budget and anything else specific to research
is a total mystery to the rest of the people in my organization, and they seem to like it that
way.
Worst thing possible....probably that we'd be obligated to do a lot of extra work for absolutely
no compensation.
The legal language would likely be okay, but the budget and anything else specific to research
is a total mystery to the rest of the people in my organization, and they seem to like it that
way. Worst thing possible....probably that we'd be obligated to do a lot of extra work for
absolutely no compensation.
151

Agree to an enrollment commitment that may exceed our ability to enroll
N/A
n/a that's my job as Research Manager
not applicable at my site
They would not get the CTA done without frequent input and prodding/cajoling by the PI. They
could commit to things we cannot deliver. They would sooner see the project stall or never
happen rather than compromise on anything (particularly regarding IP issues and indirect cost
rates). They could misunderstand the time required to complete the study
Personal liability. Inadequate access to data.
It never gets negotiated,
Underfunding, which can have a significant influence not only on decisions to participate in a
study, but also and more importantly, affects patient welfare
Make me a party to the agreement instead of my employer. commit me to indemnification.
Not negotiate appropriate timely payment schedule
Poor understanding of effort required to recruit selected types of patients and the effort
needed to complete the research
Be obligated to unrealistic deliverables
We could lose money
Underfunding
budget problems
Not sure
The most important part of the agreement for us is the budget. We will not participate in any
trial agreement where we cannot review the budget.
slower process and compensation.
The attorney handling the contract might miss or fail to address something that's related to
clinical research, as opposed to risk management for the university.
We lose the intellectual property related to the study, and that the sponsor can stop us from
publishing the results.
Too many delays resulting in missed opportunities to recruit.
Cross indemnification being included
miss key issues
As one of the owners of the site, I am cognizant of the contracts and budgets but one of my
partners handles that part of the business. I trust his judgment.
Discordance between resources and deliverables
doesn't apply to me
impractical agreements. Delays
long delay in starting trial
We will be underpaid
I could be put in a place to agree to things that I am not aware of.
Payment terms and budget may not be as fair as it should be. Indemnification might not be
covered.
152

That is currently how our organization operates which alleviated the burden on the physician
to have more thorough review for legal language, budget coverage, and institutional
requirements.
it is mostly legal issues and my institution deals with it
total chaos
Under valuing our responsibilities and duties
Deliverables would not be generated.
I have faith in the person who conducts our negotiations, however there could always be the
possibility of misunderstandings of the language, true cost, or similar item.
I understand the study and its complexities
Misrepresentation of my plans as the investigator
The budget would not get negotiated correctly
items might be missing
153

APPENDIX E

“WHAT DO YOU THINK IS THE WORST THING THAT MIGHT HAPPEN IF YOU LET YOUR
ORGANIZATION/EMPLOYER NEGOTIATE THE CLINICAL TRIAL AGREEMENT WITHOUT YOUR
INPUT?

Less immediate work for me though increased delays in study activation.
Unknown. i do not review clinical trial agreements
They would resolve problems that I could not because I don't have the experience
Better cost analysis
Better terms & conditions.
better contract done by expert
The sponsors we work with have established positive working relationships with our director.
They would understand the complications associated with negotiation.
None
Nothing
Knowledge of legal issues; Leverage; Resources
n/a
Wouldn't have to pore over every paragraph to insure site was being treated justly and fairly
and was not open to missed legal coverage
Saves me time. Experts in the area of CTAs are handling this task and not leaving it to
individuals with less knowledge and training.
May end up w/a more structured process. Free up my time.
Nothing
You will get the most complete budget and will have negotiated as much as possible to get as
much upfront costs approved.
will not happen
MY time isn't spent doing it.
N/A
a chance they would cover expenses
They would realize what it is that we do in my department
it would get processed quicker
It would free up time.
It will protect me and the university
I would be unsatisfied at times
It might get done faster.
It would not get done
N/A
154

It would save time - again, most of the language is standard and we have MSA's with many
sponsors. When we have an MSA, it greatly reduces the time involved. Also, I think that
most of it really should be handled by a legal person or a contract specialist - on the
pharma's end, they are using an attorney so it only makes sense for an attorney to be
involved on our end.
The process might get done faster.
can’t happen at my institution
Save physician's time
It will get done quickly and consistently
Less paperwork burden for me.
it would occur quickly and be reasonable
saves me time to the extent they get it right
None
It would have a more favorable budget.
Expertise
It sure would be a learning experience for them.
n/a
It would not happen.
SEE ABOVE
Unsure
Would take less of my time up front (but more downstream if they don’t get it right).
I'd have a lot more time and fewer worries.
Successful negotiations
n/a
not applicable at my site
If they would do it correctly and promptly without my input, that would save me a lot of
time.
They will identify problems that I did not anticipate
Nothing
There is no best thing that could happen if our employer negotiates an agreement without
our input-- they are not familiar with discipline specific study activities and how much time it
takes for personnel to carry them out. They require a great deal of input from us to ensure
that we are paid for actual time spent, and not fee for service regardless of pay scales
frees up my time
Better grasp of costs to insure financial viability of the study within the proposed budget.
Unlikely to get into legal trouble
We would speed up the contracts process
Adequate funding
Nothing
Successful study
They do most of it anyway. WE NEED TO REVIEW THE BUDGET.
saves time
The attorney handling the contract will identify and address potentially problematic issues
related to contracts law, in which I have no training.
155

They take care of the legal aspects.
The institution generally negotiates a better rate that allows the reasonable compensation for
coordinator time, while often the site-investigator if interested in the science agrees to lower
rates that hamper the ability of the institution to logistically carry out the study.
legal issues resolved
As one of the owners of the site, I am cognizant of the contracts and budgets but one of my
partners handles that part of the business. I trust his judgment.
Efficiency, time gained to concentrate on scientific aspects of the study
doesn't apply to me
nothing good
expedite handling issues
Legal aspect of it is their responsibilities
I would have full understanding of my responsibilities related to the contract.
Seamless, prompt payments, fair payments and no legal issues.
It is more streamlined as well as reviewed more thoroughly for meeting designed template
organizational requirements.
I don't have to waste my time on legality issues that whatever I think, will be superseded by
my institutional policy
??
That a fair agreement is accepted.
I would have more time to complete other tasks. It's a matter of trust and resource allocation.
Quicker turnaround of CTA process.
None
Clearly negotiated financial agreement
The budget would not get negotiated correctly.
n/a
i wouldn't have to make the time to do it
156

APPENDIX F

ADDITIONAL COMMENTS

I think it is common in large institutions like my own.
We try to cover all basis so that we will not lose any money and hopefully gain
No
I use a single Director of Finance to work on budget
Our turnaround time is 24-48 hours. It is our goal to support the CRO/sponsor in prompt
execution of the agreements and timely start of the clinical trials.
No
My involvement is limited to a review and edit/approval of the standard of care analysis;
otherwise, everything is handled by our research office in collaboration with the
hospital's and medical group's legal staff.
n/a
Most CTAs are well written by sponsor and cover all areas to protect both company and site.
We usually have to make minor changes only to CTA/budget concerns.
Director of Research always negotiates the contracts and budgets and for studies for the same
condition we have done in the past we try to stick to the same fee per item as we have
received in the past and we ensure we get at least a similar amount or more per subject if
we have done a previous trial that is pretty similar.
NO
we need to find a way to be more efficient at the process
It is too slow and it threatens to make us uncompetitive with commercial research sites.
We have a clinical research board. That board negotiates the contracts. All contracts are then
sent to legal. Finally they are sent to the individual investigator for final approval.
Prob has improved over the years but shod not take on trials We lose money on
it’s totally suboptimal
Our agreements are managed to protect the institution, even at the cost of suppressing
research. There is no reward for accelerating research, and only risk for making a mistake.
It we be easier for all sites if sponsors offered compensation for each item required by the
protocol for review, instead of making sites breakdown the budgets themselves. For example
a total per patient is not a breakdown of procedures and often does not include procedures
needed for a trial to be completed
N/A
We are currently re-structuring this process completely. The CRO that has been doing it was
very slow and ineffective, communicated poorly and is being dissolved. The whole process is
being streamlined (I hope) in a new clinical trials office. Will see if that works better.
157

They're handled like any other type of contract, which doesn't work out well in reality.
at our institution, everything comes to me and I forward on to the attorney, from there it
good to our staff attorney.
Attorney reviews the language of the contract except for anything related to payments
No
It seems to be a very inefficient and slow process. The research admin office is apparently
chronically understaffed, so the person charged with reviewing, further refining/negotiating
and approving CTAs (that I have either written or already extensively revised from a PI's
point of view) typically has a multi- month backlog. This process takes dozens of hours of
work distributed over months, often because every CTA ends up being a unique document
despite the fact that at least one party to the CTA contract usually has a template that both
would find acceptable apart from a few tweaks.
Very poorly and incompetently
The management of clinical trial agreements is broken at our institution--the expertise is
superficial at best, and the burden of negotiating agreements and managing task flow falls on
the shoulders of study coordinators, who are supposed to be seeing patients. Since
dysfunction stimulates change, we have been subjected to new structures and policies without
input from the primary players--PIs and coordinators. There is very little trust, so we are
forced to maintain a shadow system to protect our subjects, our trials and our integrity.
I wish we could have external advice especially on indemnification language and what is
proper
Can take a bit long if there are vacations, illnesses, etc.
They generally take too long to reach a final working document
It feels as though we continue to go through the same budget negotiations each contract,
even if we've worked with the sponsor/CRO in the past.
Most of this survey is irrelevant to my work. I do not have any clinical trial agreements with
industry.
There are too many layers, Sponsor, CRO, V P/office of Research at our University, Contracts
and administration at our University, Our Departmental office/director of budgets and
contracts, over site committees -- can't get final contract done until IRB signs off on it and
office of ethics have generated a conflict of interest management.
No
No. They have issues which they have to work out along with institutional course. I am not
particularly interested in these issues.
Variable
It is extremely time-consuming, and the message is clear that the faculty member does not
have input into the final contract's language. When the outside entity & our contracts office
are done emailing back-and-forth about a myriad of legal issues -- and changing semicolons to
colons, etc. -- the finalized document is presented to me for signature.
We run a very successful enterprise despite the continual increase in workload, increasingly
more inclusion/exclusion criteria, increase in usage of technology in the clinical research
process, flat payment structures and at times poor payment frequency due to the fact that
we understand our costs well. You cannot negotiate a fair contract without understanding
your costs and we do this better than most sites.
As owner, Medical Director and PI I review all the contracts. My wife is an attorney and assists
me when needed.
158

Too slow.
I would like to be more involved for my own professional growth.
None
No
None

Abstract (if available)

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Asset Metadata

Creator Pfeiffer, JoAnn P. (author)

Core Title Current practices of U.S. investigators in the management of the clinical trial agreement: a survey of knowledge, attitudes, perceptions, and engagement

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 02/03/2014

Defense Date 11/18/2013

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

Tag clinical trial agreement,clinical trials,Contract,industry-sponsored,investigator,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances J. (committee chair)

Creator Email joann_pfeiffer@yahoo.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-362681

Unique identifier UC11296111

Identifier etd-PfeifferJo-2238.pdf (filename),usctheses-c3-362681 (legacy record id)

Legacy Identifier etd-PfeifferJo-2238.pdf

Dmrecord 362681

Document Type Dissertation

Format application/pdf (imt)

Rights Pfeiffer, JoAnn P.

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