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Regulatory agreements for drug development collaborations: practices in the medical products industry

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Regulatory agreements for drug development collaborations: practices in the medical products industry

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REGULATORY AGREEMENTS FOR DRUG DEVELOPMENT COLLABORATIONS:
PRACTICES IN THE MEDICAL PRODUCTS INDUSTRY

by

Mary E Wilhelm

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

December 2021

Copyright 2021 Mary E Wilhelm

ii
Dedication

This work is dedicated to my family. My husband, Joe Wilhelm, provided continuous
encouragement, love, and support throughout the doctorate program. Thank you for “doing it
all” so I could focus on my research.
To my children Elizabeth, Allen, Andrew, and Aaron Wilhelm: you are the joy in my
life! Thank you for your love and support, but also your interest in my studies. It meant the
world to me.

iii
Acknowledgements
Whether it takes a village or a team, the things I have done in my life that were the most
rewarding were not accomplished alone. This dissertation is no exception and results from years
of pharmaceutical industry experience, teaching regulatory affairs courses, pursuing academic
studies and research, and sharing experiences with industry and academic colleagues. I want to
thank those who were with me in finishing this dissertation.
Foremost, I wish to thank my advisor, Dr. Frances Richmond, for her encouragement,
insight, and expertise. I have greatly enjoyed our conversations on this and other topics. Besides
my advisor, I would like to thank my dissertation committee: Drs. Nancy Pire-Smerkanich,
Susan Bain, and Roger Clemens. I appreciated your questions, comments, and assistance with
my survey and dissertation.
I extend my thanks and appreciation to the focus group participants for their valuable
insights in improving my survey for this research. My sincere thanks also go to the study
participants who shared their expertise and insight on this topic. I was honored and humbled that
294 industry professionals would take this survey and provided additional written comments that
enriched my research. I look forward to sharing the results with the medical products industry.
I wish to thank the regulatory science staff who helped me navigate the USC
administrative and course procedures. And finally, I would like to thank the other students in the
2016 Doctoral Cohort for their professional and personal support. I enjoyed sharing our studies
and experiences throughout the program and cherish the friendships I have made.

iv
TABLE OF CONTENTS
Dedication ....................................................................................................................................... ii
Acknowledgements ........................................................................................................................ iii
List of Tables ................................................................................................................................. vi
List of Figures ............................................................................................................................... vii
Abstract ........................................................................................................................................ viii
Chapter 1. Overview ........................................................................................................................1
1.1 Introduction ................................................................................................................. 1
1.2 Statement of the Problem ............................................................................................ 3
1.3 Purpose of the Study ................................................................................................... 4
1.4 Importance of the Study .............................................................................................. 5
1.5 Limitation, Delimitations, Assumptions ..................................................................... 6
1.6 Organization of Thesis ................................................................................................ 7
1.7 Definitions ................................................................................................................... 8
Chapter 2. Literature Review ...........................................................................................................9
2.1 Structure of the Literature Search ............................................................................... 9
2.2 Evolution of Bio/pharmaceutical Companies ........................................................... 10
2.3 Key Historical Events Shaping Regulatory Oversight .............................................. 11
2.4 Changes in the Organization of Biopharmaceutical Companies in the US ............... 16
2.5 Growth of the Biotechnology Industry and Academic Centers ................................ 18
2.6 Outsourcing Management ......................................................................................... 21
2.6.1 Contract Basics ............................................................................................ 21
2.6.2 Manufacturing Agreements ......................................................................... 22
2.6.3 Quality Agreements ..................................................................................... 25
2.6.4 Clinical Trial Support Agreements .............................................................. 27
2.7 Evolution of Regulatory Agreements........................................................................ 30
2.7.1 The Master File System ............................................................................... 34
2.7.2 Shared Manufacturing Arrangements .......................................................... 35
2.8 Time to Formalize Shared Regulatory Responsibilities? .......................................... 36
2.9 Approach to the Research ......................................................................................... 42
Chapter 3. Methodology ................................................................................................................47
3.1 Summary ................................................................................................................... 47
3.2 Identification of Study Participants ........................................................................... 47
3.3 Data Collection and Analysis Methodology ............................................................. 48
Chapter 4. Results ..........................................................................................................................51

v
4.1 Survey Participation .................................................................................................. 51
4.2 Demographic Profiles and Background of Respondents........................................... 51
4.3 Partnerships and Agreements Used by Respondents ................................................ 56
4.4 Awareness of Regulatory Agreements ...................................................................... 62
4.5 Companies Using Standalone Regulatory Agreements ............................................ 65
4.6 Companies Investigating but Not Implementing Regulatory Agreements ............... 82
4.7 Companies Without Standalone Regulatory Agreements ......................................... 83
4.8 Closing Questions ..................................................................................................... 96
Chapter 5. Discussion ....................................................................................................................99
5.1 Introduction ............................................................................................................... 99
5.2 Methodological Considerations ................................................................................ 99
5.2.1 Delimitations ............................................................................................... 99
5.2.2 Limitations ................................................................................................. 102
5.3 Consideration of Results ......................................................................................... 106
5.3.1 Exploration ................................................................................................ 107
5.3.2 Installation ................................................................................................. 110
5.3.3 Initial Implementation ............................................................................... 112
5.3.4 Full Implementation .................................................................................. 113
5.4 Conclusions and Future Direction ........................................................................... 117
REFERENCES ............................................................................................................................121
Appendices ...................................................................................................................................132
Appendix A. Example Regulatory Competency Frameworks ........................................ 132
Appendix B. Survey ........................................................................................................ 139
Appendix C. Comments Included for Company Approach to Regulatory Agreements . 152
Appendix D. Comments: Reasons Respondent Companies Do Not Have Regulatory
Agreements ............................................................................................................. 161
Appendix E. Comments Included for Barriers to Having Regulatory Agreements ....... 162
Appendix F. Comments: Other Ways to Cover Regulatory Requirements Than
Regulatory Agreements ........................................................................................... 163
Appendix G. Text Comments Included for Respondents Additional Information or
Comments ............................................................................................................... 164
Appendix H. Draft Checklist for a Regulatory Agreement ............................................. 169

vi
List of Tables
Table 1: Acronym and Term Definitions ........................................................................8
Table 2: Elements of a Quality Agreement ...................................................................27
Table 3: Regulatory Tasks to be Considered in Regulatory Agreements .....................40
Table 4: Outline of Implementation Stages: Questions for Regulatory Agreements ...46
Table 5: Focus Group Participants ................................................................................49
Table 6: Respondent Job Title by Size of Company .....................................................55
Table 7: Structure of Company Relationships With Partners .......................................57
Table 8: Agreement Types With Partners .....................................................................59
Table 9: Satisfied with Company Approach to Regulatory Agreements ......................61
Table 10: Not Satisfied with Company Approach to Regulatory Agreements ...............62
Table 11: Awareness of Agreements by Company Size, Job Title, and Product Type ..63
Table 12: Company Size by Approach to Partnership Agreements ...............................64
Table 13: Resources Useful to Research Regulatory Agreements .................................66
Table 14: Barriers to Developing Regulatory Agreements .............................................68
Table 15: Timing of Regulatory Agreement Introduction ..............................................71
Table 16: Hurdles to Developing Regulatory Agreements in Own Company ...............72
Table 17: Team Members Involved in Developing Regulatory Agreements .................75
Table 18: Resources Involved in Developing Regulatory Agreements ..........................76
Table 19: Methods Used to Collect Feedback on Initial Regulatory Agreements .........77
Table 20: Metrics Used to Measure Effectiveness of Regulatory Agreements ..............78
Table 21: Regulatory Agreement Elements to Include in the Revised Agreement ........81
Table 22: Resources to Research Development of Regulatory Agreements ..................83
Table 23: Respondents Not Using Regulatory Agreements by Reason .........................85
Table 24: Barriers to Having Regulatory Agreements ...................................................87
Table 25: Critical Development Elements to Include in a Regulatory Agreements .......90
Table 26: Review and Logistics Elements to Include in Regulatory Agreements .........92
Table 27: Internal Expertise Available to Implement Regulatory Agreements ..............94
Table 28: Reasons Why Little is Heard About Regulatory Agreements ........................96
Table 29: Rank Order: Reasons Why Little is Heard About Regulatory Agreements ...97
Table 30: Example Text Comments: Any Additional Information or Comments ..........98
Table 31: Comments: Satisfied with Company Approach to Regulatory Agreements 152
Table 32: Comments: Not Satisfied with Company Approach to Regulatory
Agreements ..............................................................................................157
Table 33: Comments: Reasons Companies Do Not Have Regulatory Agreements .....161
Table 34: Text Comments: Other Barriers to Having Regulatory Agreements............162
Table 35: Comments: Other Ways to Cover Regulatory Requirements .......................163
Table 36: Text Comments: Any Additional Information or Comments .......................164

vii
List of Figures
Figure 1: Growth of new molecular entity approvals and biopharmaceutical companies14
Figure 2: R&D spend versus new drugs by the US FDA (1991 – 2012) .......................15
Figure 3: Increase in specialty and biologics product sales and biologics as a percent
of drug development timeline, 2010 – 2014 ..............................................20
Figure 4: A Fully Integrated Model of Drug Development ...........................................32
Figure 5: Example Contributions: Two-company Partnership for an NDA/BLA
Submission .................................................................................................33
Figure 6: Implementation Stages ....................................................................................43
Figure 7: Active Implementation Frameworks Overview ..............................................45
Figure 8: Title Represented by Respondents ..................................................................52
Figure 9: Department/Function Represented by Respondents .......................................53
Figure 10: Organization / Company Affiliation ...............................................................54
Figure 11: Size of Organization / Company .....................................................................54
Figure 12: Product Type ...................................................................................................56
Figure 13: Regulatory Expectations Addressed with Partners .........................................60
Figure 14: Use of Regulatory Agreements With Business or Academic Partners ...........65
Figure 15: Benefits of Implementing Regulatory Agreements With Business /
Academia ...................................................................................................69
Figure 16: Timing to Review the Initial Regulatory Agreement .....................................71
Figure 17: Hurdles to Developing Regulatory Agreements With Vendor Company ......73
Figure 18: Hurdles to Developing Regulatory Agreements With Partner or Academia ..74
Figure 19: Development Elements Included in Initial Regulatory Agreements ..............79
Figure 20: Review and Logistics Elements Included in Initial Regulatory Agreements .80
Figure 21: Reasons for Not Having Regulatory Agreements ..........................................84
Figure 22: How Companies Cover Regulatory Requirements With Their Partners ........88
Figure 23: Impediments to Using Regulatory Agreements ..............................................95

viii
Abstract
As pharmaceutical companies change their business models to remain
competitive, they seek ways to reduce the costs and risks associated with drug
development. Outsourcing to contract research and manufacturing organizations can
reduce the costs of clinical trials and manufacturing but may result in a patchwork of
vendors that is difficult to integrate. Integration can be simplified by entering into more
comprehensive “preferred” partnerships with service providers and agreements with other
companies or academic organizations. Still, it can complicate the business model by
adding new legal and operational requirements. A standalone regulatory agreement has
the potential to clarify the relationships and responsibilities between partners working
jointly on a single regulated product. This study used survey methods to explore the
views of industry professionals on the need for and current use of standalone regulatory
agreements. A total of 294 respondents responsible for drug development partnering
activities participated in the survey. About half, primarily from larger companies, had
heard about regulatory agreements, and half of this smaller group had moved forward to
implement them. Benefits of implementation included clarification of regulatory roles
and responsibilities, standardized regulatory expectations between the companies, and
earlier discussion about joint regulatory strategies. The development of regulatory
agreements was challenged by the absence of templates, agency or industry guidance, or
a clear requirement by health agencies. Respondents not using regulatory agreements
had not considered them or did not see a need for a standalone agreement. The use of
regulatory agreements appeared to depend upon the type of partner, the complexity of the
relationship, and the availability of internal expertise and support.

1
Chapter 1. Overview
1.1 Introduction
The pharmaceutical industry has undergone dramatic structural change over the last few
decades. Even as recently as 20 years ago, most companies carried out their Research &
Development (R&D), analytical services, nonclinical studies, manufacturing of drug substance
and/or drug product, and clinical trials “in house”. As the costs and risks of drug development
increased, however, companies realized that efficiencies and capabilities could be gained by
outsourcing some activities (Clearwater International Healthcare, 2019; Buvailo, 2020). These
companies began to work with external contractors, such as storage and distribution suppliers,
Contract Manufacturing Organizations (CMOs), and Contract Research Organizations (CROs).
These adjunct relationships could bring considerable value. They allowed companies to add
capabilities to their development teams and to accomplish certain specialized activities more
quickly (Reepmeyer, 2006a; Reepmeyer, 2006b; Buvailo, 2020) while containing clinical and
production costs. Further, a time-limited project could be completed without requiring the
commitments, training and oversight associated with hiring new personnel within the sponsor’s
company and adding those additional ongoing costs to the company’s bottom line. The
importance of such relationships is reflected in the growth of specialist contractors. For
example, CROs responsible for parts of the clinical trials that companies outsource have
developed into a $40 Billion global industry (P&T Community, 2019).
At first, the interactions with CMOs and CROs were typically transactional. They were
often put into place before a drug was approved and were intended to take advantage of the
specialized capabilities of these specialist vendors to execute particular parts of the development
program. The deliverables were typically determined before the relationship was established and

2
the contracted agreements reflected the nature of the service. As outsourcing activities grew,
companies acquired a range of diverse contracted agreements. These might include, for example,
Quality Agreements (QAGs) governing the product’s ingredients and container, Technical and
Quality Agreements that detail the quality and testing of the product, and Supply Chain
Agreements that define terms for pricing and payment, minimum and maximum purchase
quantities, delivery lead times, product return policies, and liabilities when materials are lost
(Fraser & Thompson, 2019). Clinical trial contracts might define the responsibilities of the
sponsor, CRO and clinical site, publication and intellectual property terms, and arrangements for
record keeping, inspection, indemnification, and insurance (Sampat, 2017).
As more experience was gained with contracted interactions, contracts become more
varied and often more comprehensive. Companies became adept at putting into place broader
agreements, called Master Service Agreements (MSAs). An MSA is “one legal document that
consolidates separate but related agreements between the same signing parties” (The Law
Dictionary, n.d.). Its goal is to accelerate the contracting process and simplify future contracting
agreements (UpCounsel Inc., n.d.). The MSA will cover most details and expectations that each
partner must satisfy in order to fulfill the contract. Areas included in an MSA are confidentiality,
delivery requirements, dispute resolution, intellectual property rights and payment terms. An
MSA can make the contract process faster and simplify future contract agreements.
However, more recently, the interactions between a sponsor company aiming to
commercialize a new drug and its partners have changed in a significant way. Outsourcing has
transitioned from paying for services. It now also includes other types of business structures,
including unrestricted grants and centers created for drug discovery and partnerships with
specialized CROs, academia and biotech companies to share the financial or development risks

3
of early drug development (Reepmeyer, 2006b; Milne & Malins, 2012; Clearwater International
Healthcare, 2019; Buvailo, 2020). These types of arrangements do not lend themselves to
simpler transactional contracts because they involve activities that are less clearly defined, and
instead pursue new ideas using specialized technologies to address the increased complexities of
drugs in development. Thus, sponsor companies must look at new ways to define and gain
consensus on the various roles and responsibilities of the partners as they work in their own
spheres toward the common goal of a market approval for a new medical product. Of particular
concern is the way that the two organizations will contribute to the regulatory deliverables and
filings related to that product during the time of the partnership, which often extends over many
years. The knowledge and data generated by the multiple vendors, contractors or partners of
each company involved must be shared over the period of this longer relationship. With so much
risk if misunderstandings occur, it seems important to capture the expectations for the different
partners in a contractual way. However, the contracts may be unusual in that they specify
elements that will encompass many different activities from early development to product
approval. Further, the contracts must also take into account the need to be more flexible and
amenable to changing events and circumstances. Even though these other types of agreements
might provide insight into some of the areas that regulatory contracts might cover, the types of
agreements described as already available above are unlikely to cover all of the areas in which
clarity with regard to responsibilities and relationships are important.
1.2 Statement of the Problem
Standalone regulatory agreements have not been described in any detail in the current
literature; certainly, no research could be found to examine systematically the extent of their use
or content. This finding suggests that regulatory agreements are not yet a standard practice

4
between companies or between a company and academia when those organizations are jointly
developing a drug or combination product. More specifically, we have no clear picture of the
extent to which regulatory agreements have been introduced as part of these partnering
relationships. Further it is not clear what key regulatory requirements would be most important
to address in such an agreement. It is unlikely that one solution would be suitable for all
regulatory agreements, but common regulatory elements may be captured by most to reflect the
activities conducted and integrated by regulatory professionals during drug development. Some
of these elements could include preparation of submission documents, review of nonclinical and
clinical research reports, attendance at health agency meetings, review of product labeling,
advertising and promotion, and ownership of original submission documents and records. It is
possible that companies are relying on other existing agreements to meet this need, at least to
some extent, but we do not know if and when such an approach is viewed as adequate. We also
have little insight into the previous experiences of companies in partnership agreements and
whether they believe that a more comprehensive regulatory agreement would have been helpful.
1.3 Purpose of the Study
This study explored the current use and potential need for regulatory agreements in the
medical products industry. Industry professionals responsible for regulatory, project
management, and alliance management were surveyed to understand their experiences, if any,
with regulatory agreements in the bio/pharmaceutical industry. The initial focus for this study
was on drug companies due to the large number of drug development programs, however the
opportunity was also taken to include medical device companies for combination products. A
novel survey instrument was developed by reference to the implementation model of the
National Implementation Research Network (Fixsen et al., 2009; Bertram, Blasé & Fixsen,

5
2015), that divides implementation into stages from exploration to full implementation.
Questions explored whether some form of regulatory agreement has been attempted or
implemented, and the experience that they have had at different stages of implementation. This
approach helped to identify why or why not companies developed regulatory agreements and the
areas in which implementation of such a contract was seen to be useful or problematic. The
survey instrument was critiqued by a focus group of experts and was disseminated using a web-
based platform, Qualtrics (Qualtrics.com) that assisted with the graphical display and descriptive
statistical analysis of the data.
1.4 Importance of the Study
This study is important because it provides insight into the usefulness of a tool that might
be applied broadly in the pharmaceutical industry environment. It was a first look at industry’s
experience when its professionals try to manage formally the regulatory responsibilities between
partnering companies. The results of this study are intended to provide industry stakeholders
considering joint drug or combination product development with a better understanding of the
current status of regulatory agreements. The survey showed that although regulatory agreements
are in use by some companies, they are not employed universally. Industry stakeholders that are
not using standalone regulatory agreements may be able to find information that helps to inform
or guide implementation of such agreements and to consider what might be included in
regulatory agreements. For stakeholders that have included regulatory elements in other
company contracts, this information can also be used to align with alternative industry practices.
The results may be of broader interest to stakeholders who are not in regulatory
departments, even though the agreements are designed specifically to detail the distribution of
functions amongst regulatory partners. They could be used by legal advisors who recognize the

6
vulnerabilities of regulatory missteps, but who may be unfamiliar with all of the activities that
such agreements might cover. They could be interesting to regulatory agencies, that already
have expectations regarding other forms of agreements, and may want to understand trends in
those aspects of industry activity that are particularly relevant amongst the groups for whom they
conduct reviews or provide advice.
1.5 Limitation, Delimitations, Assumptions
Several limitations may affect the interpretation of this study. Although an extensive
search was undertaken for relevant articles on regulatory agreements, few were found. The
foundation of previous work was therefore limited to more indirect literature regarding
agreements dealing with manufacturing, quality, or clinical trial activities between medical
products companies and other types of organizations. This may have affected the development
of appropriate questions and thus limit the validity of the survey. Results of the survey depend
on securing a sufficient number of representative and eligible respondents with the necessary
experience and background. Much effort was expended to assure that respondents were sought
who were knowledgeable about the contracting agreements, but it is possible that not all views of
regulatory professionals have been collected. Further, the length of the survey was constrained
to assure that its respondents could complete the survey in a relatively short period of time. This
restricted the depth and breadth of questions that could be posed. The quality of the research
might also have been limited because this is the first time that I have worked with survey
methods.
The nature of the survey topic sets certain delimitations for this dissertation that must also
be considered when determining its external validity. First, it was confined to
bio/pharmaceutical and medical device companies and academic institutions that are involved in

7
drug development and to experienced respondents who work in these areas of outsourcing
regulatory activities. Also included were individual regulatory consultants and regulatory
consulting companies (strategy, chemistry, manufacturing, and controls (CMC), operations)
providing services to these industries. Targeted participants were senior level regulatory
professionals, project managers, alliance managers, finance, and regulatory attorneys involved in
partnerships or joint collaboration activities between medical products companies or between a
company and an academic institution, at any phase of drug development.
In this study, we assume that the participants will answer truthfully. Still, concerns about
maintaining the confidentiality of information may reduce the detail of their responses even if
assurances of anonymity and confidentiality are given.
1.6 Organization of Thesis
This thesis is organized into five chapters. Chapter 1 is an overview, introducing the
topic of regulatory agreements, the problem statement, and the purpose and importance of the
study. Also included are the organization of the thesis and definitions. Chapter 2 outlines the
literature relevant to the field of agreements in the pharmaceutical industry and defines the
framework through which the desired elements for regulatory agreements will be examined.
Chapter 3 defines the methods used to develop the study survey, and Chapter 4 details the study
results. Finally, Chapter 5 discusses the significance and validity of the study results.

8
1.7 Definitions
Table 1: Acronym and Term Definitions
Acronym / Term Definition
AGRE Association of Graduate Regulatory Educators
API Active Pharmaceutical Ingredient
APIC Active Pharmaceuticals Ingredients Committee
Biopharmaceutical A medical product manufactured in living organisms
BPTF Bulk Pharmaceutical Task Force
CMC Chemistry, Manufacturing and Controls
CMO Contract Manufacturing Organization
CRO Contract Research Organization
FDA Food and Drug Administration
GMP Good Manufacturing Practices
GSK Glaxo
IPEC International Pharmaceutical Excipients Council
MSA Master Service Agreement
NDA New Drug Application
NIH National Institutes of Health
NME New Molecular Entity
PhRMA Pharmaceutical Research and Manufacturers of America
POC Proof-of-concept
PV Pharmacovigilance
PVA Pharmacovigilance Agreement
QAG Quality Agreement
R&D Research & Development
RAPS Regulatory Affairs Professional Society
Regulatory domain
topic
A broad domain that represents a major area of tasks and responsibilities for
regulatory professionals. The domain topic area used in this dissertation was
developed by combining regulatory competency models defined by RAPS,
TOPRA, and AGRE. The eight areas are: General, foundational information;
strategic planning; premarketing/preapproval; postmarketing/postapproval;
communication and soft skills; and leadership
RCF Regulatory competency framework. A framework that describes the essential
elements or core competencies for regulatory professionals or that are expected for
students with MS degrees in regulatory studies. These frameworks are based on
key competency areas for regulatory professionals
SOCMA Society of Chemical Manufacturers and Affiliates
TOPRA The Organization for Professionals in Regulatory Affairs
TORO Transfer of Regulatory Obligations
US United States

9
Chapter 2. Literature Review
2.1 Structure of the Literature Search
A search was conducted to explore the current literature related to regulatory,
manufacturing, quality, and clinical agreements made between two or more medical products
companies, between medical products companies and academic institutions, or between medical
products companies and regulatory, manufacturing, quality, or clinical contractors. Using three
search engines (Web of Science, PubMed, and Google Scholar), I searched databases including
scholarly articles from 1945-present in medicine, medical science, and social sciences and
conferences in sciences from 1995-present. The first searches using the keyword “regulatory
agreements” returned over 200 citations in PubMed, over 4800 citations in Web of Science, and
greater than a million citations using Google Scholar. Additional keywords were added to focus
on more specific references related to pharmaceutical enterprises, including drug development,
joint, manufacturing agreements, quality agreements, clinical and clinical trial agreements,
pharmaceutical companies, biopharmaceutical companies, biotech, and academia. By narrowing
and combining search terms, the number of citations in PubMed and Web of Science, and
Google Scholar were reduced to a reviewable number of about 650 and 700, respectively.
Citations were reviewed by title and abstract, and publications were eliminated that were
unrelated to this topic. Additional searches were conducted on certain sites likely to have
information on regulatory agreements such as regulatory agencies and professional societies.
From this work, 42 citations were identified to be most relevant. In addition, attempts were
made to find references to regulatory, manufacturing, clinical, and quality agreements in non-
refereed publications such as trade publications and web-based media such as blogs and news
articles. Sources of this material included the Regulatory Affairs Professionals Society website
(www.raps.org), industry association websites such as International Pharmaceutical Excipients

10
Council of the Americas (ipecamericas.org), the Society of Chemical Manufacturers & Affiliates
(socma.org), and publications targeted to the life science industry such as PharmaVOICE
(www.pharmavoice.com) and Life Science Leader (www.lifescienceleader.com). Regulatory
and legal data from the US FDA (www.fda.gov) and Library of Congress (www.loc.gov) were
also searched. In all of the databases and websites searched, there was little information or
records related to pharmaceutical regulatory agreements. More information was available on
manufacturing, quality, and clinical trial agreements, which provided useful structure and content
for considering and evaluating existing regulatory agreements.
2.2 Evolution of Bio/pharmaceutical Companies
Pharmaceutical development and manufacture had changed markedly since the 1800s
when drugstores appeared in US cities and towns (Knowlton & Penna, 2003). Those early
businesses had a variety of forms: extensions of a physician’s shop; colonial apothecaries that
made drugs and other products; general stores that sold everything from flour to opium; drug
wholesalers that repackaged drugs and related products imported from England for resale
(Kremers & Urdang, 1976). What they had in common was the relative simplicity of their retail
operations. In such operations, the proprietor performed most of the activities “in house”. By
the 1950s, pharmacists in those stores were compounding 80% of prescriptions as tablets,
capsules, lotions, ointments, and liniments for US consumers (Guharoy et al., 2013).
However, the need for drugs in large quantities during World War II drove the
development of manufacturing facilities that became adept at manufacturing drugs in bulk
quantities. This transformation changed the risk profile of the drug supply. Compounding
pharmacies that made mistakes in their drug “manufacture” could harm only one or a few people
at a time. However, large manufacturers distributing an unsafe drug had the potential to affect a

11
much larger number of patients and thus pose a significant threat to public health. A series of
such crises, reaching back even to the immediate prewar period, increased the constraints placed
on drug manufacture over time. This, in turn, changed dramatically the business approaches of
an industry that gradually took over the role of making drugs for a health care system with
increased sophistication and demands. What follows is a condensed description of events that
affected the course of this evolution in a significant way, first to assure a safer manufactured
drug supply and then to assure that the manufacturers now responsible for that supply could
cooperate in drug production.
2.3 Key Historical Events Shaping Regulatory Oversight
Much of the early evolution of drug development and manufacture was shaped by tragic
experiences with unsafe products. Perhaps the earliest event with the greatest regulatory impact
occurred in 1937, when the S. E. Massengill Company distributed 240 gallons of Elixir
Sulfanilamide, sulfanilamide dissolved in diethylene glycol, in 633 shipments all over the
country. Over 100 people died before all of the unconsumed drug was retrieved in what was
perhaps the first organized governmental drug recall (Ballentine, 1981). Responding to the
sulfanilamide crisis, the 1938 Food, Drug, and Cosmetic Act required that companies prove their
drugs to be safe through the submission of a New Drug Application (NDA) that the Food and
Drug Administration (FDA) would review.
In 1941, the Winthrop Chemical Company distributed several lots of sulfathiazole tablets
contaminated with phenobarbital that had been manufactured in the same plant. By the time the
sulfathiazole recall was completed, nearly 300 people had been injured or killed by the
contaminated tablets from five different lots manufactured at Winthrop’s Rensselaer, New York
plant (Kremers & Urdang, 1976; Swann, 1999). The distribution of contaminated sulfathiazole

12
tablets caused the FDA to revise manufacturing and quality control requirements, which would
eventually be known as the Good Manufacturing Practices (GMPs). Soon thereafter, FDA added
requirements that some drugs undergo batch certification, a process by which companies would
submit samples from each batch lot to FDA for testing prior to release. Lot release for insulin
was first required in 1941 (Grant, 1956), and for penicillin in 1945 (United States Federal
Security Agency, 1946); it was later expanded for all antibiotics (Immel, 2001).
In 1959, the Merrill Pharmaceutical Company submitted an application to the FDA to
market thalidomide in the US for a variety of indications, including asthma, cancer, tuberculosis,
insomnia, and to treat morning sickness in pregnant women. Already approved in Europe and
sold in 48 countries, thalidomide was linked to birth defects in babies whose mothers took the
drug during gestation. By 1961, over 300 cases of birth defects were reported, and in 1962,
Merrill withdrew their US application (Hearings, 1963; FDA, 2012; Tantibanchachai, 2014).
The thalidomide crisis caused Congress to enact the Kefauver-Harris Amendment of 1963,
which greatly expanded the oversight of clinical trials. It also required drug companies to
demonstrate efficacy as well as safety of the drug before marketing and to monitor and report
serious adverse events after the drug was on the market.
As Congress gave FDA the authority to oversee pharmaceutical manufacturers with
respect to the growing collection of laws and amendments that they were passing, the FDA
responded by expanding that legal framework through multiple regulations for which they
exercised oversight. Pharmaceutical companies then had to assure compliance, first with quality
requirements that governed manufacturing and later with regulations that covered a broader
range of activities across the product life cycle from animal and clinical trials and submissions to
postmarketing activities and pharmacovigilance. All these requirements changed the business

13
models of the companies by adding a complex web of legal and operational activities. These
changes, intended to keep drug products safe during manufacture, storage, and distribution, are
key to this research and are discussed in more detail in the section on Outsourcing Management.
The second half of the twentieth century was a time of explosive expansion for the
pharmaceutical industry. Pharmaceutical companies with significant Research and Development
(R&D) activities grew in number, size, and capability. As fully integrated and autonomous
companies, they focused on developing new saleable drug entities by screening and testing large
numbers of novel compounds. They also identified new methods of development and
manufacture that allowed the companies to move the most promising compounds into clinical
studies more quickly. A metric of this change was the growth in the annual rates of New
Molecular Entities (NMEs) brought to market at this time. FDA more than doubled the annual
rate of NME approvals from 1940 to 1990 and then doubled that rate again by the end of 2000
when both NME approvals and numbers of active pharmaceutical companies appeared to peak.
Figure 1 shows the growth over time of the number of FDA-approved NMEs and the number of
active companies that have contributed one or more of those new drugs (Kinch, 2014; Kinch and
Hoyer, 2015).

14
Figure 1: Growth of new molecular entity approvals and biopharmaceutical companies
(Reprinted from Kinch and Hoyer, 2015, with permission from Elsevier)

However, some might say that the golden age of drug development is over (Garnier,
2008; Huang & Aslanian, 2012; Ubel, 2016). The last several years have experienced a
flattening of new drug introductions, and many of those have been aimed at orphan indications or
line extensions. As patents on the branded drugs expired, cheaper generic drugs began to erode
the markets of the innovative pharmaceutical giants, to the point that, in 2019, generic products
constituted about 90% of the drug sales in the US market (Inserro, 2019). At the same time, the
costs of drug development have gone up steadily (Figure 2). Increases in time and costs can be
attributed to several factors. Many of the new products are biologicals, which are well known to
be more expensive to produce (Tufts CSDD, 2006; Munos, 2009; Huang & Aslanian, 2012).
Further, the size and scope of the clinical trials for many new products have increased.
Regulatory requirements during the clinical phase have required larger and more diverse patient

15
cohorts (Munos, 2009; PhRMA, 2020). The complexity of the protocols needed to establish
safety and efficacy have made trials more expensive and cumbersome (Tufts CSDD, 2009). The
costs and lengths of clinical trials have also been affected by the growth in global markets.
Global phase 3 clinical studies are typically required in order to assure that at least some portion
of tested subjects come from subjects of countries in which the company aims to do business
because a condition of that business can be the testing of drugs on citizens of the relevant
countries (Cone, McAuslane & Walker, 2004).
Figure 2: R&D spend versus new drugs by the US FDA (1991 – 2012)
(Reprinted from (Fernald et al., 2013), with permission from Fernald et al.)

Pharmaceutical companies are also threatened by the risks that a new product may fail to
gain commercial entry. A new molecule often will undergo a very expensive development
process only to reveal an insufficient level of safety or efficacy. Companies under pressure to
perform for their stockholders may hurry an early drug candidate into clinical trials or adopt a
‘shots on goal’ strategy that emphasizes quantity over quality in the hopes of increasing the odds
of finding a successful product (LaMattina, 2011; Kinch & Hoyer, 2015; Ku, 2015). Either of

16
these strategies may result in drug failures after expensive clinical trials have been conducted.
Such failures starve resources from molecules that could have succeeded had the resources been
redirected (Kinch & Hoyer, 2015). All these challenges have forced pharmaceutical companies
to explore new models for drug development.
2.4 Changes in the Organization of Biopharmaceutical Companies in the US
In the 1990s, it was not unusual for companies to conduct most activities in-house.
Today a very different pattern is typical. Many companies attempt to spread the risk associated
with an uncertain drug development outcome by entering into joint agreements with another
company or academic institution to carry out some of the R&D activities. Thus, pharmaceutical
companies began to reduce their direct investments for in-house R&D. Consolidation trends are
reflected in the rise in numbers of mergers and acquisitions in the pharmaceutical industry during
the late 1990s and early 2000s (Gautam & Pan, 2016). Some bought rather than discovered their
new products by acquiring smaller companies with molecules in early development or by
licensing products from academia (Kremers & Urdang, 1976; Swann, 1999; Gleadle et al., 2014;
Kinch & Hoyer, 2015). Of even greater interest for pharmaceutical companies were
biotechnology companies with FDA approval experience rather than early-stage experience.
These biotechnology companies were being acquired at a rate ten times higher than the newly
established firms (Knowlton & Penna, 2003).
Some large companies also merged with other large companies to form “mega
companies”. Examples of these mergers include Astra and Zeneca, Ciba-Geigy and Sandoz,
Pfizer and Warner Lambert, Sanofi and Aventis, Glaxo and SmithKline, and Pfizer and
Pharmacia (Gautam & Pan, 2016). These mega companies supported their own multiple large
R&D centers, multiple manufacturing sites, and large sales forces. However, despite these

17
seeming advantages, the newly formed companies often became less efficient because of their
mixed governance layers and poor cultural integration. Nonetheless, companies justified these
mergers by looking at economies of scale, diversified portfolios, and business opportunities
across the healthcare spectrum as a way to counter the problems of declining R&D productivity
(Gautam & Pan, 2016).
Not all mergers yielded the results that had been anticipated. As R&D investment costs
continued to rise, the number of FDA approved drug products did not appear to increase
proportionally (Rathi et al., 2014). The increasing spending on R&D (Figure 2) has been
attributed to an overall increase in all aspects of R&D costs but appeared to be affected most
strongly by increased regulatory requirements, increased costs of clinical studies, and the use of
new technologies which require expensive capital equipment (Kaitin, 2010; Schuhmacher,
Gassmann & Hinder, 2016). The large size of the newly merged R&D organizations has also
been suggested to be associated with inefficiencies and personnel issues. A loss of scientific
discovery became problematic as R&D personnel worried about losing their jobs due to layoffs
or outsourcing (Schuhmacher, Gassmann & Hinder, 2016), and scientists lost passion for R&D
in the more procedure-bound environment (Garnier, 2008). As the number of blockbuster drugs
decreased, even the merged and typically downsized sales force often remained unjustifiably
large in the face of a diminished pipeline (Garnier, 2008).
As the more challenging consequences of mega mergers became evident, companies
looked to different strategic tactics to ensure profitability (Munos, 2009; Kaitin, 2010; Gautam &
Pan, 2016; Schuhmacher, Gassmann & Hinder, 2016). Large companies began to divest non-
core assets and focus instead on areas of strength so that their business models became leaner
and more limited in scope. In 2013, for example, Abbott split into two parts- an innovative

18
pharmaceutical business called AbbVie and a diversified healthcare company that kept the
original name (Gautam & Pan, 2016). In 2016, GlaxoSmithKline (GSK) and Novartis
exchanged certain aspects of oncology, consumer health, and vaccine portfolios to create more
focused organizations; GSK became specialized in consumer health and vaccines, whereas
Novartis focused on oncology products (Gautam & Pan, 2016).
2.5 Growth of the Biotechnology Industry and Academic Centers
At the same time that pharmaceutical companies were trying to find ways to reduce the
costs of new drug development, the biotechnology industry was growing. With less bureaucracy
and flexibility, biotechnology companies began to specialize in developing novel drugs from
biologics (Khanna, 2012). In the 1970s and 1980s, some pharmaceutical companies began to
take advantage of the capabilities of the biotechnology specialists by partnering with these
companies to identify new targeted therapies for diseases (Khanna, 2012; Kinch & Hoyer, 2015).
Today, many large pharmaceutical companies have shifted their interests to developing later-
stage assets that have already demonstrated proof-of-concept (POC), leaving early development
to be carried out by academic centers or biotechnology companies (Khanna, 2012).
The growth of biotechnology and academic centers was accelerated by changes in
legislation, including the Bayh–Dole Act of 1980. This Act gave universities the ownership of
inventions resulting from federally funded research. By so doing, the Act incentivized the
development of spinoff companies based on this university research. Universities expanded their
research infrastructure and began to encourage the kinds of research previously done only by
industry, sometimes even funded from patent revenues (Milne & Malins, 2012; Kinch & Hoyer,
2015). This trend was further driven by increases in the level of external support for what
funding agencies were beginning to characterize as “translational science”. Not only were grants

19
made available for research projects that were directed at the preclinical testing of drugs, but
activities were also spurred by a novel program through the National Institutes of Health (NIH)
called the “Clinical and Translational Sciences Initiative” (CTSI) that funded university groups
undertaking significant clinical research and methodology development. Government agencies
such as the NIH and the NCI (the National Cancer Institute that created the “Cancer Therapy
Evaluation Program” (CTEP)) recognized the need to stimulate clinical and translational
research and went as far as to create clinical trial enterprise initiatives (Khanna, 2012; Kinch &
Hoyer, 2015).
All of these initiatives shifted the balance of directed research to include many more
players with specialized skills, to whom the pharmaceutical industry could outsource certain
types of R&D. The transition was occurring at the same time as the nature of the products
themselves was evolving. More specialty biologics than small molecules were introduced to
treat primary care indications such as high cholesterol, rheumatoid arthritis, depression, and heart
disease. A comparison of the types of products earning the highest revenues in recent decades
underlines this trend. In the period between 1995 – 2005, primary care blockbuster drugs such as
Lipitor®, Celebrex®, Abilify®, and Crestor® accounted for ∼80% of revenues for the drug
portfolios of most large pharmaceutical companies. However, during the next decade, large
pharmaceutical companies were transitioning their pipelines from primary medicines to specialty
medicines and biologics to address high unmet medical needs. This trend was encouraged by
multiple factors, including a better understanding of certain disease states and scientific and
technological innovations that allowed for the development of personalized medicines,
companion diagnostics, and biologics. By 2014, biologics comprised ~20 – 60% of their
pipelines (Figure 3) (Gautam & Pan, 2016).
20
Figure 3: Increase in specialty and biologics product sales and biologics as a percent of
drug development timeline, 2010 – 2014
(Reprinted from Gautam & Pan, 2016, with permission from Elsevier)
However, research was not the only type of activity to be outsourced. To reduce costs
further, companies found opportunities to outsource activities associated with drug development
and production, including clinical trial management, manufacturing, and pharmacovigilance, to
specialty providers. This change in strategy introduced additional challenges. Legal contracts
became more important to control these new relationships and to avoid the potential
misunderstandings and conflicts that inevitably arise with interactions between different
organizations. In the sections below, I will discuss how certain types of agreements have been
put into place for specific reasons and how those agreements serve in some respects as templates
for regulatory agreements, which are less common and are the subject of the research here.

21
2.6 Outsourcing Management
In any relationship, agreements are needed to ensure that the involved parties understand
their responsibilities and align their goals more effectively. Sometimes, relationships are
developed informally, but more frequently, arrangements between companies are formalized
with a “contract”. Without a clear written contract, the details of the business relationship and
deliverables may not be clear, and this can cause misunderstandings or even legal issues for the
parties (Kaufman, 2017b).
2.6.1 Contract Basics
A contract is…
…an agreement between private parties creating mutual obligations enforceable by
law. The basic elements required for the agreement to be a legally enforceable
contract are: mutual assent, expressed by a valid offer and acceptance; adequate
consideration; capacity; and legality (Gilkis, 2019).
The first element necessary for a contract is a specific, understandable, and valid offer. The
offer must be accepted or agreed to by all parties that will be bound by the terms of the contract.
A contract does not exist if the parties cannot agree to the stated terms. Consideration is the
exchange of something of value. Typically, this is money. However, it can be intellectual
property, performance of a service, delivery of a product, or future rights to the research, for
example. Capacity requires that all parties entering into the agreement are capable of binding
themselves or their institutions to the terms of the contract. Capacity can be interpreted as age or
mental capacity for some types of contracts, but in a business setting, it also includes the
requirement that the party signing the agreement has the authority to do so for the company.
Legality refers to the requirement that the terms of the contract do not break any laws.

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2.6.2 Manufacturing Agreements
Manufacturing was one of the first areas to be outsourced by bio/pharmaceutical
companies to external contractors. By the late 1990s, 70% or more of the Active Pharmaceutical
Ingredients (APIs) used to manufacture drug products for the US market came from sources
outside of the US. Prior to 1996, three types of arrangements were typical. First were
arrangements in which global bio/pharmaceutical companies provided manufacturing of
intermediates or final products for companies of similar size in market sectors where the two
companies were not competing. In some of these cases, companies provided these services on an
informal basis, but in others, companies such as Schering Plough and Pharmacia & Upjohn had
formal divisions for their outsourced activities, and these even included specific sales teams to
promote their manufacturing and sourcing services. Second, certain operations specializing in
generic API manufacturing, primarily conducted in Europe, began to offer bulk API to a number
of generic companies. Third, large pharmaceutical companies continued to concentrate on in-
house R&D and manufacturing activities but used outside custom manufacturers with specific
formulation expertise.
From 1996-2007, several concurrent trends helped to grow the CMO industry. Some
CMOs began to expand their size and capabilities by acquiring other facilities. For example,
Lonza, a contract manufacturer specializing in small molecule API, acquired Celltech to
establish additional capabilities in the manufacturing of biologics. This trend was encouraged
when larger pharmaceutical companies whose pharmaceutical products were going off patent
looked to offload excess manufacturing capacity and sold their assets to CMOs. In some of these
deals, the facility was sold with contracts in place to produce the legacy drug products of the
previous owner. The success of the CMOs was fueled further by the in-parallel growth of CROs
that pioneered the business and legal challenges that might otherwise inhibit such relationships.

23
Pharmaceutical companies became accustomed to the logistics of using CROs, such as Quintiles,
Covance, and PPD, for clinical trial services such as data management, site monitoring, and
laboratory services. Their positive experiences with those support services validated the use of
outsourcing as an alternative model to in-house manufacturing and provided important
experience in establishing and managing contract service relationships. During this same time,
the number of smaller early-stage biopharmaceutical companies also increased as biotechnology
innovations were introduced and start-up/venture funding became available to fuel their
commercialization efforts. These smaller biopharmaceutical companies often possessed no
manufacturing capabilities and often were not interested in developing their own facilities, so
looked to CMOs for help.
As CMOs became important members of the pharmaceutical and biologics landscape,
challenges with those relationships began to emerge. Concerns began to mount that the suppliers
of those products, often from emerging economies, might not be capable of, or compliant with,
the manufacturing quality dictated by CGMPs as required by the FDA (Immel, 2001; Miller,
2017). To address these concerns, the FDA published the draft "Guidance for Industry:
Manufacturing, Processing, or Holding of Active Pharmaceutical Ingredients" in 1998 (FDA,
1998; Immel, 2001). First finalized in 2001, the guidance was revised and published in 2016 to
correspond with the internationally accepted standard, Q7, “Good Manufacturing Practice for
Active Pharmaceutical Ingredients” and named, not surprisingly, as “Q7 Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients” (FDA, 2016b). Adherence with
GMPs became a de facto requirement in most manufacturing agreements (Miller, 2017).
At the same time, contracts were needed to protect the business interests of both the
CMO and the medical products company buying the product. For example, the CMO might

24
require that the company commit to purchase a minimum volume of product on a regular basis;
alternatively, the CMO might restrict the volume that it could guarantee to supply if it has
several clients for the same product and must plan to allocate space and manufacturing time for
all their needs. If multiple manufacturing facilities are to be involved in drug production, the
scheduling, supply volumes, and financial commitments for each manufacturing operation must
be specified so that different steps or components can fit into a seamless overall process. These
contract restrictions can be problematic for the manufacturer buying API or other components
because they can limit the flexibility of the purchaser to respond to market demand by increasing
or decreasing supply volume (Laybourn, 2016; Kaufman, 2017a). In an age of just-in-time
manufacturing, such arrangements place important constraints that must be acknowledged up
front.
A contract manufacturing agreement establishes the service arrangement between the
medical products company and the manufacturer. Today, that agreement is specified in
considerable detail. It sets the terms under which the manufacturer will produce the product- the
quantity to be produced, pricing, refund policies, and product delivery. Terms vary based on the
type of drug or combination product being manufactured. However, common key components
will specify ordering, payment terms, shipping, and inventory management. Other
considerations include terms to address early termination, intellectual property, liability risks,
and measures to be taken if the product fails to meet product specifications or regulatory
requirements (USLegal, n.d.; Wright, n.d.). On one side, the CMO partner will also want to
document scheduling, including a minimum lead-time for placing manufacturing orders. On the
other, the company will want to document the scheduling of product receipt and the nature of
product specifications. Thus, it will set a timetable and pay penalties if critical raw materials or

25
intermediates are not delivered on time or in compliance with the specifications. The medical
products company will also identify the quality and regulatory standards to be met by the CMO
that might affect final drug product specifications, but also requirements for the API, excipients,
and intermediate drug products used in the process (Laybourn, 2016; Kaufman, 2017a).
The medical products company remains responsible for the quality of the manufactured
product even when components are outsourced. It therefore must have mechanisms in place to
assure that the CMO is compliant with specifications and regulations. The stance of the FDA
related to the relative responsibilities of the purchaser and CMO is illustrated by the 2010
warning letter (Knowlton & Penna, 2003) to River's Edge Pharmaceuticals, LLC for violations
relating to this relationship:
In addition, when requested on inspection, you were unable to provide supportive
documentation that you have qualified your CMO. Your quality agreement explicitly
requires that (b)(4) maintain sufficient facilities, resources, and a qualified work
force. However, there is a lack of assurance that you hired a CMO capable of
manufacturing homeopathic drug products which comply with CGMP (FDA, 2010).
At the 2011 Parenteral Drug Association/FDA Conference, FDA Director Richard
Friedman from CDER’s Office of Compliance, Division of Manufacturing and Product Quality
made it clear that FDA is paying closer attention to contractual relationships because outsourcing
activities have been increasing. Dr. Friedman warned pharmaceutical companies to expect
questions during FDA inspections on how they are monitoring their CMOs (International
Pharmaceutical Quality, 2011).
2.6.3 Quality Agreements
Manufacturing agreements have become complex as more and more quality requirements
are included in them. Both the CMO and sponsor company are responsible to meet regulatory
rules regarding manufacturing quality. Thus, a standalone QAG was developed to document the

26
roles and responsibilities of the CMO and sponsor company with respect to this important aspect
of manufacturing operations. A QAG “is a comprehensive written agreement between parties
involved in the contract manufacturing of drugs that defines and establishes each part’s
manufacturing activities in terms of how each will comply with CGMP” (FDA, 2016a). Some
activities, such as process control and procedural documentation, will be embedded deeply in the
manufacturing operations and will require the contracting third-party manufacturer to have
systems that are followed rigorously. Thus, the contractor will have responsibilities for assuring
compliance with these requirements. Other elements, such as the requirement to conduct internal
audits and to report deviations, may not be the sole responsibility of the contractor. The
contracting pharmaceutical company then would have or share those specific obligations with the
CMO. The contract must state clearly whether the sponsor, the contract facility, or both will be
responsible for carrying out each activity. However, neither the sponsor nor the contract facility
can delegate their related roles or legal or regulated responsibilities to comply with CGMPs
through a QAG or any other method (FDA, 2016a).
QAGs have become standard in the bio/pharmaceutical industry. Not surprisingly then,
templates have been developed by certain trade groups to which the suppliers belong- the Bulk
Pharmaceutical Task Force, an affiliate organization of the Society of Chemical Manufacturers
and Affiliates (Bulk Pharmaceutical Task Force, 2010); The International Pharmaceutical
Excipients Council (ipecamericas.org); and The Active Pharmaceutical Ingredients Committee
(i.e., the European association of API and intermediate manufacturers) (specialty-
chemicals.eu/apic-active-pharmaceutical-ingredients-committee). In addition, FDA published a
guidance document that identifies the elements of a QAG (FDA, 2016a). A list of typical
elements in a QAG are identified in Table 2.

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Table 2: Elements of a Quality Agreement
Source: (FDA, 2016a)
Element Description
Purpose / Scope Covers the contract manufacturing services to be provided
Definitions Precise definitions to be agreed upon by the company and CRO
Resolution of disagreements How quality or other issues will be resolved
Manufacturing Activities Most important section from a CGMP perspective. Documents
activities associated with the manufacturing process including
the quality unit (internal, external and regulatory agency audits,
product release, and contact information of key personnel),
facilities and equipment, materials management, product
specific considerations (product/component specifications,
defined manufacturing operations, including batch numbering,
expiration/retest dating, storage and shipment, lot disposition,
process validation, including design, qualification, and ongoing
verification and monitoring), laboratory controls, and
documentation.
Change Control Initiation of changes by either the CMO or company, reporting,
review (if applicable) and approval of changes to include raw
materials manufacturing processes, testing procedures, shipping
methods, lot numbering and container closure systems.
Revisions to Quality Agreement Lifecycle of the Quality Agreement

2.6.4 Clinical Trial Support Agreements
Manufacturing contracts were only one part of the growing strategy to outsource many
types of specialized activities that could streamline the development and commercialization
processes for pharmaceutical companies. One area of particular importance has been the
outsourcing of clinical trials because these activities have become such a large component of
pharmaceutical R&D spending. Typically, pharmaceutical companies have turned to CROs
specialized in the conduct of clinical trials to constrain costs and improve timelines for study
startups. In 2010, about 30% of the pharmaceutical R&D budget was allocated to the cost of

28
CRO support (Tierney, 2010). By 2017, 55% of the pharmaceutical R&D spending was on
services that included CROs and other functional providers (McSpiritt, 2018).
Like manufacturing agreements, clinical trial support agreements between the sponsor
company and the CRO(s) evolved to document the responsibilities between parties. The
agreements could be for a single study under a standalone contract or for multiple clinical trials,
documented by a Master Service Agreement (MSA). An MSA includes “terms setting out the
scope of the parties’ activities, compensation, compliance obligations, confidentiality,
intellectual property ownership, and publication rights” (Practical Law Life Sciences, 2019b).
Many of the elements of the agreements are similar to those in quality agreements because both
types of activities are heavily regulated. However, the terms are often particularly detailed
because the clinical trial has a complex range of embedded activities and deliverables, including
the conduct of tests and laboratory analyses, the reporting of adverse events, and the global
interactions with sites whose cultures and local requirements vary.
Several elements included in these agreements relate specifically to regulatory
responsibilities. One element is the Transfer of Regulatory Obligations or TORO. Although the
sponsor company is ultimately accountable for the clinical trial, the sponsor may transfer some
of the related duties to a CRO. This transfer of obligations is documented in the TORO because
any legal obligation not specifically identified in writing is assumed to be retained by the sponsor
company. Also included in the MSA is the division of labor when responses to regulatory
requests must be generated and communicated. Because regulatory authorities may request
information from the sponsor or application holder at various times, the MSA will typically
include a provision that requires CROs to handle or forward such requests quickly when received
(Practical Law Life Sciences, 2019a). Assuring clear and comprehensive coordination between

29
the sponsor and CRO is critical for the success of the drug development strategy. Costs of a
failed partnership can include the obvious lost time and money but can also include a negative
trial outcome or a Complete Response Letter (CRL) from the FDA when it detects clinical
deficiencies. These outcomes can damage the reputation and financial outlook for the company
to such an extent that it loses substantial revenue or investment and must reduce the size of its
product portfolio and workforce (Diaz, 2018).
FDA requires that an outsourcing sponsor have both QAGs and TOROs with its
partnering CROs. Its increasing attention to the role played by CROs in the early 2000s is
reflected by FDA’s publication of WLs directed at clinical partners that have failed to put these
agreements in place. In addition, FDA will track the violations identified at a CMO during its
site inspection back to the sponsor company responsible for the product. In a WL issued to
Sanofi Aventis in October 2007, for example, FDA listed deficiencies regarding their
responsibilities as the study sponsor. FDA called out specifically its relationship with the CRO,
PPD Development, in the WL. It stated that “it is the sponsor's responsibility to ensure
adherence to each requirement of the law and relevant FDA regulations” (FDA, 2007). At that
time, no additional WL was sent to the CRO.
In contrast, in 2009, the enforcement of clinical monitoring activities appeared to shift in
a way that held both the sponsor and CRO responsible for deficiencies. In an August 2009 WL
sent to the study sponsor, Johnson & Johnson (J&J), FDA called out J&J’s failure to ensure
proper monitoring of its clinical trial studies in a WL that redacted the name of the deficient
CRO. However, four months later, the CRO, ICON, also received a redacted WL that could be
associated with J&J by matching the timing of the referenced study. In the ICON WL, FDA
states:

30
FDA regulations require that sponsors, or CROs to whom such responsibilities have
been transferred, ensure proper monitoring of clinical investigations. Our
investigation found that ICON failed to properly ensure monitoring of the studies
referenced above. Inadequate monitoring resulted in deficiencies in recordkeeping
with respect to case histories and drug accountability by clinical investigators
participating in the above-referenced studies (FDA, 2009).
In this case, FDA went beyond holding the sponsor uniquely responsible and instead held the
CRO responsible for those obligations transferred by the sponsor (GxP Perspectives, 2009).
Since that time, several examples of noncompliance can be seen in WLs that FDA posted
on its website. In 2010, following two site inspections, FDA found significant examples of
misconduct at Cetero Research, a CRO that performed bioequivalence and pharmacokinetic
testing for multiple pharmaceutical companies. After FDA inspectors identified examples of
falsified data and manipulated samples, FDA notified the pharmaceutical industry that sponsors
might have to repeat clinical tests conducted by Cetero between April 2005 and June 2010 if
those studies used Cetero’s tests to support their marketing applications. Companies with
pending applications were required to retest drug samples using a different laboratory or, in the
case of ANDA applications, to repeat their clinical bioequivalence testing. As part of this
investigation, FDA requested study information from Cetero, including drug name, study
number, and the associated name of the drug sponsors to follow up with the sponsor companies
regarding the findings found at the CRO (Silverman, 2011). These types of challenges illustrate
how intimately tied are the activities of sponsors and their supporting service organizations and
how vulnerable the sponsor companies can be to failures in the conduct of their service
providers.
2.7 Evolution of Regulatory Agreements
Manufacturers have not confined their outsourcing and partnership activities to service
organizations. Public-private partnerships, open innovation models, and industry-academic

31
partnerships (Khanna, 2012) added to emerging industry relationships not only with contractors
but also with other companies, often through strategic alliances (in-licensing, joint development
or joint venture agreements) or even mergers, to become highly integrated pharmaceutical
networks (Figure 4). These integrated models assisted large pharma to streamline its businesses
and to share the risk that early-stage assets might fail (Kaitin, 2010). Their management is the
relatively mature result of many years of experience and lessons learned through relationships
with different types of service agreements. However, such relationships demand a further level
of attention to regulatory arrangements to ensure that the legal and regulatory requirements are
respected and that information needed for later-stage development and approval activities is
available in a useable format. This is often done formally through a “joint development
agreement” that defines the business arrangement between the parties to combine their resources
to accomplish specific activities (Respondek & Respondek, 2018). These joint activities can
include conducting research, running clinical trials, or joint market development. A joint venture
provides immediate access to the other company’s know-how and resources which can speed up
the time to bring the drug product to market (Galambos & Sturchio, 1998; Respondek &
Respondek, 2018).

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Figure 4: A Fully Integrated Model of Drug Development
(Reprinted from (Kaitin, 2010), with permission from John Wiley and Sons)

Why this matters might be illustrated by a simple hypothetical example in which a
biotech company (Company A) partners with a large pharmaceutical company (Company B).
Company A has developed a novel therapeutic biologic and has completed nonclinical, Phase 1
safety, and Phase 2 dose finding studies before partnering with Company B. Company B has
completed additional nonclinical studies and Phase 3 pivotal trials. Additionally, it has further
developed the manufacturing process for the Phase 3 supplies and commercial launch, has
managed and coordinated the submission of the NDA or BLA, and has developed the launch
materials and package insert. The relationship between these two companies to submit a
marketing application is diagrammed in Figure 5. Note that the companies in this relationship
share the common goal of submitting a single application for marketing permission but will also
have several interactions with those regulatory agencies as a precursor to the submission.

33
Figure 5: Example Contributions: Two-company Partnership for an NDA/BLA
Submission

The different contract agreements already discussed in this chapter may be relevant to
this example and may have elements that address some of the regulatory obligations. However,
requirements related to regulatory activities may be treated superficially in long legal agreements
for manufacturing, quality, or clinical studies that have different goals and narrowly targeted
deliverables. As suggested above, companies outsourcing their manufacturing have often split
the quality requirements into separate contracts or agreements to ensure that those requirements
gain the attention they deserve. However, relatively little attention seems to have been paid to
the development of standalone agreements related to the assignment of responsibilities for
regulatory submissions, interactions, and compliance. This lack of attention to “regulatory
agreements” can become problematic as companies adopt disseminated models based on
partnerships or other integrated models (Kaitin, 2010; Gautam & Pan, 2016). Two first steps

34
toward managing these types of issues- master file agreements and shared manufacturing
arrangement- are recognized historically to address a few, but certainly not all, of the problems
that can be envisioned in such relationships.
2.7.1 The Master File System
Perhaps the most widely used precedent to a regulatory “agreement” has been the “master
file” system that has been in place since at least 1989 when FDA published the “Drug Master
Files: Guidelines”. A Drug Master File (DMF) allows two or more commercial entities to
contribute to a single drug investigational or marketing submission. Most commonly, it is used
by a supplier…
…to provide confidential, detailed information about facilities, processes, or articles
used in the manufacturing, processing, packaging, and storing of human drug
products. DMFs can contain other types of information as well (e.g., toxicology
information, shared system REMS (risk evaluation and mitigation strategy)) (FDA,
2019a).
The key aspect of importance for such files is in their ability to protect the trade secrets and other
proprietary information of suppliers. The sponsor can reference a DMF in its investigational
(e.g., IND) or marketing application (e.g., NDA, ANDA, or BLA) to allow the FDA to access
confidential information to which the sponsor is not privy; this material will then be available in
confidence to the regulatory agency during its review of an application. Similar “master files”
can be referenced for devices or device components in situations in which the device will be part
of a final marketed drug/device combination product (FDA, 2019b). A drug or device master
file is different from a CMO or CRO contract in how proprietary information is shared with the
FDA. Using a DMF, the sponsor has no access to privileged information provided to the
regulator directly from the service provider or vendor, but in a contract, the sponsor obtains the

35
information from the service provider and then submits the information itself, as part of the
submission package.
2.7.2 Shared Manufacturing Arrangements
Shared manufacturing arrangements are a second way that two or more companies can
share information with the FDA as part of a regulatory submission. In FDA’s 1992 policy
statement, FDA recognized cooperative manufacturing arrangements that involved more than
one manufacturer:
Shared manufacturing is an arrangement in which two or more manufacturers are
licensed and responsible for specific aspects of the manufacture of a product, but
none is licensed for all aspects of the manufacture of the product. A common shared
manufacturing arrangement is one in which one manufacturer is responsible for an
intermediate product and another for the final product (FDA, 2008).
In this arrangement, each manufacturer submits a separate BLA describing its own facilities and
operations. As a result, the sponsor that references a shared manufacturing arrangement does not
have access to all the necessary information to fully describe the manufactured intermediate or
final product. Nonetheless, the manufacturer responsible for the commercialization of the final
drug product is…
…to assume primary responsibility for providing data demonstrating the safety,
purity, and potency of the final product. We also expect the licensed finished product
manufacturer to be primarily responsible for any postapproval obligations, such as
postmarketing clinical trials, additional product stability studies, complaint handling,
recalls, postmarket reporting of the dissemination of advertising and promotional
labeling materials (FDA, 2008).
The NDA or BLA holder must work with other manufacturer(s) in a shared
manufacturing relationship to assure that the information needed to meet this obligation is
supplied to the FDA. As with a DMF, the sponsor company’s relationship with the company
providing a shared manufacturing agreement limits its ability to see all of the information that is
salient to the submission. FDA reviews each BLA as part of the review process, and deficiencies

36
in either of the applications (the sponsor BLA or the shared manufacturing BLA) may be a basis
for a refusal-to-file decision or a complete response letter.
2.8 Time to Formalize Shared Regulatory Responsibilities?
As large pharmaceutical companies have evolved, their relationships have moved from
using vendors to using “preferred” vendors (Valazza & Wada, 2001; Khanna, 2012; Brooks,
2017), and in the last decade, to partnering with smaller pharmaceutical or biotech companies.
These alliance partnerships require a new level of sharing in order to assure that regulatory
submissions are developed efficiently and effectively and to reduce the vulnerabilities inherent in
the informal allocation of responsibilities and requirements. Thus, recent attention has been
directed at constructing more formalized regulatory agreements that, like other formalized
agreements, can protect both companies from misunderstandings and disappointments.
What would such an agreement entail? Regardless of the complexity of the relationship,
it is important to identify the regulatory responsibilities of each party to ensure that the sponsor
and partnering companies will have access to the information needed to meet regulatory agency
requirements throughout the full life cycle of drug development. At the same time, proprietary
information must be protected in some way. Thus, it is important to understand what advantages
a more formalized “regulatory agreement” might provide that the master files and joint BLA
systems cannot.
A thorough search of the literature provided no systematic evaluation of the required
elements for a regulatory agreement. However, the experience gathered in the construction of
other types of contracts provides a useful starting point to consider what types of clauses should
be found in a comprehensive regulatory agreement. Certain regulatory elements can be extracted
by reviewing the manufacturing, quality, and clinical agreements already used in the

37
pharmaceutical industry. For example, quality agreements with CMOs will typically cover the
requirements and arrangements for internal audits and inspections; regulatory teams will need to
have access to certain types of those records, so they must be involved in those activities. It
would also be important to specify the roles to be taken by the parent and partner company
during preapproval, routine surveillance, and for-cause inspections by health agencies because
regulatory personnel are typically involved in those interactions as well.
Perhaps the most important objective of the regulatory team is to obtain the information
needed to produce key components of regulatory submissions for an investigational or marketed
product. On the manufacturing and quality side, these might include elements available in
manufacturing contracts of procedures such as raw material and product specifications,
manufacturing process descriptions, testing procedures, and manufacturing and testing
validations. Arrangements for communication between a CMO and sponsor company must also
be addressed as a required element. Sponsor companies…
…that hold an approved drug application should be aware of application and
approval requirements that could affect manufacturing activities. Both parties to a
quality agreement should share relevant information to ensure compliance with
CGMP and other applicable requirements of the FD&C Act” (FDA, 2016a).
The agreement should also define the ownership of data and the process for the review, approval,
storage, and retrieval of documents required to support drug development. It would also identify
how change controls would be handled over time. Some of this information may be available in
a quality agreement if such an agreement exists and is sufficiently comprehensive.
Certain elements normally associated with clinical trial agreements also have regulatory
implications and should be addressed in a regulatory agreement. These might include the
management of patient confidentiality, data ownership, patent relationships and rights,
publication relationships, and rights and documentation requirements. In addition, other high-

38
risk issues might include risk management measures for subject injury, such as site
indemnification or compensation for harm (UCI Office of Research, 2019).
Pulling these already identified regulatory activities into a standalone regulatory
agreement is relatively straightforward. But additional elements also core to the preparation of
successful submissions or the planning of interactions with regulatory agencies over the lifecycle
of a drug product. These may be harder to identify without previous documents to define them.
A starting point to determine additional elements would be to characterize the activities
conducted by the regulatory professional from product concept through obsolescence and then
ensure that regulatory agreements include the required information and activities related to those
activities. In the literature reviewed here, no systematic documentation of these activities was
found. However, the literature contains competency frameworks that define the roles of
regulatory professionals, and these seem related quite directly to the activities that form part of
their responsibilities.
At least five frameworks describing regulatory competencies exist, but three appear to be
referenced most commonly. In 2014, the Regulatory Affairs Professionals Society (RAPS)
released a Regulatory Competency Framework (RCF) and Guide that “describes the essential
elements of what is required of regulatory professionals” (RAPS, 2016). That framework in
2013 initially had four domains but was updated in 2015 and again in 2018 to incorporate eight
domains that include both regulatory-specific and more general professional competencies. The
Organization for Professionals in Regulatory Affairs (TOPRA) (TOPRA, 2020a) developed a
competency framework in 2017 (TOPRA, 2020b) that included five competency domains
(Drago, Alsbury & Connolly, 2017). The Association of Graduate Regulatory Educators
(AGRE) also developed a competency framework with five key competency domains to be used

39
by educators of regulatory graduate programs to create consistency between these programs
(AGRE, n.d.; Drago, Alsbury & Connolly, 2017). Appendix A contains the core competencies
and descriptions of activities for each of these organizations. Bridges (2019) compared the
RAPS, TOPRA, and AGRE competency models by combining the domains in each model to
develop eight all-encompassing domain areas. These eight areas include: general, foundational
information; strategic planning; premarketing/preapproval; postmarketing/postapproval;
communication and soft skills; leadership; business acumen; and ethics. Table 3 shows some of
these important tasks sorted by six domain topic areas (Bridges, 2019) that encompass the core
competencies, tactical and strategic activities, and soft skills needed by regulatory professionals
to perform their jobs. These areas could be considered by partnering companies as areas where
they might need to specify certain requirements.

40
Table 3: Regulatory Tasks to be Considered in Regulatory Agreements
(Modified from: Bridges, 2019)
Domain topic area Regulatory tasks
1
important for companies in partnership
General, foundational
information
• Develop regulatory procedures, policies and SOPs
• Develop and retain documentation to comply with quality regulations
• Develop negotiation strategies with regulatory agencies
• Establish and maintain collaborative relationships with stakeholders
• Effectively manage resources
• Create and implement crisis management plans and procedures
• Analyze and advise on global requirements
Strategic planning
• Develop overarching regulatory strategies for new drug commercialization
• Develop plans for timely approvals in US and international markets
• Identify scope of clinical data to support approvals and claims
• Define the content, coordinate and prepare submissions for clinical trials
• Approve and execute changes to strategies based on changing regulations
• Integrate regulatory considerations into global entry and exit strategy
Premarketing/ preappoval
• Prepare and submit electronic and paper regulatory submissions
• Archive records
• Prepare cross functional teams for interactions with regulatory authorities
• Attend health authority meetings
• Evaluate benefit–risk balance of pharmaceutical products
• Identify, monitor and submit applicable reports or notifications
• Provide guidance on preapproval and GCP inspections
• Review and approve publicly disseminated information
• Review and assess proposals on regulatory paths and clinical plans
Postmarketing/
postapproval
• Agree to health authority postmarketing commitments
• Develop clinical development plans for phase 4 trials
• Track, manage and report product-associated complaints, recalls, market
withdrawals and vigilance reports
• Negotiate line extensions for commercialized product with regulatory authorities
• Provide required information in support of product reimbursement
• Review and approve labelling, advertising and promotion
• Prepare, review and approve required reports, supplemental submissions and other
postmarketing commitments to maintain product registrations
• Submit changes and supplemental dossiers to regulatory authorities to update
product information
Communication and soft
skills
• Exchange information with stakeholders within and outside the company
• Negotiate with regulatory authorities
• Maintain communication logs with regulatory authorities
• Prepare regulatory documents and reports
• Analyze communications from health authorities and respond appropriately
• Interpret and address health authority queries
• Research and present alternate approaches
Leadership
• Articulate the organization’s strategic vision to relevant others
• Incorporate regulatory strategy to expedite drug development
• Build and sustain partnership across organization as well as outside the
organization to achieve common goals and outcomes
• Share knowledge and lessons learned across organization
1
It is possible that the regulatory tasks would fit in multiple domains, however, to avoid redundancy, they have been assigned to
only one domain area

Using the domains listed in Table 3, a systematic picture of the regulatory and business
needs of the partnering companies can be developed to map many of the additional regulatory

41
elements to be included in regulatory agreements. No one-size-fits-all agreement is likely to be
possible, but rather a specific agreement might use this set of activities as a “pick list” around
which to tailor its negotiations and eventual consensus. For this list, elements appropriate at the
preapproval stage would address how the companies will together determine the sources,
accuracy, and presentation of data to regulatory agencies. They might also include how to
allocate responsibilities to generate content and the arrangements to be made for document
review. An agreement often has to become quite detailed. For example, the requirements of
document review and management might specify how often those reviews will take place, how
many review cycles should normally be expected, and who will handle edits and comments.
Ownership of the regulatory documents will probably specify where the documents will be held
and to whom they will be available. Another important element to include in an agreement
would be the review and approval of draft and final drug product labeling. However, these
activities are not limited to the deliverables but also the communication processes and the
handling of disagreements, for example. A similar approach might be used for regulatory
agreements that extend into the postapproval stage, where activities would include
responsibilities related to adverse event reporting and communication to regulators regarding
actions as diverse as manufacturing or formulation changes, modified labeling, advertising, and
promotion, or complaints and recalls.
The complexity of pharmaceutical partnerships is magnified when more than two
companies are involved. The example above involving Biotech Company A and Large
Pharmaceutical Company B could also include multiple CRO and CMO relationships with each
company or could become even more complicated if one of the partners were undergoing some
form of merger with another company at the same time. Given all of these requirements and

42
communication channels, it seems apparent that informal approaches are unlikely to be
satisfactory. However, it is not clear whether companies have begun to formalize their
regulatory relationships using standalone regulatory agreements, and if they have, what is the
nature of their content. Further, it is not clear whether the regulatory teams are finding
difficulties with the shared relationships and how they see that this might be improved, whether
using formalized agreements or some other type of solution.
2.9 Approach to the Research
If our primary questions are related to the “whether and why” of implementing
formalized regulatory agreements, it seems fitting to use a well-established implementation
framework to organize the questions being asked in the survey. Although implementation
science is a relatively new area of study, it is increasingly recognized as important to guide the
introduction of a new program or practice. A pioneer in the field of implementation science,
Dean Fixsen, has published several key articles on implementation frameworks (Fixsen et al.,
2005; Fixsen et al., 2009) in which the stages of implementation were defined. Four stages of
implementation commonly identified in these frameworks are Exploration, Installation, Initial
Implementation and Final Implementation (See Figure 6).

43
Figure 6: Implementation Stages
(Reprinted from Blanchard et al., 2017, with permission from Elsevier)

In stage 1, Exploration, the goal is “to assess whether implementation is feasible and to
create readiness for implementation” (Blanchard et al., 2017). This can involve several activities
that include an assessment of needs and fit and an identification of capabilities that will lead to
team formation. In the context of this dissertation, I will explore the fit between the
implementation of standalone regulatory agreements and the usefulness of these agreements to
address the needs of the bio/pharmaceutical industry. Of interest would be whether the
companies were aware or interested in such agreements, whether they had previous experience
on which they could build, and how they educated themselves about structuring such
agreements. At the end of this stage, a decision to go forward or to abandon further activities
related to the development of a regulatory agreement is generally taken. Stage 2 begins once the
decision to implement an innovation has been made. At this stage, tasks are identified to ensure

44
that the required structure and support are in place. To implement regulatory agreements, these
tasks could include drafting these agreements, settling on common wording and definitions to be
used, and training personnel in the structure and meaning of the different included elements.
Stage 3, Initial Implementation, is the stage at which the first attempts to put a plan into action
will take place. It builds on the initial work started in stages 1 and 2. It might for example,
involve the preliminary discussion and implementation of the first regulatory agreement which
might serve as a type of pilot from which experience is gained. Finally, stage 4, Full
Implementation, “occurs as new learnings become integrated into practice and practitioners are
appropriately providing the program or service with skill and quality” (Blanchard et al., 2017).
This might be interpreted in the context of regulatory agreements to be the state in which
regulatory agreements are accepted as part of standard company practice as they develop joint
product-development projects, and systems are put into place to negotiate and incorporate these
agreements on a regular basis, possibly using some form of template or standard operating
procedure.
Over time, variants of his model have been suggested by a number of researchers. Some
have organized the knowledge driving implementation into five key elements, called Active
Implementation Frameworks (AIFs) by The National Implementation Research Network (Duda
& Wilson, 2015) (see Figure 7).

45
Figure 7: Active Implementation Frameworks Overview
(Reprinted from Blanchard et al., 2017, with permission from Elsevier)

The literature described above suggested the implementation of regulatory agreements
was at a relatively early stage. Thus, I expected that much of the information that I could gain
would come from a focus on the first two stages of implementation: exploration and installation.
Of particular interest were the factors brought to bear on decisions to implement an agreement of
some type. However, some companies had progressed to an implementation stage. From these
respondents, it was important to understand their experiences and challenges in the
implementation process, to yield lessons learned for others. The table below suggests the type of
questions that might be relevant to each of the stages, but the final survey is attached in
Appendix B.

46
Table 4: Outline of Implementation Stages: Questions for Regulatory Agreements
Exploration
• Does the company have a standard approach to contracts with other
companies or vendors?
• Has the company heard of using regulatory agreements?
• Has the company investigated the use of regulatory agreements for their
joint projects? Are any regulatory requirements already included in other
agreements for their joint products?
• Is the company exploring implementation with the goal of a decision on
use?
Installation
• Does the company have the relevant expertise to comply with the
regulatory requirements identified? Who is leading and who is a member of
the installation team?
• Does the company assign resources to installing a regulatory contract? To
which department are the resources given?
• Who is responsible for drafting a regulatory contract? What educational
guidance or structure (procedures and policies) and resources (time, staff,
funding) are used during this task?
• How is the company identifying the critical elements to be included?
• What have been the hurdles and lessons learned?
Initial
Implementation
• How will feedback be collected the initial regulatory agreement?
• What elements have been included in the initial agreement? What were the
lessons learned?
• Have systems been developed concurrently to permit modifications to the
agreement? What is the timing to review and modify the regulatory
elements?
Full
Implementation
• Is there an SOP to guide regulatory agreements as standard practice?
• Is a regulatory agreement a compulsory part of any new joint venture?
• What metrics are being used to measure the effectiveness of the regulatory
agreement?
• What has been the level of satisfaction with the current state of
implementation?
• Have the companies committed to provide the required on-going
leadership, structure and support to maintain the elements in the regulatory
agreements?

47
Chapter 3. Methodology
3.1 Summary
The purpose of this exploratory study was to survey professionals employed in the
medical products industries on their views and experiences regarding the use of standalone
regulatory agreements to document regulatory responsibilities between two or more parties
involved in joint drug development. Using the implementation framework as a basis for
collecting information, this study used an electronically administered survey to evaluate if
standalone regulatory agreements have been adopted by industry, to identify desired elements
that should be included in a regulatory agreement, and to gauge satisfaction with the use or non-
use of standalone regulatory agreements.
3.2 Identification of Study Participants
The study sought to explore the views and experiences of professionals working at
sponsor and vendor companies within the medical products industries as well as individual
consultants and regulatory consulting companies (strategy, CMC, or operations) that provide
services to these industries. Participants included representatives with experience in drug
development and represented functions including regulatory, quality, clinical, product
development, legal, finance, project management, business development, or alliance
management. The targeted participants were mid- to senior-level employees by title who were
familiar with the views of their company with respect to the topic. Respondents were sought by
their background, the function they represented and role in their company. No questions were
asked regarding the geographic area (US, EU, ROW) in which they worked.
To ensure that a broad range of opinions were gathered, participants were identified
through a variety of channels, including my LinkedIn network, personal referrals, social

48
networking platforms, and professional associations. Potential participants were solicited
through social media or by email to determine their willingness to participate. Interested parties
were encouraged to nominate others to participate, using the snowball technique to expand the
pool of potential participants.
3.3 Data Collection and Analysis Methodology
A self-administered online survey instrument based on the implementation framework
outlined in Chapter 2 was developed on the web-based survey platform, Qualtrics
(http://www.qualtrics.com/). Most questions were configured using multiple-choice, scaled,
matrix, or rank-order formats. Branching questions were used to allow participants to skip
questions that do not match with their current experience. Open text fields were added so that
respondents could provide additional depth by offering written comments. Questions were
designed to solicit input on the current use or possible need for regulatory agreements between
partnering companies or a company and academia. The survey length was controlled to ensure
that it could be completed within a 15-minute time period.
Prior to issuing the survey, a focus group comprised of 8 participants from industry and
academia was used to critique the organization of the survey and the relevance and clarity of
each question. Focus group members were also asked if gaps existed that should be addressed.
The focus group participants (Table 5) were selected based on their knowledge or experience in
partnerships with pharmaceutical companies from either an industry or academic perspective or
because they had experience with other types of compliance agreements used in medical
products industries. Participants with extensive survey preparation and development were also
invited to provide insights on the overall structure of the survey. The survey was updated based

49
on their feedback. The focus group was asked to conduct a final review of the revisions to
ensure that their comments and action items were addressed appropriately.
Table 5: Focus Group Participants
List of focus group participants from academia and industry that validated the survey tool.
Name Title Institution/Industry
Frances Richmond, PhD
Director, D K Kim International
Center for Regulatory Science,
USC Regulatory Science
Academia
Nancy Pire-Smerkanich, MS,
DRSc
Assistant Professor, Department
of Regulatory and Quality
Sciences in the School of
Pharmacy, USC Regulatory
Science
Academia
Susan Bain, MS, DRSc
Assistant Professor, Department
of Regulatory and Quality
Sciences in the School of
Pharmacy, USC Regulatory
Science
Academia
Kristina Vlaovic, MS
Vice President, Regulatory
Affairs & Pharmacovigilance in
Biotechnology Industry
Industry
Peter Lassoff, PharmD, DRSc

Senior VP, Head of Regulatory
in Contract Vendor
Industry
Wendi Lau, MS, DRSc
Vice President, Operational
Improvement & Reporting
Excellence in Pharmaceutical
Industry
Industry
Laura (Rasky) Kupsch, MS

Vice President, Quality
Assurance in Biotechnology
Industry
Industry

The final survey had 42 questions with 3 skip-logic branches (Appendix B). The final
survey was deployed electronically to the target population and was open for data collection
between October 4 and November 26, 2020. Results were confidential and collected
anonymously, and saved electronically.
Results were summarized using descriptive statistics including graphical representation
and cross-tabulation. Any open text and comment fields were examined and analyzed to identify
any trends or common elements. One question used a rank order format so that respondents

50
could rank their preferences. A rank score was calculated by applying a weight to each response.
Because this question used a 5-point scale, the number of responses where the option was ranked
as 1 (or most likely) was multiplied by 5, the number of responses where the option was ranked
as 2 was multiplied by 4, and so on. The total weighted score for each option was summed to get
the final rank option. The scores were then sorted from highest (1) to lowest (5).

51
Chapter 4. Results
4.1 Survey Participation
The survey was disseminated between October 4 and November 26, 2020. Links to the
survey were sent directly to 1194 participants for whom I had personal contact information or
contact information derived through LinkedIn. Of these potential participants, 294 started the
survey, and 244 completed at least one question, providing a response rate of 20% (244/1194)
and a completion rate of 83% (244/294). An additional 50 participants accessed the survey using
an anonymous link and completed at least one question. Combining both methods of
participation, 294 respondents completed at least one question. Any personal or identifying
information was removed to assure the anonymity of the respondents.
4.2 Demographic Profiles and Background of Respondents
The first block of questions in the survey collected demographic information regarding
the professional profiles of respondents and the type and size of companies with which they
work. Most commonly, respondents identified their positions as Director (42%, 122/288)
(Figure 8), followed by Vice President/C-Suite (33%, 96/288). The remainder had job titles
including Consultant (9%, 26/288), Manager (7%, 20/288), Specialist/Associate (4%, 12/288)
and Attorney/Legal Counsel (2%, 5/288). Seven respondents (2%, 7/288) selected other. Their
comments are included after Figure 8.

52
Figure 8: Title Represented by Respondents
Which title is most closely aligned with your current responsibilities?

Other Comments n=7
• Regulatory Affairs Officer
• Project Manager, RA
• Chairman & CEO
• Retired and part-time biotech consultant
• Senior Director Development, Regulatory Affairs
• Former VP/C-Suite
• CEO

Most respondents worked in regulatory affairs/quality assurance (77%, 219/286). Other
functions included R&D (12%, 35/286), alliance management / business development (3%,
9/286), legal affairs (2%, 6/286) and finance (<1%, 1/286). Sixteen respondents (6%, 16/286)
had functions that differed from the offered choices, as specified after Figure 9.

Count

53
Figure 9: Department/Function Represented by Respondents
What is your primary job function?

Other Comments n=16
• Regulatory Affairs/Pharmacovigilance
• Safety
• safety, medical [sic]
• Chairman & CEO
• strategy [sic]
• Submission standards implementation. Submission strategy. Clinical/Non-clinical studies. Biostatistics.
• COO
• Oversee regulatory affairs, quality assurance and all research and development functions
• Development including Regulatory, Clin Ops, QA, Project management
• Regulatory and Medical Affairs for Skincare
• Toxicology and regulatory affairs
• Drug Safety
• CEO
• Manufacturing and Supply Chain Operations
• PV Surveillance
• Program & Alliance Management

Most respondents worked for sponsor companies (76%, 218/286) (Figure 10), followed
by consultancies (15%, 43/286), clinical support organizations (6%, 17/286), and law firms or in-
house counsel work settings (1%, 3/286). Five (2%) selected other, specified as “Collaborator
with Sponsor”, “Retired”, “Manufacturer”, “Research Institute” or “Academia”.
Count

54
Figure 10: Organization / Company Affiliation
Which statement best describes your work setting?

Respondents were employed by companies with a diverse range of sizes (Figure 11).
Over 40% had fewer than 200 employees (42%, 120/288), 31% (88/288) had 201 – 2000
employees, 17% (48/288) had 2001 – 50,000 employees and 11% (32/288) had more than 50,000
employees.
Figure 11: Size of Organization / Company
Which statement best describes the size of your overall organization?

Count
Count

55
A cross-tabulation was performed to explore respondents’ job titles relative to the size of
the company for which they worked. As shown in Table 6, most respondents were at or above
the Director level and worked in companies with up to 2000 employees. The number of Vice
President/C-Suite participants was similar in companies up to 2000 employees and then declined
as the company size increased. The number of responding Directors increased as the size of the
company increased. The percent of other respondents remained fairly consistent; the largest
number of consultants worked with companies with less than 200 employees, and the most
managers worked in companies with 201 – 2000 employees.
Table 6: Respondent Job Title by Size of Company
This table provides a cross-tabulation of job title versus company size. Percent is calculated on
both the column total and on the total number of respondents (n=288)

Which statement best describes the size of your overall
organization?
Question Choice Total Less than
200
employees
201 - 2000
employees
2001 -
50,000
More than
50,000
employees
Which title is
most closely
aligned with
your current
responsibilities?
Total Count (All) 288 120 88 48 32
Vice President /
C-Suite
96 47 33 12 4
Director 122 35 35 29 23
Manager 20 4 11 4 1
Specialist /
Associate
12 4 4 2 2
Attorney / Legal
Counsel
5 1 3 0 1
Consultant 26 25 0 1 0
Other 7 4 2 0 1
Vice President /
C-Suite
33%
1
39%
1
(16%)
2

38%
1

(11%)
2

25%
1

(4%)
2

13%
1
(1%)
2

Director 42% 29% (12%) 40% (12%) 60%
(10%)
72% (8%)
Manager 7% 3% (1%) 13% (4%) 8% (1%) 3% (0%)
Specialist /
Associate
4% 3% (1%) 5% (1%) 4% (1%) 6% (1%)
Attorney / Legal
Counsel
2% 1% (0%) 3% (1%) 0% (0%) 3% (0%)
Consultant 9% 21% (9%) 0% (0%) 2% (0%) 0% (0%)
Other 2% 3% (1%) 2% (1%) 0% (0%) 3% (0%)
1
Percent is calculated on column total
2
Percent is calculated on total number of respondents (n=288)

56
As shown in Figure 12, 65% of respondents (188/288) worked with pharmaceuticals,
57% (164/288) with biologics/biotechnology products, 33% (95/288) with medical
devices/diagnostics, and 32% (92/288) with combination products. Ten respondents (3%,
10/288) worked with product areas that differed from the offered choices, as specified after
Figure 12. The number of selections greatly outnumbered the number of responses, indicating
that many had experience with more than one product type.
Figure 12: Product Type
With which product types do you work? (choose all that apply)

Other Comments n=10
• Food Additives (2 respondents)
• Cosmetics
• Gene Therapy
• Industrial chemical
• Veterinary biologicals
• Cosmetics
• Dietary supplements (2 respondents)
• Cell and Gene Therapies

4.3 Partnerships and Agreements Used by Respondents
Respondents were offered several options to describe their relationships/arrangements
with pharmaceutical (P), biologics/biotechnological (B), medical device (D), support-service and

57
vendor (V) companies, academic institutions (A), and consultancies (C). Regardless of the type
of organization, most companies memorialized their partnerships with formal agreements (55%-
87%) (Table 7). Preferred partner/vendor relationships accounted for less than 8% of
relationships with consultants and pharmaceutical, biotech, and academic organizations but were
somewhat more frequent for partnerships with device companies and support-service and vendor
organizations (D: 11%, V: 23%). Informal agreements and research grants were rare (< 5%) with
most types of organizations except academic institutions. About 10% of academic agreements
were informal, and 19% involved research grants. Seven comments were provided to specify
other choices. These are listed below Table 7.
Table 7: Structure of Company Relationships With Partners
What type of relationships does your company have with your partners? (choose all that apply)
(n=286)
1
value of zero due to rounding

Respondents were also asked to describe the types of agreements that are the base for
manufacturing, quality, clinical, regulatory, and other partnering relationships. For quality

58
agreements, two types of contracts were most common: Standard template (48%, 117/243);
personalized contract (46%, 111/243). Six percent (15/243) indicated that they do not use
quality agreements. For agreements with other types of partners, companies appeared to use a
standard template less often than a personalized contract: Manufacturing agreements (31%,
72/236 versus 56%, 132/236); clinical agreements (39%, 93/237 versus 52%, 123/237);
regulatory agreements (33%, 81/245 versus 53%, 129/245). Thirty-seven respondents indicated
that their company used other agreements and 21 expanded on that choice by providing
comments (Table 8). Some respondents also identified that they do not use agreements for
partnerships: manufacturing 14% (32/236), clinical 9% (21/237) or regulatory 14% (35/245).

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Table 8: Agreement Types With Partners
Please describe your company's approach to using partnership agreements for each of the following types
of agreements. (choose all that apply) (n=277)
Agreement Type Standard template
used for all
partners
Personalized contract
depending on the type
of partnership
Do not use Total
% Count % Count % Count Count
Manufacturing
Agreements
31 72 56 132 14 32 236
Quality Agreements 48 117 46 111 6 15 243
Clinical Agreements 39 93 52 123 9 21 237
Regulatory Agreements 33 81 53 129 14 35 245
Other

30 11

40

15 30 11 37

Agreement
Type
Other Comments n=21
Not
Specified by
Respondent
• Engagement letters
• Mods made to support specificity of need in all cases. Cannot delete sections, must provide
rationale if section is not needed [sic]
• We generally use the CRO/CMO or institutions template for most things as it is preferred by
the vendors and easier for us to just compare our internal SOP and checklist to ensure
everything we need is covered in the vendor agreement.
• We try to standardize as much as possible but will customize based on the nature of the
arrangements / services provided.
• We use a standard template that is then modified as appropriate for the vendor/service in
question.
Standard
Template
• Customer designed agreements
• Full service agreement including quality, clinical and Regulatory [sic]
• PV
• Pharmacovigilance Agreements
• TORO
Personalized
Contract
• Authorized representatives, notified bodies and auditing organizations
• Co-Development Agmts [sic]
• License Agreements
• License and Collaboration Agreements
• Logistic
• Most contacts are based on vendor templates that undergo functional and legal review
• Supply Agreements, Service Agreements
• We have PVA agreements in place
• blend of template (ours or theirs) and personalized ones [sic]
• safety
Do Not Use
• Nonclinical

When asked whether regulatory expectations are addressed by the current contracts or
agreements with their vendors (CDMOs/CROs), most respondents were either somewhat (57%,

60
159/276) (Figure 13) or extremely satisfied (19%, 53/276). However, 13% (37/276) were neither
satisfied nor dissatisfied. Infrequently, respondents were somewhat (9%, 24/276) or extremely
dissatisfied (1%, 3/276). When asked whether regulatory expectations are addressed in current
contracts or agreements with business or academic partners, most were either somewhat satisfied
(55%, 154/278) (Figure 13) or extremely satisfied (21%, 59/278). However, 17% (46/278) were
neither satisfied nor dissatisfied, 6% (17/278) were somewhat dissatisfied, and 1% (2/278) were
extremely dissatisfied.
Figure 13: Regulatory Expectations Addressed with Partners
How satisfied are you that regulatory expectations are addressed by contracts or agreements you are
currently developing A: with your vendors (CDMOs/CROs)? (n=276) B: with your business or academic
partners? (n=278)

When respondents were asked, “Are you satisfied with your company's approach to
regulatory agreements?”, two-thirds (67%, 174/258) were satisfied, and the remaining one-third
were not (33%, 84/258). Respondents were then invited to expand on those choices. Comments
from the 146 respondents who answered yes were sorted according to features that they
considered to add value, including: documented, standardized, flexible, controlled, and/or helpful

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to facilitate broader stakeholder involvement (Table 9). The 81 negative comments identified
dissatisfiers, including: not standardized, not considered or lack of experience, not detailed or
specific enough, not clearly defined, not considered important, and not required or included in
other agreements (Table 10). A comprehensive list of all comments is included in Appendix C.
Table 9: Satisfied with Company Approach to Regulatory Agreements
Are you satisfied with your company's approach to regulatory agreements? Why or why not? (n=146)
Comment
Grouping
Yes Because… Example Comments
Documented • In spite of the fact that the company engages with very diverse partners, the regulatory agreements
have been clear and concise in their description of the scope of activities covered by the agreements,
and in highlighting the responsibilities of involved parties in the various processes. This has
consistently resulted in mostly seamless execution.
• The agreement includes a detailed scope of expectations and responsibilities.
• there are clean definitions and responsibilities identified.
Standardized • We have an agreement with every commercial partner
• We fully get a standardized template thru outside counsel once a year
• Standard industry language generally accepted or little modifications which save time
Flexible • Having separate, customized agreements allows us to work with vendors who have specific expertise
or in a certain location. This allows us to be flexible, and to get the right expertise for each project
• Agreements are fit for purpose and adjusted to the size of the company, while still being solid and
compliant.
• free-form agreements - it depends on the experience of the client and how close they are to late stage
development
Control • all have formal review by Regulatory Affairs
• For those we currently use, we have carefully vetted them for compliance and have extensive
oversight of their operations
• We negotiate each one to fit the purpose
Stakeholder
Involvement
• Functional areas participate in development of contracts and can ensure needs are being addressed
• Extensive Legal and deals transaction lawyers input. Support to ensure functional rights are clear up
front, with details in addendum up front. [sic]
• We have a formal process that has been vetted by all of the relevant stakeholders and so far it works.
We have not used stand-alone regulatory agreements, instead we put this information in our formal
contracts.
Addressed in
Other
Agreements
• We don't have standalone regulatory agreements. There are regulatory clauses in all our Quality and
Partnership/Manufacturing agreements.
• For the PV agreements which cover regulatory intelligence for safety reporting, these are working
documents that have detailed regulations and guidances behind them. They have also been subject to
numerous regulatory inspections and audits.
• Regulatory requirements and responsibilities are defined in our legal agreements, quality
agreements, or both. Development and commercial agreements are used based on the product stage.

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Table 10: Not Satisfied with Company Approach to Regulatory Agreements
Are you satisfied with your company's approach to regulatory agreements? Why or why not? (n=81)
Comment
Grouping
No Because… Example Comments
Not
Standardized
• Varying expectations on personal preference by stakeholders vs actual regulatory requirements.
The agreements tend to get skewed with requirements that are not fully aligned to reg requirements.
• There is no formal template for regulatory work as it is tailored from project to project.
Not
Considered
or Lack of
Experience
• Not all the pertinent players (those working on the studies) are reviewing the documents. The C-
level people are making the decisions for those running the studies, and the C-level folks don't have
their feet in the trenches knowing how the studies are actually being performed.
• It's a widely distributed process, with varying levels of knowledge and transparency.
Not Detailed
or Specific
Enough
• In some cases the agreements were not detailed/specific enough and this created ambiguity with
respect to how to proceed or differences in how we worked between partnerships. Sometimes
partners were not held accountable for not adhering to Items in the agreement. Agreements were
not updated to include more specific details surrounding the format of deliverables.
• Our agreements could have been more specific in the following areas:
-whose templates would be used to deliver regulatory submission content to the partner
-format (ms word/pdf)
-location of reviews (partner SharePoint or our SharePoint)
-standard mechanism/location for sharing content between partners
-what information we would expect to receive (copies of submissions, correspondence, questions,
commitments) so that we could have a better historical record of what had been filed where. [sic]
Not Clearly
Defined
• The details of regulatory agreements may not be fully considered. This is due, at least in part, to
softer deliverables associated with regulatory. With other parties, such as CDMO/CROs,
deliverables are tangible and straightforward to define. [sic]
• Unique to each company (time involved for legal, QA/RA review is extensive). Prefer an industry-
recognized template.
Not
Considered
Important
• Regulatory agreements are often considered of second tier importance to commercial terms... until
there is a compliance problem and then the regulatory agreement becomes business critical.
unfortunately, memory is fleeting and things fall back when new executives come on board. [sic]
• Seen as something that has to be done but really not considered to be an important part of the
agreement. Very little time and thought put into it.
Not Required
or Included in
Other
Agreements
• The company does not currently have stand-alone regulatory agreements. The regulatory aspects
are covered in master services agreements and/or quality agreements. I think having a specific
regulatory agreement would be very useful to ensure regulatory expectations for both parties are
clear.
• There is generally just a small section or even just some sentences within the quality section that
relate to regulatory matters. And then we need to have separate agreements for new regions, etc.
that are outside of the main commercial supply agreement. I think there should be a regulatory
document the same as a Quality Agreement.

4.4 Awareness of Regulatory Agreements
The experience of respondents was almost evenly split when asked, “Have you heard of
using standalone regulatory agreements developed formally as a separate document…?” (yes:
54%, 152/283; no: 46%, 131/283). A cross-tabulation was performed to explore whether
respondents who had heard of regulatory agreements were influenced by the company's size or
level in the organization. As shown in Table 11, respondents in all size companies and at all

63
levels of the organization had heard of using regulatory agreements; the responses were similar
between those who had and had not heard of these agreements irrespective of company size.
Table 11: Awareness of Agreements by Company Size, Job Title, and Product Type
This table provides a cross-tabulation of company size, the respondent’s title, and the product
type supported versus awareness of the use of regulatory agreements (n=283)

Have you heard of using standalone regulatory agreements
developed formally as a separate document to cover some of
these aspects during product development and
commercialization?
Question Choice Total Yes No
Total Count (All) 283 152 131
Which
statement best
describes the
size of your
overall
organization?
Less than 200 employees 117 55 62
201 - 2000 employees 86 47 39
2001 - 50,000 48 33 15
More than 50,000 employees 32 17 15
Less than 200 employees 41%
1
36%
1
(19%)
2
47%
1
(22%)
2
201 – 2000 employees 30% 31% (17%) 30% (14%)
2001 – 50,000 17% 22% (12%) 12% (5%)
More than 50,000 employees 11% 11% (6%) 12% (5%)
Which title is
most closely
aligned with
your current
responsibilities?
Vice President / C-Suite 95 51 44
Director 120 67 53
Manager 20 10 10
Specialist / Associate 12 4 8
Attorney / Legal Counsel 5 3 2
Consultant 24 13 11
Other 7 4 3
Vice President / C-Suite 34%
1
34%
1
(18%)
2
34%
1
(16%)
2
Director 42% 44% (24%) 41% (19%)
Manager 7% 7% (4%) 8% (4%)
Specialist / Associate 4% 3% (1%) 6% (3%)
Attorney / Legal Counsel 2% 2% (1%) 2% (1%)
Consultant 9% 9% (5%) 8% (4%)
Other 3% 3% (1%) 2% (1%)
With which
product types
do you work?
(choose all that
apply)
Biologics / Biotechnology 162 88 74
Pharmaceuticals 185 96 89
Combination Products 91 47 44
Medical Devices / Diagnostics 94 57 37
Other 9 5 4
Biologics / Biotechnology 57% 58%
1
(31%)
2
57%
1
(26%)
2

Pharmaceuticals 65% 63% (34%) 68% (31%)
Combination Products 32% 31% (17%) 34% (16%)
Medical Devices / Diagnostics 33% 38% (20%) 28% (13%)
Other 3% 3% (2%) 3% (1%)
1
Percent is calculated on column total
2
Percent is calculated on total number of respondents (n=283)
Another cross-tabulation was created to understand the use of manufacturing, quality,
clinical, regulatory, or other agreements according to company size. The largest companies

64
(greater than 50,000 employees) most commonly used standard templates for all of these
agreement types, whereas the smaller companies more commonly used personalized contracts.
Table 12: Company Size by Approach to Partnership Agreements
This table provides a cross-tabulation of company size by the company’s approach to using
partnership agreements (n=288)

Which statement best describes the size of your overall
organization?
Question Choice Total Less than 200
employees
201 - 2000
employees
2001 -
50,000
employees
More than
50,000
employees
Please
describe your
company's
approach to
using
partnership
agreements
for each of the
following
types of
agreements.
(choose all
that apply)
Total Count (All) 288 120 88 48 32
Manufacturing Agreements
Standard template 72 18 25 13 16
Personalized contract 132 65 39 20 8
Do not use 32 18 8 4 2
Standard template 25%
1
15%
1
(6%)
2
28%
1
(9%) 27%
1
(5%)
2
50%
1
(6%)
2
Personalized contract 46% 54% (23%) 44% (14%) 42% (7%) 25% (3%)
Do not use 11% 15% (6%) 9% (3%) 8% (1%) 6% (1%)
Quality Agreements
Standard template 117 37 42 20 18
Personalized contract 111 56 28 18 9
Do not use 15 11 4 0 0
Standard template 41% 31% (13%) 48% (15%) 42% (7%) 56% (6%)
Personalized contract 39% 47% (19%) 32% (10%) 38% (6%) 28% (3%)
Do not use 5% 9% (4%) 5% (1%) 0% (0%) 0% (0%)
Clinical Agreements
Standard template 93 28 30 18 17
Personalized contract 123 63 38 14 8
Do not use 21 14 6 1 0
Standard template 32% 23% (10%) 34% (10%) 38% (6%) 53% (6%)
Personalized contract 43% 53% (22%) 43% (13%) 29% (5%) 25% (3%)
Do not use 7% 12% (5%) 7% (2%) 2% (0%) 0% (0%)
Regulatory Agreements
Standard template 81 26 26 16 13
Personalized contract 129 62 34 23 10
Do not use 35 14 13 2 6
Standard template 28% 22% (9%) 30% (9%) 33% (6%) 41% (5%)
Personalized contract 45% 52% (22%) 39% (12%) 48% (8%) 31% (3%)
Do not use 12% 12% (5%) 15% (5%) 4% (1%) 19% (2%)
Other
Standard template 11 3 3 1 4
Personalized contract 15 7 6 0 2
Do not use 11 7 2 2 0
Standard template 4% 3% (1%) 3% (1%) 2% (0%) 13% (1%)
Personalized contract 5% 6% (2%) 7% (2%) 0% (0%) 6% (1%)
Do not use 4% 6% (2%) 2% (1%) 4% (1%) 0% (0%)
1
Percent is calculated on column total
2
Percent is calculated on total number of respondents (n=288)
Those who had heard about such agreements were asked if their companies had
investigated the use of standalone regulatory agreements in their collaborations with other

65
medical product companies or with academic institutions. As shown in Figure 14, 40% (61/151)
had investigated and implemented the use of standalone regulatory agreements whereas 34%
(51/151) had not. In addition, 12% (18/151) had investigated standalone regulatory agreements
and were in the process of developing them, whereas 8% (12/151) had investigated these types of
agreements but did not go forward. Only a few, 6% (9/151), were not involved in collaborations
with other companies or academic institutions.
Figure 14: Use of Regulatory Agreements With Business or Academic Partners
Please think about your collaboration projects with other pharmaceutical, biotechnology, or device
companies or with an academic institute. Has your company investigated the use of standalone regulatory
agreements for any of these collaborations?

4.5 Companies Using Standalone Regulatory Agreements
Respondents were asked about resources that they found valuable when first researching
the development of regulatory agreements. Most respondents ranked each of the five proposed
choices as available and useful. Previous contracts used in other departments were considered
available and useful by 82% (54/66) of respondents. The other 18% were divided between
finding them available but not useful (9%, 6/66) or unavailable (9%, 6/66). Regulatory agency
documents and regulations were described as available and useful by 76% (51/167) of

66
respondents, but as available and not useful by 22% (15/67); only 1% (1/67) indicated that they
were unavailable. When asked about using consultants, 67% (40/60) found consultants to be
available and useful, but 25% (15/60) found them available but not useful and 8% (5/60)
unavailable. Information from industry meetings/seminars was described as available and useful
by 58% (35/60), available but not useful by 30% (18/60), and unavailable by 12% (7/60).
Respondents identified government presentations to be available and useful by 45% (27/60) of
respondents, available but not useful by 37% (22/60), and unavailable by 18% (11/60). Six
respondents selected other resources: Four of who found them to be available and useful, and one
each who found other resources to be available but not useful, and one who found other
resources not available (Table 13).
Table 13: Resources Useful to Research Regulatory Agreements
When you first considered putting regulatory agreements in place, what resources did you find valuable
in researching the development of regulatory agreements? (choose all that apply)( n=71)
Resource Available and useful Available but not
useful
Not available Total
% Count % Count % Count Count
Regulatory Agency
Documents/Regulations
76 51 22 15 1 1 67
Previous Contracts in
Other Departments
82 54 9 6 9 6 66
Information from Industry
Meetings or Seminars
58 35 30 18 12 7 60
Government Presentations 45 27 37 22 18 11 60
Consultants 67 40 25 15 8 5 60
Other
a
67 4
b
17 1 17 1 6
a
Other/not specified: “regulatory needs and state of the art regulations”, “Clinical's scope of work and submission plans”
b
Other/available and useful: “Internal collaboration with executive team”, “historical knowledge of team members”

Companies that had developed regulatory agreements were also asked about barriers that
they faced during the early development, from a list of 8 options. About half (52%, 34/65)
(Table 14) ranked a low understanding of what was needed as a major barrier, a further 29%
(19/65) as a minor barrier and 18% (12/65) as no barrier at all. Insufficient resources were
considered to be a major barrier by 39% (24/62) and a minor barrier by 37% (23/62) but were not

67
considered as a barrier by 24% (15/62). A similar distribution of responses was associated with
two other possible barriers: no templates available (major barrier 35%, 23/65; minor barrier 35%,
23/65%; not considered a barrier 29%, 19/65) and insufficient drafting experience (major barrier
30%, 19/63; minor barrier 33%, 23/63%; not considered a barrier 37%, 19/63).
The remaining 4 areas were not considered to be a barrier by most companies.
Only 12% and 27% of respondents considered the fact that regulatory agreements were not
required by regulatory agencies as a major or minor barrier (7/60 and 16/60, respectively); most
did not regard it as a barrier (62%, 37/60). Insufficient guidance/information from industry
groups was a major or minor barrier for 8% (5/59) respectively and 41% (24/59); about half
(30/59) did not consider it to be a barrier. Insufficient information from regulatory agencies was
considered a major barrier by 14% (8/59), a minor barrier by 41% (24/59), and not a barrier by
46% (27/59). Finally, the fact that no need was identified within the company was a major
barrier for 23% (14/61), a minor barrier for 36% (22/61), and not a barrier by 41% (25/61).
Eight respondents identified other barriers, and seven appended comments (Table 14).

68
Table 14: Barriers to Developing Regulatory Agreements
Think of one of the first regulatory agreements that you developed. At those early stages, what did you
find to be the barriers when developing that regulatory agreement? (choose all that apply) (n=66)
Item Major barrier Minor barrier Not considered a barrier Total
% Count % Count % Count Count
Insufficient information
from regulatory agencies
14 8 41 24 46 27 59
Insufficient
guidance/information from
industry groups
8 5 41 24 51 30 59
No templates available 35 23 35 23 29 19 65
Insufficient drafting
experience
30 19 33 21 37 23 63
Not required by regulatory
agencies
12 7 27 16 62 37 60
No need identified within
the company
23 14 36 22 41 25 61
No resources available
within the company
39 24 37 23 24 15 62
Low understanding of
what is needed
52 34 29 19 18 12 65
Other
a
75 6
b
13 1 13 1 8
a
Other/not specified: “Work for a large company with agreements already in place”, “Getting contracts executed is usually a
more urgent priority than improving the contract templates.”,
b
Other/major barrier: “Lack of leadership understanding importance of including regulatory/quality clauses in agreements.”,
“Need for internal clarification on specific roles and responsibilities”, “starting from scratch was intimidating but necessary”,
“Collaboration and information sharing with the executive team; the executive team feeling like this was not a priority to do
business with the supplier”, “Internal alignment”

Most respondents whose companies had implemented standalone regulatory agreements
found them to be advantageous. Ninety percent (61/68) (Figure 15) identified that the
agreements clarified roles and responsibilities for regulatory activities; 79% (34/68) that they
standardized regulatory expectations between the companies and 66% (45/68) that they
encouraged earlier discussion about joint regulatory strategies. Two respondents (3%, 2/68) felt
they that did not have enough experience to answer, and none (0%, 0/68) saw no benefits. Three
respondents (4%, 3/68) chose other and provided comments (Figure 15).

69
Figure 15: Benefits of Implementing Regulatory Agreements With Business / Academia
What benefits were observed when a standalone regulatory agreement was implemented between your
company and a partner company or academia? (choose all that apply)

Other: “Avoided legal and relationship challenges”, “Leadership in other (non-RA/QA) areas starting to consider regulatory and
quality issues early-on in partnering.”, “Clarity for legal issues that may arise from recalls, AE.and MDRs” [sic]

The next block of questions in the survey explored the point at which companies plan to
develop regulatory agreements with different types of partners. Most commonly, regulatory
agreements with consultants were planned and developed at the time of selection (46%, 31/67)
(Table 15), although some developed the regulatory agreement simultaneously with the
development of the main partner or master service agreement (22%, 15/67) or after the main
partner agreement was signed (7%, 5/67). A similar distribution of responses was seen for
regulatory agreements with partnering companies: at the time of selection (42%, 29/69); when
the main partner agreement is first developed (35%, 24/69); or after the main partner agreement
is signed (16%, 11/69).
The timing of agreements with CROs was split: at the time of selection (38%, 25/65) or
when the main partner agreement is first developed (37%, 24/65). Relatively few planned to

70
develop their regulatory agreements after the main partner agreement had been signed (12%,
8/65). Agreements with CDMOs were planned more commonly at the time that the main partner
agreement is first developed (41%, 26/64) rather than at the time of CDMO selection (33%,
21/64) or after the main partner agreement is signed (8%, 5/64). Agreements with academic
institutions were most commonly developed at the time of selection (32%, 21/65) or at the time
the main partner agreement is first developed (26%, 17/65) rather than waiting until the main
partner agreement has been signed (14%, 9/65). A few companies did not plan to use regulatory
agreements with certain partners. Nine percent did not plan to use them with consultants (6/65)
or academic institutions (6/65), 6% with vendors (4/65) or CROs (4/65) and 3% (2/64) with
CDMOs. None had no plans to use them with pharmaceutical companies. Several respondents
did not know if they would use regulatory agreements with academic institutions (18%, 12/65),
CDMOs (16%,10/64), CROs 6% (4/65) or partnering companies (5%, 5/69).

71
Table 15: Timing of Regulatory Agreement Introduction
If your company is exploring the use of regulatory agreements with other companies, vendors (CDMO,
CRO), or consultants, at what point of the business relationship do you plan to develop these
agreements? (choose all that apply) (n=70)
Partner
At time of
selection
When master
agreement is
developed
a
After master
agreement is
signed
b
Do not
plan to use
Do not know Total
% Count % Count % Count % Count % Count Count
Partner
companies
42 29 35 24 16 11 0 0 7 5 69
Vendor -
CDMO
33 21 41 26 8 5 3 2 16 10 64
Vendor -
CRO
38 25 37 24 12 8 6 4 6 4 65
Academic
institutions
32 21 26 17 14 9 9 6 18 12 65
Consultants 46 31 22 15 7 5 9 6 15 10 67
a
At the time the main (master service) partner agreement is first developed
b
After the main (master service) partner agreement is signed

Respondents were also asked at what point the agreement would be reviewed for possible
modification after signing the initial agreement. Most commonly, reviews took place at least
yearly (39%, 27/69) (Figure 16) or when changes were needed (33%, 23/69). Fewer companies
conducted these reviews at milestone events (17%, 12/69), at multiple times per year (6%, 4/69),
or at no planned future date (4%, 3/69).
Figure 16: Timing to Review the Initial Regulatory Agreement
How soon after signing the initial agreement will you review and possibly modify the elements of the final
regulatory agreement?

72
Respondents were asked about impediments to the introduction of standalone regulatory
agreements in their companies from a list of 6 choices (Table 16). All of the choices appeared to
present a major or minor hurdle: insufficient resources (major 48%, 27/56; minor 52%, 29/56),
lengthy implementation time (major 44%, 24/54; minor 56%, 30/54), insufficient expertise
(major 46%, 21/46; minor 54%, 25/46), absence of guidance or templates (major 40%, 19/47;
minor 60%, 28/47), lack of management support (major 41%, 17/41; minor 59%, 24/41) and
failure to recognize the need for such agreements (major 43%, 20/46; minor 57%, 26/46). Three
respondents identified other hurdles (major 67% (2/3) and minor 33% (1/3)) (Table 16).
Table 16: Hurdles to Developing Regulatory Agreements in Own Company
For this question, think about your past experience as you initiated the use of regulatory agreements.
What hurdles did you have to overcome to introduce the use of standalone regulatory agreements in your
company? (choose all that apply) (n=65)
Hurdle Major impediment Minor impediment Total
% Count % Count Count
Insufficient resources 48 27 52 29 56
Too much time needed to
implement
44 24 56 30 54
Expertise not available in your
company
46 21 54 25 46
Information or template not
available to guide the process
40 19 60 28 47
Management support not
available
41 17 59 24 41
Need for regulatory
agreements not recognized
43 20 57 26 46
Other
a
67 2
b
33 1 3
a
Other/not specified major or minor: “Because it is not standard practice to have a regulatory standalone, the required resources
are reluctant to commit to doing something different that may be more time consuming the first time around”
b
Other/major impediment: “Management responsibility”
Respondents then identified impediments when working with vendor companies
(CDMO or CRO). Concerns with legal indemnity/liability were identified most often (43%,
29/67) (Figure 17). Other impediments identified by about a third of respondents included: need
for regulatory agreements not recognized (34%, 23/67); too much time needed to implement
(33%, 22/67); insufficient resources and expertise not available in the vendor company (both

73
31%, 21/67); and information or template not available to guide the process (30%, 20/67) (Figure
17). Less frequently identified as impediments when working with vendors were management
support not available 18% (12/67) and other (6%, 4/67). Sixteen percent (11/67) of respondents
identified no hurdles, and 2% (3/67) chose do not know or cannot answer (Figure 17).
Figure 17: Hurdles to Developing Regulatory Agreements With Vendor Company
What hurdles did you have to overcome when working with your vendors (CDMO, CRO) to implement the
use of regulatory agreements in your company? (choose all that apply)

Other: “N/A, regulatory concerns incorporated in main agreement”, “cost implications”, “people are just lazy and or do not want
to invest the time, unfortunately it was a finding during an ausit so we had to implement RA and QA agreements” [sic], “NA”

Respondents were also asked to identify the impediments faced when implementing
regulatory agreements with their partner company or academic institution. Half (47%, 33/70)
(Figure 18) identified concerns with legal indemnity/liability as the greatest impediment. This
was followed in order of frequency by: need for regulatory agreements not recognized (36%,
25/70), expertise not available in the vendor company (34%, 24/70), too much time needed to
implement (31%, 22/70), and insufficient resources and information or template not available to

74
guide the process (both 24%, 17/70). An additional impediment less frequently identified with
their partner company or academic institution was management support not available (16%,
11/70). Seven percent of respondents (5/70) did not know/could not answer, 9% (6/70) answered
none, and 4% (3/70) answered other, with associated comments appended after Figure 18.
Figure 18: Hurdles to Developing Regulatory Agreements With Partner or Academia
Now think about your partner agreement(s) that included either another pharmaceutical, biotechnology,
or device company, or an academic institution. What hurdles did the partner company appear to face
when they developed regulatory agreements with your company? (choose all that apply)

Other: “Not an isdue”[sic], “usasing their templat instead of our s” [sic], “Inflexibility to templated content”

The structure of the teams that develop regulatory agreements were examined next. Most
used a regulatory affairs expert as the team Lead (L) (67%, 46/69) or included him/her/them as a
team Member (M) (28%, 19/69). Only 6% (4/69) did Not Involve (NI) regulatory affairs. Other
functions frequently identified as having a role on the team were legal/contracts (L 39%, 28/72;
M 58%, 42/72; NI 3%, 2/72) and quality (L 36%, 25/69; M 51%, 35/69; NI 13%, 9/69). Less
frequently represented were: project management (L 21%, 14/68; M 47%, 32/68; NI 32%,
22/68); alliance management (L 22%, 14/65; M 38%, 25/65; NI 40%, 26/65); business

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development (L 26%, 18/68; M 41%, 28/68; NI 32%, 22/68); finance (L 14%, 9/66; M 58%,
38/66; NI 29%, 19/68); commercial affairs (L 12%, 8/65; M 26%, 17/65; NI 62%, 40/65) and
other (L 29%, 5/17; M 41%, 7/17; NI 29%, 5/17). Fifteen comments were included to clarify
other, and about half of these (7/15) identified clinical functions (Table 17).
Table 17: Team Members Involved in Developing Regulatory Agreements
Which departments provide members for the team that is tasked with developing regulatory agreements in
your company? (choose all that apply) (n=73)
Team Lead (L) Team Member (M) Not involved (NI) Total
Functional Area % Count % Count % Count Count
Regulatory Affairs 67 46 28 19 6 4 69
Legal/Contracts 39 28 58 42 3 2 72
Quality 36 25 51 35 13 9 69
Project Management 21 14 47 32 32 22 68
Alliance
Management
22 14 38 25 40 26 65
Business
Development
26 18 41 28 32 22 68
Finance 14 9 58 38 29 19 66
Commercial Affairs 12 8 26 17 62 40 65
Other
a
29 5
b
41 7
c
29 5 17
a
Other/not specified: “Pharmacovigilance”, “R&D, supplier wuality” [sic]
b
Other/L: “Clinical Operations”, “Clinical Operations” “Clinical operations”, “Depends”, “Engineering”,
“Manufacturing/Product Development”,
c
Other/M: “Clin Ops”, “Clinical Development”, “Clinical Operations”, “Drug Safety”, “Including clinical as a team member
would be beneficial”, “Pharmacovigilance”, “R&D”

Companies relied on different resources to identify the critical elements included in
regulatory agreements. Almost all (91%, 63/71) (Table 18) consulted and found useful their
internal experience or expertise; only a few (6%, 4/69) did not find internal resources useful.
Also found to be useful were the structure/contents of other contracts by 85% (57/67), and not
useful by only 10% (7/67). A majority, 77% (49/64), also relied on the scope of current and
previous partnerships; 14% (9/64) did not find other partnerships to be useful. Somewhat more
than half found government documents (56% 37/66) and external consultants (54%, 36/67) to be
useful resources; a quarter did not find government documents (23%, 15/66) to be useful, and

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13% (9/67) did not find external consultants to be useful. Some respondents did not consult
certain resources: internal experience or expertise (3%, 2/69%); the structure and contents of
other contracts (4%, 3/67); scope of partnership with this and previous companies (9%, 6/64);
government documents (18%, 12/66) or external consultants (33%, 22/67). Nine respondents
(100%, 9/9) indicated that other resources were not used.
Table 18: Resources Involved in Developing Regulatory Agreements
On what or who has your company relied on to identify the critical elements included in regulatory
agreements? (choose all that apply) (n=71)
Resource Consulted - useful Consulted - not
useful
Not used
% Count % Count % Count Total N
Internal experience or
expertise
91 63 6 4 3 2 69
External consultants 54 36 13 9 33 22 67
Government documents 56 37 23 15 18 12 66
Structure/contents of other
contracts
85 57 10 7 4 3 67
Scope of partnership with this
and previous companies
77 49 14 9 9 6 64
Other 0 0 0 0 100 9 9

When asked, “Does your company collect feedback from a multi-disciplinary team
(internal or external stakeholders) regarding the effectiveness of the initial regulatory
agreement?”, the majority of participants responded affirmatively (59%, 43/73), and the
remainder (41%, 30/73) negatively. When asked how that feedback is collected, a majority used
most of the methods listed in Table 19: team meetings - internal (52%, 13/25); team meetings -
with partner company (56%, 15/27); management feedback - internal (50%, 13/26); management
feedback – partner company (54%, 15/27) and formal survey (20%, 5/25). The methods
sometimes used were: team meetings – internal (48%, 12/25); team meetings- with partner
company (44%, 12/27); management feedback – internal (46%, 12/26); management feedback -
partner company (35%, 9/26) and formal survey (24%, 6/25). Some respondents did not use:

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internal management feedback (4%, 1/26); management feedback from the partner company
(12%, 3/26), and formal surveys (56%, 14/25). No respondents indicated internal or partner
meetings were not used to collect feedback (0%, 0/25, and 0/27, respectively). Other methods
used to collect feedback were indicated as mostly used or not used 50% (2/4 each); two
comments were provided as shown in Table 19.
Table 19: Methods Used to Collect Feedback on Initial Regulatory Agreements
How did you collect specific feedback on the effectiveness of the initial regulatory agreement from both
internal and external stakeholders? (choose all that apply) (n=28)
Method to collect
feedback
Mostly used Sometimes used Not used Total
% Count % Count % Count Count
Team meetings -
internal
52 13 48 12 0 0 25
Team meetings - with
partner company
56 15 44 12 0 0 27
Management feedback
- internal
50 13 46 12 4 1 26
Management feedback
- partner company
54 14 35 9 12 3 26
Formal survey 20 5 24 6 56 14 25
Other 50 2
a
0 0 50 2 4
a
Other: “Too early for formal assessment”, “physical audit”

Respondents were also asked to provide comments to the question: “What metrics (if
any) are being used to measure the effectiveness of the regulatory agreement? Example metrics
could include quality measurements, Key Performance Indicators (KPIs), cost savings”. The 16
comments, listed in Table 20, pointed most commonly to cost savings and KPIs.

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Table 20: Metrics Used to Measure Effectiveness of Regulatory Agreements
What metrics (if any) are being used to measure the effectiveness of the regulatory agreement? Example
metrics could include quality measurements, Key Performance Indicators (KPIs), cost savings.
Comments for Metrics n=16
• Cost savings
• KPIs to meet business needs on timeliness and compliance
• KPIs and cost savings
• Cost savings
• Still working on it. Main one is efficiency
• Milestones and KPIs
• On time, on budget
• Audit findings
• KPIs & cost savings
• frequency of changes or updates
• quality measurements, Key Performance Indicators (KPIs), cost savings, time to market, good
validated analytical methods, well reviewed and docunments- protocols, reports, new quality
documents [sic]
• Cost savings and KPI
• KPIs, Annual contract reviews
• None
• N/A
• None

Respondents were also asked their views on their company’s commitment to provide
leadership, structure, and support to maintain the elements in their regulatory agreements. Most
(64%, 43/67) were satisfied with their company’s commitment. Only 6% (4/67) were not
satisfied, and 30% (20/67) were not sure.
Next, the elements included in the initial regulatory agreement were explored by dividing
them into development, review, and logistics categories. Each of the six elements offered as
choices for development was selected by over 50% of respondents (Figure 19) in the following
order of frequency: roles in regulatory submissions (86%, 60/70); adherence to regulatory
procedures (77%, 54/70), development of regulatory strategy (74%, 52/70); regulatory requests
authoring, review, and approval (74%, 52/70); attendance at agency meetings (56%, 39/70);

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postmarketing activities (56%, 39/70). Ten identified other elements (14%, 10/70) with
comments, shown in Figure 19.
Figure 19: Development Elements Included in Initial Regulatory Agreements
What development elements were included in the initial regulatory agreement? (choose all that apply)

Other: “Help with other areas as needed”, “Trial master file and Records management”,
“Compliance/conformity to established standards/guidances (ISO, ICH, ...)”, “Documentation handling
and ownership”, “Do not know”, “Source documents.”, “Metrics: deviations, CAPA and
audit/inspection finding reviews”, “reporting responsibility”, “Oversight of GLP and GMP compliance”,
“communication between the companies”

Respondents were next asked about additional elements included in the company’s initial
regulatory agreement to address review and logistics elements. Over 50% of respondents chose
all of the 4 suggested review elements (Figure 20): report review and approval (73% , 51/70);
timing for review/modification of agreement (60%, 42/70); labeling review and approval (59%,
41/70); review cycles for documents – number and timing (54%, 38/70). More variability was
seen for responses related to the
Other: “reporting responsibility”, “communication between the companies”, “Trial master file and Records management”,
“Source documents.”, “Oversight of GLP and GMP compliance”, “Metrics: deviations, CAPA and audit/inspection finding
reviews”, “Help with other areas as needed”, “Documentation handling and ownership”, “Compliance/conformity to established
standards/guidances (ISO, ICH, ...)”

Four suggested logistics elements: management of records (84%, 59/70); governance and
communication processes (77%, 54/70); matrix defining roles for responsible, accountable,
consulted, and informed parties (63%, 44/70); crisis management roles and responsibilities (44%,
31/70). Three respondents (4%, 3/70) selected other, adding safety reporting and notifications of
audits, inspections, and adverse events (Figure 20).
Count

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Figure 20: Review and Logistics Elements Included in Initial Regulatory Agreements
What review or logistics elements were included in the initial regulatory agreement? (choose all that
apply)
Other: “Requirements for safety reporting”, “Notification of audits, inspections, adverse (reportable) events.”, “Do not know”

When asked about additional elements they would include in the next revision of their
company’s regulatory agreement, 35 respondents had comments that could be grouped according
to reoccurring themes: compliance, roles and responsibilities, document review, processes, and
miscellaneous (Table 21).

Count

81
Table 21: Regulatory Agreement Elements to Include in the Revised Agreement
What elements, if any, would you include in the next revision of the regulatory agreement that you did not
have in the initial regulatory agreement n = 35
Category Comment
Compliance • More shifting liability clauses
• Clearer milestone agreements
• Crisis management (n=2)
• Penalties for non compliance
• Consequences for lack of performance
Roles and
Responsibilities
• Attendance AND roles/responsibilities for agency interactions (Written, telephone, and face to
face)
• More specific detail of what each company is responsible for even though the document is
currently a template format to allow for more explicit documentation of who does what, when,
how, and any responsibilities of the other party for review, approval, editing, etc
• specific roles of individuals
• Sign off by wider range of functional areas of both parties.
• Specific roles and responsibilities of consultants
• Matrix defining RACI
• In general, the partnership template we utilize provide consistency. Some partnerships may be
different (i.e. EU right only, not including US, or specific regions) so outlining of regional
specific RA requirement, including R/R in each region will be key to avoid future confusions.
• More assignment of roles and crisis arrangements. Review period.
Document Review • Timing for review/modification
• Process/cycles for drafting and review of agreement; continuous maintenance of agreement.
• Turnaround time for documents from CRO
Process • Process workflow diagram for collecting, reviewing, approving, storing and submission.
• Audits
Miscellaneous • The matrix mentioned above is very good
• Not there yet. We lack consistency.
• Regulatory due diligence.
• Database management and compliance
• info sharing
• More information on project teams and levels of involvement for submissions.
• A commitment from the supplier that they will maintain qualified and knowledgeable regulatory
and quality resources to support the commitments within this agreement, in case the current
resources are fired, laid off, or leave the company.
• Key performance indicators
• All items listed above
• Assumptions for the agreement
• N/A or n/a (n=5)
• not sure

Respondents were asked, “Does your company have a standard operating procedure to
guide regulatory agreements as standard practice?” Similar numbers did not have an SOP (47%,
32/68; 53%, 36/68). When asked, “Is a regulatory agreement required for any new joint drug
development venture between your company and another pharmaceutical, biotechnology, or

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device company or with an academic institution?”, most (78%, 45/58) indicated that a regulatory
agreement is required and the remaining 22% (13/58) responded that it is not.
4.6 Companies Investigating but Not Implementing Regulatory Agreements
Respondents whose companies had investigated but not implemented regulatory
agreements were asked about the resources that they found valuable when researching the
development of regulatory agreements. Of the 12 that responded, all (100%, 12/12) (Table 22)
found regulatory agency documents/regulations to be available, but only 75% (9/12) considered
them useful. The other listed resources were also seen to be available and useful in the following
order: previous contracts in other departments (e.g., manufacturing, quality, clinical) (available
and useful 67%, 8/12; available but not useful 17%, 2/12; not available 17%, 2/12), information
from industry meetings or seminars (available and useful 40%, 4/10; available but not useful
20%, 2/10; not available 40%, 4/10), government presentations (available and useful 30%, 3/10;
available but not useful 30%, 3/10; not available 40%, 4/10), consultants (available and useful
50%, 5/10; available but not useful 30%, 3/10; not available 20%, 2/10). Although other was not
selected by any of the respondents, one comment was added and is included in Table 22.

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Table 22: Resources to Research Development of Regulatory Agreements
When you first considered putting regulatory agreements in place, what resources did you find valuable
in researching the development of regulatory agreements? (choose all that apply) (n=12)
Resource Available and
useful
Available but not
useful
Not available Total
% Count % Count % Count Count
Regulatory Agency
Documents/Regulations
75 9 25 3 0 0 12
Previous Contracts in Other
Departments (e.g.,
manufacturing, quality,
clinical)
67 8 17 2 17 2 12
Information from Industry
Meetings or Seminars
40 4 20 2 40 4 10
Government Presentations 30 3 30 3 40 4 10
Consultants 50 5 30 3 20 2 10
Other
1
0 0 0 0 0 0 0
1
Other was not selected but one comment was included: “Contacts in other healthcare companies.”

4.7 Companies Without Standalone Regulatory Agreements
Respondents in companies without standalone regulatory agreements were asked why
these agreements were not in place. They chose the suggested reasons in the following order:
challenging to have another standalone agreement (26%, 42/164); the company does not see a
need for it (23%, 38/164); had not thought of it (18%, 30/164); good idea, but not enough
information yet available (12%, 20/164) and other company does not see a need for it (2%,
3/164). Thirty-one respondents (19%, 31/164) responded other and included comments, some
shown in Figure 21 and all shown in Appendix D. Representative comments were grouped by
reoccurring themes: included in other more extensive agreements/contracts; premature/ too
demanding; complicated; not sure; and does not apply.

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Figure 21: Reasons for Not Having Regulatory Agreements
What is the reason your company does not have standalone regulatory agreements?

Theme Example Comments
Included in a broader
agreement/contract
• regulatory roles and responsibilities are addressed as part of a bigger ancillary
agreement but not as standalone agreement
• Regulatory requirements are combined with license, quality and/or other agreements.
• Covered under Quality or Manufacturing agreements (in principle, if not actual
practice)
• All elements that would be contained within a stand-alone Agreement are addressed
within the more broad Agreement/contract.
Premature/too
demanding
• The concept has not been vetted from my knowledge- vetting is critical before
further consideration.
• Moving to fast and RA is brought in to late
• no right time or circumstance yet
• It may be for our large studies but smaller studies t does not happen due to our lega
team being overwhelmed [sic]
Not sure • Not sure, since not discussed Maybe because the people making the agreements
don’t do as good of a job getting input from stakeholders in other functions.
• I believe it may have been considered, but similar to above, the ability to implement
and pull through may pose part of the issue
• We may have these, though I’m unaware
Complicated • We generally have a regulatory plan, which is lifecycle controlled and referenced in
the contractual agreement. Making this part of the contracting process would
bottleneck contracting (which already takes too long) and reduce our flexibility
• There is not the expertise available to enable an agreement, especially since there is
no standard available.
• A stand alone agreement adds complexity to managing the other company and may
increase compliance risk.
Does not apply • I’m a consultant so don’t decide for client
• WE do with specific regulatory consultants, but not with aharmaceutical partners
[sic]
• Generally redundant, require legal review.

Count

85
To understand further why the companies of some respondents did not have regulatory
agreements, two subsets, including those whose companies had and had not investigated such
agreements were cross tabulated against the reasons for not having regulatory agreements, shown
in Figure 21 (Table 23). In both cases, the most common reasons were because their companies
did not see a need for such agreements or that it was challenging to have another standalone
agreement. Other was also often selected by respondents in both subgroups. Table 23 below is a
cross-tabulation of the respondent subgroups that have not investigated or investigated, but did
not implement regulatory agreements by the reasons their company did not have regulatory
agreements (n=55).
Table 23: Respondents Not Using Regulatory Agreements by Reason
Use of regulatory agreements with business or academic
partners
Question Choice Total Investigated
but did not go
forward
Have not investigated
Reasons for
not having
regulatory
agreements
Total Count (both subgroups) 55 12 43
Had not thought of it 4 0 4
Good idea, but not enough
information yet available
5 0 5
Challenging to have another
standalone agreement
14 3 11
Your company does not see a
need for it
15 3 12
Other company does not see a
need for it
1 0 1
Other 16 6 10
Had not thought of it 7%
1
0%
1
(0%)
2
7%
1
(7%)
2

Good idea, but not enough
information yet available
9% 0% (0%) 12% (9%)
Challenging to have another
standalone agreement
25% 25% (5%) 26% (20%)
Your company does not see a
need for it
27% 25% (5%) 28% (22%)
Other company does not see a
need for it
2% 0% (0%) 2% (2%)
Other 29% 50% (11%) 23% (18%)
1
Percent is calculated on column total
2
Percent is calculated on total number of respondents in both subgroups (n=55)

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Respondents in companies that have not yet developed regulatory agreements were also
asked about barriers they might anticipate. Identified most often were no support internally in
the company (49%, 80/162) (Table 24) and no experience in drafting -- not sure where to start
(40%,65/162). Three barriers related to a lack of information: no templates available (36%,
58/162); no guidance or other information available from industry groups (31% (50/162); and no
guidance documents or other information available from regulatory agencies 30% (48/162). A
similar number of respondents considered the fact that these were not important/required by
regulatory agencies (31% (51/162) to be a barrier. The least chosen barrier, no understanding
from the partner as to what is needed, was identified by 24% (39/162) of respondents. Twenty-
eight respondents identified other barriers and provided comments. Example comments are
shown in Table 24; all are included in Appendix E.

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Table 24: Barriers to Having Regulatory Agreements
What do you think are the barriers to having regulatory agreements? (choose all that apply)
(n=162)
Item Barrier Choice
% Count
No guidance documents or other
information available from regulatory
agencies
30 48
No guidance or other information
available from industry groups
31 50
No templates available 36 58
No experience in drafting -- not sure
where to start
40 65
Not important/required by regulatory
agencies
31 51
No support internally in the company
(no perceived need, no resources
available)
49 80
No understanding from the partner as to
what is needed
24 39
Other 17 28

Example Comments for Other Barriers
• Time to draft; typically RA items are included in either a Quality Agreement and/or PV/Safety
Agreement
• I think they would be a great idea similar to a PV agreement. I think part of the problem is that the
people making the overarching contracts with the partners and managing the agreement process are
not residing in the functions that are doing the day-to-day work with the partners. Therefore the
importance of having a regulatory agreement might not be clear to them. I think the master contract
should call out the subfunctional agreements that will need to be created upon kick off of the
relationship/partnership. I would also recommend including in the agreement a periodic review to
ensure that it remains up-to-date from lessons learned/areas that need to be further detailed. [sic]
• Benefit /Risk need to be weighed
• Not a lot of precedent, not a perceived best practice.
• Lack of understanding the importance of prospectively defining the terms of the Agreement
between the parties.
• Another separate agreement to maintain.
• Better to integrate reg requirements into overall clinical or other agreements. Ensures process is
highly integrated.

Respondents whose companies had no regulatory agreements were asked how regulatory
elements are covered in their current partnerships with other companies or vendors. The
majority indicated that these elements are included in other formal contracts or agreements,
including Master Service Agreements (83%, 137/166) (Figure 22) or that they used work orders
or scope-of-work documents instead (45%, 75/166). Thirteen percent (13%, 21/166) employed

88
informal agreements or relationships, while 5% have not required regulatory agreements in their
partnerships. Nineteen (11%, 19/166) respondents chose other and provided their comments.
Example comments are shown after Figure 22; all are included in Appendix F.
Figure 22: How Companies Cover Regulatory Requirements With Their Partners
How does your company ensure that regulatory requirements are covered in their current
partnerships with other companies and vendors? (choose all that apply)

Example Other Comments
• Formal transfer of obligations (TORO)
• Regulator Plan documents developed under each agreement at kickoff, then maintained through lifecycle
• Only registration of devices or facilities has been included in the quality agreements
• regulatory elements are often left to informal or secondary agreements as the persons involved in crafting the
agreements only touch on reg requirements at a high level and not in enough detail
• It is included in Quality agreement or other type of agreement (Distributor agreement or some other
Controlled document)
• require ISO13485 and assume that's enough
• Boilerplate Agreement with Addendum or Appendix defining milestones, number of hours not to be
exceeded, timeframes for reporting progress, phases of work product, etc.

Respondents were asked about critical development elements that they would include to
ensure that regulatory requirements are covered if they were to implement a standalone
regulatory agreement. Most identified that regulatory agency inspections would be necessary for
Count

89
all (A) (55%, 89/162) (Table 25) or some (S) (28%, 45/162) agreements but a few respondents
(5%, 12/162) indicated that this was nice-to-have, but not necessary (N) or that it would be
included in a different agreement (D) (12%, 19/162). Only 2% (4/162) of respondents felt that
inspections would not need to be covered (NN). Most would also include manufacturing in their
agreements for all (A 48%, 78/163) or some (S 30%, 49/163) partners; other respondents would
include this in a different agreement (D 14%, 23/163). Only 2% (4/163) considered this element
to be nice-to have but not needed (6%, 9/163). A majority of companies would also incorporate
regulatory submissions (A 46%, 75/163; S 40%, 65/163; N 3%, 5/163; D 6%, 10/163; NN 5%,
8/163), regulatory strategy (A 37%, 61/163; S 45%, 74/163; N 8%, 13/163; D 5%, 8/163; NN
4%, 7/163) or regulatory requests (A 37%, 61/164; S 48%, 78/164; N 7%, 12/164; D 4%, 7/164;
NN 4%, 6/164). The remainder of the elements that were identified as necessary for all or some
agreements including postmarketing commitments or requirements (A 36%, 59/163; S 38%,
62/163; N 9%, 15/163; D 6%, 9/163; NN 11%, 18/163); health agency meetings (A 35%,
56/161; S 39%, 63/161; N 17%, 27/161; D 4%, 6/161; NN 6%, 9/161); regulatory procedures (A
29%, 46/161; S 35%, 57/161; N 20%, 33/161; D 5%, 8/161; NN 11%, 17/161) and advertising
and promotional materials (A 25%, 41/163; S 45%, 74/163; N 11%, 18/163; D 7%, 11/163; NN
12%, 19/163). A modest number of other elements resulted in 11 text comments (Table 25).

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Table 25: Critical Development Elements to Include in a Regulatory Agreements
If you were to consider implementing a standalone regulatory agreement with one of your
business partners (pharmaceutical/biotechnology/device company) or an academic institution,
what critical development elements would you consider including to ensure the regulatory
requirements are covered? (choose all that apply) (n=164)

Element Other Comments n=11
Necessary
for all
• ADE reporting
• Governance
• Statistical rationale, design risk analysis and GXP
Necessary
for some
• Level of necessity increases as product progresses from early dev to commercial
• PV submission activities; labeling
• Time frame of the agreement
Incidence of
including
element not
specified
• Completely dependent upon the specific scope of work that the customer requires
to be performed. Sometimes (rarely) it's all of the above elements. Usually it's one
or several of the above elements.
• I'm not sure I understand the premise of these questions. Everything depends on
what you are doing with your business partner. Is it a CRO? A university running a
tox study? A joint venture partner? API manufacture? All of these listed items are
important, but not relevant to many arrangements a company would have with it's
vendors and partners. So it's impossible to answer this question generically. [sic]
• due diligence
• Some of the categories might be more or less relevant depending on the specific
terms of the collaboration partnership, stage of development, and responsibilities
shared/split, development and commercialization strategy.
• List of contacts for each of the elements of the agreement

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Respondents were also asked about review and logistics elements that would be
important to include to ensure regulatory requirements are covered with partners. More than
three quarters found records necessary for all (A) (56%, 92/163) (Table 26) or some (S) (29%,
48/163) agreements; many fewer (7%, 7/163) indicated that records would be nice-to-have but
not necessary (N) or included in a different agreement (D) (9%, 14/163). Only 2% (3/163) of
companies felt these inspections are not needed (NN). A similar distribution of responses was
seen for the choice of governance, communication, and escalation process, viewed as important
for all (A 56%, 91/163), some (S 29%, 47/163), nice-to-have (N 7%, 11/163) or included in a
different agreement (D 6%, 10/163). Only 2% (4/163) considered these not needed. Most would
also include labeling (A 40%, 65/162; S 48%, 77/162; N 3%, 5/162; D 6%, 9/162; NN 4%,
6/162), protocols/reports (A 42%, 68/161; S 43%, 70/161; N 6%, 10/161; D 4%, 7/161; NN 4%,
6/161), responsibility matrix (RACI) (A 46%, 74/160; S 34%, 54/160; N 14%, 23/160; D 1%,
1/160; NN 3%, 4/160), and crisis management plans and procedures (A 41%, 68/161; S 38%,
61/163; N 9%, 14/161; D 8%, 13/161; NN 4%, 7/161) in all or some agreements. Less selected
were the use of templates (A 17%, 27/160; S 43%, 69/160; N 31%, 50/160; D 1%, 1/160; NN
8%, 13/160), and a process flow map (A 28%, 44/160; S 38%, 61/160; N 25%, 40160; D 3%,
5/160; NN 6%, 10/160). A few respondents also selected other and provided 8 text comments
included after Table 26.

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Table 26: Review and Logistics Elements to Include in Regulatory Agreements
If you were to consider implementing a standalone regulatory agreement with one of your
business partners (pharmaceutical/biotechnology/device company) or an academic institution,
what critical review and logistics elements would you consider including to ensure the
regulatory requirements are covered? (choose all that apply) (n=163)

Incidence to include the element Other Comments n=8
Necessary for all • Progress risk management
• Some examples to fill the templates
Necessary for some • Time frame of agreement
Incidence of including element not specified • Liability
• Same issue as with prior question - the relevance
of all of these issues depends on what you're doing
with the other company.
• Shared environment for reviews, collaboration,
hand-off of information.
• Totally dependent upon the scope of the work to
be performed.
• org chart / staffing assignments

When asked if their companies had the relevant internal expertise to implement
regulatory agreements, most respondents identified that internal expertise was available (A)
versus not available (NA): regulatory affairs (A 81%, 132/163; NA 13%, 21/163) (Table 27);
quality (A 71%, 115/163; NA 21%, 34/163); legal/contracts (A 64%, 104/162; NA 27%,
43/162); finance (A 62%, 100/161; NA 12%, 20/161); business development (A 59%, 94/160;

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NA 18%, 28/160); project manager (A 57%, 93/162; NA 28%, 46/162); alliance management (A
41%, 65/160; NA 34%, 54/160); and commercial affairs (A 36%, 58/160; NA 28%, 45/160).
Respondents also identified functions that would not be involved (NI) or they did not know (NK)
the involvement, in regulatory agreements. Identified most often were: commercial affairs (NI
19%, 30/160; NK 17%, 27/160); finance (NI 14%, 22/161; NK 12%, 19/161); alliance
management (NI 11%, 17/160; NK 15%, 24/160); business development (NI 11%, 17/160; NK
13%, 21/160); and project management (NI 9%, 14/162; NK 6%, 9/162). Functions identified
less often included: regulatory affairs (NI 1%, 1/163; NK 6%, 9/163); legal/contracts (NI 1%,
1/162; NK 9%, 14/162); and quality (NI 1%, 1/163; NK 8%, 13/163). Chosen infrequently by
respondents were other functions. Most respondents indicated that these functions would either
not be involved, or they did not know if other expertise would be needed, to implement
regulatory agreements: Although a few respondents indicated that if needed, this other expertise
was available (A 13%, 2/15; NA 0%, 0/15; NI 27%, 4/15; NK 60%, 9/15).

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Table 27: Internal Expertise Available to Implement Regulatory Agreements
If your company decided to implement a standalone regulatory agreement with their business
partners (pharmaceutical/biotechnology/device company) or an academic institution, do you
think your company currently has the relevant internal expertise to implement these agreements?
(choose all that apply) (n=163)
1
Other/function would not be involved: Medical Affairs

Respondents were asked about their views on hurdles that they anticipated when first
implementing regulatory agreements within their own companies, with other companies, or with
academia. They most frequently identified that hurdles would be present in their own
companies. These included challenges with resources to implement (69%, 95/137); insufficient
information or templates to guide the process (68%, 88/129); insufficient management support
(67%, 83/124); understanding of why regulatory agreements are needed (64%, 81/126); and
needed time to implement within partnerships (62%, 74/120). Fewer respondents identified that
insufficient internal expertise (38%, 48/127) was an impediment within their own company.
When considering impediments when working with the partner, however, a lack of internal
expertise was the most often identified impediment (38%, 48/127). It was followed by: time to
implement within partnerships (30%, 36/120); no internal management support (23%, 29/124);
resources needed to implement (20%, 27/137); no understanding of why regulatory agreements

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are needed (20%, 25/126); and the absence of information or template to guide the process (19%,
24/129). Respondents less frequently noted impediments when working with academia in a
partnership. Insufficient internal expertise (24%, 31/127) was identified most often, followed
by: no understanding of why regulatory agreements are needed (16%, 20/126); information or
template not available to help guide the process (13%, 17/129); resources needed to implement
(11%, 15/137); no internal management support to implement (10%, 12/124); and time to
implement within partnerships (8%, 10/120). A few participants chose other but gave no
comments.
Figure 23: Impediments to Using Regulatory Agreements
What hurdles do you see in implementing the use of regulatory agreements with a business
partner (pharmaceutical/biotechnology/device company) or an academic institution? (choose all
that apply)

Count

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4.8 Closing Questions
At the end of the survey, all respondents were presented with two final questions. First,
they were asked why so little information about regulatory agreements is found. Respondents
ranked the choices from one to five, with one being the most likely reason. When asked to rank
order the reasons why little is heard about regulatory agreements (Table 28), the most highly
ranked was that these regulatory elements were covered in other contracts (Table 29). This was
followed by value unclear (ranked second), had not thought of it (ranked third), and informal
relationships are sufficient (ranked fourth). Substantially ranked lower were other reasons.
Fourteen comments were provided and are included after Table 29.
Table 28: Reasons Why Little is Heard About Regulatory Agreements
Why do you think we hear little about standalone regulatory agreements in the pharmaceutical
industry? Please rank the following (1 being the most likely reason) by dragging and dropping
each item. (n=225)
Why Little is Heard About
Regulatory Agreements
1
(most likely)
2 3 4 5
(least likely)
Value unclear 47 101 56 20 20
Had not thought about it 39 62 86 33 33
Covered in other contracts 130 38 46 9 9
Informal relationships are sufficient 4 21 32 156 156
Other 5 3 5 7 7

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Table 29: Rank Order: Reasons Why Little is Heard About Regulatory Agreements
Why Little is Heard About
Regulatory Agreements
n=225
Rank Score Ranking
Covered in other contracts 967 1
Value unclear 867 2
Had not thought about it 800 3
Informal relationships are sufficient 668 4
Other 73 5

Ranking Other Comments n=14
1 (most likely) • Companies may not be aware of regulatory agreements or have the time/resources to draft,
review, revise, and then approve these agreements.
• Confidential contract information is not disclosed to the public
• Not required by regulators, unlike Quality Agreements
• These are not legally required, and normally covered outside of contractual agreements,
allowing some flexibility of management on both sides
• do not know
2 • 1/Not required by regulatory agencies. [sic]
• Mostly, there is no need for a standalone regulatory agreement.
3 • Companies equating a TORO document with a regulatory agreement.
• No Health Authority guidance or mandate
4 (No comments provided for this value)
5 (least likely) • Covered in the Quality Agreement
• Focus on Service and/ or Quality agreements
• N/A
• None
• is not recognized as current best practice in industry

Respondents were also offered the option to provide any additional information or
comments that could contribute to understanding of the topic or to provide additional
information regarding standalone regulatory agreements. The comments of 68 respondents who
provided feedback have been divided into three themes on the use of regulatory agreements:
needed/add value (26%, 18/68); not needed/covered in other agreements (34%, 23/68); mixed or
miscellaneous comments (40%, 27/68). Example comments for each of these themes are listed
in Table 30. All 68 comments are included in Appendix G.

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Table 30: Example Text Comments: Any Additional Information or Comments
In the space below, please provide any additional information or comments that could contribute
to my understanding of your views for the use of standalone regulatory agreements. Thank you.
(n=68)
Use of Regulatory Agreements – Needed / Add Value
Standalone regulatory agreements can be helpful when adding to the responsibilities or services requested from a
vendor for a specific project or time period as it allows the flexibility of a separate agreement without having to go
through the full contract again.
This is a unmet need in the industry. As companies continue to build collaborations and partnerships, regulatory
implications are overlooked and become complicated. To have a framework agreed to upfront will allow smooth
working relationships and lessen the burden caused by unclear expectations.
I think one of the best ways to convince your own company of the benefit of a standalone quality agreement is to be
able to show them examples of situations where a project went sideways because of something that was not included
in any of the agreements. If possible show the financial, reputational and/or regulatory implications of these
examples and how a simple standalone regulatory agreement could have kept it from happening.
I think it is a very good idea to have stand-alone regulatory contracts. Many times the regulatory considerations are
embedded in the Master Services Agreements and the Quality Agreements. I think having a clear regulatory contract
that the regulatory parties on each side can refer to would really help to assure the regulatory expectations are clear
which would theoretically lead to improved regulatory outcomes.

However, regulatory contracts are not commonly used so it would 10take some initiative to introduce them.
Guidance and templates would be very useful.

Use of Regulatory Agreements – Not Needed / Covered in Other Agreements
In a small organization, the effort to execute multiple agreements exceeds the value of improved clarity that they might
provide.
I believe companies feel bombarded with agreements, and they seem to be bleeding into each other. We have supply
agreements (which contain specifications), specification agreements (which include quality and regulatory information), and
quality agreements (which seemed to have morphed from a simple agreement between the quality groups at the respective
companies to a legal contract). Because of this, legal review is extensive, multiple interpretations are possible, back-and-forth
over several months is required. I am not certain if it is possible to add another agreement to this practice.
Any major pharma has its own RA department. If any external help is needed, other contracts already in place would cover an
RA agreement too.
These agreements appear to be one-of-a-kind which makes it difficult to use across many activities.

Use of Regulatory Agreements – Mixed or Miscellaneous Comments
Standalone agreements should supplement internal staff. If internal staff for regulatory is not available, management is
deficient.
We have always found it simpler to manage a single agreement with each partner. We're moving toward a more modular
structure to allow certain aspects to be kept confidential while others are shared more widely. There are also some challenges
in deciding whether to use their template, our template, or some portions of each.
New concept, mostly included within a Service or Quality agreements. A stand-alone Regulatory agreement is unusual.
If standalone agreements are done they should be considered an addendum or in some way linked to the umbrella agreement.
Often the regulatory agreements cover more than just regulatory - they required actions by other functions so they need to be
visible/known to all impacted by the agreement.

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Chapter 5. Discussion
5.1 Introduction
Numerous types of agreements have become important in order to facilitate industry
partnerships and services related to manufacturing, quality, and clinical trials. However,
agreements to share regulatory responsibilities are discussed only rarely in the literature. Using
the four stages of implementation (exploration, installation, initial implementation, and final
implementation) as a framework to guide this research, I sought to understand the extent to
which regulatory agreements have been introduced to structure the sharing of regulatory
responsibilities in partnering relationships. In cases in which they are used, the research further
explores the requirements most important to address in the agreement. The results from this
research paint a more systematic picture of current and best practices through the views of
regulatory experts in the medical product industries. However, because this research is at a
foundational stage, I first describe below a few limitations and delimitations that will affect the
conclusions that can be drawn.
5.2 Methodological Considerations
5.2.1 Delimitations
The survey topic of this study might be considered by some as unusually specialized. It
delimits the survey population in two important ways. First, it is relevant to bio/pharmaceutical
companies that work in joint ventures or partnerships involving shared responsibilities for
regulatory activities. Not all companies will be included in this group. For example, it might
have limited application to companies that research, develop, manufacture, and perform its
clinical trials and pharmacovigilance activities in house. However, such companies are
becoming relatively rare. Drug development and commercialization involves a multitude of

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regulatory activities that are often shared between partner bio/pharmaceutical companies,
medical device companies, contract vendors for relevant services and/or academic institutions,
all involved in the development of a single product. Partnering to share these regulatory and
other drug development activities can allow companies to contain research and development
costs and reduce development risks while quickly adding experience across the early- to late-
stage continuum (Reepmeyer, 2006a; Reepmeyer, 2006b; Buvailo, 2020). Thus, the restriction
in scope that might have been seen in the past as very narrow now reflects a substantial and
growing proportion of companies that could profit from the results of this study.
Second, it was delimited to a specialized group of senior-level individuals involved in
partnerships or joint collaborations. Again, this type of person might have been considered
relatively rare even a decade ago. However, the changes in business structure described above
often occur when developing complex products such as biological and advanced therapy
products. These types of companies require especially large and talented teams of individuals
who cannot easily conduct their activities in silos. Their approaches to joint activities involve a
sophisticated integration of business and regulatory decisions. The fact that I was able to engage
with so many potential participants for this survey suggests that large numbers of professionals
exist for whom regulatory partnerships and relationships are not a mystery. It is further
supported by findings that the 294 respondents entering the survey were mostly able to proceed
past the demographic questions that eliminated individuals who did not have experiences with
partnerships or were not involved in drug development.
What was also considered in scope for the present study were not only individuals
working for medical products companies but also individual consultants and regulatory
consulting companies (strategy, CMC, or operations) that provide “insourced” services. The

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expert focus group that reviewed the survey was influential in suggesting that these stakeholders,
who are also involved in regulatory agreements, should be included. However, some comments
from consultants questioned whether the approach to regulatory agreements was applicable to
consulting agreements with individuals who might serve within the set of partnerships as
additional contributors. Additional research to understand further the use of consultants in
companies, either in traditional standalone roles, as might be typical for small companies at an
early stage (GEP,2019; Knapp & Verdame, 2020), or as supporting personnel for large-scale
projects where they function to expand the group of experts in one of the partner companies and
the need for, and differences in, the use of regulatory agreements, could provide additional
insight.
As suggested above, the world of drug development and commercialization is changing
rapidly. The present survey was conducted at a time when the growth in biologics and other
types of breakthrough products has been exponential (Figure 3). Whether these results presage
changes that would change respondent views on some questions remains to be seen. In addition,
it was distributed during the COVID-19 pandemic, when drug development and distribution
were altered dramatically by the need to pivot supply chains, manufacturing, and personnel to
treat a disease for which new biologics and vaccines were key (Berman, 2020; FDA, 2020; Solis-
Moreira, 2020). This pandemic may have stressed regulatory systems to a point where the need
for and content of regulatory agreements may have been seen as more pressing than it would
have been even a few years previously.
Respondents were sought according to the relevance of their backgrounds and job
functions. However, no attempt was made to discriminate the participants according to the
geographic area (US, EU, ROW) in which they worked. Differences in legal and regulatory

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requirements exist in different countries, so additional research may be needed to understand
whether the use of regulatory agreements varies by country in which the work is performed.
However, most of the companies that develop complex medical products intend to market those
products broadly in multiple jurisdictions, and many of the joint ventures required for such
operations will occur across national boundaries (Gautam & Pan, 2016). Thus, it is likely that
the business and regulatory relationships will require more generic approaches to agreements and
contracts than would be dictated in a single jurisdiction. A more international approach,
therefore, appeared warranted to assure the broadest information about this topic possible.
5.2.2 Limitations
Because almost no information on regulatory agreements could be identified in the
literature, survey questions regarding these agreements were based on elements that were in part
extracted from manufacturing, quality, or clinical trial agreements between companies. Some of
the elements in these other types of agreements are like those that might be also relevant to the
management of regulatory logistics and oversight needed when working with partnering
companies or service providers. To consider other activities that are specific to the regulatory
function, additional resources were reviewed, including the current use of Drug Master Files and
Shared Manufacturing Arrangements and different regulatory frameworks to determine
additional areas of work to be conducted by the regulatory professional from product concept
through obsolescence. However, regulatory agreements need to go further because they must
assure that each party will have access to the information needed to meet regulatory agency
requirements throughout the full life cycle of drug development. Nonetheless, judgment was
needed to develop suitable questions. The use of the expert focus group to critique the question

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wording was considered to be an important element in the survey development phase, as has
been suggested elsewhere (Morgan, 1997b; Morgan, 1997a; O'Brien, 2013).
However, even a well-designed survey is not useful unless it can be deployed to an
appropriate sample of respondents. In this instance, key stakeholders to the success of regulatory
partnerships are those who work at medical product companies, vendor organizations, consulting
firms, or academic organizations. Senior representatives of companies were considered most
likely to have the required experience in developing partnership agreements. However, this
requirement posed a challenge. First, it was difficult to identify appropriate respondents who
have the specific type of experience in regulatory partnering to be able to provide meaningful
views. Respondents were also needed to represent medical products companies, vendor
companies including consultants, and academia, as well as the various functions within the
company that may be involved with regulatory agreements. Although personal contacts in these
industries were utilized, a ‘wider net’ was felt to be needed and was developed by using
networking and posting on social media such as LinkedIn and the RAPS Forum to reach a
sufficient number of senior individuals. A larger sample size also increases the likelihood that
the results reflect the experience and views of the population that the sampling is intended to
represent (Johnson & Wislar, 2012).
Emails that included a request for help can be more effective in encouraging participation
in online surveys (Petrovčič, Petroč & Lozar Manfreda, 2016). The finding that almost three-
quarters of the respondents represented senior management at the director level or higher and
represented regulatory affairs, quality assurance, R&D, alliance management/business
development, legal or finance speaks to the success of this approach to secure a reasonable
sampling of appropriate individuals.

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Success at reaching an appropriate respondent pool is often measured by response rate.
Higher response rates provide more data for analysis and thus more confidence in trends or
statistical analysis of the results. In addition, higher response rates can reduce the concern for
nonresponse bias, which can increase the credibility of the findings (Rogelberg & Stanton,
2007). However, rates can vary depending on many factors, including the type of data collection
(electronic versus traditional mail), failure to deliver the surveys to the targeted population, and
the reluctance of the recipients to respond (Baruch & Holtom, 2008). Further, survey response
rates have been declining over the past several decades (Johnson & Wislar, 2012), with response
rates for internet surveys identified to be lower than for surveys distributed by traditional mail
(Sinclair et al., 2012; Nulty, 2008; Kaplowitz, Hadlock & Levine, 2004). Given the many
factors that can affect the response rates of electronic surveys, it is perhaps not surprising that
reported rates vary widely, from <5 to 73% (Cook, Heath & Thompson, 2000; Baruch &
Holtom, 2008; Sinclair et al., 2012).
Possibly more relevant to this research study were studies that found a considerably
lower response rate for executive than non-executive respondents (Cycyota & Harrison, 2006;
Baruch & Holtom, 2008; Anseel et al., 2010). Executives in pharmaceutical companies, like
those in the studies mentioned above, may be busy individuals who may be unwilling to commit
time to a survey. Further, it is possible that some may not have even received the survey because
it could have been screened by company internet filters or administrative assistants. Executives
may also be wary of surveys because they fear that they will be asked to share company
proprietary or protected information. Concerns about maintaining the confidentiality of
information may reduce the detail of their responses even if assurances of anonymity and
confidentiality are given. Confidentiality is an important factor in influencing response rate and

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given the targeted population was senior executives in medical products companies and concerns
with privacy and confidentiality may have influenced the amount of information provided
(Couper et al., 2008; Saleh & Bista, 2017). Despite these limitations, individuals are more likely
to respond to surveys that address a topic of professional or personal interest (Cycyota &
Harrison, 2002). The response rate of 20% for the present survey thus seems to be in line with
response rates seen in a number of recent studies.
However, more important than response rate is response quality. Surveys with even a
10% response rate may be considered as viable if those respondents are appropriate and able to
provide rich data based on their knowledge (Nair, Adams & Mertova, 2008). Cook et al. (2000)
identified that response representativeness, the degree to which the sampled respondents are
different from the survey population, is a better metric than response rate by itself. A survey
with a high response rate but whose respondents differ greatly in their views compared to those
of the targeted population may introduce bias, and thus be less useful than a survey with a lower
response rate from a random representative group of respondents (Johnson & Wislar, 2012).
Response representativeness was measured in this study from the demographic profiles showing
that more than half of the respondents worked with pharmaceuticals or biologics/biotechnology
products, and almost a third worked with medical devices/diagnostics or combination products.
Further, they represented a range of job functions, including regulatory affairs, quality assurance,
R&D, alliance management, business development, legal, and finance.
Another limitation to a study such as this might be the possibility that respondents leave
the survey before reaching the end. However, for this study, such a problem was not in
evidence. A strong level of engagement was suggested by the high completion rate of 83%. The
high completion rate was gratifying to see because so many design factors can affect survey

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completion. Some of these include the length of the survey, the types and difficulty of the
questions, and even the use of a progress bar (Liu & Wronski, 2018). Strong engagement was
also suggested by the extensive comments provided by respondents. These comments were
particularly valuable in providing deeper insights into the opinions and experiences of the
respondents and will be used as examples to illustrate representative views in this discussion.
One factor that was considered important to achieving the high completion rates in this
study was the well-known effect of survey length (Herzog & Bachman, 1981; Bogen, 1996;
Galesic & Bosnjak, 2009; Liu & Wronski, 2018). To limit survey length, questions must be
clear and well-linked to the research question and framework. The use of a focus group
representing the target population allowed me to test the design of the survey questions, seek
clarification on the clarity and usefulness of the questions, and identify alternative wording
(Stewart, Shamdasani & Rook, 2007). However, a limitation on length comes at a cost because
it necessarily reduces the scope of the topics that could be explored (Curtis et al., 2017).
Alternative methods of organizing and managing partnerships, therefore could not be explored in
any depth and may be useful topics for additional research.
5.3 Consideration of Results
This research set out to determine the “whether and why” of implementing formalized
regulatory agreements in the medical products industries. As indicated by Fixsen,
implementation science can be used to guide to assess the introduction of a new program or
practice by dividing those considerations into the four stages that he designates as exploration,
installation, initial implementation, and final implementation (Fixsen et al., 2005; Fixsen et al.,
2009). These stages will be used to organize the discussion below. A closer look at results
relating to the four stages may shed light on the reasons why some companies and not others

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have chosen to implement regulatory agreements as standalone documents and what lessons have
come from that experience.
5.3.1 Exploration
An important beginning question regarding the use of regulatory agreements is simply
whether they are being used at all. In this study, it appeared as if about half of the respondents
had heard about “regulatory agreements”, suggesting that their implementation is not universal
but also not rare. Commonly, those who had not heard of such agreements were employed by
small companies, where more respondents had not heard of regulatory agreements than had.
Further, even if the regulatory agreements may be on the radar for small companies, some seem
to question their value. Their positions are illustrated by several survey comments, such as the
following:
In a small organization, the effort to execute multiple agreements exceeds the value of
improved clarity that they might provide.
Small companies such as mine don't necessarily have a business model to take
development projects through to commercialization. Sometimes the objective is take
to value inflection point and sell. So these agreements make more sense for larger
companies who want to take projects to approval and commercialization [sic]

Those in larger companies were more frequently aware of regulatory agreements. This
may not be surprising. As companies grow in size, they may outsource a broader range of
activities to CROs and CMOs to supplement their development teams and to accomplish certain
specialized activities more quickly (Buvailo, 2020; Reepmeyer, 2006a; Reepmeyer, 2006b).
They also may partner with other smaller academic centers or biotechnology companies as they
shift their own interests to the acquisition and development of later stage assets which then they
can market broadly. They also may enter into partnership with other companies that are better
situated in certain foreign markets as they attempt to secure wider global sales (Khanna, 2012;

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Ku, 2015). Respondents in these larger companies may therefore become more familiar with
regulatory agreements at the same time as they establish other contracts, such as quality or
clinical trial agreements, that are also designed to specify the responsibilities of each party.
These larger companies have also evolved toward using standardized templates rather than
personalized contracts for each type of partner so that their contracts can be constructed more
efficiently and predictably across multiple partners. Nonetheless, the fact that most respondents
worked for companies that had no SOP in place for writing regulatory agreements would seem to
indicate that regulatory agreements are not yet implemented fully in these highly regulated
industries.
Of respondents who had investigated the use of regulatory agreements with their business
or academic partners, about half went the step further to put such agreements in place. For some,
the use of such agreements appeared to be taken for granted.
These agreements have been "best Practice" for decades and are now becoming
regulatory requirements (EU 2017/745 & 746) [sic]
This left a substantial minority, however, who chose not to move forward with the
implementation of regulatory agreements. In some cases, their company did not see a need to
develop these standalone agreements, in part perhaps because these agreements are not required
by health agencies. In others, it may have been because the required elements were covered in
other agreements, such as quality or clinical agreements, that are already in use. Those types of
agreements typically must have regulatory elements and responsibilities as part of the contract.
For example, a quality agreement should stipulate the regulatory requirements relevant to
material sourcing and supply, authoring, review, and provision of quality documents needed for
registration dossiers, or notification of regulatory personnel of audit findings or changes

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affecting the regulatory status of the facility (Pazhayattil, 2008; IPEC, 2009; FDA, 2016a; APIC,
2017; Jardine, 2020).
Similarly, contracts with laboratories carrying out animal studies must work with
regulatory departments to assure that the testing plan is suitable to support the initial selection of
dosages to be used in human proof-of-concept studies ((ICH, 2009; van Meer, Graham &
Schuurman, 2015; Regulatory Info, 2019) and that subsequent GLP reports are adequate to be
included in regulatory submissions. Contracts are needed when conducting a clinical trial with
the help of a CRO to memorialize the transfer of regulatory obligations (TORO) and describe in
writing which of the sponsor’s obligations described in 21 CFR 312 will be assumed by the
partner (FDA, 2020). Perhaps their familiarity with those agreements was responsible for the
view of some that another agreement was not needed to clarify how responsibilities will be
shared:
We generally incorporate regulatory activities in overall agreements/contracts. We
are also a very large company and prefer to handle global regulatory requirements
ourselves and thereby generally retain those responsibilities.

Several comments in the survey appeared to suggest that respondents who worked with
medical devices might have been more familiar with the use of regulatory agreements and, in
fact, may have considered them to be required in the medical devices industry. One respondent
commented on their company’s approach to regulatory agreements: “They need to become more
complete to address EU MDR requirements.” [sic]. Nonetheless, inspection of the referenced
MDR requirements suggests that they do not have, in fact, specific requirements in this regard.
Instead, for example, the Guidance on Qualification and Classification of Software in Regulation
(EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR (2019) states only that
“Manufacturers must ensure that all regulatory requirements for placing on the market and

110
conformity assessment have been fulfilled.” This statement is no more definitive than what is
found in the regulations and guidance for the pharmaceutical industry, such as in the FDA’s
guidance for quality agreements with CMOs (FDA, 2016a) or its regulation governing the
transfer of obligations to a CRO (FDA, 2020). Both simply point to the need to assure
compliance with regulatory requirements. These comments also spurred me to perform a cross-
tabulation to see if medical device companies were more aware of standalone regulatory
agreements than other types of companies, but no clear difference was apparent.
5.3.2 Installation
Regardless of the respondent’s type of organization, most were using some form of
formal agreement with their current partners to frame manufacturing, quality, clinical,
regulatory, and other types of relationships. This appears to be consistent with trends suggesting
that a growing list of activities are accomplished through collaborative business relationships that
can no longer be managed effectively by informal agreements or simpler preferred partner
arrangements (Reepmeyer, 2006a; Kapler & Puhala, 2010; Milne and Malins, 2012; Clearwater
International Healthcare, 2019; Buvailo, 2020). Previous experience with simpler agreements
may have resulted in miscommunications that served to educate the partners about critical
elements that should been included in future agreements. Such “lessons learned” would be
particularly important given the paucity of text material that can be consulted on this subject.
Thus, it may not be surprising that respondents developing regulatory agreements looked to
precedence or corporate memory and relied most commonly on individuals in the company with
relevant expertise or on the content of other contracts already in use. Some of the challenges
identified here suggest areas in which respondents found it difficult to obtain guidance, for
example, when templates or precedent materials were not available to guide their drafting efforts.

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The absence of readily available templates for regulatory agreements is unlike the situation for
other vendor and partnership agreements, including manufacturing, quality, laboratory testing,
and clinical trial services, which all have readily available templates or regulatory guidance
(IPEC, 2009; APIC, 2012; PIC/S, 2018; GovHK, 2013; MHRA, 2015; Downey, 2016; FDA,
2016a; APIC, 2017).
A key aspect of installation is often considered to be the allocation of needed resources to
go forward (Bertram, Blase & Fixsen, 2015; Fixsen et al., 2021; Fixsen et al., 2005). As noted
above, few respondents were dissatisfied with their company’s commitment of resources, but
almost a third were not sure. Unlike other regulatory activities that might involve considerable
allocations of money and people, writing a regulatory contract would not seem to be an
expensive undertaking. What did seem to be a bigger problem for some respondents was a lack
of support from senior management and other business functions that typically take
responsibility for the structure and organization of the company’s partnerships. For example,
two comments noted that such agreements would be easier if the legal department were to be
more positive about supporting their development. Their lukewarm involvement might be due at
least in part to the fact that the use of such agreements is so new, and that many have mixed
opinions about the benefit versus effort, as reflected by some of the comments such as that
below:
There is great value in creating regulatory agreements for clear understanding of
roles and responsibilities between partners - but unless there is a clear business/legal
need (We went to trouble of creating one as we are the US regulatory Agent for a
foreign sponsor) it is difficult to advocate for internally in the context of elements
being in the MSA and 'too many other agreements' in a small company such as ours.

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5.3.3 Initial Implementation
The progression from planning to implementation of a regulatory agreement will
transition through an initial implementation phase (Bertram, Blase & Fixsen, 2015; Blanchard et
al., 2017; Fixsen et al., 2021) when the first few agreements are formulated and piloted.
Although most respondents indicated they had the necessary internal expertise available to
implement regulatory agreements, results here suggest that companies initially struggle when
writing their agreements because they lack sources of information or templates to suggest best
practices. Instead, the most common resource continued to be the contracts that other
departments had developed to structure their activities in the quality or clinical domain, for
example. The fact that many respondents were challenged by the absence of specific regulatory
templates is not surprising. A Google search directed specifically at the search term “templates
for pharmaceutical regulatory agreements” (conducted July 11, 2021) listed numerous sources
describing quality, manufacturing, or clinical trial agreements but no specific information about
regulatory agreements. Regulatory agency documents were also reported to be important
additional sources of guidance for some, but nearly one-quarter of respondents found that
documentation from regulatory agencies was not useful. Further, even more respondents found
that the usual sources of education on which regulatory professionals rely- trade meetings,
government presentations, or consultants-, fell short of their expectations. All of these findings
point to a need for better guidance and educational tools.
How can this problem be addressed? Certain professional organizations, such as the
Drug Information Association (DIA) and the Regulatory Affairs Professionals Society (RAPS),
have annual meetings and specialized workshops where logistical and organizational topics are
presented on topics as broad as conflict resolution and negotiation to the logistics of clinical trial
execution and compliance activities (DIA, 2021; RAPS, 2021). These would seem to be well-

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positioned to provide further education and debate about the structure and use of regulatory
agreements.
Without a clear set of guidelines or a template, most groups creating their first templates
would need to develop their own list of topics to be included in their agreements. It is not
surprising that the respondents most commonly identified such elements to be the roles of
different partner organizations in formulating regulatory submissions, developing strategies, and
adhering to regulatory procedures, including review and approval procedures. Failure to define
these types of roles and responsibilities can result in miscommunication, unclear performance
measures, wasted resources, and delays in decision making (Noffke, 2007; Babiak & Thibault,
2009; Hunter, 2011). Further, the initial implementations of regulatory agreements appeared to
provide opportunities for learning so that additional elements that had been missing could be
added to subsequent iterations. Even though respondents were offered at least 14 options for
elements that might appear in an agreement, respondents were able to identify many more that
they would recommend to others. The fact that 48 respondents offered additional elements and
that 40 comments about needed elements were provided across relevant questions would seem to
underline the importance of a comprehensive approach to such agreements to assure most value
from them.
5.3.4 Full Implementation
Most respondents with regulatory agreements suggested that their initial regulatory
agreements included most of the basic development, review, and logistics elements that I
provided as options in the survey questions. However, their additional comments suggested that
these offered elements were only a starting point. As newer versions of regulatory agreements
were developed, respondents identified certain logistical and management elements that would

114
strengthen the contract. Some of these expanded on issues associated with the division of roles
and responsibilities for each company, such as the timing of reviews and delivery of
documentation, or on penalties for noncompliance or lack of performance. Also suggested were
elements to define how key processes, such as decision making and dispute resolution, will be
handled. Specifying how such issues are to be handled can increase the usefulness of an
agreement and support legal actions should the partner prove unreliable (LegalNature, n.d.;
Akalp, 2016). These many elements identified by the respondents inspired me to structure a
checklist for elements that might be used as a starting point in the construction of a typical
regulatory agreement between partners with a specific focus on agreements that involve shared
responsibilities for regulatory submissions (Appendix H). Of course, no one template will be
suitable for all situations. Some of these elements would be inappropriate for agreements with
other partners, and additional elements might be added to address activities unanticipated by the
appended checklist.
As companies evolved to established stages of full implementation, some tried to identify
ways in which they could improve their regulatory agreements and, consequentially, their
relationships with vendors or partner companies. Such gap analyses are not simple undertakings
and are made more difficult by the fact that no external agency or organization yet requires that
companies use regulatory agreements. Thus, their appropriateness in a given situation will
depend on the ideas and support of internal stakeholders (Ali & Khan, 2016; Bonney, 2018). In
most companies with such agreements, the support that was available appeared to be welcomed
by the relevant regulatory teams and management. However, as previously noted, a significant
minority of respondents seemed to less satisfied with the internal support that was offered. It
was therefore interesting that teams for these agreements often failed to include members from

115
the general administration and legal departments, for example, from commercial affairs, finance,
business development and alliance management. The value of having a broadly based team has
been previously recognized for other types of activities, such as quality activities, so that the
elements to be covered are more comprehensive. Comparisons between development teams with
more or less variety in their membership might help to identify whether adding more members
improved the agreement or merely slows it down, so may be an area worthy of further study
(Montgomery et al., 2020).
How do companies know if their regulatory agreements have been effective? A
proportion of companies appeared to use relatively sophisticated evaluations, such as defining
Key Performance Indicators (KPIs) related to outcomes, including cost savings, compliance, or
efficiency, to assess the effectiveness of their agreements. However, even without such tools,
respondents appeared to have favorable views regarding the usefulness of regulatory agreements.
These are reflected in numerous comments, including positive outcomes such as “clarity for legal
issues that may arise from recalls, AE.and MDRs” [sic] and “avoided legal and relationship
challenges”. Some of these observations are consistent with what others have identified as a key
role for regulatory agreements- to add clarity to what has been described as “a fuzzy interface
between the collaborating firms” (Kapler & Puhala, 2010). When an agreement is developed, an
opportunity presents for early discussions of areas that might otherwise become problematic.
The value of these agreements thus can be considered as a type of “preventive action” for issues
that might otherwise become serious problems. However, these types of advantages are difficult
to quantify by traditional metric-based approaches.
Results also showed that regulatory agreements were put into place most commonly at
the time when the partner was either first selected or when the two companies were developing a

116
main partner agreement. In either case, the development of an agreement gives an opportunity to
discuss the allocation of responsibilities and the management of logistics quite early in the
relationship. At this point, it can be important to resolve any issues that can lead to potential
misunderstandings. Regulatory agreements also seem to become more important as the division
of labor and extent of the collaborative activities become more complex. Thus, such agreements
might be recommended for situations in which companies go beyond contracting simple or
standard tasks to addressing complicated and coordinated activities between the partners
(Noffke, 2007; Kapler & Puhala, 2010). One comment identified this need:
This is a[n] unmet need in the industry. As companies continue to build
collaborations and partnerships, regulatory implications are overlooked and become
complicated. To have a framework agreed to upfront will allow smooth working
relationships and lessen the burden caused by unclear expectations.

Will the regulatory agreement become a requirement rather than a “nice-to-have” in the
future? Beginning steps in this direction may be suggested by the guidances that currently exist
but these are far from proscriptive. Under US regulations, 21 CFR 312.52 “Transfer of
obligations to a contract research organization” specifies that
A sponsor may transfer responsibility for any or all of the obligations set forth in this
part to a contract research organization. Any such transfer shall be described in
writing” (FDA, 2020).

The ICH Consensus Guideline, an addendum to the ICH E6(R1): Guideline for Good Clinical
Practice ICH E6(R2), also includes the statement that:
A sponsor may transfer any or all of the sponsor's trial-related duties and functions to
a CRO, but the ultimate responsibility for the quality and integrity of the trial data
always resides with the sponsor. The CRO should implement quality assurance and
quality control.” (Section 5 Sponsor: section 5.2.1 ((ICH, 2016).

117
However, these statements only serve to indicate the sponsor’s ultimate responsibility for the
conduct of the work and do not go so far as to identify how this requirement should be satisfied.
In this regard, the regulatory agreement differs from, for example, its most likely sister
agreement, the quality agreement. FDA has expressed an expectation that companies will have
quality agreements with key suppliers and has even gone so far as to specify the nature of such a
document to include the materials or services to be provided by each party and elements that can
affect quality. Some of these elements, such as documentation, change control, materials
management, product specifications, and laboratory controls, are relatively easy to standardize.
Other requirements, such as audits and inspections or the communication mechanisms between
the parties, may be more difficult to put into place because they can vary in timing and depth
according to the changing profile of the work as time passes (FDA, 2016a; Katz, 2017; Mason,
2017).
5.4 Conclusions and Future Direction
The present study suggests that the regulatory agreements are evolving in a direction like
that seen previously for manufacturing, quality, and clinical trial agreements in regulated
industries. However, at this time, the value of standalone regulatory agreements has mixed
reviews. Without a clear requirement from regulatory agencies or the availability of agency or
industry guidance, usefulness appears to be defined on the basis of other variables, including the
type of partner, the complexity of the relationship, and availability of internal expertise and
support from management and business/legal groups. Without standalone agreements, some
companies have chosen to include some of the relevant elements in other types of existing
agreements. However, such an approach can leave out important issues that need to be defined.
Even with a standalone agreement, not all potential issues are easy to capture. These challenges,

118
related to the more diffuse nature of the regulatory role, was well stated by one of the
respondents:
The details of regulatory agreements may not be fully considered. This is due, at least
in part, to softer deliverables associated with regulatory. With other parties, such as
CDMO/CROs, deliverables are tangible and straightforward to define.

Nevertheless, regulatory activities are particularly important in pharmaceutical development,
where each day of delay can subtract from the patent life of the product and deny access to
important new treatments. Regulatory agreements would seem to be judicious, then, for
partnering relationships in which regulatory sharing is extensive.
The results presented here illuminate certain areas in which more attention might simplify
the development of regulatory agreements. First is the need for better guidance regarding how to
structure a regulatory agreement. It was clear that regulatory professionals are struggling with
their relationships and would appreciate more guidance that would help them to identify key
regulatory elements related to regulatory compliance and submission deliverables. Best practices
can be suggested from the numerous comments in this research. The initial checklist that I have
developed (Appendix H) might be a useful starting point. However, it would seem important
that professional organizations and individual companies go beyond this first attempt to consider
how such agreements might be fine-tuned for different types of partnering activities. Regulatory
activities vary greatly from simple contracts specifying defined deliverables, such as labeling
translations, to complex, multiyear interactions to develop a biologics license application as part
of a joint venture. Not all of these will be best handled by a standalone regulatory agreement.
For example, situations in which deliverables are obvious might be handled more efficiently by a
master service agreement. However, the cost of not having a regulatory agreement must be

119
balanced against the risk consequent to misunderstandings or underperformance if the
interpersonal and communication elements are not included.
To my knowledge, this research describes the first structured survey on the topic of
regulatory agreements. Its findings suggest several areas that would be interesting to explore in
further research. It might be interesting, for example, to look specifically at case studies of
regulatory interactions and agreements in joint ventures in which the partnering companies have
had extensive regulatory interplay. These examples might illustrate areas to which special
attention should be paid, in order to avoid the pitfalls inherent in managing of two or more
regulatory departments, each with its own culture and sense of purpose. Understanding
alternative methods of organizing and managing partnerships in these industries may also be
useful to gain insight into the value of different kinds of strategies for structuring their
relationships. Additional considerations might also come into play when the partnering
relationships involve subordinate relationships with consultants. In some cases, that consultant
might be acting as the primary regulatory leader, a common approach taken in small, early-stage
companies. In other cases, consultants might assist a regulatory team temporarily for large-scale
projects, where they act to expand the group of experts in one of the partner companies.
Regulatory agreements with the principal partners then might have to include specific elements
related to the use of personnel outside of the partnering organizations.
It would also be useful to understand better whether the location and cultural set of the
partnering entities create special problems that could be mitigated to some extent by discussion
and inclusion in a regulatory agreement. Issues as simple as holiday arrangements, work
patterns, and language of operation can create challenges and misunderstandings. Differences in

120
legal and regulatory requirements exist in different countries, and these too could complicate
regulatory agreements between partners in different geographies.
A company is always free to accept or reject the implementation of standalone regulatory
agreements. However, the decision of whether to implement such an agreement would seem
easier to make if the industry had a better understanding of how others have used such
agreements to advance their business objectives and how they could be put into place efficiently.
The research presented here is a first step in this direction.

121
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Appendices
Appendix A. Example Regulatory Competency Frameworks
RAPS RCF: EXAMPLE RESPONSIBILITIES IDENTIFIED BY COMPETENCY
(RAPS, 2016)
Domain Regulatory Professional Responsibilities
Regulatory Frameworks &
Strategy
• Assists in the development of regulatory procedures and SOPs
• Evaluates the regulatory environment and contributes to providing
internal advice throughout the product lifecycle (e.g., concept,
development, manufacturing, marketing) to ensure product compliance
• Negotiates with regulatory authorities throughout the product lifecycle
• Integrates regulatory considerations into the organization’s global
product entry and exit strategy
• Identifies issues early in the development or research phase that could
impact regulatory strategy, submissions and/or product launches for
complex and/or critical products
• Leads efforts to incorporate regulatory strategies to expedite
development for products intended for serious or life-threatening
medical conditions or that address unmet medical needs (e.g., orphan,
conditional approval, breakthrough therapy)
Product Development &
Registration
• Assesses the acceptability of quality, preclinical and clinical
documentation for submission filing to comply with applicable
regulations
• Evaluates risks of product and clinical safety issues during
clinical phases and recommends regulatory solutions
• Provides strategic input on regulatory requirements to R&D and
clinical leads for complex and/or critical products.
• Compiles and organizes materials for presubmission reports and
communications
• Assists in the preparation of dossiers and submission packages
for regulatory agencies
• Tracks the status of applications under regulatory review and
provides updates to the regulatory team
• Maintains logs of communication and outcomes with regulators
and other relevant internal or external stakeholders
• Evaluates proposed preclinical, clinical and manufacturing
changes for regulatory filing solutions and proposes plans for
changes that do not require submissions
• Provides knowledge and guidance on preapproval inspections,
GCP inspections and clinical investigator relationships
• Identifies, monitors and submits applicable reports (e.g., Serious
Adverse Events) or notifications (e.g., changes in manufacturing)
to regulatory authorities during the clinical research process
• Ensures clinical and nonclinical data are consistent with the
regulatory requirements and support the proposed product claims
• Provides regulatory information and guidance for proposed
product claims/labeling

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Domain Regulatory Professional Responsibilities
• Prepares and submits electronic and paper regulatory
submissions according to applicable regulatory requirements and
guidelines
• Works with cross functional teams for interactions with
regulatory authorities including panel meetings and advisory
committees
• Reviews and approves publicly disseminated information on
product submission approval status
• Reviews and assesses proposals to regulatory authorities on
regulatory paths and clinical plans
• Leads key negotiations and interactions with regulatory
authorities during all stages of the development and review
process
• Leads the regulatory team’s engagement in evaluation of risk and
safety issues for complex and/or critical products and
recommends regulatory solutions during preapproval/clinical
phases
• Participates in risk-based decisions on compassionate use/special
access approvals based upon patient needs and risk assessment
Postapproval/Postmarket • Tracks and maintains files on annual licenses, registrations and
listings
• Maintains systems to track, manage and report product-
associated events
• Participates in implementation of regulatory strategy and
processes for handling recalls and communication to
stakeholders (e.g., Dear Healthcare Professional letters, patient
letters, distributor letters, and health authorities)
• Reviews and approves advertising and promotion to ensure
regulatory compliance
• Assures postmarket regulatory requirements are met (e.g.,
required reports, supplemental submissions and other
postmarketing commitments.)
• Reviews and approves required reports, supplemental
submissions and other postmarketing commitments to maintain
product registrations
• Reviews and approves enforcement action/responses
• Submits notifiable changes and supplemental dossiers to the
appropriate regulatory authorities to update product information
and/or instructions for use to reflect current state of product
knowledge
• Reports product safety issues to regulatory authorities as
required, to comply with local, regional and global regulations
• Provides required information (e.g., clinical data) in support of
product reimbursement requests
• Provides regulatory input and appropriate follow-up for
inspections and audits

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Domain Regulatory Professional Responsibilities
Scientific & Health Concepts • Identifies and proactively responds to scientific and/or clinical
advances that impact healthcare product development and
regulation.
Ethics • Takes all possible steps to prevent and resolve any real, apparent
or potential conflicts of interest between one’s official
responsibilities and his or her private affairs
• Abides by and upholds the laws and regulations of the authorities
under which he or she operates and his or her organization’s
internal/external policies and directives
Communication • Assists in preparation for meetings with regulatory agencies and
other stakeholders
• Assists in the preparation of briefings and other information
documents
• Communicates with peers and supervisors and ensures alignment
on issues, questions and goals. Prepares strategy/briefing
documents for panel hearings and informational meetings
Business Acumen • Preserves confidentiality of product information as appropriate.
Reviews change controls to determine the level of change and
consequent submission requirements
Leadership • Wins support and buy-in from sponsors, partners and
stakeholders by effectively satisfying stakeholder interests and
concerns while advocating a clear direction forward; and coaches
others to do the same. Builds and sustains partnership across
organizational boundaries and functions as well as outside the
organization to achieve common goals and outcomes. Ensures
knowledge and lessons learned are shared across organizational
boundaries.

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EXAMPLE COMPETENCIES FROM THE TOPRA RCF (DRAGO ET AL., 2017)
Strategy Communication
Business and Organisational
Awareness
Technical Core
Establishing • Collect data relevant
to the essential
regulatory question,
issue, or problem
• Co-author basic regulatory
documents and reports
• Recognise the importance
of negotiation skills
• Recognise and respect
confidentiality and comply
with relevant codes of
conduct
• Recognise the meaning and
significance of conflicts of
interest
• Explain the role of regulatory
professionals and their
interrelationships with other
functions in the organisation
• Complete low-risk
regulatory assignments
under appropriate
supervision
• Explain the
interrelationship between
law, regulation and
guidance
• Use a systematic
approach to accomplish
assigned tasks
• Prioritise work to meet
timelines
• Explain the importance
of working as a team
and operate effectively
as a member of a multi-
disciplinary team
Consolidating • Contribute to the
development of
regulatory
recommendations
and decisions
• Recognise potential
regulatory issues,
solutions, and
opportunities
• Employ effective technical
and regulatory writing skills
to author standard
regulatory documents and
reports
• Identify potential conflicts of
interest and their significance
• Identify gaps in the
evidence base supporting
submissions
• Apply technical expertise
in multi-disciplinary
teams
• Explain key aspects of
the healthcare product’s
development process
• Advise on risk -based
approaches, as
appropriate
• Review labelling and
advertising for regulatory
compliance
• Review regulatory
submissions
• Identify skills and
abilities that allow a
regulatory professional
to represent the function
effectively as a member
of a multi-disciplinary
team

136
Strategy Communication
Business and Organisational
Awareness
Technical Core
Driving • Develop regulatory
strategies to bring
new healthcare
products to market
that support business
objectives and are in
compliance with
regulatory
requirements
• Analyse communications
from health authorities and
respond appropriately
• Manage regulatory plans for
complex projects
• Appraise the chance of
regulatory success in
bringing a new healthcare
product to the market
• Lead regulatory activities
for major projects
• Review the regulatory
implications of the
outcome of the analysis
of quality, nonclinical
and clinical data
• Develop standard
operating procedures
(SOPs) and policies
• Develop negotiation
strategies with
regulatory agencies
and/or the regulated
industry
Influencing • Formulate
defensible
regulatory strategies
and
recommendations
for complex issues
• Explain data
requirements to
support product
claims
• Review and approve
inspection and audit
communications
• Perform due diligence
• Assess regulatory impact and
risk, and develop risk
management
recommendations
• Explain opportunities for
alignment of business
objectives with regulatory
requirements
• Manage organisational
change
• Evaluate benefit–risk
balance of healthcare
products
• Assess regulatory needs
for pre- and
postmarketing
submissions
• Advocate for necessary
changes both internally
and externally
• Establish and maintain
collaborative
relationships with
stakeholders
• Effectively manage
resources
• Devise novel
approaches to regulatory
challenges
• Create and implement
crisis management plans
and procedures

137
AGRE CORE COMPENTENCIES FOR GRADUATES OF MS PROGRAMS IN
REGULATORY STUDIES (AGRE, n.d.)
REGULATIONS
Concept: Obtain and apply broad knowledge of domestic and international law, regulations, and
guidance documents covering pre- and postmarket requirements for at least one category of medical
products, including combination products.

A graduate will be able to
• Identify and interpret regulations and guidance documents for domestic and international
agencies relevant to medical products
• Describe the origins of regulations related to medical products. Support product development
teams to bring new medical products to US and international markets:
o Advise on applicable requirements
o Plan and coordinate preparation of market approval submissions and clinical trial
submissions where necessary
o Negotiate approvals for clinical trial and market approval submissions with regulatory
authorities
• Support postmarket compliance with FDA and international regulatory requirements:
o Advise on applicable requirements
o Identify medical product design and manufacturing changes requiring regulatory approvals
and obtain approvals
o Review labeling and advertising for regulatory compliance
o Advise on requirements for postmarket clinical trials
o Prepare required postapproval reports
o Advise on medical product issues that may require corrective actions and/or recalls

QUALITY
Concept: Examine quality systems and standards and their impact on product and public safety as
well as the importance of quality products from the perspective of healthcare providers.

A graduate will be able to
• Implement quality systems to support the development, manufacturing and monitoring of
medical products
• Analyze and advise on global requirements involved in marketing regulated products
• Describe validation studies
• Create and adhere to standard operating procedures
• Develop and retain documentation to comply with quality regulations
• Describe quality principles throughout the product lifecycle in order to manage risk
• Develop a system to comply with personnel quality requirements, including training
• Accomplish audits that test the existing systems

138
CLINICAL
Concept: Obtain and apply broad knowledge of US Food and Drug Administration (FDA) and
international requirements for the approval and conduct of pre- and postmarket clinical studies with
regulated products. Understand the basic principles of clinical study design and clinical data analysis.
A graduate will be able to
• Explain the basics of clinical trial regulations in the US and key international markets
• Advise on requirements for product types that require clinical trials:
o Identify the scope of clinical data necessary to support market approvals
o Identify requirements for postmarket clinical studies
o Plan and prepare submissions to support pre- and postmarket clinical trials
• Describe basic clinical paradigms commonly used to determine safety and effectiveness/efficacy
• Describe the process of writing clinical study objectives and endpoints
• Define the content, and coordinate and prepare submissions for clinical trials
• Advise on the conduct of ethical clinical studies according to international standards
• Describe the common methods for analysis of clinical data

STRATEGY
Concept: Recognize the factors that influence domestic and international regulatory decisions.
Develop methods to incorporate regulatory trends and practices. Think strategically about product
development, market approvals and marketing.
A graduate will be able to
• Contribute effectively to multidisciplinary teams
• Apply lessons from the history of domestic and international regulations and product
requirements and stay current with changes and advances that could affect future requirements
• Develop strategies to bring new medical products to market to support business objectives:
o Describe appropriate bench, animal and clinical requirements
o Develop plans for timely approvals in US and international markets
o Identify risks and unknowns with marketing strategies
• Develop strategies to balance business objectives and compliance with regulatory requirements:
o Apply strategic planning to design and manufacturing changes, postmarket clinical trials and
required regulatory reporting
• Accomplish business goals within the regulatory parameters

COMMUNICATION
Concept: Develop interpersonal, critical thinking and interpretation skills. Develop written and oral
communication skills, with the scope and flexibility to address audiences with differing size,
knowledge and priorities. Write and present clearly and concisely in an audience-appropriate
manner.
A graduate will be able to
• Identify and employ audience-appropriate communication strategies
• Write clear and concise technical documents and letters
• Critique own and others' written and oral communications to facilitate continual improvement
• Prepare and deliver effective presentations:
o Design effective slides
o Speak confidently to an audience
o Interpret and address questions effectively
• Analyze and respond appropriately to communications from FDA and other entities:
• Work effectively in multidisciplinary committees:
o Demonstrate interpersonal skills to establish and support credibility
o Explain relevant regulatory issues clearly
o Research and present alternate approaches

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Appendix B. Survey

140

141

142

143

144

145

146

147

148

149

150

151

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Appendix C. Comments Included for Company Approach to
Regulatory Agreements
Table 31: Comments: Satisfied with Company Approach to Regulatory
Agreements
Are you satisfied with your company's approach to regulatory agreements? Why or why not?
Yes because - Text
Yes because: we have great procedures.
reg agreements itself are managed by regulatory
the company makes a solid effort to capture all areas in sufficient detail that need to be laid out and
agreed on
these are not mandated but encouraged
They are clear.
Functional areas participate in development of contracts and can ensure needs are being addressed
Small company, still putting processes in place, but making forward progress.
Pragmatic and enforceable
It works
my team has direct involvement with the authoring and approval of such agreements.
We have an agreement with every commercial partner
We fully get a standardized template thru outside counsel once a year
There is opportunity to add additional wording to address any specific regulatory needs.
Essential elements covered with respect to roles and responsibilities.
Over the years we have learned from our mistakes and developed processes, templates and governance
to ensure more consistency and fewer gaps; nothing is perfect but itâ€™s so much better now than it
used to be. [sic]
I am personally involved in the details
Adequate oversight and cross-functional review
the immediate responsible team works directly with the Legal personnel to craft any language that is
specifically needed for any particular agreement or to review any negotiated text of the agreements to
ensure that the agreement matches our level of requirement/expectation.
We take a flexible approach. Where required, we use standard template and in some instance use
customized versions depending on the need.
Yes, because they are personalized for the specific partner and the applicable jurisdiction.
For the most part, I believe we've covered all aspects, although there will always be things that manage
to slip, we've covered the regulatory aspects quite thoroughly.
It is included in the Quality Agreement. We are a small company so functions can be combined
we are the interface between the customer and the government regulatory agency.
In spite of the fact that the company engages with very diverse partners, the regulatory agreements have
been clear and concise in their description of the scope of activities covered by the agreements, and in
highlighting the responsibilities of involved parties in the various processes. This has consistently
resulted in mostly seamless execution.
We don't have standalone regulatory agreements. There are regulatory clauses in all our Quality and
Partnership/Manufacturing agreements.

153
Yes because - Text
Vendors/partners are compliant with the agreements.
Reg affairs is involved in drafting agreements
The regulatory information described below is in our quality agreement.
We take a wholistic cords functional approach thereby ensuring all functional needs are clear and
addressed
They know it needs to be in place and quality dept wants to do it correctly
I am consulted early in the process to provide input.
Include regulatory requirements but can tailor to specific needs of the relationship.
Covers most required areas and allows.some flexibility [sic]
Requirements are being met.
Actually, yes and no...
CRO/CRAs: seem to have a better handle on outlining roles and responsibilities and sticking with that.
Some challenges with coming to realistic timelines.
Partners: Individualized RA agreement, but doesn't seem to be well managed. There was an
understanding that we would support partner company with strategy and handling of document prep and
submissions. In reality, we have often been tasked with preparing documents and been left ""out of the
loop"" on key strategic decisions. [sic]
Clear expectations
Customizable
Extensive Legal and deals transaction lawyers input. Support to ensure functional rights are clear up
front, with details in addendum up front. [sic]
Appear to address necessary topics and have not experienced problems
The scope is well defined and the budget is realistic
No, itâ€™s challenging, time consuming to amend, which is inevitable.
it works
No issues
There is a formal process that is vetted through a committee
Regulatory reviews and provides comment to ensure all areas are addressed properly
They maintain consistent regulatory commitments to not only FDA but global regulations.
The key business contracts have included responsibilities listed in the paragraph below.
nice to have a template but only if it is good but still must modify for each.
close collaboration with the legal department
As a consultant, I am flexible to my client's needs.
Standard approach works well.
Allows adaptation based on need
Relationship controls
It addresses the regulatory requirements and meet the business needs.
Standard templates
They cover the tasks being required in detail
I think we could include more details about applicable regulations
We are very small and have a small circle of companies we work with.
they are based in open communication and value concrete deliverables.
arrive at a contract that suits the compnay that is hiring my company [sic]

154
Yes because - Text
at least from my perspective, they seem thorough and clear as to expectations and requirements.
I feel they are thoughtful and fair.
Having separate, customized agreements allows us to work with vendors who have specific expertise or
in a certain location. This allows us to be flexible, and to get the right expertise for each project.
I am new to the company and have not seen the contracts. However, we have been successful in the past.
of compliance
very experienced team with lots of exp[ertise - who know the potential pitfalls and risks [sic]
It spells the responsibilities of each party.
consistency
We are very careful and elective
compliant with regulations.
They allow for fulfilling all requirements.
Not relevant as an R&D Consultant
Proposals for services are detailed and hourly costs included and estimated cost for services are provided
with timelines as applicable.
In general yes, but for combo products and rare disease I note that contractual milestones are often tied
to language more typical of small molecule drug development and sometimes require interpretation.
I always check particular issues like CDMO references appropriate cGMP vs QSR, CRO references ISO
(eg 13485, 14155) as well as typical ICH if approached for the product, and that partner agreements
arenâ€™t linked to phase 1/2/3 if combined ph 1/2 or feasibility study only are required. [sic]
RA and qA are involved in the process [sic]
Very specific for each client.
flexible. can be customized
We do not have stand-alone regulatory agreements.
Depends on the partners, their geographic regions, some are more onerous because of local/regional
requirements
Regulatory affairs is able to review and provide input into the agreement.
We have a great template that can be customized.
I am in control of that section of the agreements.
We have a formal process that has been vetted by all of the relevant stakeholders and so far it works. We
have not used stand-alone regulatory agreements, instead we put this information in our formal
contracts.
I develop them.
We use very few of these.
As a small company the approach facilitates faster contracting and legal can handle the bandwidth with
little pushback.
Revisions are made as regulations change.
Attempt to be proactive and to minimize company's liability exposure
Agreements are fit for purpose and adjusted to the size of the company, while still being solid and
compliant.
CDMOs care about things that affect their compliance. Typically, marketing authorizations or
registrations don't impact them day-to-day.
I wrote them and they address all elements below
they are accurate, following ISO 13485

155
Yes because - Text
I review them to ensure there're legally binding.
they are thoroughly reviewed by experienced regulatory leaders and regulatory legal staff
hey are clear and limited in scope
of an experienced team, with knowledge of current guidelines
Individually tailored to the project.
Legal mitigation and forces discussion of needs
These are usually built into master service agreement and customized as needed
they take the time to define responsibilities
They set clear agreed upon expectations
We meet regulatory, technical, quality and business requirements.
The agreement includes a detailed scope of expectations and responsibilities.
don't use standalone regulatory agreements
Scope of work, milestones, responsibilities clearly defined.
Yes they are defined and reviewed before finalized
the approach is customized to the partner and situation and the agreements tend to adequately cover
numerous scenarios
All services are included and keep consistent
For those we currently use, we have carefully vetted them for compliance and have extensive oversight
of their operations
all have formal review by Regulatory Affairs
We are a small enough company to keep the contracts simple. However, once we expand our clinical
trials outside of the US, we will need more sophisticated agreements.
Regulatory requirements and responsibilities are defined in our legal agreements, quality agreements, or
both. Development and commercial agreements are used based on the product stage.
We negotiate each one to fit the purpose
they keep them reasonably broad to allow for some freedom in changes in scope of work as project
develop
It covers all the elements required for a successful exchange of information between the two companies
Defined deliverables
Defined expectations
We follow our the clients internal SOPs (first), governmental regulations (USP, EU, FDA,EPA,
OSHA0JP, others, and our internal SOPS secondary)and Agreed upon with customer
Goinfg forward we are addressign critical regulatory items. Past agreements most likely were not so
detailed. [sic]
We have not had problems with the agreement that is the agreements have been serving their purpose.
Rigorous process driven by experienced people.
I did not yet see issues arising from regulatory agreements
they are robust and harmonized
regulatory, quality, and clinical departments are involved in the creation of these agreements.
For the PV agreements which cover regulatory intelligence for safety reporting, these are working
documents that have detailed regulations and guidances behind them. They have also been subject to
numerous regulatory inspections and audits.
as a consultant I need formal agreement with my client companies to outline duties and responsibilities.
It is my job as their regulatory conslutant to make sure that the agreements with their vendors are clear,

156
Yes because - Text
especilly for regulatory issues. Some use firm templates. Others use more free-form agreements - it
depends on the experience of the client and how close they are to late stage development [sic]
They are in contract format and is similar across different vendors.
Standard industry language generally accepted or little modifications which save time
Agreements take into considerations regulatory requirements and expectations
Useful QC system
The agreements are very detailed so when we need to edit we donâ€™t forget items. [sic]
It is adequately explained identifying key areas
They are thorough and expectations are addressed.
critical elements were included to ensure that roles, responsibilitiess are met. [sic]
we control the agreements and thus are satisfied on what we have developed and agree to
there are clean definitions and responsibilities identified.
The important aspects are covered.
for a small company, they are committed to putting safety and compliance first, regardless of the cost
Workable agreements. Not perfect.
they serve the purpose.
our products are still in the early stages of development (Ph1b/2a). I suspect that there is further need for
a more detailed approach with later stage/ commercial products.
Our legal agreements are long-standing and have withstood the test of time and challenges, legal and
otherwise.
The agreements are, as noted above, fairly standardised with some modification to adapt to the specific
services requested. The process is fairly well defined.
Somewhat. We ensure that all updated/ current regulatory guidelines are incorporated into these
agreements.
With the current size and projects my company are working in, having standardized language in
contracts for contract service providers is more efficient.
I trust our RA team.
The agreements are mutually agreed upon.

157
Table 32: Comments: Not Satisfied with Company Approach to Regulatory
Agreements
Are you satisfied with your company's approach to regulatory agreements? Why or why not?
No because - Text
there are too many vendors involved in the process. I believe it best to try to use one vendor that
provides a full service to avoid vendors reporting to vendors.
choose not to answer
We do not have standard expectations/language agreed and incorporated into any contrats at this time.
[sic]
sometimes an afterthought - or not specific enough. Raising awareness with Legal and BD has helped on
those agreements. CROs not so much.
Regulatory agreements are often considered of second tier importance to commercial terms... until there
is a compliance problem and then the regulatory agreement becomes business critical. unfortunately,
memory is fleeting and things fall back when new executives come on board.
Not detailed enough for responsibilities
It is simply following an old school check box mentality but not ensuring quality are designed in
In some cases the agreements were not detailed/specific enough and this created ambiguity with respect
to how to proceed or differences in how we worked between partnerships. Sometimes partners were not
held accountable for not adhering to Items in the agreement. Agreements were not updated to include
more specific details surrounding the format of deliverables.
Our agreements could have been more specific in the following areas:
-whose templates would be used to deliver regulatory submission content to the partner
-format (ms word/pdf)
-location of reviews (partner SharePoint or our SharePoint)
-standard mechanism/location for sharing content between partners
-what information we would expect to receive (copies of submissions,correspondence, questions,
commitments) so that we could have a better historical record of what had been filed where. [sic]
Gaps exist in ensuring all aspects of regulatory and quality are addressed in these agreements
They are not always negotiated by people skilled in regulatory
regulatory is often times "thrown in" to gain clinical trial experience and we are not able to demonstrate
our true capabilities
Formalized processes (SOPs) not always followed, and lack of compliance not addressed by Area (i.e.
sales and marketing, R&D) leadership.
Should be more standardized
The details of regulatory agreements may not be fully considered. This is due, at least in part, to softer
deliverables associated with regulatory. With other parties, such as CDMO/CROs, deliverables are
tangible and straightforward to define.
Unless initiated by Regulatory, often we are not considered in the contract review
Time for negotiations are too long
They need to be more explicit, more detailed
although extensive regulatory elements may not be applicable in some circumstances, they are not
explicitly defined in current agreements to the extent that would be ideal.
Agreements are too specific and still don't fully cover everything and what happens in the real world.
So we end up debating who is responsible to make the decision or pay for it.

158
No because - Text
Usually thought of last and add ons tend to be reactive. Leads to problems later on wet deliverables.
Getting better about getting this resolved up front
Unique to each company (time involved for legal, QA/RA review is extensive). Prefer an industry-
recognized template.
we don't have separate regulatory agreements with partners
We consider regulatory affairs issues, but only among many other issues
They are fixed while the regulatory environment evolves
Many times they are very broad and any remaining rules are only listed in a regulatory manual/SOP t
could be listed as an attachment to the main contract
there are no formal regulatory agreements but rather regulatory expectations within the consulting
agreement or MSA.
we are young and still developing out governance structures. All future-state at this point.
Change control issues are difficult to control for contractually in early development
Varying expectations on personal preference by stakeholders vs actual regulatory requirements. The
agreements tend to get skewed with requirements that are not fully aligned to reg requirements.
Not all the pertinent players (those working on the studies) are reviewing the documents. The C-level
people are making the decisions for those running the studies, and the C-level folks don't have their feet
in the trenches knowing how the studies are actually being performed.
The company tends to rely on the template and not the scope of the project.
FDA will eat us alive when they find out what we are using
Frequently regulatory isnâ€™t actually participating to a meaningful extent during the discussions.
When associated with a clinical CRO the clinical group frequently takes point. [sic]
They are written by risk averse lawyers, they need to embrace change management and TQM type
principles
Most (not very recent) contract aim to build in flexibility but this led to escalation because parties
disagreed about the details.
they are not specific enough for the various types of activities and responsibilities
Unfortunately these donâ€™t often get into the details that are needed. For example, it might not
outline authoring of documents, review/approval processes, or required support when questions arise
from Health Authorities. [sic]
Regulatory sections of agreements tend to be variable if not using our internal template.
Regulatory Agreements or elements of them are incorporated into Quality Agreements.
They do not have a complete understanding of teh Regulatory requirements of the country [sic]
There have not been standalone regulatory agreements. In principal, Regulatory considerations may be
included in manufacturing or quality agreements or other agreeements. However these agreements have
generally been prepared and negotiated by non-regulatory business groups functions with inadequate
input from the Regulatory function. [sic]
Boilerplate agreements do not accurately communicate the unique requirements of each partnership.
at times the agreements are not all inclusive and lag activity.
Often included as part of the quality agreement but not a standalone document with regulatory-specific
considerations that might be too granular for a contract/quality agreement.
Don't always have specific regulatory agreements.
Reg agreement stand-alone documents do not exist, RA considerations are part of a larger document
driven by the BD groups and legal

159
No because - Text
process/procedure details are often left vague or agreements do not cover the day to day or change
management in enough detail for changes to be implemented seamlessly.
Typically the project management team leads all agreements, and the regulatory section (if applicable) is
not always sent to me (the regulatory affairs director) prior to execution. There is also a misconception
in my company that a TORO serves as a business agreement.
The standard templates used do not always apply to all types of products (Device, cosmetics, and Rx)
and they tend to be US centric.
The company does not currently have stand-alone regulatory agreements. The regulatory aspects are
covered in master services agreements and/or quality agreements. I think having a specific regulatory
agreement would be very useful to ensure regulatory expectations for both parties are clear.
They often don't address all the issues.
Research and development teams consider regulatory as â€œ slowing them downâ€. [sic]
Standalone regulatory agreements are not used consistently with our vendors/in contracts. As a result,
clear definition of roles, responsibilities and ownership of regulatory activities sometimes lacks clarity
and/or lack specificity when captured in larger activity agreements.
There is no formal template for regulatory work as it is tailored from project to project.
It's a widely distributed process, with varying levels of knowledge and transparency.
Mostly agreements are not well reviewed via interdisciplinary team.
Lack of consistent approach or expectations by academic partners
Business Development personnel do not always have sufficient expertise to adequately anticipate
regulatory needs.
They need to become more complete to addess EU MDR requirements. [sic]
They are inconsistently utilized or applied
I don't see most of them.
Seen as something that has to be done but really not considered to be an important part of the agreement.
Very little time and thought put into it.
n/a
Often times regulatory aspects of agreemtns do not receive adequate input and review by the regulatory
function, so final agreements may not convey clear or complete requiremens/expectations. [sic]
No. The contract lacks detail re: expected number of submissions, accurate assessment of fees, detailed
expectations from the Sponsor and consequences for lack of performance (e.g. reduces fees).
I am unsatisfied with my company's approach to regulatory agreements. For example, my company has
agreements with vendors (CMOs) for reagents/materials. It is almost always a struggle to obtain
information from these CMOs to support regulatory submissions.
In some instances, a more thorough and detailed listing of regulatory responsibilities should be included
in the agreements.
there was no regulatory department leading to worries that things were overlooked
Generally. Regulatory issues are not considered in depth.
not specific enough
They don't have a formal template for a regulatory agreement.
We don't really have them although there is text in the clinical agreements around regulatory roles and
responsibilities
There is generally just a small section or even just some sentences within the quality section that relate
to regulatory matters. And then we need to have separate agreements for new regions, etc. that are

160
No because - Text
outside of the main commercial supply agreement. I think there should be a regulatory document the
same as a Quality Agreement.
it is very difficult and time-consuming to try to cover all the bases.
I don't think it is used across the board or we have our own plan on what should be included. We are
reactive to these instead of proactive.
Templates bear no resemblance to current regulatory requirements
They generally put us at a disadvantage.
Don't think that they are detailed enough.
only recently have the right people being part of the contract reviews
They do not always account for details upfront that become imperative for working efficiencies once the
working relationship begins
Have had to adjust contracts using change orders - insufficient due diligence. Getting better though.

161
Appendix D. Comments: Reasons Respondent Companies Do Not
Have Regulatory Agreements
Table 33: Comments: Reasons Companies Do Not Have Regulatory Agreements
What is the reason your company does not have standalone regulatory agreements?
Text Comments n=31
Maybe because the people making the agreements don’t do as good of a job getting input from
stakeholders in other functions.
Moving to fast and RA is brought in to late
Often the relationship is larger than just the regulatory component
The concept has not been vetted from my knowledge- vetting is critical before further consideration.
Not sure, since not discussed
Quality Agreement typically addresses the example items that would be in a regulatory agreement.
Incorporated into quality agreements.
regulatory roles and responsibilities are addressed as part of a bigger ancillary agreement but not as
standalone agreement
It may be for our large studies but smaller studies t does not happen due to our lega team being
overwhelmed [sic]
This specific scenario does not apply to my consulting business
I am not involved in the process so I can't provide an answer to this
A stand alone agreement adds complexity to managing the other company and may increase compliance
risk.
no right time or circumstance yet
My company is not very proactive
I’m a consultant so don’t decide for client
We generally have a regulatory plan, which is lifecycle controlled and referenced in the contractual
agreement. Making this part of the contracting process would bottleneck contracting (which already
takes too long) and reduce our flexibility
Covered under Quality or Manufacturing agreements (in principle, if not actual practice)
Generally redundant, require legal review.
We may have these, though I’m unaware
we just expand the quality agreement to cover some regulatory things
All elements that would be contained within a stand-alone Agreement are addressed within the more
broad Agreement/contract.
Separate agreements increase time and effort to execute.
Already included in the MSA and the quality agreement.
I believe it may have been considered, but similar to above, the ability to implement and pull through
may pose part of the issue
WE do with specific regulatory consultants, but not with aharmaceutical partners [sic]
Regulatory requirements are combined with license, quality and/or other agreements.
not sure
Have only used reporting agreements not regulatory specifically
IT depends on the specificity of the overall agreement between sponsor and other institution type
There is not the expertise available to enable an agreement, especially since there is no standard
available.
We build everything into our contacts with a high level of detail.

162
Appendix E. Comments Included for Barriers to Having Regulatory
Agreements
Table 34: Text Comments: Other Barriers to Having Regulatory Agreements
What do you think are the barriers to having regulatory agreements? (choose all that
apply)
Other Comments n=28
separate reg agreements are already used where needed. WHere they are not used is because large umbrella
agreement is in place [sic]
have not yet had opportunity to influence/determine scope and wording for use in agreements.
Agreements are generally applicable across multiple functions and there are not typically separate functional
agreements within
Time to draft; typically RA items are included in either a Quality Agreement and/or PV/Safety Agreement
I think they would be a great idea similar to a PV agreement. I think part of the problem is that the people making
the overarching contracts with the partners and managing the agreement process are not residing in the functions
that are doing the day-to-day work with the partners. Therefore the importance of having a regulatory agreement
might not be clear to them. I think the master contract should call out the subfunctional agreements that will need to
be created upon kick off of the relationship/partnership. I would also recommend including in the agreement a
periodic review to ensure that it remains up-to-date from lessons learned/areas that need to be further detailed. [sic]
There aren't any particular barriers. Legal and Regulatory decide what agreements are needed.
Benefit /Risk need to be weighed
Majority of regulatory items are covered under Pharmacovigilance agreements. No need for a regulatory agreement
if 1 sponsor in the contract has dole reg responsibility and accountability with regulators. Ends up being futile and if
it’s just process/courtesy review for the business alliance sponsor then it does not necessarily need to be created
over above terms for mutual consent matters already generally specified in master business agreement.
Build requirements into Quality Agreement
Contained within other agreements so company doesn't need a separate agreement. Having an additional agreement
would mean additional resources to negotiate it.
Stand alone regulatory documents increase comlexity and may increase compliance risk. [sic]
no need if covered already in the agreement
Regulatory team is stuck in 1990
slows contracting and bogs down legal unnecessarily
Lack of experience with this type of agreement (both in company and in partner)
MSA and QA cover these requirements
Not a lot of precedent, not a perceived best practice.
At times this is include in other agreements, but very high level.
don't believe there are necessarily any barriers in our company; these types of activities are covered in our overall
agreements
No comment
Can more readily build into master agreement
regulatory-related items are covered in other agreements already.
Lack of understanding the importance of prospectively defining the terms of the Agreement between the parties.
Effort
Another separate agreement to maintain.
Each is probably unique so merits its own agreement
Better to integrate reg requirements into overall clinical or other agreements. Ensures process is highly integrated.
Incorporating regulatory agreements as part of the complete agreement with the vendor/consultant/CRO.

163
Appendix F. Comments: Other Ways to Cover Regulatory
Requirements Than Regulatory Agreements
Table 35: Comments: Other Ways to Cover Regulatory Requirements
How does your company ensure that regulatory requirements are covered in their current
partnerships with other companies and vendors? (choose all that apply)
Other Comments n=19
Formal transfer of obligations (TORO)
See response above
Included in Quality Agreement
RA agreement is covered by the QA agreement.
Standalone Quality Agreements, other agreements as relevant to relationship
transfer of regulatory obligations document
Regulator Plan documents developed under each agreement at kickoff, then maintained through lifecycle
Mostly incorporated into the Quality Agreement.
Included in the Formal Agreement
Only registration of devices or facilities has been included in the quality agreements
regulatory elements are often left to informal or secondary agreements as the persons involved in crafting the
agreements only touch on reg requirements at a high level and not in enough detail
It is included in Quality agreement or other type of agreement (Distributor agreement or some other Controlled
document)
Some aspects are covered in Quality Agreements.
No comment
require ISO13485 and assume that's enough
Boilerplate Agreement with Addendum or Appendix defining milestones, number of hours not to be exceeded,
timeframes for reporting progress, phases of work product, etc.
RA dept reviews MSA and QA
Joint Managemnt and Steering Cmte groups with regulatory participation [sic]
Quality Agreements

164
Appendix G. Text Comments Included for Respondents Additional
Information or Comments
Table 36: Text Comments: Any Additional Information or Comments
In the space below, please provide any additional information or comments that could
contribute to my understanding of your views for the use of standalone regulatory
agreements. Thank you.
Other Comments n=68
It was a little unclear when starting this survey, as a consultant, whether a regulatory agreement encompassed
consulting agreement,ents for regulatory services. It later appeared to refer more to agreements for regulatory
services between larger organizations where services have to be standardized across large, matrixed teams [sic]
Standalone agreements should supplement internal staff. If internal staff for regulatory is not available,
management is deficient.
Multiple agreements are challenging to draft, review, come to agreement and finalize; for most companies. It takes
time, expertise and effort upfront to come up with templates. Then to get the other companies to agree to the
templates is a bit like starting all over again every time; requiring resources.
I do agree that standalone Reg agreements would add value.
regulatory requirements are covered by the requirements in Quality/Technical Agreements (GMDP), and/or
SDEA/PVAs and/or MSAs.

There really is no need for a standalone Regulatory Agreement. These requirements are covered by GXPs and as
such the GXP agreement in place should cover Reg requirements. QA professionals understand regulatory and very
much are expert inf the regulatory requirements that need documented agreements between different parties.

A standalone Regulatory Agreement would only add to risk of Regulatory departments acting in isolation without
the buy-in of the truly responsible/accountable department (QA).
Standalone regulatory agreements can be helpful when adding to the responsibilities or services requested from a
vendor for a specific project or time period as it allows the flexibility of a separate agreement without having to go
through the full contract again.
RACI is critical as is legal liability. Legal need to own the process through formal templates.
From big pharma partners, I often hear a reluctance to consider additional ancillary agreements beyond a supply,
quality, and PV agreements. If you could convince the big law firms of the value, it seems that making this change
to the license and collaboration agreement templates would go a long way in making this a standard approach.
i think your questions have covered the issues [sic]
Companies need to think wholistically about key consideration and determine what's the most efficieint way to
address each. Determine if a consolidated approach (having regulatory and quality considerations) captured in a
single documents for efficiency and reduction in document burden. [sic]
Stand alone agreements may not have the flexibility to navigate through an unknown event such as Covid-19. The
agreement may restrict or slow down critical processes. For smaller companies, the greatest cost to the organization
is time.
The need to review other regulations and standards around the need for these documents instead of using one
regulation that does not address the use or discuss why it is needed in pharmaceuticals is needed or should be
utilized which in pharma it is not always done.
This is a unmet need in the industry. As companies continue to build collaborations and partnerships, regulatory
implications are overlooked and become complicated. To have a framework agreed to upfront will allow smooth
working relationships and lessen the burden caused by unclear expectations.
One issue has been US focus and almost 'forgeting' OUS [sic]

165
Other Comments n=68
I think some of the questions were difficult to answer when it's unclear if you were asking about partnership
agreements, CROs, or with vendors.

With vendors, I think a contract is usually used as the regulatory agreement with kick off meetings to align on roles
and responsibilities, as well as expectations, communication plans, and governance.

With partners, a stand alone regulatory agreement may be needed or it could be part of the safety and/or quality
agreement. A contract would not be used in this case, so some sort of regulatory agreement would be needed.

Working with CROs could be similar to a vendor or a partner.
As a consultant, i need to make this clear when I engage. For my clients, I need to make sure they understand
exactly what is going to happen, especially for CROs and CDMOs. This often is not clear, even though it is part of
the general engagement contract. For academic sites, regulatory reporting is often a very nebulous area where they
think they have experience, but in fact do not have experience. Academic studies are NOT sufficient to insure that
the academic site understands how to do a commercial study and report the correct information. [sic]
Continuing management and monitoring of the supplier is the only way to ensure compliance to these agreements.
Most of these agreements are a paper work activity that is not monitored for compliance. It is only when something
goes wrong that everyone starts to look at the agreement. Having a working group/committee from both parties
continually monitor and review the effectiveness of these contracts is the best way to ensure compliance.
Additionally, each party should report on the compliance of these agreements during management review meetings.
Agreement on use of CROs for specific management of submissions. Discussion of ex-US management and use of
in-country affiliates/representives. [sic]
More awareness on Regulatory agreements and their application is needed.
I don't at all agree with my (former) company's views on this, but anything regulatory received very short shrift
even though the company had a candidate in an early clinical trial.
We generally incorporate regulatory activities in overall agreements/contracts. We are also a very large company
and prefer to handle global regulatory requirements ourselves and thereby generally retain those responsibilities.
What is the difference in scope between Quality Agreements and regulatory agreements? In the past, Quality
Agreements have covered some, but not all, regulatory aspects.
I think one of the best ways to convince your own company of the benefit of a standalone quality agreement is to be
able to show them examples of situations where a project went sideways because of something that was not
included in any of the agreements. If possible show the financial, reputational and/or regulatory implications of
these examples and how a simple standalone regulatory agreement could have kept it from happening.
I wish I could be more helpful but my current sponsor company is very small and at the early stages of clinical trial
implementation. In my experience, most CRO contracts outline most regulatory responsibilities adequately enough
for clinical trials.
In a small organization, the effort to execute multiple agreements exceeds the value of improved clarity that they
might provide.
In my opinion, if the Parties engage with one another, an Agreement covering the terms related to regulatory
deliverables can be addressed as a subset of, or Addendum/Appendix to, other standard terms of professional
Agreements and contracts, e.g., confidentiality, patent rights, indemnification, insurance requirements, payment
terms, taxes, termination, severability, which state law applies, etc.
I am familiar with engaging CROs, CMOs and consultants under a master service agreement (MSA) followed by a
statement of work (SOW).
In addition, we develop a transfer of regulatory responsibilities (TORO) document using a template to outline the
CRO’s responsibilities for a given clinical trial. The TORO is submitted to the FDA and used during regulatory
authority inspections.
N/A
We have always found it simpler to manage a single agreement with each partner. We're moving toward a more
modular structure to allow certain aspects to be kept confidential while others are shared more widely. There are
also some challenges in deciding whether to use their template, our template, or some portions of each.
These are most often built into other relationships, and are sometimes included in quality agreements which are
required by some regulators, see FDA guidance

166
Other Comments n=68
The process for developing a standalone regulatory document can be challenging but it forces the team to actively
comtemplate each regualtory step/activity and how they should be managed/optimized for the program. The
process often reveals gaps in knowledge/information/expectations and helps proactively address those gaps to
minimize risk later. [sic]
I think it's a good topic and something being over looked in industry. Note that there's a lot of side benefits that
could come out of it. It could speed up auditing process. It could facilitate discovery of gaps in communication,
expectations, metrics, etc.
New concept, mostly included within a Service or Quality agreements. A stand-alone Regulatory agreement is
unusual.
We are asked to review contracts/agreement upon request from Business Development or Sourcing Departments.
Occasionally we are asked for regulatory opinions informally prior to contracts being drafted. RA involvement is
based on stage of development which requires different levels of expertise.
Our company ensures that all critical regulatory activities and procedures are clearly delineated in our contractual
agreements with all of our partners
I think it is a very good idea to have stand-alone regulatory contracts. Many times the regulatory considerations are
embedded in the Master Services Agreements and the Quality Agreements. I think having a clear regulatory
contract that the regulatory parties on each side can refer to would really help to assure the regulatory expectations
are clear which would theoretically lead to improved regulatory outcomes.

However, regulatory contracts are not commonly used so it would take some initiative to introduce them. Guidance
and templates would be very useful.
I believe they are necessary and very underutilized. I believe that a well written regulatory agreement will
encompass many regulatory responsibilities that need to fall on the manufacturer and distributor that erases the grey
areas in regulatory. A regulatory agreement is just as important as a quality agreement.
I think this would be helpful to have or ensure there is an agreement or understanding of roles, expectations,
responsibilities covered in a separate agreement or part of the quality or supply agreement. Having a clear
understanding of this for both parties and all involved would help with managing the partnership and program.
better regulatory guidance and templates
These agreements have been "best Practice" for decades and are now becoming regulatory requirements (EU
2017/745 & 746)
I've worked in a bio company which partner with other pharma to develop and market new products. The Alliance
Management played a very big role in managing all aspects of working together, from resource, project mgmt, to
budgeting. I thought it worked very well and I was involved in meeting with Alliance mgmt and Legal from both
sides to discuss Regulatory process and roles and responsivities. Alliance mgmt also manage joint project team
meetings with focus on building good working relationship. Once a year they conduct survey and shared the results
at the joint project team meetings. The survey mostly focus on the teamwork, process improvement,
communication, and mutual respect, etc. [sic]
Particularly in smaller startup or emerging companies, partnership deals and agreements are often developed
quickly and informally by a handful of comparatively inexperienced people who may not understand the
complexities involved. Often times there is an understandable desire or pressure to get a deal done, but there is
insufficient recognition of the need to come back afterwards to dot the I's and cross the T's.
Regulatory requirements are usually covered in other agreements such as the Quality Agreement. I think because of
the combination of lack of FDA guidance documents along with companies simply have not thought about creating
a standalone Regulatory Agreement, it is not commonly encountered.
My scope of practice is more in regulatory, so most of the agreements with business partners are focused on
regulatory, sometimes the business relationships include related areas such as clinical and reimbursement, or
quality/compliance. In our situation there are not too many hurdles.
None.
Regulatory requirements are covered in MSA and QA
I think these are critical both for the company and its partner. These will help to avoid long, drawn-out
conversations and about roles and responsibilities, and will provide a strong foundation for a collaborative
relationship.

167
Other Comments n=68
Some partners are more mature than others and standard contracts are okay, but we are actively identifying places in
the starting templates to be more specific where in the past we thought it was a good idea to remain flexible. This
backfired with less mature partners.
We use master service agreements that include confidentiality, terms and condition.
Then we add individual scoops of work to the MDA with the details of the services, cost and timing.
regulatory agreements are typically included, as applicable, within the context of other agreements.
As of now, we have formal contracts, master services agreements, scopes of work and each of these may also
involve a quality agreement depending on the nature of the work. To implement another standalone agreement,
which is readily cover in the ones i have already noted, seems unnecessary. The only place I can see for this is if
the partner is unfamiliar with regulatory requirements, and if that were the case, I would wonder why there would
be an agreement in the first place. [sic]
One should assess current agreements and work to add robustness and flexibility.
Quality and supply agreements are more typically drafted and implemented, particularly for manufacturing per
QMS and GMP requirements. Clinical development and associated regulatory responsibilities are typically covered
within CRO master service agreements. Regulatory agreements are often managed by internal company
structure/governance and the CRO/vendor/business partner responsibilities are defined in master service or
consulting agreements. Especially in smaller companies where there is a more limited governance structure, the
regulatory decision making is centralized/closely managed by a small # of individuals and limits the need for
regulatory agreements. It makes more sense where in-house reg strategy and relevant cross-functional expertise are
not available and therefore the sponsor relies on the vendor for this expertise. Reg agreements may also be
warranted where those responsibilities are not defined in other executed documents/agreements. Lead times for
regulatory submissions are typically set by Reg submissions vendors as well, so the deliverable date to the vendor
would determine the submission date. Strategy for date of submission to health authorities is typically a sponsor
decision. Deliverable dates/expectations should be in the vendor contracts so it seems that Regulatory agreements
could be added to the consulting/service agreement rather than a standalone agreement, as the reason for most of the
development work/services are to support a regulatory submission.
I believe that the legal policies of a company can hinder the development of stand-alone regulatory agreements,
especially when dealing with Investigator Sponsored Studies or other small studies. This is especially noticeable in
smaller companies with tight headcount. I know as the manager in charge of these studies this type of document
would be received well by me but it would add to the review timeline at institutions which is already extensive.
If standalone agreements are done they should be considered an addendum or in some way linked to the umbrella
agreement. Often the regulatory agreements cover more than just regulatory - they required actions by other
functions so they need to be visible/known to all impacted by the agreement.
I believe companies feel bombarded with agreements, and they seem to be bleeding into each other. We have
supply agreements (which contain specifications), specification agreements (which include quality and regulatory
information), and quality agreements (which seemed to have morphed from a simple agreement between the quality
groups at the respective companies to a legal contract). Because of this, legal review is extensive, multiple
interpretations are possible, back-and-forth over several months is required. I am not certain if it is possible to add
another agreement to this practice.
Some great benefits for speeding up early stage deliverables.
I like the idea of standalone regulatory agreements, especially since Regulatory would be responsible for ensuring
compliance between company and CMO (or other). Currently, I see aspects of a regulatory agreement in Quality
Agreements and Quality must ensure compliance but Quality doesn't always know what is happening in Regulatory.
Example in QAg, CMO must have input/review 30 days prior to a submission yet Quality doesn't know the timing
and can't ensure CMO has the draft submission within the required time.
This seems like something that should be driven by stage of development, as well as the regualtory requirements in
different countries. It would also require appropriate resourcing, and potentially a position that is a blend of
Regulatory and Legal. [sic]
One huge hurdle to getting clinical trials running are site agreements. anything to speed up that process could save
months. I have often wondered if a "Chinese menu" approach would work that a site could chose from a short
menu of standard options that would be available.. for instance- A) right to publish: allow site data to be published
only after study is concluded: b) you are the study KOL- you get to write the entire study for publication or C) no
publication rights..D) your site PI -if it enrolls XX participants will be listed as a co-author. [sic]

168
Other Comments n=68
I'm afraid I've missed some critical element of the line of questioning. All of the companies I've worked with do
use "standalone regulatory agreements" at least in the sense of a Quality Agreement where needed. But there are so
many different kinds of relationships, vendors and suppliers in the pharma development process that many
regulatory issues are not in play for that relationship, so I just can't answer the questions as asked. Somebody will
have responsibility for those functions, but it might be done internally by the company itself or spread among
different partners, and thus not be material to a particular agreement with a partner. And if the partner has a big role
in e.g., clinical supply, trials, or commercialization, then a standalone regulatory agreement wouldn't capture all the
other aspects of the relationship that need to be dealt with. Often, many of the regulatory, pharmacovigilance, and
agency-interaction elements mentioned in the survey are included in the main agreement. So I apologize if my
answers aren't useful to you!
As almost any substantial agreement is vetted thru corporate attorneys, nuance is required to assure that
commitments, responsibilities, and authorities are fair and realistic. Often, legal counsel tries to just avoid
responsibility (risk) and makes a true collaborative agreement thorny.
Any major pharma has its own RA department. If any external help is needed, other contracts already in place
would cover an RA agreement too.
My company deals only with Generic Drugs, and as such, does not have as many components to a drug submission
to FDA. We also only file and distribute within the US and US territories. Therefore, I just don't see the need for a
separate agreement. Major items are covered in our Quality Agreements, and other are handled on a more informal
basis. Additionally, if we own the application (ANDA), then we are responsible for the approval and submission of
any document that goes to FDA. Nothing goes without our approval as ANDA holder/sponsor.
A template or decision tree to ensure completeness of the agreement would be very useful. The standalone
regulatory agreement could be very useful for a partnership that would change over time, i.e. following
development, approval, and into the post market setting.
Small companies such as mine don't necessarily have a business model to take development projects through to
commercialization. Sometimes the objective is take to value inflection point and sell. So these agreements make
more sense for larger companies who want to take projects to approval and commercialization. [sic]
These agreements appear to be one-of-a-kind which makes it difficult to use across many activities.
RA departments are typically very lean (esp in smaller companies) and to implement a document/system that is
likely covered in other agreements is not efficient.
There is great value in creating regulatory agreements for clear understanding of roles and responsibilities between
partners - but unless there is a clear business/legal need (We went to trouble of creating one as we are the US
regulatory Agent for a foreign sponsor) it is difficult to advocate for internally in the context of elements being in
the MSA and 'too many other agreements' in a small company such as ours.

169
Appendix H. Draft Checklist for a Regulatory Agreement
Category Elements
Company and
Organizational
Information
 Companies in this agreement
o Contact information
 Commitment to maintain qualified and knowledgeable
regulatory and quality resources to support the commitments
within this agreement, in case team members are fired, laid
off, or leave the company
Product or
Service
 Product or service covered by the agreement
Regulatory
Authorization
and Compliance
 Access and maintenance to required registrations, licenses and
authorizations
 Compliance/conformity to established standards/guidance
 Oversight of GLP and GMP compliance
 Inclusion of shifting liability clauses
 Crisis management plan
 Penalties for non-compliance
 Database management and compliance
 Regulatory due diligence
Regulatory
Documents and
Records
 Documents Process
o Lead times, deliverable dates, turnaround times,
expectations
o Management of authoring/review/modification/approval
o Number of review cycles
 Records management –
o Handling
o Ownership
o Availability of source documents
 Examples/Templates
o Trial master file
o TORO
o Nonclinical study reports
o Clinical study reports
Communications
 Governance, decision making, and escalation processes
 Regulatory Communications
o Lead times, deliverable dates, turnaround times,
expectations
o Responsibility for
authoring/review/modification/approval
o Responsibility for reporting responsibilities
 Company Communications
o Information sharing plan
 Assumptions underlying the agreement
 Notification of audits, inspections, adverse (reportable) events

170
Category Elements
Roles and
Responsibilities
 Specific detail related to each party’s responsibilities
 Specific roles of individuals
 Sign off by wider range of functional areas for both parties.
 Specific roles and responsibilities of consultants
 Matrix defining accountabilities and responsibilities (RACI)
 Regional specific RA requirements, including R/R in each
region
 Roles for crisis arrangements
 Definition of teamwork, process improvement, and mutual
respect
 Consequences for lack of performance
Regulatory
Submissions
 Applications, Supplements and Amendments
o Deliverable dates, turnaround times and expectations
o Responsibility for
authoring/review/modification/approval
 Labeling review and approval
Health Agency
Meetings
 Strategy for interactions
 Preparation of meeting materials
 Preparation for in-person or face-to-face meetings
 Attendance and roles/responsibilities for agency interactions
(Written, telephone, and face-to-face)
Health Agency
Requests
 Responsibility and timing for
authoring/review/modification/approval
 Reporting strategy
Regulatory
Procedures
 Regulatory strategy
 Labeling review and approval
 Postmarketing and lifecycle maintenance activities
Agreement
Management
 Template or decision tree to ensure completeness of the
agreement
 Process/cycles for drafting and review of agreement
 Timing for review/modification of agreement: minimum of
yearly or following major milestones: development, approval,
and into the post market setting
 Clearer milestone agreements
 Process workflow diagram for collecting, reviewing,
approving, storing and submission
 Audits of processes and records to verify compliance
 Process improvement
 Metrics
o Deviations, CAPA and audit/inspection finding reviews
o Key Performance Indicators
Publications
 Rights and permissions to publish
 Timing of publications
 Authorship of publications

Abstract (if available)

Abstract As pharmaceutical companies change their business models to remain competitive, they seek ways to reduce the costs and risks associated with drug development. Outsourcing to contract research and manufacturing organizations can reduce the costs of clinical trials and manufacturing but may result in a patchwork of vendors that is difficult to integrate. Integration can be simplified by entering into more comprehensive “preferred” partnerships with service providers and agreements with other companies or academic organizations. Still, it can complicate the business model by adding new legal and operational requirements. A standalone regulatory agreement has the potential to clarify the relationships and responsibilities between partners working jointly on a single regulated product. This study used survey methods to explore the views of industry professionals on the need for and current use of standalone regulatory agreements. A total of 294 respondents responsible for drug development partnering activities participated in the survey. About half, primarily from larger companies, had heard about regulatory agreements, and half of this smaller group had moved forward to implement them. Benefits of implementation included clarification of regulatory roles and responsibilities, standardized regulatory expectations between the companies, and earlier discussion about joint regulatory strategies. The development of regulatory agreements was challenged by the absence of templates, agency or industry guidance, or a clear requirement by health agencies. Respondents not using regulatory agreements had not considered them or did not see a need for a standalone agreement. The use of regulatory agreements appeared to depend upon the type of partner, the complexity of the relationship, and the availability of internal expertise and support.

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Asset Metadata

Creator Wilhelm, Mary E. (author)

Core Title Regulatory agreements for drug development collaborations: practices in the medical products industry

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2021-12

Publication Date 09/16/2021

Defense Date 07/28/2021

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

Tag biotechnology,combination product,Contracts,global,medical device,OAI-PMH Harvest,outsourcing,partnerships,pharmaceutical companies,submissions,vendors

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Clemens, Roger (committee member), Smerkanich, Nancy (committee member)

Creator Email mary.wilhelm@gmail.com,mewilhel@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC15918128

Unique identifier UC15918128

Legacy Identifier etd-WilhelmMar-10071

Document Type Dissertation

Format application/pdf (imt)

Rights Wilhelm, Mary E.

Type texts

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

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