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Evaluation of FDA-sponsor formal meetings on the development of cell and gene therapies: a survey of industry views

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Evaluation of FDA-sponsor formal meetings on the development of cell and gene therapies: a survey of industry views

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Content Evaluation of FDA-Sponsor Formal Meetings on the Development of Cell and Gene Therapies:
A Survey of Industry Views
by
Eugene Babcock
A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE
August 2024
Copyright 2024 Eugene Babcock

ii
Dedication
I dedicate this dissertation to my family – to my wife and my two daughters. Thank you
for your patience as I pursued and completed my studies. I also dedicate this dissertation to my
parents, who encouraged me to pursue this doctoral degree.

iii
Acknowledgements
This dissertation is the culmination of eight years of study and research at USC in the
Regulatory Science program. I want to thank all of those who helped me in my journal and
acknowledge those individuals who supported me with this dissertation. First, I want to thank my
advisor and thesis committee chair, Dr. Susan Bain, for her mentorship, encouragement, and
continued support. I am grateful for her expertise and experience on this topic, and my work has
benefitted from her guidance. I want to thank the members of my thesis committee: Dr. Frances
Richmond, Dr. Eunjoo Pacifici, and Dr. Hai Luong. I appreciate your time reviewing my
qualification materials, your insightful questions and constructive comments, and your assistance
in developing my survey and reviewing my dissertation. I want to thank my focus group
participants for their time and valuable insights for improving my survey for this research
project. Last, I want to give my sincere thanks to the survey participants who shared their
opinions and experiences on this topic and shared my survey with their colleagues. I look
forward to sharing the results with my colleagues in the industry.

iv
TABLE OF CONTENTS
Dedication....................................................................................................................................... ii
Acknowledgements........................................................................................................................ iii
List of Tables ................................................................................................................................ vii
List of Figures................................................................................................................................ ix
Abstract.......................................................................................................................................... xi
Chapter 1. Overview ......................................................................................................................12
1.1 Introduction............................................................................................................... 12
1.2 Statement of the Problem.......................................................................................... 15
1.3 Purpose of the Study ................................................................................................. 16
1.4 Importance of the Study............................................................................................ 17
1.5 Limitation, Delimitations, and Assumptions ............................................................ 18
1.5.1 Limitations................................................................................................... 18
1.5.2 Delimitations ............................................................................................... 19
1.5.3 Assumptions................................................................................................ 20
1.6 Organization of the Thesis........................................................................................ 20
1.7 Definitions................................................................................................................. 20
1.7.1 Definition of Key Terms.............................................................................. 21
1.7.2 Acronyms..................................................................................................... 22
Chapter 2. Literature Review.........................................................................................................23
2.1 Introduction............................................................................................................... 23
2.2 Literature Search Strategy......................................................................................... 23
2.3 Background............................................................................................................... 25
2.3.1 History of Cell Therapies............................................................................. 25
2.3.2 History of Gene Therapies........................................................................... 27
2.4 Regulation of Cell and Gene Therapy Products........................................................ 31
2.4.1 Statutes and Regulations.............................................................................. 31
2.4.2 Guidance Documents................................................................................... 35
2.4.3 Expedited Programs..................................................................................... 36
2.5 FDA Formal Meetings with Sponsors of Medical Products..................................... 40
2.5.1 Background on FDA Formal Meetings ....................................................... 40
2.5.2 Purpose, Definition, and Importance of Formal Meetings .......................... 41
2.5.3 Meetings throughout the Product Lifecycle ................................................ 42
2.5.3.1 Meetings prior to the Submission of an Investigation New
Drug Application ............................................................................ 44
2.5.3.2 Meetings after Submission of an Investigation New Drug
Application ..................................................................................... 45

v
2.5.3.3 Meetings during Review of a Biologics License Application ........ 46
2.5.3.4 Meetings after Approval of a Biologics License Application ........ 47
2.5.4 Procedure to Request and Prepare for a Formal Meeting............................ 47
2.5.5 Timing and Advice from Meetings.............................................................. 53
2.5.6 Meetings for other Medical Products .......................................................... 54
2.5.7 Recent Changes in Meeting Management ................................................... 55
2.6 Lessons from Approved Cell and Gene Therapy Products....................................... 56
2.7 Stakeholder Views of Agency-Sponsor Meetings .................................................... 62
2.7.1 Industry Views............................................................................................. 62
2.7.2 Current Industry and Regulator Views........................................................ 64
2.7.3 PDUFA Meeting Management.................................................................... 65
2.7.4 One Recent Example of Industry-FDA Interactions.................................... 69
2.8 Research Approach and Framework ......................................................................... 71
Chapter 3. Methodology ................................................................................................................78
3.1 Introduction............................................................................................................... 78
3.2 Survey Development................................................................................................. 78
3.3 Focus Group.............................................................................................................. 80
3.4 Survey Distribution................................................................................................... 81
3.5 Data Analysis............................................................................................................ 83
Chapter 4. Results..........................................................................................................................86
4.1 Survey Participation.................................................................................................. 86
4.2 Demographic Profiles of Respondents...................................................................... 86
4.3 Context Evaluation.................................................................................................... 92
4.4 Input Evaluation...................................................................................................... 100
4.5 Process Evaluation .................................................................................................. 105
4.6 Product Evaluation.................................................................................................. 124
4.7 INTERACT Meeting............................................................................................... 141
4.8 Final Question......................................................................................................... 147
Chapter 5. Discussion ..................................................................................................................149
5.1 Overview of Research............................................................................................. 149
5.2 Considerations of Study Methodology.................................................................... 149
5.2.1 Limitations................................................................................................. 150
5.2.2 Delimitations ............................................................................................. 153
5.3 Consideration of Results......................................................................................... 155
5.3.1 Framework................................................................................................. 156
5.3.2 Context....................................................................................................... 156
5.3.2.1 Reliance on FDA .......................................................................... 157
5.3.2.2 Intended Use of Meetings............................................................. 158
5.3.3 Input........................................................................................................... 159

vi
5.3.3.1 Regulatory Experience.................................................................. 160
5.3.3.2 Availability of Information........................................................... 161
5.3.3.3 Timing of the FDA Meeting......................................................... 162
5.3.4 Process....................................................................................................... 162
5.3.4.1 Availability of Industry and FDA Resources ............................... 163
5.3.4.2 Preference for Meetings over Written Responses......................... 164
5.3.4.3 Greater Detail in Regulatory Feedback ........................................ 167
5.3.5 Product....................................................................................................... 168
5.3.5.1 Effectiveness of FDA-Sponsor Meetings..................................... 168
5.3.5.2 Impact of Regulatory Feedback.................................................... 170
5.3.5.3 Sustainability of FDA-Sponsor Meetings..................................... 171
5.3.6 INTERACT ............................................................................................... 172
5.4 Conclusion and Recommendations......................................................................... 174
5.5 Future Research....................................................................................................... 176
References....................................................................................................................................178
Appendices...................................................................................................................................190
Appendix A. List of Acronyms and Abbreviations......................................................... 190
Appendix B. Data on Approved Cell and Gene Therapy Products................................. 191
Appendix C. Data for PDUFA Meeting Management.................................................... 199
Appendix D. Finalized Survey........................................................................................ 200
Appendix E. Cross-Tabulations...................................................................................... 216

vii
List of Tables
Table 1: Search Term Results from Search Engines 24
Table 2: Table of Expedited Programs 38
Table 3: Summary of Milestone Meetings during Development 43
Table 4: Summary of Meeting Types and Timelines 49
Table 5: Combined CBER and CDER Meeting Management Performance by Fiscal
Year (FY 2008 to FY 2020) 68
Table 6: Overview of the CIPP Evaluation Framework 76
Table 7: Structure of Survey based on CIPP Framework 79
Table 8: Weighted Scores of Usefulness of Resources for Technical Information 95
Table 9: Weighted Rank Scores of Advantages of FDA-Sponsor Meetings 98
Table 10: Weighted Rank Scores of Drivers for FDA Feedback 100
Table 11: Weighted Scores of Agreement amongst Respondents on Organizational
Readiness 103
Table 12: Respondent Opinions on Internal Organizational Resources 103
Table 13: Weighted Scores of Respondent Views on Meeting Request 107
Table 14: Weighted Scores of Respondent Views on Meeting Package 110
Table 15: Weighted Scores of Respondent Views on Written Responses 113
Table 16: Weighted Scores of Respondent Views on Meeting Conduct and Minutes 118
Table 17: Weighted Rank Scores of Changes to Improve Meeting Process 122
Table 18: Respondent Opinions on Improving FDA Meeting Procedures 122
Table 19: Weighted Rank Scores of Advantages from the FDA Feedback 129
Table 20: Weighted Scores of Respondent Views on Drivers of FDA Feedback 131
Table 21: Summary of Respondent Views of Impact of FDA Advice and
Recommendations 133
Table 22: Cross-tabulation of Implementation of FDA Feedback against Outcome on
Product Development 134
Table 23: Weighted Scores of Respondent Views on Concerns with obtaining FDA
Feedback 136
Table 24: Summary of Respondent Views on Other Concerns with obtaining FDA
Feedback 137
Table 25: Weighted Rank Scores of Factors influencing Respondent’s Use of FDA
Meetings 140
Table 26: Text Responses from Respondents about the INTERACT Meeting 145
Table 27: Text Responses of Respondent Experience with the INTERACT Meeting
Process 147
Table 28: Final Comments from Respondents 148
Table 29: List of Acronyms and Abbreviations 190
Table 30: Data for Approved CGT Products in the U.S. by Year (2010 to 2022) 191

viii
Table 31: Data for Regulatory Designations and Approval of CGT Products 192
Table 32: Data for Regulatory Review of Approved CGT Products 194
Table 33: Data for Outcome of Approved CGT Products 196
Table 34: Data for CBER and CDER Meeting Requests by Fiscal Year (FY 2010 to FY
2021) 199
Table 35: Cross-tabulation of Time since FDA-Sponsor Meeting and Outcome of
Meeting Request 216
Table 36: Calculation of Difference in Weighted Scores 217
Table 37: Frequency of INTERACT Meeting Topics 218

ix
List of Figures
Figure 1: Number of Gene Therapy IND Applications per Year (1988 – 2019) 29
Figure 2: Number of Active Advanced Therapy Clinical Trials Worldwide by Industry
and Phase or by Therapeutic Area in 2022 30
Figure 3: Flowchart to Determine the Statutory Authority for a Cell- or Tissue-Based
Product 34
Figure 4: Stages of Biological Product Development and FDA-Sponsor Meetings during
Development 43
Figure 5: Timeline of Sponsor and FDA Actions before and after a Meeting 52
Figure 6: Number of CGT Products Approved in the U.S. in 2010-2022 57
Figure 7: Regulatory Designations and Approval of CGT Products 58
Figure 8: Therapeutic Areas of Approved CGT Products 59
Figure 9: Regulatory Review and Outcome of Approval of CGT Products 60
Figure 10: Combined CBER and CDER Meeting Requests by Fiscal Year (FY 2010 to FY
2021) 66
Figure 11: Illustration of the CIPP Evaluation Framework 74
Figure 12: Distribution of Medical Product Experience 87
Figure 13: Distribution of Type of Organization 88
Figure 14: Distribution of Size of Organization 89
Figure 15: Distribution of Functional Area amongst Respondents 89
Figure 16: Distribution of Length of Experience amongst Respondents 90
Figure 17: Distribution of Stage of Product Development 91
Figure 18: Distribution of Number of FDA-Sponsor Meetings 91
Figure 19: Distribution of Experience with FDA-Sponsor Meetings 92
Figure 20: Distribution of Usefulness of Resources for Technical Information 94
Figure 21: Distribution of Rank of Advantages of FDA-Sponsor Meetings 97
Figure 22: Distribution of Rank of Drivers for FDA Feedback 99
Figure 23: Distribution of Agreement amongst Respondents on Organizational Readiness 102
Figure 24: Distribution of Respondent Views on Meeting Request 106
Figure 25: Distribution of Respondent Views on Meeting Package 109
Figure 26: Distribution of the Outcome of the Meeting Request 111
Figure 27: Respondent Satisfaction with Written Responses 112
Figure 28: Distribution of Respondent Views on Written Responses 113
Figure 29: Distribution of Clarifying Questions after receiving Written Responses 114
Figure 30: Respondent Satisfaction with Preliminary Responses 115
Figure 31: Distribution of Respondent Views on Meeting Conduct 117
Figure 32: Distribution of Respondent Views on Meeting Minutes 118
Figure 33: Clarifying Questions after receiving Meeting Minutes 119

x
Figure 34: Distribution of Rank of Changes to Improve Meeting Process 121
Figure 35: Ability to receive Milestone Meetings 124
Figure 36: Ability to receive Non-Milestone Meetings 125
Figure 37: Ability to receive Interdisciplinary Meeting 126
Figure 38: Respondent Opinion on Effectiveness of FDA Meeting 127
Figure 39: Distribution of Ranking of Advantages from the FDA Feedback 128
Figure 40: Distribution of Respondent Views on Drivers of FDA Feedback 130
Figure 41: Implementation of FDA Advice and Recommendations 132
Figure 42: Respondent Views of Impact of FDA Advice and Recommendations 132
Figure 43: Distribution of Respondent Views on Concerns with obtaining FDA Feedback 136
Figure 44: Ranking of Factors influencing Respondent’s Use of FDA Meetings 139
Figure 45: Overall Rating of Respondent Opinion on FDA-Sponsor Meeting 141
Figure 46: Distribution of Respondents who Requested an INTERACT Meeting 142
Figure 47: Distribution of Topics in the INTERACT Meeting Request 142
Figure 48: Distribution of Respondent Views on Preparation of the INTERACT Meeting
Package 144
Figure 49: Respondent Opinion on Impact of INTERACT Meeting 145
Figure 50: Distribution of Respondent Views on INTERACT Meeting 146
Figure 51: Respondent Satisfaction with INTERACT Meeting 147

xi
Abstract
Although cells and tissues have long been transplanted in human medicine, recent
scientific advancements have enabled the use of human cells and tissues as medical products for
a broader number of indications with an increasing number of clinical trials in phases of
development. One of the main mechanisms to obtain feedback from the Food and Drug
Administration (FDA) about the technical aspects of cell and gene therapies (CGTs) is through
meetings with the Agency. Both industry and regulators value good communication through
meetings, but industry sponsors may not be using them effectively. Further, FDA often struggles
to handle the high volume of meeting requests. Attention to facilitating regulatory feedback has
assumed greater importance recently because clinical and product quality issues have become
bottlenecks for the regulatory review and licensure of CGTs. This exploratory study used an
electronic survey directed at regulatory professionals with relevant experience in developing
these products and interacting with FDA. An evaluation framework informed the research
questions and supported the analysis and interpretation of the findings. Results showed that the
primary objectives for seeking regulatory feedback were to obtain FDA agreement on proposed
study designs to generate data and to resolve issues encountered during development as the
primary advantage of an FDA meeting was a perceived reduction in the risk of potential
setbacks. The results revealed potential areas for improvements, including the responsiveness
and reliability of industry and FDA resources, the industry preference for meetings over written
responses, and the desire for greater detail in the regulatory feedback. Although FDA-sponsor
meetings were viewed as beneficial, some issues were recognized that could affect their
effectiveness and sustainability.

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Chapter 1. Overview
1.1 Introduction
Cell and gene therapies offer a novel approach to treat serious illnesses. Although cells
and tissues have long been transplanted in medicine, recent scientific advancements, particularly
through genome editing, have facilitated the use of human cells and tissues as medical products
for a broader number of indications, including cancers, autoimmune disorders, and other serious
conditions. Their treatment opportunities are reflected by an increasing number of clinical trials
to evaluate cell therapies, gene therapies, and genetically-modified cell therapies in multiple
phases of clinical development. The Food and Drug Administration (FDA) anticipates that the
number of investigational new drug (IND) applications and biologics license applications
(BLAs) for cell and gene therapies (CGTs) will grow even further over the next decade (Drago et
al., 2021).
Because CGTs can offer substantial clinical benefit compared to previous treatments,
they are often candidates for expedited development programs that can shorten the clinical
development timelines to speed access to patients (Iglesias-Lopez et al., 2021). Examples of such
expedited development programs include breakthrough therapy or regenerative medicine
advanced therapy (RMAT) designations (Chhina et al., 2022). However, shortened pathways
reduce the time available for sponsors to accumulate the process and product knowledge needed
to assure a safe and effective product with consistent quality. Expedited development programs
do not lessen or change the technical requirements that CGT products must fulfill for licensure
(FDA, 2014b, Salazar-Fontana, 2022). Thus, they can challenge robust data generation during
development, for example, by reducing the number of clinical studies or subjects to understand

13
clinical safety and long-term efficacy and by reducing the time available for comprehensive
process and product characterization to understand product quality.
CGT products must adhere to the same statutory and regulatory requirements as
traditional biological products but have additional requirements specific for cells and tissues. The
FDA has published guidance documents specifically for CGT products to provide scientific and
regulatory recommendations to manufacturers. These guidance documents, however, provide
general recommendations and some documents have not been updated in over ten years. Thus,
one of the main mechanisms for sponsors to obtain feedback from the FDA about specific
technical aspects is through meetings with the Agency, which are aimed to foster the
development of these therapies (FDA, 2017b). Expedited development programs allow for a
greater number of meetings and interactions with the FDA to facilitate development (FDA,
2014b). Those meetings can occur during preclinical development, during clinical development,
and after licensure. They can provide the sponsor with valuable product-specific regulatory
feedback on development plans.
Sponsors may seek formal meetings or informal interactions with the FDA to obtain
feedback on product development plans at critical points in the regulatory process (Feigal et al.,
2012). Although both industry and regulators value good communication through meetings,
industry sponsors may not be using them effectively or efficiently. However, it is unclear how
helpful sponsors find these meetings during the early stages of development, when only limited
information is available upon which strategies might be based. Further, the number of meetings
may be restricted even for products under accelerated programs because the FDA struggles to
handle the high volume of meeting requests (Kish, 2020). FDA’s task becomes more challenging

14
because they must meet performance goals spelled out in legislation regarding the frequency and
handling of meetings.
The importance of facilitating regulatory feedback about technical issues has become
clearer because clinical and product quality issues have become bottlenecks for the regulatory
review and licensure of CGT products in the U.S. Several CGT products in late stages of
development have recently experienced delays related to clinical study design, product
manufacturing, and testing. For example, bluebird bio held the milestone end-of-phase 2 and preBLA meetings that would be expected for a breakthrough gene therapy, as well as additional
meetings, yet the FDA still refused to file the BLA by claiming that the filing had major CMC
deficiencies (bluebird bio, 2020). Similarly, Iovance held multiple meetings with the FDA over
three years to discuss pivotal clinical study designs and potency assays for licensure of its cell
therapy, yet the company consistently failed to reach agreement on suitable potency assays
(Iovance Biotherapeutics, 2021). These issues may become more vexing in the future as
companies advance their CGT products to late-stage development and then seek licensure. Better
alignment is needed between the technical expectations of regulatory agencies and the industry
sponsors of these types of therapies to avoid conflicting and inconsistent approaches across the
biotechnology industry that can delay product development and patient access. Expedited
development programs to accelerate the development timeline will not be advantageous if
development of process and product characterization lags behind the clinical development and
becomes rate-limiting. The problems are compounded because CGTs are commonly based on
novel technologies whose likely success clinically is unknown. This challenge makes it hard to
predict the length of the clinical trial period because the number of subjects needed to assure

15
sufficiently robust data can vary depending on clinical outcomes at the early stages and the
nature of the data that would be acceptable to support a marketing application.
1.2 Statement of the Problem
Although the FDA has established a regulatory framework for biologics and CGTs, it
may be difficult for developers to understand how to comply with these regulatory requirements.
The usefulness of published guidance documents may be limited because these documents
provide only general and even evolving advice. Changes in Agency expectations could result in
delays or discontinuation of product development or unexpected costs in obtaining regulatory
approval. Moreover, the FDA has so far approved only a small number of CGT products that can
serve as precedents for developers, and these approved products may not be indicative of what
regulators may require for approval of forthcoming therapies. Given that CGT products may be
granted an expedited development program, we do not know whether sponsors engage in
planning of their accelerated programs by meeting with the FDA early in development to
position itself for that opportunity. Even then, an expedited development program cannot
guarantee faster development or regulatory review, because these programs do not change the
standards for product approval. Communication with the FDA through formal meetings and
informal interactions becomes essential to obtain product-specific feedback during development.
Formal meetings with regulatory agencies appear to be the best way currently available
by which sponsors can decide on the most appropriate ways to collect technical information on a
product’s benefits and risks. The purpose of meetings between a sponsor and the FDA is to
resolve questions and issues raised during the development of a product (FDA, 2017b).
However, these meetings have their risks. Although a sponsor may have opportunities for
communications with the FDA and receive feedback from the FDA, the FDA may raise issues

16
that delay the development and approval process. A sponsor may fail to reach agreement with the
FDA on a study design or fail to obtain authorization to start a study. If a sponsor is unable to
address the concerns raised by the FDA, then it may not be able to complete studies successfully
or to receive FDA approval.
Effective meetings rely on a sponsor’s ability to formulate relevant questions and
proposals given the available data and stage of development. Efficient use of meetings relies on a
sponsor’s ability to use the minimum number of meetings whilst achieving the maximum benefit
of relevant regulatory feedback. All sponsors are expected to engage with the regulators and seek
scientific advice related to the development and review of their investigational new biologics and
biological product marketing applications. When sponsors utilize formal meetings or informal
interactions with the FDA to seek this advice, we assume that development and approvals tend to
be faster, but we do not know whether this has been improved by a better understanding of the
technical or regulatory requirements, whether that feedback has been timely or meaningful, or
whether sponsors and regulatory agencies have a misalignment in terms of the technical
expectations. This study sought primarily to explore this problem and evaluate the usefulness of
FDA meetings.
1.3 Purpose of the Study
The purpose of this study was to improve our understanding of the biopharmaceutical
industry’s views regarding formal meetings with the FDA during the development of CGT
products. This study investigated the views of regulatory professionals who work in industry,
academic, or government institutions and have experience with investigational or
commercialized CGT products. It captured their experiences interacting with the FDA on the
development of these products. In doing so, it sought to identify what those professionals saw as

17
the barriers to successful communication and interpretation of discussions with the Agency and
to identify the best practices for surmounting these challenges. Further, it explored the nature,
timing, and quality of communications between the FDA and sponsors, as well as assessed the
effect of meetings on the efficiency of drug development and regulatory review.
The study used an electronic survey to measure responses from regulatory professionals
working in the industry with experience interacting with the FDA. An evaluation framework
informed the research questions and supported the inquiry, analysis, and interpretation of the
findings (Stufflebeam, 1966). A focus group of academic and industry experts with experience in
CGTs, biological products, and survey development reviewed the survey. The survey was
distributed using Qualtrics.
1.4 Importance of the Study
Much remains uncertain about the prospects of the many CGT products in clinical
development despite the much-lauded approvals of CGT products over the past decade. Some of
the early-stage products will undoubtedly encounter technical challenges related to clinical, nonclinical, and quality aspects during their development, which must be overcome to produce a
licensed product. Developers will therefore continue to need consultations with the FDA on the
most appropriate study designs and methods to navigate these challenges. Despite the number of
Agency meetings annually, much remains to be known about the views of regulatory
professionals regarding the usefulness of formal meetings. These meetings impose administrative
burdens on industry stakeholders to prepare for them. Understanding the experience of sponsors
as they engage and seek regulatory feedback from the FDA and seek regulatory feedback should
help new developers to anticipate how to deal best with FDA interactions as they advance their
CGTs toward the goal of commercialization.

18
Furthermore, the findings may be useful for stakeholders outside of the
biopharmaceutical industry. Academic or government principal investigators of clinical studies
may have a limited understanding of the way meetings can be used as a resource for guidance
related to the regulation of potential products on which they may be working. Additionally,
regulators may want to understand industry perspectives and practices given their dual roles of
protecting the public health by ensuring that medical products are safe and effective but at the
same time advancing the public health by facilitating the development of medical products. The
findings may be useful to regulators as they try improving interactions with industry. Formal
meetings impose administrative burdens on the FDA to review documentation, prepare feedback,
and administer meetings, as well as consume the valuable time of FDA reviewers. The findings
may inform the Agency about the appropriate targeting of their outreach and guidance efforts.
1.5 Limitation, Delimitations, and Assumptions
1.5.1 Limitations
This study had limitations that impacted or influenced the interpretation of the findings
from the study. First, the survey participants were employed in the biopharmaceutical industry
and represented the views from the industry perspective. The study did not look at the
interactions from other viewpoints such as those of the regulators. Second, the survey
participants may have been reluctant to share their opinions or to participate in the study
altogether because the information may be deemed as proprietary. I addressed this limitation to
some extent by avoiding questions that asked for proprietary information and by providing
assurance that the responses were anonymous, but I could not guarantee that some potential
respondents were nevertheless wary of participation. Third, some survey participants failed to
complete the entire survey possibly because they found the survey too long. I therefore obtained

19
an incomplete picture of their views and reduce the size of the dataset obtained from later
questions. I addressed this limitation by restricting the number of questions. This approach
limited the depth and breadth of the survey, but it may have increased the likelihood of survey
completion. Last, the survey had a small number of participants because only a limited number
of pharmaceutical companies were developing CGT products; their valuable employees may
consider themselves too busy to add participation in a survey to an already demanding workload.
However, a small sample size of respondents might reduce the generalizability of the findings.
1.5.2 Delimitations
This study was delimited intentionally to restrict the scope of the study. First, it was
delimited to industry professionals who had experience primarily with CGT products and
interactions with the FDA. Industry professionals should have been knowledgeable of regulatory
requirements and expectations. They should have been involved with regulatory agency
interactions, IND applications, BLAs, and lifecycle management of CGT products. Second, the
scope was delimited to clinical, non-clinical, and quality aspects of CGT product development.
Third, the study was delimited in geographical location to the United States (U.S.) and engaged
potential respondents who worked for organizations operating in the U.S. (e.g., sponsoring a
clinical trial in the U.S.). The study considered the regulatory framework in the U.S. and
interactions with the FDA. Regulatory frameworks and procedures are different in foreign
jurisdictions so experiences of potential participants with other regulatory Agencies may have
blurred the understanding specifically of the U.S. system. Last, the study was delimited in time.
The survey collected industry views between a defined start date and stop date, and the
discussion of those findings represented the respondent’s views during the period of the study.

20
Those results may become less predictive for the future as the industry and regulations evolve
over time.
1.5.3 Assumptions
Certain assumptions were made about the survey participants. I assumed that the survey
participants were honest and truthful in their responses and opinions. Assurances of anonymity
of participants and confidentiality of responses were provided to prospective survey participants
to mitigate potential concerns and encourage honesty and truthfulness. Also, I assumed that
survey participants held sufficient qualifications (e.g., knowledge, training, experience, or any
combination thereof) to provide meaningful answers to the survey questions. Unqualified
participants would have provided uninformed responses to the survey questions and affected the
validity of the results.
1.6 Organization of the Thesis
This research thesis has five main components. Chapter 1 provides an overview of the
problem to be studied, states the purpose and importance of the study, and explains the
limitations of the research approach. Chapter 2 provides a literature review that summarizes the
relevant scientific and regulatory literature that represents the current state of knowledge on this
topic. Chapter 3 describes the methodology used to investigate and analyze the problem. Chapter
4 reports an analysis of the survey data. Chapter 5 discusses the results of the survey, assesses
the significance and validity of the findings, and offers recommendations for future research. The
appendix includes the finalized survey questions.
1.7 Definitions
The following key terms and acronyms are defined to help the reader understand the
context of each term in this thesis.

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1.7.1 Definition of Key Terms
Key terms used in this thesis are defined below.
Applicant – An applicant means any person who submits or plans to submit an
application to the FDA for pre-market review, e.g., a Biologics License Application (21CFR§3,
2022).
Biological product – A biological product is a virus, therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product
that is applicable to the prevention, treatment, or cure of a disease or condition in humans
(21CFR§600, 2022).
Cell therapy – Cell therapy refers to the administration of autologous, allogeneic, or
xenogeneic living cells, other than transfusable blood products, for therapeutic, diagnostic, or
preventive purposes. Manufacture of products for cell therapy typically involves the ex vivo
propagation, expansion, selection, or other alteration of the biological characteristics (FDA,
1998).
Formal meeting – A formal meeting includes any meeting that is requested by a sponsor
or applicant (also known as a requester) following the procedures defined by the FDA and
includes meetings conducted in any format (i.e., face-to-face, teleconference, or written response
only) (FDA, 2017b).
Gene therapy – Gene therapy refers to medical interventions based on modification of the
genetic material of living cells. Cells may be modified ex vivo for subsequent administration to
humans, or they may be modified in vivo by a gene therapy product administered directly to the
subject (FDA, 1998).
Sponsor – A sponsor means a person who takes responsibility for and initiates a clinical
investigation. The sponsor may be an individual or pharmaceutical company, a governmental

22
agency, an academic institution, or other organization (21CFR§312, 2022). A sponsor refers to
the “sponsor” of an Investigational New Drug Application in the U.S.
1.7.2 Acronyms
A list of acronyms commonly used in this thesis is provided in Appendix A.

23
Chapter 2. Literature Review
2.1 Introduction
Cell and gene therapies (CGTs) have undergone highs and lows over the past three
decades as they became realistic treatments for certain severe diseases. The development of these
new technologies, and the translation of those technologies to patient care, continues to advance
the field, which is constantly evolving. It is common for consultations to occur between
developers of new drugs and the FDA because these communications are important for
promoting an understanding of the regulatory process and ensuring regulatory compliance. The
regulatory feedback from these consultations can have a profound impact on the course of
product development.
This chapter describes the history of the cell and gene therapy field over the past 30 years
and the important changes in regulations that have occurred over this time. It then describes more
specifically the current process for seeking regulatory feedback through FDA-sponsor formal
meetings, which are the focus of this dissertation, and then highlights the challenges and trends.
2.2 Literature Search Strategy
A comprehensive search was conducted to assess the state of knowledge related to FDAsponsor meetings and CGTs. Using the National Library of Medicine (NLM), PubMed, and
Google Scholar, I searched for journal articles, books, and other scholarly literature on the topics.
Search terms included “cell therapy”, “gene therapy”, “FDA-sponsor meeting”, and other terms
and combinations of terms, which are listed in Table 1. This initial search generated over 10,000
citations from the NLM, over 400,000 citations from PubMed, and over 5,000,000 citations from
Google Scholar (Table 1). The search term “FDA-Sponsor Meeting” narrowed the search by
generating 11 citations from NLM, two citations from PubMed, and 191 citations from Google

24
Scholar. Variations of terms, such as “FDA meeting”, “FDA formal meeting”, “FDA-sponsor
meeting”, and “FDA-sponsor conference”, were employed to identify the greatest number of
citations. Combinations of terms, such as “FDA-sponsor meeting, Cell therapy”, were included
to narrow the search.
Table 1: Search Term Results from Search Engines
Search Term National Library
of Medicine PubMed Google Scholar
Cell and Gene Therapy 6,387 253,370 4,250,000
Cell Therapy 3,149 481,849 4,750,000
Gene Therapy 10,344 469,430 5,270,000
FDA Meeting 1,583 2,243 1,360,000
FDA Formal Meeting 749 34 158,000
FDA-Sponsor Meeting 11 2 191
FDA-Sponsor Conference 6 0 148
FDA-Sponsor Meeting, Cell and Gene
Therapy 5 0 62
FDA-Sponsor Meeting, Cell Therapy 3 0 90
FDA-Sponsor Meeting, Gene Therapy 5 0 83
Source: Original table created by the author from searches of the National Library of Medicine
(https://www.nlm.nih.gov/), PubMed (https://pubmed.ncbi.nlm.nih.gov/), and Google Scholar
(https://scholar.google.com/).
After narrowing the search to sources that appeared relevant by evaluating their content,
the review of those most pertinent sources formed the basis of the material outlined in this
chapter. Publications were excluded if the language was not English. Articles that discussed
FDA-sponsor meetings for drugs and biological products and articles describing developmental
challenges of CGTs were retained and used in this literature review. Those that discussed FDAsponsor meetings for medical devices or other medical products were excluded from this review.
While reading relevant articles, I reviewed the bibliography of these articles to identify
additional citations that the initial web searches might have missed; some of those additional
materials have been included in this review. Additional sources outside of the mainstream
academic literature included the FDA website, company websites, and websites of professional

25
organizations. These sources not only yielded articles, but also regulatory guidance documents,
announcements, presentations, and miscellaneous other materials related to the development of
CGTs and FDA-sponsor meetings; those additional citations have been included in this review.
After narrowing the search, the materials obtained in this way still included over 1,000 items.
Approximately 150 documents, which included peer-reviewed articles, books, regulatory
guidance documents, presentations, and trade journals, were judged to be relevant and
constituted the basis of the literature review that is described in this chapter.
2.3 Background
2.3.1 History of Cell Therapies
For much of medical history, treatments have relied on some form of drug or device.
However, the history of CGTs is more recent. The first known example of a cell-based therapy,
and perhaps the first systemic use of cells as a therapy, was bone marrow transplantation. In
1958, Dr. E. Donnall Thomas, a physician in New York, performed a bone marrow transplant on
a pediatric patient with leukemia (Thomas et al., 1959). The patient failed to respond to
chemotherapy, and after irradiation to eradicate the cancer cells and kill the patient’s bone
marrow cells, bone marrow from a healthy identical twin was collected and transplanted into the
patient to replace the destroyed tissue. The transplant caused a temporary remission and restored
the marrow function. Later, in 1968, Dr. Robert Good performed a bone marrow transplant
between two individuals who were not identical twins but matched for histocompatibility (Gatti
et al., 1968). The recipient, a 5-month-old infant with an immune deficiency, received leukocytes
and bone marrow cells from a donor sibling; this reconstituted the immune system of the infant
without lethal side effects. After the successful development of bone marrow transplantation, this

26
type of cell therapy became the standard of care for patients with hematological diseases and
immune disorders (Gratwohl et al., 2010).
Traditional drug products like small molecules or recombinant proteins typically exert
their pharmacological effect through biochemical pathways but this has limited their therapeutic
use in certain diseases. In some diseases, for example, cells or tissues are compromised by
malfunctioning cells, insufficient cells, or inflammation (Sánchez et al., 2012). Cell therapy
offers the potential capability to replace or repair these damaged or destroyed cells and restore
the lost function, thus improving the health of the patient. In the cases of patients with leukemia
or immune deficiency, transplanting immune cells restored the lost function of the bone marrow.
Cell therapies are now being investigated for various conditions, for example to rebuild damaged
cartilage in joints, repair spinal cord injuries, and treat cancers and autoimmune disorders.
Although these therapies use cells and tissues in the form that they are produced naturally
by the body, novel therapies can use stem cells to grow cells or tissues in the laboratory for
transplantation. Pluripotent stem cells have the potential to differentiate into all types of human
tissue and therefore have broad utility in regenerative medicine applications that involve the
restoration of damaged tissues. Human pluripotent stem cells were first derived from blastocysts
that were produced by in vitro fertilization and were called embryonic stem cells (Thomson et
al., 1998). Subsequently, a breakthrough discovery showed that the expression of a combination
of transcription factors can reprogram somatic cells into pluripotent stem cells, then called
“induced” pluripotent stem cells (Takahashi and Yamanaka, 2006). This capability has created
opportunities to extend the reach of regenerative cell therapies beyond simple transplantation
(Robinton and Daley, 2012).

27
2.3.2 History of Gene Therapies
Gene therapies had a slower and perhaps rougher start. From their conceptual beginnings
in the 1970s, gene therapy approaches took twenty years to enter a first-in- human clinical trial.
This approved clinical trial protocol for a gene therapy, in 1989, proposed to investigate the
feasibility of genetically-modified tumor infiltrating lymphocytes for patients with melanoma
(Rosenberg et al., 1990). The first gene therapy trial started in 1990 with the treatment of a 4-
year-old child who was immunocompromised because of a defective adenosine deaminase
enzyme (Anderson, 1990). In that study, a gamma-retroviral vector introduced a normal copy of
the gene into the patient’s T cells, which were then infused back into the patient. The subsequent
immune improvements allowed the patient to live outside of previously needed isolation.
The success of this first trial motivated others to launch clinical trials to treat a diversity
of disease states. However, the field encountered a major setback in 1999 when a patient died
during a gene therapy trial (Somia and Verma, 2000). Clinical investigators attributed the
complications to a severe immune response triggered against the recombinant adenovirus used to
introduce the generic material into the patient’s cells. The FDA sharply criticized the conduct of
the trial, put clinical holds on all gene therapy trials at the clinical site, and investigated gene
therapy trials across the country (McCarthy, 2000). Gene therapy and the safety of viral vectors
came under rigorous scrutiny. Progress in the field slowed considerably for the next decade.
The recent revival of gene therapy has been attributed to the advancements in design and
manufacture of viral vectors. Adenoviruses were found to be too immunogenic, and they were
questioned as suitable tools for gene therapy (Somia and Verma, 2000). Thus, new types of viral
vectors were developed to improve the safety profile. One example was the adeno-associated
virus, a desirable vector because it was not known to cause disease in humans and could be
engineered to target specific types of cells (Somia and Verma, 2000). Furthermore,

28
advancements in manufacturing technology allowed the large-scale production and purification
of viral vectors with high infectious titers for ex vivo and in vivo applications (Merten et al.,
2016).
Recently, a new approach to gene therapy using chimeric antigen receptor (CAR) T cell
immunotherapy has achieved clinical success and regulatory approval. To produce these
therapies, patient T cells are collected by apheresis and transported to a manufacturing site to
undergo processing. A viral vector is used to insert a transgene into the host cell genome to
encode for a CAR protein, which confers activity against a targeted antigen. After cell expansion
and formulation, the transduced cells are transported back to the clinical site and infused into the
patient. In 2017, the FDA approved Kymriah (tisagenlecleucel) for the treatment of relapsed or
refractory B cell acute lymphoblastic leukemia (Maude et al., 2018) and Yescarta (axicabtagene
ciloleucel) for the treatment of relapsed or refractory large B cell lymphoma (Neelapu et al.,
2017). Additional autologous CAR T cell therapies have received regulatory approval in the U.S.
and abroad since 2017. Moreover, the development of allogeneic CAR T cell therapies with gene
editing to improve safety is an active area of research to reduce the cost of this complex
therapeutic approach and improve the technical and supply challenges of the autologous CAR T
cell therapies (Depil et al., 2020). Overall, genetically modified CAR T cells represented a
breakthrough in the field of gene therapy.
CGTs are also poised for an expansive future. Conventional gene therapy approaches
introduce a functional copy of a gene into the host cell, but do not interfere with the original
defective gene. New technologies in genome editing can modify DNA to repair or delete the
original defective gene. Site-specific genetic modifications can change a single nucleotide or
insert or delete entire genes using nucleases, through methods such as the clustered regularly

29
interspaced short palindromic repeat (CRISPR)–CRISPR associated 9 (Cas9) nucleases (Dunbar
et al., 2018). If these technologies can be produced to fulfil the performance and quality
expectations of a therapeutic modality, then genome editing may outperform conventional gene
therapy approaches that rely on viral vectors and form the basis for a next generation of gene
therapies.
All the developments of the last several decades have provided an increasing record of
therapeutic successes and an even greater escalation in development programs (Hanna et al.,
2017). The FDA has illustrated this trend by mapping the increase in IND applications submitted
for investigational gene therapies as shown in Figure 1 (Lapteva et al., 2020).
Figure 1: Number of Gene Therapy IND Applications per Year (1988 – 2019)
The shaded area corresponding to each year indicates the number of gene therapy IND applications
submitted to the FDA in that year.
Source: Reproduced with permission from (Lapteva et al., 2020).
By the end of the first half of 2022, 2,093 trials were being pursued globally. Of these,
776 trials were in Phase 1, 1,117 in Phase 2, and 200 in Phase 3; these trials were evenly split
between industry or non-industry (academic or government institutional) sponsors (ARM, 2022)

30
(Figure 2). North America leads globally in trial numbers with 808 active trials (ARM, 2022). As
shown in Figure 2, about half of these trials were in oncology (ARM, 2022).
Figure 2: Number of Active Advanced Therapy Clinical Trials Worldwide by Industry
and Phase or by Therapeutic Area in 2022
Source: Original figures created by the author based on (ARM, 2022). The therapeutic area is unknown for 317
trials, which are not shown in the figure.

31
2.4 Regulation of Cell and Gene Therapy Products
The FDA is certainly aware of the growing importance of CGTs and has attempted to
provide the support that companies might need as they pursue their product development. Such
attention is important because the Agency regulates the development, manufacture, labeling,
approval, promotion, and other aspects of biologics. Developers are required to navigate the
preclinical, clinical, and commercial requirements to conduct clinical studies and seek approval
of products. The process of obtaining regulatory approvals and subsequent compliance with the
appropriate statutes and regulations require substantial time and financial resources, so reducing
hurdles related to misunderstandings or bottlenecks can be key to the success or failure of the
new product.
The FDA considers CGTs to be biological products because they are made from natural
sources and intended to treat diseases (FDA, 2023a, Salazar-Fontana, 2022). The Center for
Biologics Evaluation and Research (CBER) at FDA oversees human biological products, and its
Office of Therapeutic Products (OTP) takes responsibility for the oversight of cell and gene
therapy products (FDA, 2023a, Husain et al., 2015, Salazar-Fontana, 2022). In this role, CBER
regulates clinical studies, provides scientific advice to manufacturers for product development,
and approves marketing applications (FDA, 2018a). CBER publishes guidance documents to aid
developers in satisfying the requirements of the applicable statutes and regulations.
2.4.1 Statutes and Regulations
Cell and gene therapies are governed by several statutes, the most impactful of which in
the U.S. are the Food Drug and Cosmetic Act (FDC Act) of 1938 and the Public Health Service
Act (PHS Act) of 1944 (FDA, 2023a, Kepplinger, 2015). The FDC Act gave the FDA authority
to oversee the safety and quality of drugs, including the oversight of Good Manufacturing

32
Practices (GMPs) in the production of drugs to meet minimum quality requirements. The PHS
Act gave the FDA authority over biological products and introduced provisions for licensing new
biological products through an application process called the biologics license application
(BLA). Later, the Kefauver-Harris Amendment in 1962 gave the FDA authority to require
evidence of efficacy before granting approval (Kepplinger, 2015). More recently, the 21st
Century Cures Act of 2016 established a new designation called Regenerative Medicine
Advanced Therapy (RMAT), which offered an expedited option for eligible biological products
that have the potential to address unmet medical needs (FDA, 2019b). These statutes are
implemented through regulations, which interpret these laws and describe how the FDA enforces
them.
To meet its statutory obligations, the FDA established a framework for regulating human
cells, tissues, and cell- and tissue-based products, codified in May 2005 as 21 CFR Part 1271.
The goals of this regulatory framework were to prevent the use of contaminated tissues and the
transmission of infectious diseases, to prevent improper handling or processing that might
contaminate or damage the tissues, and to ensure that clinical safety and efficacy are
demonstrated for cells and tissues that are highly processed (FDA, 1997). This regulation
established a tiered, risk-based approach illustrated by the decision tree in Figure 3. Exempt from
the requirements of 21 CFR Part 1271 were “same surgical” procedures (FDA, 2017c). Of those
that are non-exempt, two pathways are available. Human cells and tissues that meet certain
conditions would not be subject to premarket approval but comply only with Good Tissue
Practices (GTPs). To qualify, these “361 products” must meet the following four criteria: (1) the
cells or tissues are minimally manipulated, (2) the product is intended for homologous use, (3)
the manufacturing process does not involve combining the cells with another article, and (4) the

33
product does not have a systemic effect and it is not dependent on metabolic activity for its
function (21CFR§1271, 2022). Riskier human cells and tissues that do not meet these criteria, so
called “351” products, would have to comply with GMPs, biological product standards, and
premarket approval. Examples of 351 products include cultured cells, genetically modified cells,
and unrelated allogeneic hematopoietic stem cells (FDA, 2018c).
This dissertation is concerned with the developmental aspects of 351 products, which
necessarily include CGTs. A 351 product must prove clinical efficacy as a prerequisite to
licensure. To do this, the manufacturer would have to submit an IND application for clinical
studies, regulated under 21 CFR Part 312, which would include chemistry, manufacturing, and
controls (CMC), nonclinical test results, and any clinical information from previous human
clinical experience to FDA (21CFR§312, 2022, Husain et al., 2015). However, biological
products then must meet the provisions of the PHS Act, which identifies that commercial
approval will depend on then submitting an application for a biologics license (21CFR§601,
2022). Regulations governing BLAs are detailed in 21 CFR Part 601 and are additionally subject
to regulations in 21 CFR Parts 600-680. Biological products must also comply with 21 CFR
Parts 210 and 211, which cover GMPs, because they also meet the definition of a drug under the
FDC Act.

34
Figure 3: Flowchart to Determine the Statutory Authority for a Cell- or Tissue-Based
Product
Source: Original figure created by the author based on (21CFR§1271, 2022, FDA, 2017c, FDA, 2020c, Mendicino
et al., 2019).

35
2.4.2 Guidance Documents
The path to market for CGTs is complicated, so the FDA has attempted to help the
applicant through guidance documents that assist in the interpretation of the regulatory
requirements (Husain et al., 2015). These guidance documents describe the FDA’s current
interpretation on a particular topic but are not legally enforceable (21CFR§10, 2022). Thus, they
are recommendations unless a specific regulatory or statutory requirement is cited. A sponsor can
adopt an alternative approach to satisfy the applicable requirements with sufficient justification.
As of December 2022, over 25 guidance documents have focused on CGTs (FDA, 2023a). The
earliest guidance, from 1998, provided general recommendations for CMC and nonclinical
aspects of product development. Subsequent documents cover administrative topics such as
preparation for expedited development programs or technical topics such as CMC, clinical
considerations of early-phase trials, and long-term follow-up for delayed adverse events,
preclinical studies, and environmental assessments (Husain et al., 2015). The CMC topics, for
example, include an overview of the CMC information for gene therapy INDs, testing of
retroviral vectors, potency tests, characterization of cell substrates, and CMC information for cell
therapy INDs. FDA also publishes more general or disease-focused guidance documents
appropriate for a broader range of drug products, such as GMPs for phase 1 clinical studies and
considerations for container closure systems; these would also be applicable for biological
products (FDA, 2023a, Husain et al., 2015).
Guidance documents typically lag scientific advancements, so their recommendations
may quickly become outdated. This can reduce their value for novel technologies. For example,
the guidance on potency testing was finalized in 2011 and its recommendations for assay design

36
and implementation may no longer be valid for more recently developed CGTs (FDA, 2011a).
An outdated guidance can mislead new or inexperienced companies as they attempt to use them
as a basis for product development strategies. Moreover, minimal guidance is not yet available
on topics important to late-stage development of CGTs.
2.4.3 Expedited Programs
Guidance documents are not the only way that FDA is trying to facilitate the more
efficient development of new drugs with clinical promise. Products that treat serious conditions
or address unmet medical needs are of particular concern, so FDA has established programs to
expedite their development and review. The FDA created the following principal programs:
accelerated approval in 1992, priority review in 1992, fast track designation in 1997,
breakthrough therapy designation in 2012, and regenerative medicine advanced therapy
designation in 2016 (FDA, 2014b, FDA, 2019b, Lapteva et al., 2018, Salazar-Fontana, 2022,
Vaggelas and Seimetz, 2019, Kepplinger, 2015). Table 2 summarizes the qualifying criteria and
benefits of these expedited programs. A product could qualify for more than one program. These
expedited programs are intended to help ensure that drugs for serious conditions, especially those
with few available treatments, are available to patients as quickly as possible. The effect of CGT
products is often large compared to that of available therapies, and they often benefit from these
expedited programs. However, these programs do not change the statutory requirements to
demonstrate safety and efficacy prior to marketing approval and therefore the benefits of these
therapies must still justify their risks (FDA, 2014b). One of the mechanisms to accelerate
availability is through increased interactions with the FDA during product development, which is
a feature of fast track, breakthrough therapy, and RMAT designations (Table 2). These
interactions allow discussion between a trial sponsor and FDA on study designs and other

37
important topics that may allow a sponsor to conduct a faster and more efficient clinical
development program (Dye et al., 2015, FDA, 2014b, FDA, 2019b, Vaknalli, 2017, Hwang et
al., 2017). These three designations may also allow a rolling review of the BLA, whereby the
FDA begins reviewing portions of the application before receiving the complete application
(FDA, 2014b, FDA, 2019b). This may facilitate a faster approval. Similarly, priority review
commits the FDA to review the BLA faster than it would otherwise be reviewed (FDA, 2014b).
Additional attention has been paid to products that treat a rare disease, a category into which
CGTs often fit. Since 1992, FDA has granted orphan drug designation to such products, allowing
a sponsor to receive certain financial and legal incentives (FDA, 2022a, Vaggelas and Seimetz,
2019).

38
Table 2: Table of Expedited Programs
Source: Table was adapted by the author from (FDA, 2014b, FDA, 2019b, Hwang et al., 2017). When to request during development
Discuss request with
FDA review division
during development
Sponsor should request
priority review at time
of BLA submission
Sponsor should request
fast track with the IND
or thereafter but no
later than the pre-BLA
meeting
Sponsor should request
with the IND or
thereafter but no later
than the end-of-phase 2
meeting
Sponsor should request
fast track with the IND
or thereafter but no
later than the end-ofphase 2 meeting
Benefits
Approval based on a surrogate
endpoint that is likely to predict
clinical benefit
Shorter review of BLA (from the 10
months of standard review to the 6
months of priority review)
• Actions to expedite development
and review (e.g., frequent
interactions with FDA review
team for a fast track product,
priority review)
• Rolling BLA review
• Intensive guidance on
development (e.g., frequent
interactions with FDA)
• Organizational commitment
(e.g., FDA project lead and
experienced reviewers)
• Rolling BLA review
• Other actions to expedite BLA
review (e.g., priority review)
• All benefits as breakthrough
therapy (including early and
frequent interactions with FDA)
• Possible accelerated approval
Qualifying criteria
Intended to treat a serious condition,
provides an advantage over available
therapies, and demonstrates effect on
surrogate endpoint that is likely to predict
clinical benefit
Intended to treat a serious condition and
provide a significant improvement in
safety or efficacy if approved
Intended to treat a serious condition and
data demonstrate potential to address
unmet medical need (i.e., limited or no
treatment options)
Intended to treat a serious condition and
preliminary clinical evidence suggests a
substantial improvement on a clinicallysignificant endpoint over available
therapies
Drug is a regenerative medicine therapy,
intended to treat a serious condition, and
preliminary clinical evidence indicates the
potential to address an unmet medical
need (i.e., limited or no treatment options)
Type
Approval
Pathway
Designation
Designation
Designation
Designation
Program
Accelerated
Approval
Priority
Review
Fast Track
Breakthrough
Therapy
Regenerative
Medicine
Advanced
Therapy

39
Three approved products–Rethymic and Stratagraft, which are somatic cell therapies, and
Breyanzi, which is a genetically-modified T-cell immunotherapy–received RMAT designation
(FDA, 2021f, FDA, 2021g, FDA, 2021e). This designation provides the benefits of breakthrough
therapy designation, but the qualifying criteria are lower because clinical data must only show a
potential benefit rather than an improvement over existing therapies (FDA, 2019b). This lower
hurdle incentivizes industry to apply for RMAT designation, and industry has expressed
considerable interest. As of May 2019, 100 requests were submitted, and 34 products were
granted RMAT designation (Marks, 2019). Breakthrough therapy and RMAT designations both
offer increased interaction between sponsors and the FDA during development (e.g., an
interdisciplinary meeting, non-milestone Type B meetings, as explained below) to provide
sponsors with regulatory feedback on their clinical, nonclinical, and CMC questions. This
feedback, in principle, could make development more efficient by avoiding unnecessary studies
and reducing time and cost of others (FDA, 2019b, Lapteva et al., 2018, Vaggelas and Seimetz,
2019).
It may be too early to assess the impact of RMAT designation on the successful
development of CGTs, but this designation should be considered in the development and
regulatory strategy of these products in the U.S. Expedited pathways do not reduce the
evidentiary standards for approval (FDA, 2014b, Salazar-Fontana, 2022). Thus, the development
program for a CGT in such a program must be capable of acquiring the needed data in a shorter
time frame. Because often such programs reduce the length of the clinical trial period (Vaggelas
and Seimetz, 2019), pressure is placed on the scale-up and quality activities to complete the
necessary analytics and validations in a shorter time frame. It can then be difficult for a sponsor
to ensure the availability of sufficient, high-quality product at the time of marketing approval

40
(Salazar-Fontana, 2022). These challenges reinforce the critical role of Agency interactions to
solve as many problems as possible in the early stages of development.
2.5 FDA Formal Meetings with Sponsors of Medical Products
Sponsors of a new drug talk with the FDA at various times during product development.
In some cases, the FDA initiates the interaction. The FDA will communicate the outcome of
reviews when a sponsor submits an IND or BLA, for example. The Agency may also
communicate through information requests when submissions have deficiencies or to issue a
clinical hold on a clinical investigation (21CFR§312, 2022). In these cases, the sponsor can
provide more information (21CFR§312, 2022). In other cases, sponsors initiate the interaction.
The most formalized of these requests are for meetings with the FDA to prospectively discuss
their product and receive regulatory feedback. These communications can occur throughout the
lifecycle of the product: from before IND submission, to clinical development, and then later to
BLA review and post-approval (FDA, 2017b). The issues discussed at those meetings can be
central to assuring an effective and efficient product development program.
2.5.1 Background on FDA Formal Meetings
FDA-sponsor meetings have a long history. Formalized meetings between FDA and drug
developers have been reported to take place as early as 1970s (Kaitin and Walsh, 1992, DiMasi
and Manocchia, 1997). Interestingly, in the 1980s industry was sometimes skeptical of the value
of meetings and expressed concern that meetings to obtain FDA-sponsor agreement could delay
drug development because of the time needed to prepare the submissions, wait for the review,
and resolve disputes (Horger, 1981). Part 312 in Title 21 of the CFR describes formal meetings
for the End-of-Phase 2 (EOP2) and pre-New Drug Application (pre-NDA) milestones as far back
as 1987 and for the pre-IND and End-of-Phase 1 (EOP1) milestones as far back as 1988

41
(21CFR§312, 2022). However, more recently, the formal meetings have been hardened into
performance requirements for the Agency. In 1997, the FDA Modernization Act (FDAMA) reauthorized the Prescription Drug User Fee Act (PDUFA) of 1992, which in turn authorized the
FDA to collect fees as part of the drug review and approval process (FDA, 2005). As part of this
legislation, FDAMA expanded FDA’s scope of work to improve communication between FDA
and sponsors during drug development (FDA, 2005, Milne, 2006). Performance goals and time
frames were specified for FDA responses to meeting requests, for scheduling meetings, and for
preparing meeting minutes. Additional goals included responses to other sponsor submissions,
such as special protocol assessments and clinical holds (FDA, 2005, Milne, 2006). The PDUFA
legislation also reauthorized user fees for drug submissions that allowed the Agency to increase
the staffing, which was needed to increase FDA-sponsor interactions for scientific and regulatory
consultations (FDA, 2005). As a continuing recognition of their importance, meeting
management goals continue in the current PDUFA VII legislation (FDA, 2021b).
2.5.2 Purpose, Definition, and Importance of Formal Meetings
CBER and the Center for Drug Evaluation and Research (CDER) have published
guidance for sponsors of PDUFA-regulated products on formal meetings. That guidance defines
a formal meeting as a “planned and structured meeting between FDA review staff and sponsor
representatives to discuss the development or review of a drug or biological product” (FDA,
2017b). It also outlines standard procedures to request a formal meeting in one of three formats:
face-to-face, teleconference, or written responses only (FDA, 2017b). Formal meetings are
intended to be substantive and pre-planned meetings that can have a significant impact on the
development or review of a product (DiMasi and Manocchia, 1997). They provide a mechanism
for advising sponsors on the most appropriate ways to collect technical information on a

42
product’s benefits and risks (21CFR§312, 2022). These data can be garnered from many sources,
including nonclinical laboratory and clinical studies that demonstrate that the product meets
standards for safety, purity, and potency, as well as data on manufacturing methods and product
quality (21CFR§601, 2022). Meetings allow a sponsor to ask for guidance on the best study
designs and methods to generate those data. They can also help to resolve disputes between
sponsors and the FDA (21CFR§312, 2022).
Formal meetings provide several benefits by improving the design of needed studies and
reducing activities that could waste time and money (21CFR§312, 2022, Vaknalli, 2017). This
might result in faster development and a more complete BLA. Efficiencies gained from the
advice can result in better use of the company’s limited scientific and economic resources
(Vaknalli, 2017). Advice on clinical studies might save human subjects from participating in
poorly designed studies that would fail to generate useful data. Better designed studies allow the
potential benefits to be maximized while potential harms are minimized.
2.5.3 Meetings throughout the Product Lifecycle
Formalized FDA-sponsor meetings can occur throughout the development lifecycle of a
product but certain critical points in the development process are often touchpoints for these
interactions. These “milestone” meetings are shown in Figure 4. They include pre-IND, end-ofphase 1 (EOP1), end-of-phase 2 (EOP2), and pre-BLA meetings (21CFR§312, 2022). The timing
and purpose of these four milestone meetings are listed in Table 3. FDA grants the meetings if
the stage of development matches the requested milestone. Milestone meetings can be
multidisciplinary and cover regulatory, CMC, clinical, or nonclinical topics. Non-milestone
meetings, such as the comprehensive meeting for products granted an expedited program, are
also possible. They are not listed in Table 3 but are described below.

43
Table 3: Summary of Milestone Meetings during Development
Milestone
Meeting Timing of Meeting Purpose of the Meeting
Pre-IND
Prior to submission
of the initial IND
application
To obtain feedback on the design of preclinical studies, to
discuss the design of the Phase 1 clinical study, and to discuss
the product manufacturing and testing needed to start human
studies to assure safety of subjects.
End-ofPhase 1
(EOP1)
After completion of
Phase 1 studies and
before start of Phase
2 studies
To review and agree on the design of the Phase 2 clinical
studies, which may provide the appropriate data to support the
product’s safety and effectiveness for a marketing application.
End-ofPhase 2
(EOP2)
After completion of
Phase 2 studies and
before start of Phase
3 studies
To evaluate the Phase 3 clinical study plan and to identify any
additional information needed for a BLA.
Pre-BLA Prior to submission
of the original BLA
To identify any problems prior to the submission, to identify the
clinical studies that will be used as the primary evidence for
safety and efficacy, to familiarize FDA reviewers with the
submission, and to discuss the approach for formatting and
structuring the data.
Source: Original table created by the author from (FDA, 2017a, FDA, 2017b, FDA, 2022c).
Figure 4: Stages of Biological Product Development and FDA-Sponsor Meetings
during Development
Source: Original figure created by the author (FDA, 2017a, FDA, 2017b, FDA, 2022c, FDA, 2022e).

44
2.5.3.1 Meetings prior to the Submission of an Investigation New Drug Application
The earliest opportunity for a sponsor to meet with the FDA is during early preclinical
development. The INitial Targeted Engagement for Regulatory Advice on CBER producTs
(INTERACT) meeting, previously known as the pre-pre-IND meeting (Feigal et al., 2012), is an
informal, non-binding consultation for CBER-regulated products (e.g., cell or gene therapies) to
address issues in advance of a future pre-IND meeting (FDA, 2022c) (Figure 4). It has no
defined timeframe. The Agency recommends that the sponsor will have completed some
preliminary studies with the investigational product but will not have conducted all studies
planned for the nonclinical module of the IND (FDA, 2022c). An INTERACT meeting is not
intended to replace a pre-IND meeting. Instead, it is meant to provide sponsors with initial
advice from the FDA on the CMC and pharmacology/toxicology approaches, to aid the design of
preclinical proof-of-concept studies and identify uncertainties that sponsors should address
further (FDA, 2022c). These discussions can be most helpful for novel products, which can have
unique challenges related to new technologies, unknown safety profiles, complex manufacturing
processes, or different testing methodologies (FDA, 2022c).
A sponsor may also request to meet with the FDA in a pre-IND meeting before the
submission of the IND application. The pre-IND meeting, shown in Figure 4, is the first
milestone meeting (21CFR§312, 2022). This meeting typically addresses the design of the CMC
and nonclinical studies, the phase 1 clinical study, and the presentation of data in the IND
(21CFR§312, 2022, Feigal et al., 2012, Vu and Pariser, 2015). At this meeting, a sponsor can
raise issues so that they can be addressed before the IND submission (Feigal et al., 2012, Vu and
Pariser, 2015). After submission of the IND application, the FDA has 30 days to review the
adequacy of information and respond with a clinical hold or the IND goes into effect

45
(21CFR§312, 2022). If discussions with the FDA are effective, then the number of deficiencies
and concerns with that IND can be minimized.
2.5.3.2 Meetings after Submission of an Investigation New Drug Application
A sponsor may later request to meet with the FDA in an EOP1 meeting when data from
the phase 1 study are available (Figure 4). This meeting will focus on the design of the phase 2
clinical studies (21CFR§312, 2022), whose data will be needed to provide evidence of safety and
efficacy for the investigational drug. EOP1 meetings are usually held for products intended to
treat serious conditions or for expedited products in which the phase 2 study may become the
pivotal study (FDA, 2017b), as was previously the case for several of the CGT products.
Meetings at the end of a phase 2 clinical study, the EOP2 meetings (Figure 4), are then
held to consider whether to proceed with phase 3 studies, to evaluate the design of those and
other studies and to identify any additional information that may be needed for a potential
marketing application (Feigal et al., 2012, 21CFR§312, 2022). EOP2 meetings should be held
before the start of phase 3 studies, but the scheduling of the EOP2 meeting is not intended to
delay the phase 3 studies (21CFR§312, 2022). If agreements cannot be reached with the FDA at
the EOP2 meeting, then additional discussions become necessary to resolve any issues before
resources are committed for the phase 3 studies (Feigal et al., 2012).
Finally, a sponsor can request a pre-BLA meeting before the submission of a marketing
application to discuss the proposed content of the BLA (Figure 4). The meeting is typically
multi-faceted: to discuss any unresolved problems in the study outcomes, to identify any
ancillary studies to buttress arguments of safety and efficacy, and to familiarize FDA reviewers
with the information that will be submitted (21CFR§312, 2022). The exchange of information at
this stage can reduce delays in review of a BLA (Feigal et al., 2012).

46
Sponsors of products that receive either BT or RMAT designation are eligible for an
additional formal meeting, called an Initial Comprehensive Meeting, after a product is granted
BT or RMAT designation (FDA, 2014b, FDA, 2019b). This meeting is intended to be a
multidisciplinary comprehensive discussion of the overall development program, including the
planned clinical studies and plans for the expedited activities required by CMC and
manufacturing (FDA, 2022d). All non-milestone meetings for products with BT or RMAT
designation are scheduled as Type B meetings (discussed in detail in Section 2.5.4) (FDA,
2019b, FDA, 2017b). However, a product receiving BT or RMAT designation late in
development (e.g., after a pre-BLA meeting) will not need an Initial Comprehensive Meeting
(FDA, 2019b, FDA, 2022d).
2.5.3.3 Meetings during Review of a Biologics License Application
No milestone meetings are held during the regulatory review of a BLA, but opportunities
continue to exist for meetings between the FDA and an applicant. Two meetings occur during
BLA review: the mid-cycle and the late-cycle meetings (Figure 4). The mid-cycle
communication is typically a teleconference between the CBER reviewers and the applicant that
takes place after CBER’s internal mid-cycle review meeting for that application. It updates the
sponsor about the progress and questions related to the BLA review (FDA, 2022e). Similarly, a
late-cycle teleconference may be held to discuss the status of the review (FDA, 2022e). In this
meeting, the Agency can identify if additional data or analyses are needed and whether the
submission of that information would trigger an extension of the goal date for the BLA review
(FDA, 2022e).
An additional meeting, with an advisory committee to the FDA, is sometimes also held
for new or challenging BLAs, to expand the scientific input and generate external

47
recommendations by experts. Unlike other meetings, this meeting is held as a public hearing
(21CFR§14, 2022, Feigal et al., 2012). The Cell, Tissue, and Gene Therapies Advisory
Committee is responsible for reviews of cell and gene therapy products (FDA, 2019a). An
application can be presented to an advisory committee if the product is the first in its class or has
review concerns or controversial issues that need the outside input from the committee members
(FDA, 2017f). These committees can provide advice to FDA about the clinical safety, clinical
efficacy, product quality, and overall benefit-risk profile of new products (FDA, 2017d).
2.5.3.4 Meetings after Approval of a Biologics License Application
Formal meetings can also be held for approved products. They may be appropriate, for
example, to obtain FDA input on planned BLA supplements, such as efficacy supplements or
significant manufacturing changes. These meetings are managed like other Type B or Type C
meetings, described further in Section 2.5.4. For example, a sponsor may request a pre-BLA
meeting for an efficacy supplement for a BLA that has ongoing clinical studies under an IND
(FDA, 2017b, FDA, 2022c). All other meeting requests are considered by the FDA on a case-bycase basis, to determine if a meeting is needed or if regulatory feedback can be provided during
review of a BLA supplement (FDA, 2017b, FDA, 2022c). Such meetings, usually scheduled as
Type C meetings, typically are done through written responses only (WRO) (FDA, 2017b, FDA,
2022c).
2.5.4 Procedure to Request and Prepare for a Formal Meeting
Sponsors can request one of six types of meetings: Type A, Type B, Type B (EOP), Type
C, Type D, or INTERACT, according to the criticality of the discussion (summarized in Table 4)
(FDA, 2017b, FDA, 2022c). Type A and B meetings are usually conducted as face-to-face or
teleconference meetings, whereas Type B pre-IND, Type C, Type D, and INTERACT meetings

48
may not involve direct conversation with the sponsor, but rather a written response to questions.
Type A meetings usually discuss a stalled development program or address a safety issue (FDA,
2017b, Sharma et al., 2016) such as a serious adverse event that has triggered a clinical hold.
Type B meetings are pivotal meetings to discuss the overall development program, typically
before or after a major regulatory submission, such as an IND or BLA (FDA, 2017b). Like Type
B meetings, Type B (EOP) meetings occur at major milestones, e.g., EOP1 and EOP2, to
primarily address clinical development issues (FDA, 2017b). It is the FDA practice to grant only
one of each Type B meeting (i.e., one pre-IND, one EOP1, one EOP2, and one pre-BLA
meeting) for each application (FDA, 2017b, FDA, 2022c). Type C meetings are an umbrella
category of meetings that do not meet the criteria of Type A and B meetings (FDA, 2017b). Type
D meetings are focused on a narrow set of issues (e.g., one or two issues only) (FDA, 2022c).
INTERACT meetings are intended for products with novel issues early in a development
program (FDA, 2022c). The feedback from these “meetings” is typically WRO, so it lacks an
opportunity to discuss issues in a face-to-face or teleconference format.

49
Table 4: Summary of Meeting Types and Timelines
Meeting Type A Type B Type B
(EOP) Type C Type D INTERACT
Intention of
the meeting
Intended for
stalled
development
programs or
for safety
issues
Intended as
routine
meetings,
usually before
or after a
regulatory
submission
Intended for
discussions
at the end of
a clinical
phase
Intended as
any meeting
other than a
Type A, B, B
(EOP), D, or
INTERACT
Intended to
focus on a
narrow set
of issues
Intended for
novel issues in
early
development
Examples
Dispute
resolution
Clinical holds
Special
Protocol
Assessment
Post-action
meeting 1
Meeting after
issuance of
RTF letter
Pre-IND
Preemergency use
authorization
Pre-BLA
Post-action
meeting 2
REMS or
PMR
BT or RMAT
designation
EOP1
EOP2
Use of new
surrogate
endpoints
Establishment
issues
Follow-up
question
after a
formal
meeting
Narrow
issue
Novel
questions
about design
of
pharmacology/
toxicology
studies, CMC
issues
FDA
response to
meeting
request
14 days 21 days 14 days 21 days 14 days 21 days
FDA
meeting
scheduling
time frame
or WRO
issued
30 days 60 days 70 days 75 days 50 days 75 days
Requester
meeting
package due
to FDA
At the time of
the meeting
request
At least 30
days before
the scheduled
meeting
At least 50
days before
the
scheduled
meeting
At least 47
days before
the scheduled
meeting
At the time
of the
meeting
request
At the time of
the meeting
request
Meeting
length 60 minutes 60 minutes 60 minutes 60 minutes Not
specified Not specified
FDA
preliminary
responses
sent to
sponsor (for
No later than
2 days before
the meeting
No later than 2
days before
the meeting
No later
than 5 days
before the
meeting
No later than
5 days before
the meeting
No later
than 5 days
before the
meeting
No later than 5
days before
the meeting

50
Meeting Type A Type B Type B
(EOP) Type C Type D INTERACT
F2F and TC
meetings)
Requester’s
response to
FDA
preliminary
response
(cancel or
proceed
with F2F or
TC
meetings)
No later than
24 hours
before the
meeting
No later than
24 hours
before the
meeting
No later
than 3 days
after receipt
of
preliminary
responses
No later than
3 days after
receipt of
preliminary
responses
No later
than 3 days
after receipt
of
preliminary
responses
No later than 3
days after
receipt of
preliminary
responses
FDA
meeting
minutes
issued
Within 30 days after the meeting
Within 30
days after the
meeting, WRO
serve as the
meeting
minutes
Abbreviations: BLA, Biologics License Application; BT, Breakthrough Therapy; EOP, end-of-phase; F2F, face-toface; IND, Investigational New Drug; INTERACT, Initial Targeted Engagement for Regulatory Advice on CBER
producTs; PMR, post-marketing requirement; REMS, Risk Evaluation and Mitigation Strategy; RMAT,
Regenerative Medicine Advanced Therapy; RTF, refuse to file; TC, teleconference; WRO, written response only.
1 Post-action meetings that are requested less than three months after an FDA regulatory action other than an
approval (e.g., issuance of a complete response letter).
2 Post-action meetings that are requested more than three months after an FDA regulatory action other than an
approval (e.g., issuance of a complete response letter).
Source: Table adapted from (FDA, 2017a, FDA, 2017b, FDA, 2022c).

51
As noted above, breakthrough therapy or RMAT designated CGT products are eligible
for more frequent interactions with the FDA. In these cases, a sponsor can request a Type B
Initial Comprehensive Meeting (FDA, 2022d, FDA, 2019b). Subsequent meetings for BT or
RMAT designated products are classified as Type B meetings even when standard practice
would dictate that the meeting would be classed as Type C (FDA, 2017b). The Initial
Comprehensive Meeting and additional Type B meetings provide the “increased interactions”
with FDA that are supposed to increase the speed of development for these designated products.
Requesting and preparing for a meeting must follow defined procedures. The timelines
associated with each meeting type are provided in Table 4 and the procedure is illustrated in
Figure 5. First, the sponsor (now known as a “requester”) submits a written meeting request to
the FDA and the appropriate review division or office (FDA, 2017b). The meeting request
should contain enough information to allow the Agency to evaluate the usefulness of a meeting
(FDA, 2017b). The Agency reviews the meeting request and decides whether to deny the request
(FDA, 2017b). If the meeting is granted, then the Agency notifies the requester in writing
according to the timetable shown in Table 4. If the meeting is denied, usually because it deems
the program to be immature and not yet ready for such a discussion, will write to state the
reasons for the denial (FDA, 2017a).

52
Figure 5: Timeline of Sponsor and FDA Actions before and after a Meeting
Sponsor/requestor actions are shown in blue on the top and FDA actions are shown in red on the bottom.
The time between actions is indicated by the arrows and shown in gray for those activities that have a
PDUFA performance goal.
Source: Original figure created by the author (FDA, 2017a, FDA, 2017b, FDA, 2022c).
Once granted a meeting, the requester prepares a meeting package that includes the
purpose of the meeting, a list of final questions for discussion, and data to support the discussion
(FDA, 2017b). A well-prepared meeting package is considered critical for a productive
discussion and exchange of information (FDA, 2017a). The requester must submit the meeting
package according to defined timetables, listed in Table 4, so that Agency reviewers have
enough time to review the information and prepare their preliminary responses (FDA, 2017a).
About two to five days before the scheduled meeting, FDA sends preliminary responses
in writing to the requester (FDA, 2017b). If the requester is satisfied with the preliminary
responses and believes that no further discussion would be productive, the meeting can be
cancelled. Alternatively, the requester may be satisfied with some preliminary responses and can
revise the agenda to focus on questions that need further discussion, according to the timeline in

53
Table 4. However, the requester cannot submit new questions and information after receiving the
preliminary responses (FDA, 2017b).
All meeting types are one hour long (FDA, 2017b). Thus, the requestor is challenged to
use the allotted time effectively. During the meeting, the requester should not ask new questions
or present new data not already in the meeting package (FDA, 2017a). The requester can take
notes, so that the FDA and requester can summarize the discussion topics and agreements at the
end of the meeting. This assures a mutual understanding of meeting outcomes (FDA, 2017b).
FDA issues official meeting minutes within 30 days after the meeting to memorialize any
agreements or disagreements (FDA, 2017b). The requester should review the meeting minutes
and notify the FDA of any significant difference in their interpretation of the meeting outcomes.
However, the meeting minutes are usually not altered except to correct a mistake.
Face-to-face or teleconference meetings are the sponsor’s only opportunity to clarify the
Agency’s preliminary responses to the questions in the meeting package. The FDA does not
accept follow-up or additional questions after the meeting is held. A sponsor would need to
submit a new meeting request for a Type D meeting to ask these follow-up or additional
questions. For WRO, a sponsor can request clarification in a single follow-up request but cannot
ask new questions (FDA, 2017b). WRO are most likely to be received for pre-IND and Type C
meetings and not the more critical EOP1, EOP2, or pre-BLA milestone meetings.
2.5.5 Timing and Advice from Meetings
It is important that sponsors carefully consider the timing of meetings and other
communications to gain feedback at the appropriate time in development if that information is to
be most helpful. Pre-IND and pre-BLA meetings should be held far enough ahead of the planned
submission to allow that feedback to be addressed without delaying the planned submission, but

54
not so early that the meeting package is inadequate. If the meeting is premature, the FDA might
not be able to provide full feedback (FDA, 2017a, Feigal et al., 2012). A similar strategy should
be considered for the EOP1 and EOP2 meetings. Although these meetings should occur after the
phase 1 or phase 2 trials, respectively, so that the sponsor has collected clinical data to share,
they can alternatively occur after the start of the phase 2 or phase 3 trials, respectively.
Regardless, they should be held in advance of planned clinical studies to allow needed
modifications to the study design (FDA, 2017a, Feigal et al., 2012).
In a formal meeting, the FDA responds to a sponsor’s questions in the meeting package.
However, simply following the Agency’s advice may not guarantee approval of a regulatory
application. In a regulatory review of an IND application, for example, FDA has a broader set of
considerations, such as assuring that the proposed clinical study assures the safety and rights of
the subjects (21CFR§312, 2022), so undiscussed issues could trigger a clinical hold. In the
regulatory review of a BLA, the FDA assesses whether the product’s benefits outweigh its
known and potential risks based on the totality of the clinical, nonclinical, and CMC data
submitted in the BLA (21CFR§312, 2022). The regulatory feedback from meetings may
facilitate these assessments if the sponsor followed the Agency’s earlier feedback and conducted
studies appropriate to yield data capable of better supporting the regulatory filing.
2.5.6 Meetings for other Medical Products
Formal meetings between the FDA and sponsors are available for multiple types of
medical products. It is expected that sponsors of a drug or biological product can request
meetings with CDER or CBER, respectively (FDA, 2017b). This expectation exists because the
centers must adhere to the meeting management goals set out by the PDUFA re-authorizations
for medical products (FDA, 2017b). Formal meetings for drugs follow the same procedure and

55
have the same meeting types and milestone meetings as biological products. Biosimilar
biological products, generic drug products, and medical device-drug combination products can
also have formal meetings with the appropriate center for that type of product (FDA, 2018d,
FDA, 2020b, FDA, 2021c). These may have implications for the developer if the new CGT has,
for example, a device component such as a specialized delivery system.
2.5.7 Recent Changes in Meeting Management
In September 2022, Congress passed the FDA User Fee Reauthorization Act, which reauthorized PDUFA (FDA, 2022b). One part of the PDUFA reauthorization focused on enhancing
CBER’s review of CGT products by hiring more staff and publishing additional guidance
documents (Chhina et al., 2022, FDA, 2021b). Another part identified the need for more
interactions (Chhina et al., 2022). As a result of the legislation, FDA introduced two meeting
types for sponsors. First, the already discussed INTERACT meeting will be promoted to a
milestone meeting early in preclinical development (FDA, 2021b), to facilitate IND-enabling
studies for novel products or products with technical challenges. Second, a new meeting type, the
Type D meeting will be introduced to allow sponsors to ask a narrow set of questions (on no
more than two topics) and receive a quick response (Chhina et al., 2022, FDA, 2021b, FDA,
2022c). For example, a sponsor will be able to use a Type D meeting to ask a follow-up question
from a new issue raised after a formal FDA meeting, such as a Type B EOP2 meeting (FDA,
2021b). Previously, a sponsor could not ask a follow-up question after receiving preliminary
responses or in a formal meeting; a new meeting request would trigger a full meeting procedure,
usually a Type C meeting with a long response time. Additionally, PDUFA will introduce a
follow-up opportunity for sponsors to ask clarifying questions to confirm that they have an
accurate understanding of the Agency’s responses after meetings or WRO for all meeting types

56
(FDA, 2021b). These features will likely increase demand on the Agency’s resources to support
sponsors. Although the PDUFA re-authorization will allow CBER to increase hiring, it remains
to be seen whether the increased number of staff will be able to handle an increase in demand.
Nevertheless, these changes in PDUFA reflect the Agency’s consideration that meetings are a
valuable and critical resource for sponsors.
2.6 Lessons from Approved Cell and Gene Therapy Products
It is clear that the FDA has made some effort to develop mechanisms for interactions that
have been enhanced for CGT and other novel products. What is not so clear is how successful or
useful these meetings have been seen to be by the major stakeholder, the industry using those
meetings. However, insights into their use and usefulness might be gained from the available
information coming from published materials associated with recently approved products.
Although the developmental path for CGTs has been rough, successes are now in evidence. The
FDA approved 27 CGT products between 2010 to 2022, listed in Figure 6. Many of the first
approvals were for somatic cells or cord blood; approvals for gene therapies lagged other product
types with approvals only in the last decade. Their regulatory histories are documented in the
Summary Basis for Regulatory Action that the FDA published for each product (FDA, 2010,
FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA, 2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b,
FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d, FDA, 2017f, FDA, 2017e,
FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA, 2021d,
FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

57
Figure 6: Number of CGT Products Approved in the U.S. in 2010-2022
These products are grouped into four categories: somatic cells, cord blood, viral vectors, and genetically
modified cells.
Source: Original figure created by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA,
2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d,
FDA, 2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA,
2021d, FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).
Many CGT products are intended for rare diseases or offer substantial clinical benefits
compared to prior therapies. These were therefore eligible for an expedited program and are
listed in Appendix B by category with date of approval, therapeutic area, type of approval, and
granted regulatory designations. Because this research is focused on CGTs, cord blood products
have been excluded; their licensure follows a unique regulatory pathway relying on previously
submitted clinical data (FDA, 2014a). About three-quarters of the 19 products on the remaining
list were granted orphan drug designation (74%, 14/19) (Figure 7). Over two-thirds (68%, 13/19)
received breakthrough therapy designation, but fewer than one-fifth (16%, 3/19) had RMAT
designation, presumably because this designation did not exist before December 2016. Three-

58
quarters (74%, 14/19) received priority review of the BLA. Most products received regular
approval (89%, 17/19) and only two products received accelerated approval (11%, 2/19). As
shown in Figure 8, most products were intended for hematology, immunology, or cancer
indications. Overall, these products generally received and likely benefited from an expedited
regulatory pathway.
Figure 7: Regulatory Designations and Approval of CGT Products
Source: Original figure created by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA,
2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d,
FDA, 2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA,
2021d, FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

59
Figure 8: Therapeutic Areas of Approved CGT Products
Source: Original figure created by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA,
2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d,
FDA, 2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA,
2021d, FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).
It is important to examine the regulatory review and conditions of approval of these
products to understand the issues that the companies encountered when submitting their BLAs. A
tabulated summary of the regulatory actions and post-marketing requirements (PMRs) and
commitments (PMCs) is provided in Appendix B. It is apparent from this material, also
illustrated in Figure 9, that about half of the products (53%, 10/19) received a refuse-to-file
(RTF) or complete response (CR) letter. Such an action requires the company to make a major
amendment to the BLA, which will delay the approval often by months or even years. In these
situations, the sponsor would amend the BLA but then receive additional feedback that required
more work and, potentially, a re-submission of the BLA. The objections identified by the FDA
were primarily related to quality or clinical deficiencies. The remaining nine of 19 products had

60
no major objections during the review. The FDA also sought expert advice for almost half of the
products (42%, 8/19) through an advisory committee meeting, warranted by the complexity and
scientific novelty of these advanced therapies, their target diseases, and the uncertainty of their
clinical programs.
Figure 9: Regulatory Review and Outcome of Approval of CGT Products
Source: Original figure created by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA,
2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d,
FDA, 2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA,
2021d, FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).
Although several CGT products now have approvals, those approvals were not without
conditions. Most CGT products were approved with clinical data from only one pivotal study
rather than two well-controlled studies typically demanded for traditional drugs approvals (refer
to Appendix B). The limited clinical data from the study provided a sufficiently favorable

61
risk/benefit profile to warrant expedited approval. However, FDA typically conditioned the
approval on further post-market study to assess long-term toxicities or uncertainties about longterm efficacy. As shown in Figure 9, 15 of 19 products (79%) had at least one post-marketing
requirement, almost all of which consisted of observational studies to further assess long-term
safety. Thirteen of 19 products (68%) also had at least one post-marketing commitment, almost
all of which centered on the analytical methods used for characterization, release, or stability
testing of the product.
There seems to be no question that expedited approaches have been able to shorten the
timelines for drug and biological products. Pregelj and colleagues reported that products granted
breakthrough therapy designation had slightly faster development times (Pregelj et al., 2021).
Ribeiro and colleagues found that oncologic products approved with breakthrough therapy
designation between 2006 and 2018 were more likely to be based on single-arm clinical studies
with smaller clinical data sets (Ribeiro et al., 2020). However, the compressed timelines when
clinical trials are shortened must reverberate across other development activities. This
consequence is reflected in the number of PMRs and PMCs. Most approved products had at least
one PMR and at least one PMC that warranted post-marketing studies. These consequences have
been observed more broadly for other products developed under accelerated timelines. Kajiwara
and Shikano observed that the FDA requested numerous PMCs for products granted
breakthrough therapy designation; the CMC-related PMCs were related to specifications and test
methods to ensure product quality (Kajiwara and Shikano, 2020). The authors suggested that the
shortened timelines gave the company insufficient manufacturing experience to establish
appropriate specifications and validate test methods. They raise the question whether all the FDA
meetings that were held during development were useful in identifying these problems in

62
advance and in avoiding other problems. If so, why were companies unable to take the advice
and deal with the problems prior to BLA submission?
2.7 Stakeholder Views of Agency-Sponsor Meetings
2.7.1 Industry Views
If FDA meetings are as important as many legislators and regulators believe, the
discussions should be actionable, to improve development and approval times. This
improvement is difficult to measure definitively because so little data exists, especially for CGT
products. Some hints might come from a relatively old study conducted by DiMasi and
Manocchia in the 1990s to examine the impact of FDA-sponsor meetings and other factors on a
broader field of drugs approved by FDA CDER from 1987 to 1995, a time frame that saw 196
drug approvals, none of which were CGT products (DiMasi and Manocchia, 1997). They
collected data from surveys sent to pharmaceutical firms and obtained information for 170 of the
drug approvals, though it is unclear whether these 170 were representative of the 196 drugs.
Results showed that sponsors used meetings extensively: 91% of the 170 drugs were associated
with at least one meeting and nearly half had three or more meetings. Of these 170 drugs, only
10% had a pre-IND meeting, 44% had an EOP2 meeting, and 52% had a pre-NDA meeting.
These data suggest that most meetings, if even held, were scheduled late in development rather
than at the pre-IND or phase 1 period. These results are contrary to current stakeholder
recommendations for early discussions with the Agency (Drago et al., 2021, Feigal et al., 2012,
Husain et al., 2015, Iglesias-Lopez et al., 2021, Marks, 2019, Salazar-Fontana, 2022, Wonnacott
et al., 2008). DiMasi and Manocchia went further by exploring whether early meetings were
associated with shorter mean development times from IND filing to NDA submission (DiMasi
and Manocchia, 1997). They found that this period was shorter for drugs with a pre-IND or

63
EOP2 meeting than drugs without such meetings. The authors acknowledge that other factors
may have affected the length of the development and approval process. Interestingly, multiple
meetings held in phase 3 and during NDA review were associated with longer approval times.
The regulatory landscape has changed since the publication of this study. At that time, no
PDUFA performance goals were established and no BT or RMAT designations existed.
Furthermore, the study was delimited to new chemical entities and biological products reviewed
by CDER rather than CBER.
In 2004, Berndt and colleagues completed a study of industry and the FDA to identify
opportunities for improving the drug development process (Berndt et al., 2006). They
interviewed 49 people working in corporate development or regulatory positions and eight FDA
staff responsible for drug evaluation. Participants were asked to rate the quality of their
communications with the FDA, including FDA-sponsor meetings. The authors heard from both
industry and FDA that FDA focused more attention on product safety and efficacy and less
attention on helping to speed development. Industry interviews further suggested that
communication with the FDA could be improved. Notably, some identified that the perceived
quality of regulatory feedback during phase 1 appeared to be poorer than that during phase 3;
however, the authors did not elaborate on their definition of “quality”. Further, industry
interviews appeared to favor additional communications with the Agency during development
because “communication leads to increased collaboration, and increased collaboration leads to
successful drug development.” Overall, the authors’ work suggested that both industry and the
FDA value meetings as a form of communication, though both stakeholders perceive the need
for improvements. However, like the DiMasi study, this study was published almost 20 years ago
and before the introduction of BT and RMAT designations, which increased the interaction

64
between industry and FDA during development (FDA, 2019b). Industry experience with these
two designations may have changed their perceptions of communication with the FDA. Further,
the results are not specific to CGT products, none of which had been approved in 2004. More
research is needed to evaluate the impact of FDA-sponsor meetings on emerging technologies,
such as CGT products, given the changes in the regulatory landscape.
2.7.2 Current Industry and Regulator Views
Effective interaction between the FDA and industry is critical to navigate the regulatory
process (Drago et al., 2021, Dye et al., 2015, Feigal et al., 2012, Salazar-Fontana, 2022,
Thomasson, 2021). It is especially important when developing CGTs, which pose unique
challenges to demonstrating safety, efficacy, and quality. Kajiwara and Shikano recommend that
Agency meetings for products granted an expedited pathway may not have enough time in
development to collect an extensive dataset based on clinical or manufacturing experience.
Discussions with regulatory authorities may help to clarify the dataset required for approval so
that fewer expensive post-market commitments for testing or trials would be required (Kajiwara
and Shikano, 2020). Regulators share a similar perspective and encourage sponsors to request
formal meetings for cell and gene therapy products. Peter Marks, the current director of CBER,
encourages early discussions with sponsors regarding CGT product development (Marks, 2019,
Marks, 2022). Others recommend pre-IND meetings for CGT products to discuss the planned
content of an IND application that might otherwise result in a clinical hold (Husain et al., 2015,
Vu and Pariser, 2015). FDA’s own analysis of such clinical holds for CGT products revealed that
most clinical holds were lifted after the sponsor received advice from the FDA and submitted a
complete response to address the concerns (Wonnacott et al., 2008). The Agency believed that
the clinical holds could have been avoided if the sponsors had used guidance documents and

65
formal meetings more effectively to address technical and clinical requirements (Wonnacott et
al., 2008). FDA also recommends formal meetings and communication during clinical
development to assure that the sponsor’s development strategy can meet the requirements for a
licensed product (Husain et al., 2015). FDA has decades of experience with CGT products
gained through evaluation of IND applications (Fink, 2009). Because it can review confidential
information in multiple regulatory applications for investigational and licensed products, it is a
repository of knowledge related to a wide range of approaches to generate relevant data. Thus, it
is uniquely positioned to provide sponsors with important advice, albeit without disclosing
privileged information (Holston, 1993).
2.7.3 PDUFA Meeting Management
Although the FDA actively encourages sponsors to request meetings, it struggles to meet
the demand for such meetings. The FDA annually publishes PDUFA performance reports with
data on requests and subsequent management of meetings (e.g., the number of requests by
meeting type, the timelines associated with FDA responses). Appendix C details some of these
data extracted from the PDUFA performance reports (FDA, 2015a, FDA, 2020a, FDA, 2021a,
Kish, 2020). Results show that required meetings are posing an increased workload for FDA
(Figure 10). The number of requests for Type A meetings remained relatively consistent;
however, requests for Type B and Type C meetings increased considerably and consistently. A
sharp increase was observed in FY 2020 and FY 2021, likely due to pandemic-related activities.
In the most recent fiscal year with data (FY 2021), the Agency received 4,558 meeting requests:
6% of requests were for Type A meetings (255/4,558), 50% for Type B (2,290/4,558), 7% for
Type B (EOP) (339/4,558), and 37% for Type C (1,674/4,558).

66
Figure 10: Combined CBER and CDER Meeting Requests by Fiscal Year (FY 2010 to
FY 2021)
The number of meeting requests for Type A, Type B, and Type C are shown in blue, orange, and grey,
respectively. Type B (EOP) meetings are combined with Type B.
Source: Original figure created by the author with data obtained from (FDA, 2015a, FDA, 2020a, FDA, 2021a,
Kish, 2020).
It has historically been challenging for CBER and CDER to meet their management
commitments. One performance goal in the documented period, from 2008 to 2020, was to act
on at least 90% of the milestones by the goal date; its inconsistent degree of success is shown in
Table 5. In the most recent fiscal year with data (FY 2020), FDA only met or exceeded 3 of 14
procedural goals, although it had a score of 75% or more in all goal categories. Least problematic
were the goals for responding to meeting requests and most problematic were those associated
with scheduling meetings. Based on the information, it is only possible to assess the percentage
of missed goals and not the magnitude of those missed goals. For example, the Agency could
miss the performance goal by one day or one month, which both count as a missed goal, but
greater magnitudes would have a bigger impact on a sponsor’s development timeline. It is also
unclear to what extent the failures delayed CGT product development. However, these

67
shortcomings contrast with findings that the FDA met or exceeded nearly all performance review
goals for marketing applications, efficacy supplements, and manufacturing supplements (FDA,
2021a, Kish, 2020).

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Table 5: Combined CBER and CDER Meeting Management Performance by Fiscal
Year (FY 2008 to FY 2020)
Performance for submission/request types that met the goal (90% or more reviews completed by the
PDUFA goal date) is shown in green, and performance that did not meet the goal is shown in red.
Submission/
Request
Type
Performance by Fiscal Year (%)
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Type A
Meeting
Requests
63 74 65 79 85 91 90 96 90 91 93 90 91
Type B
Meeting
Requests
83 80 76 85 85 89 91 91 92 92 90 91 92
Type B
(EOP)
Meeting
Requests
- - - - - - - - - - 80 82 83
Type C
Meeting
Requests
81 78 76 82 87 87 88 86 92 92 92 89 89
Type A
Meetings
Scheduled
58 64 66 84 94 92 73 64 75 75 75 71 76
Type B
Meetings
Scheduled
77 69 73 90 93 91 71 72 69 69 63 65 75
Type B
(EOP)
Meetings
Scheduled
- - - - - - - - - - 74 76 80
Type C
Meetings
Scheduled
79 74 78 88 91 92 80 80 77 77 75 76 78
Type A
Written
Response
- - - - - - - - - - 67 67 77
Type B
Written
Response
- - - - - 71 79 76 77 77 77 81 82
Type B
(EOP)
Written
Response
- - - - - - - - - - 57 73 83
Type C
Written
Response
- - - - - 78 86 81 85 85 84 81 79
Preliminary
Response for
Type B
(EOP)
Meetings
- - - - - - - - - - 85 87 82
Meeting
Minutes 61 69 68 83 85 87 90 89 93 93 91 92 93
Source: Original table created by the author with data obtained from (FDA, 2020a, FDA, 2021a, Kish, 2020).

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It would be ideal to obtain meeting management data for CBER office responsible for
CGT products in order to understand the dynamics of meeting requests and performance goal
achievement over time. The available data, however, are not stratified by office or even by
center. Nevertheless, certain patterns emerge that show, in general, an increased demand from
sponsors for regulatory feedback especially for Type B meetings, which are the major milestone
meetings during development (i.e., pre-IND, EOP1, EOP2, and pre-BLA), and an Agency
constantly struggling to meet this demand.
2.7.4 One Recent Example of Industry-FDA Interactions
Current practices can also be illuminated by an evaluation of recent experiences. A case
study can be particularly useful to explore a complex issue in detail and in its real-life context to
better understand the issue (Crowe et al., 2011). One recent example offers insight into the ways
that a company used Agency interactions as part of its development strategies. This case
illustrates the difficulty of meeting management between industry and FDA and the need for
better communication in these interactions.
Iovance Biotherapeutics was developing autologous cell immunotherapies for the
treatment of cancer and wanted to commercialize these therapies in the U.S. (Iovance
Biotherapeutics, 2021). Its main product was lifileucel, which was a tumor-infiltrating
lymphocyte (TIL) therapy. TIL therapy increases the number of the patient’s cancer-specific T
cells, which could reduce or eliminate the cancer. The FDA has not yet approved a TIL therapy.
Iovance conducted a Phase 2 trial and, in September 2018, held an EOP2 meeting to discuss the
clinical data. The FDA acknowledged that a randomized Phase 3 study may not be feasible for
the patient population and a single-arm cohort of the Phase 2 study may be acceptable for
licensure. Also, the FDA recommended validating a potency assay prior to starting this new

70
cohort. Based on these discussions, Iovance added the new cohort to their Phase 2 trial and
implemented a potency assay. They initiated the new cohort in early 2019 and completed dosing
in January 2020 with the expectation to submit a BLA in the second half of 2020 (Iovance
Biotherapeutics, 2021).
Although Iovance started to build infrastructure for commercialization capabilities, these
efforts proved premature. In October 2020, after a Type B meeting, Iovance announced that the
company and the FDA failed to agree on the required potency assays (Iovance Biotherapeutics,
2021), which would be required for licensure (21CFR§610, 2022). The FDA wanted Iovance to
refine an existing potency assay and develop a new potency assay. One or more potency assays
are not unreasonable for products with multiple modes of action (FDA, 2011a). As a result of the
regulatory feedback, Iovance postponed their BLA submission to 2021. Iovance submitted
potency assay data to the FDA, and, in May 2021, received more feedback regarding the potency
assays. Following this feedback, Iovance continued assay development and validation of the
potency assays and engaged in further discussions with the FDA in the second half of 2021.
These additional issues resulted in another delay in the expected BLA submission from 2021 to
the first half of 2022 (Iovance Biotherapeutics, 2021).
Despite seeking scientific advice and receiving regulatory feedback on multiple
occasions, Iovance repeatedly encountered setbacks in the development of their investigational
product. Relevant potency assays should have been developed to assess the biological function of
the product, and these assays should have been implemented prior to initiating the pivotal
clinical trial, and they should have been validated prior to submission of the BLA (FDA, 2011a).
Iovance had multiple meetings with the FDA over three years to help develop the appropriate
potency assays. Despite using meetings as part of their development strategy, Iovance struggled

71
to implement assays that would satisfy the expectations of the regulators. A disconnect occurred
between the company and the FDA, which resulted in a significant delay in the clinical
development of lifileucel, Such delays caused additional expenses that could be expected to
strain the finances of a clinical-stage company, as well as make a new medicine unavailable to
patients. However, from this case study, it was not clear whether the company was satisfied with
the interactions and yet was unable to deal with the scientific issues, or whether the meetings
were constructed in a way that was less than optimal.
2.8 Research Approach and Framework
Regulatory professionals in companies are entrusted to assure a sponsor’s compliance
with applicable global regulatory requirements at each stage of product development. As the
primary channel of communication with the regulatory authorities, those professionals
coordinate and prepare for the meetings between the regulatory authorities and their companies.
FDA-sponsor formal meetings impose administrative burdens on industry to develop needed
information packages, interpret the regulatory feedback, and incorporate advice into the product
development plans. Given the perceived utility of these meetings, it appears worthwhile to
collect the views of stakeholders regarding the strengths and weaknesses of meeting
requirements and logistics. Because regulatory professionals are at the center of the interactions,
they have had unique experiences with the regulatory authorities that can provide valuable
insight into the effectiveness and utility of FDA-sponsor meetings from the viewpoint of industry
stakeholders.
The literature describes several types of evaluations that could be used to examine
regulatory feedback obtained through FDA-sponsor formal meetings. Van Marris and King
describe three main categories of evaluation that may be appropriate based on the maturity of the

72
program and the kind of information that is of interest (Van Marris and King, 2007). A formative
evaluation is usually performed at an early stage of planning or implementation. This type of
evaluation typically yields a needs assessment to look at the possible scope, resource needs, and
context for a program (Van Marris and King, 2007). A process evaluation is better suited to
retrospective studies, after a program as already been implemented. It examines how a program
is operating, whether it has been implemented according to plan, and whether problems have
emerged (Scriven, 2007, Van Marris and King, 2007). A summative evaluation is best performed
on programs that have been underway or completed. It evaluates the overall impact of a program
to determine whether it made a difference, by meeting its stated goals and objectives (Van Marris
and King, 2007).
Kahan provides an overview of several evaluation frameworks (Kahan, 2008). One
framework that is well-established for this study is the CIPP evaluation framework, first
developed by Daniel Stufflebeam for the systematic evaluation of educational programs
(Stufflebeam, 1966, Stufflebeam, 1967). It provides a comprehensive framework that combines
elements of formative, process, and summative evaluations that can be usefully applied to the
study of regulatory feedback obtained through FDA-sponsor formal meetings.
The CIPP framework is a versatile tool for evaluation. It has been employed in various
disciplines, such as education, where amongst other projects it has been used to improve reading
instruction (Nicholson, 1989) and improve instruction in school systems (Felix, 1979). In
healthcare, the CIPP framework has been used more recently to evaluate nursing programs
(Lippe and Carter, 2018), patient safety programs (Farley and Battles, 2009), and government
infection prevention programs (Kahn et al., 2014). Regardless of the type of application, each
study reported benefits of using the framework to guide program evaluation.

73
CIPP is an acronym that has four principal topic areas: Context, Input, Process, and
Product evaluation (Stufflebeam, 1967) (Figure 11). Using this framework, a researcher can
probe areas in which improvements appear to be needed. At the center of the CIPP evaluation
framework, shown by an inner circle in Figure 11, are the values that should be identified and
used to specify what is most important in the evaluation (Stufflebeam, 2003). A middle circle,
divided into four sections, identifies the certain foci for each stage of the evaluation. The outer
circle indicates the four types of evaluation: context, input, process, or product evaluation. To
apply the CIPP framework to the study proposed here, I consider the inner circle to represent the
FDA’s two-fold mission and value statements of protecting the public health by ensuring the
safety and efficacy of human drugs, biological products, and medical devices; and of advancing
the public health by helping to speed innovations that make medical products safer and more
effective (FDA, 2018f). These fundamental concepts will guide this evaluation and provide the
foundation for creating the evaluation criteria.

74
Figure 11: Illustration of the CIPP Evaluation Framework
Source: Original figure created by the author based on (Stufflebeam, 2003).
The first stage of the CIPP evaluation framework is context evaluation. Here, the
researcher examines the background and setting of a program. The objectives are to define the
relevant context, to identify the program beneficiaries and their needs, and to diagnose the
problems underlying those needs (Stufflebeam, 1967, Zhang et al., 2011). This evaluation
involves assessing the circumstances for planning and conducting a comprehensive series of
meetings with the FDA, performing a needs assessment, and identifying what resources are
available (Stufflebeam, 1967). In this research study, the context evaluation may include
determining the expectations and needs of sponsors from consultations with the FDA.
The second stage is input evaluation. Here, the researcher identifies the strategies for the
program. The objective is to determine how to utilize the resources to use the meeting
opportunities effectively (Stufflebeam, 1967). This evaluation involves identifying and assessing
the program capabilities, examining the options for achieving the program’s goals, and

75
developing the procedures for those plans (Stufflebeam, 1967, Zhang et al., 2011). Resources,
time, and budget are considerations for achieving a program’s goal. In this research study, the
input evaluation may determine what resources are available for sponsors and their familiarity
with the regulatory program.
The next stage is process evaluation. After a program is underway, the researcher
evaluates the overall progress in implementing a program to provide information to program
administrators for continuous improvement and control. The objective is to identify defects in the
procedural design of a program or in its implementation (Stufflebeam, 1967). This information is
used to ensure that the program operates according to its design, to refine the program design
under operating conditions, and to revise procedures for better control of a program that could
not have been made during the preparation of the program (Stufflebeam, 1967, Stufflebeam,
1971). In this research study, the process evaluation may examine the logistics of the regulatory
program from the perspective of sponsors who have used the program to obtain regulatory
feedback.
The fourth and final stage is product evaluation. In this stage, the researcher assesses the
consequences of a program. The objective is to connect output information (e.g., whether a
program is fulfilling its stated goals) to the program’s objectives and to bring together the
context, input, and process information collected in the first three stages (Stufflebeam, 1967).
This evaluation involves measuring criteria associated with the program’s objectives and
comparing those measurements with pre-defined standards or interpreting the outcome in terms
of the input and process information (Stufflebeam, 1967, Zhang et al., 2011). This information is
used to continue, modify, or terminate a program. In this research study, the product evaluation
may seek to determine whether regulatory feedback through FDA-sponsor formal meetings made

76
a difference in the product development plans, whether sponsors were satisfied with the
regulatory program, and any positive or negative outcomes of the program.
Table 6 provides an overview of the CIPP framework. The table provides a description of
each of the four evaluations, as well as the key question asked in each stage, and the objective,
methods, and decision-making use of each evaluation.
Table 6: Overview of the CIPP Evaluation Framework
Attribute Context
Evaluation Input Evaluation Process
Evaluation
Product
Evaluation
Description
Examine the
background and
setting of a
program
Identify strategies for
the program
Examine the
activities of the
program
Assess the
effectiveness of a
program
Question What should we
do? How should we do it? Are we doing it
correctly? Did it work?
Objective
To diagnose the
problem and
assess the needs
for the program
To assess what
activities are
achievable for the
program
To ensure that the
program is being
implemented as
intended and to
identify problems in
the implementation
To assess whether
the program was
effective and had
an impact
Methods
Using methods
such as surveys,
literature reviews,
interviews, and
focus groups
Using methods such
as literature reviews,
interviews, focus
groups
Using methods such
as surveys,
document reviews,
on-site observations,
case studies,
interviews, and
focus groups
Using methods
such as surveys,
document reviews,
on-site
observations, case
studies, interviews,
and focus groups
Decisionmaking
For goal-setting,
to provide a
foundation for
deciding what
programs are
needed
For planning, to
determine what
resources are
available and to
decide which
activities are the most
feasible
For actions, to
optimize the
program and to
provide information
that can be used to
understand the
impact of the
program
For outcomes, to
decide whether the
program should be
continued,
modified, or
terminated
Source: Original table created by the author based on (Nicholson, 1989, Stufflebeam, 1966, Stufflebeam, 1967,
Stufflebeam, 2003).

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Based on the description of the CIPP evaluation framework, this framework offers a
systematic approach that is an appropriate tool for this study (Stufflebeam, 1967, Stufflebeam,
1971, Stufflebeam, 2003). It is a comprehensive framework that examines the whole context
surrounding a program, including the initial planning that gave rise to the program, the operation
of the program, and the outcomes of the program (Kahan, 2008). Moreover, the CIPP framework
is strongly oriented towards stakeholders and program beneficiaries because the evaluation seeks
contribution from stakeholders for their insights (Stufflebeam, 2003). This was important to
understand the experiences and perceptions of industry professionals in this study. One concern
about its use is that the CIPP framework can be time-consuming to complete because it can be a
complex evaluation that considers multiple factors (Finney, 2019, Kahan, 2008). Placing a
stronger focus on certain aspects of the evaluation may help address this concern.
The research study explored the biopharmaceutical industry’s views regarding formal
meetings and informal interactions with FDA in the development of CGT products. I used
Stufflebeam’s CIPP evaluation framework to structure a survey of industry to gain insight into
their perspectives and experiences with their FDA interactions. From those results, I tried to
determine whether the goals of this program were being fully realized for these advanced
therapies and where improvements to the design and use of meetings could be identified.

78
Chapter 3. Methodology
3.1 Introduction
This study evaluated how regulatory professionals with experience working with
biological and/or CGT products view the opportunities and challenges associated with FDA
meetings. The study explored how professionals’ current practices related to the use of formal
meetings to obtain guidance and direction from the FDA whether their experiences reveal
weaknesses to overcome or opportunities to improve interactions between the FDA and
sponsors.
The literature outline in Chapter 2 helped to inform and to construct the development of
the initial survey, using the CIPP framework as an organizing principle. A focus group was used
to critique the survey questions and improve the survey. The survey was administered to
professionals whose past or current positions indicate experience with biological and/or CGT
products.
3.2 Survey Development
The survey instrument was created using the web-based survey application, Qualtrics
(www.qualtrics.com). Qualtrics allowed for the capability to ask a wide variety of question
types, as well as skip-logic functionality, customization of the survey appearance, mailing lists
for distribution, and the capability to export data into another application for analysis. The
finalized survey contained approximately 37 questions with yes/no, multiple-choice, ranked
order choice, rating scale choice, and Likert scale question formats. Comment fields were
included to allow respondents to provide fuller written responses. These written responses
contributed to the research by providing opinions that could not be captured in the closed-ended
questions.

79
The survey was structured in two main parts: questions collecting demographic
information followed by questions based on the CIPP framework. The initial questions collected
demographic information from the respondents to establish their backgrounds. The subsequent
questions were grouped according to the themes of the selected framework. The four stages of
the CIPP evaluation framework were used to establish the high-level structure of the survey:
context evaluation assessed the setting and needs for a program; input evaluation assessed the
planning and structuring of a program; process evaluation assessed the implementation of a
program; and product evaluation assessed the outcome of a program (Stufflebeam, 1967,
Stufflebeam, 1971). Based on feedback from the focus group, a question was added to ask
respondents whether they had experience with an INTERACT meeting: if respondents had such
experience, then six additional questions would be asked; otherwise, skip-logic would take the
respondent to the final question, which was a free-text question to close-out the survey. The
structure of the survey is provided in Table 7. The current literature and analysis described in
Chapter 2 drove the development of specific questions.
Table 7: Structure of Survey based on CIPP Framework
Section Description of Section Number of Questions
1 Demographics 9
2 Context Evaluation 4
3 Input Evaluation 3
4 Process Evaluation 8
5 Product Evaluation 11
6 INTERACT 1 (or 7)
7 Survey Close-Out 1
Total Number of Questions 37 (or 43)

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3.3 Focus Group
A focus group was used to review the initial survey and provide feedback to improve the
survey. The focus group consisted of six individuals with backgrounds in academia and industry.
The participants were selected based on their experience with biological and CGT product
development, FDA meetings, and survey development. The focus group reviewed the initial set
of questions and question types; critiqued the questions for suitability, clarity, and overall
organization; and provided suggestions to improve the survey’s validity and clarity.
Approximately two weeks prior to the meeting, the participants in the focus group were
provided with the proposed agenda and meeting package. This document contained the abstract,
the Chapter 1 overview, the Chapter 2 research approach and framework, the Chapter 3
methodology, and the survey questions. Participants were asked to review the meeting package
before the meeting so that the meeting could focus on a discussion of each question.
The focus group convened in an online meeting using the video conferencing platform,
Zoom (www.zoom.com), to accommodate remote attendees in different locations. The focus
group was scheduled for two hours on 02 October 2023. I led the focus group and my
dissertation advisor, Dr. Susan Bain, moderated the meeting. At the beginning of the meeting, I
provided a brief introduction to the research study and survey design. I reviewed each survey
question with the group, and all questions were reviewed within the two-hour meeting. During
the meeting, I wrote notes based on the comments and proposed edits from the participants.
The focus group reviewed each question in the draft survey and provided feedback to
revise the survey. The draft survey consisted of 40 questions. If participants believed that a
question was unclear, then they recommended revisions to improve the clarity. If participants
believed that a question and/or answer choice was unnecessarily long, then they recommended
revisions to write them succinctly. Participants recommended soliciting respondents from

81
academic research institutions with FDA meeting experience for early-phase investigational
products. Questions were revised to allow for respondents with experience with FDA written
responses only, as well as denied meetings and cancelled meetings. Participants recommended
the addition of free text fields for some multiple choice and yes/no questions for certain answer
choices to obtain a brief explanation for choosing an answer choice to understand rationales.
Some multiple-choice questions were changed to rank order questions to understand the relative
importance of the answer choices. Participants also recommended inserting a subsection in the
survey and ask respondents about their experience with INTERACT meetings because this
meeting type was new and not well documented in the published literature. As a result, one
question was added to ask whether a respondent had experience with an INTERACT meeting: if
the respondent selected “yes”, then skip-logic would add six additional questions about this
topic; otherwise, skip-logic would take the respondent to the final question of the survey.
Following the focus group meeting, the survey was revised to incorporate the feedback
from the focus group participants. I reduced the survey length from 40 questions to 36 questions,
and added one question for the INTERACT meeting, which yielded a total of 37 questions in the
finalized survey with potentially six more questions about the INTERACT meeting. These
changes were implemented to achieve a finalized survey. The survey was intended to take
between 15 and 20 minutes to complete. The finalized survey is provided in Appendix D. This
revised and finalized survey was then distributed to prospective respondents.
3.4 Survey Distribution
The ability to successfully distribute the survey was validated by sending the finalized
survey to three individuals. This step verified that the email notifications were received, the links
to the survey worked, the questions were formatted correctly, responses could be submitted, and

82
analysis of responses could be performed. Any functionality issues with the survey were
identified and resolved prior to the administration of the survey.
After validation, the survey was distributed electronically to professionals working in
academic institutions, in research institutes, and in the biopharmaceutical industry. The survey
was deployed on 14 December 2023 using Qualtrics and active until 30 March 2024.
The survey sought to obtain responses from respondents who had relevant experience.
The potential respondents for the survey included regulatory professionals who worked in
industry, in academic, or in government institutions and had experience with investigational or
commercialized CGT products. To find potential respondents, I reviewed publicly submitted
comments to draft FDA guidance documents for CGT products to identify a name and corporate
email address of the regulatory affairs individual who was responsible for signing the submitted
comments. Such individuals were already participating in revising FDA guidance in this field
and could share their experiences through my survey. I compiled a list of names and emails in a
contact list (or mailing list) in Qualtrics. This contact list was augmented with potential
respondents with whom I was familiar and knew had the appropriate backgrounds. Each person
on the contact list received an email message with the survey invitation. The survey invitation
contained a message asking the individual to participate in my research study. The message
described the topic, purpose of the research, estimated time to complete the survey, assurance of
anonymity and confidentiality of responses, and a personalized link to the survey. The message
also included an anonymous link to share the survey with colleagues, as well as an opt-out link
for individuals to decline participation in the survey. The survey anonymized both the names of
participants and their affiliated institutions. Participation was voluntary and without financial
compensation. Respondents were offered to be provided with a summary of the results after the

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survey had been analyzed as an incentive for their participation. Qualtrics was programmed to
send weekly reminder emails to contacts who had not completed the survey until the survey was
stopped, as well as send a thank you email to all participants who completed the survey.
Further, potential respondents were identified through professional networks, referrals by
colleagues, and general networking. The survey was posted on the social media platform
LinkedIn. This platform allowed me to contact individuals using the messaging feature.
Individuals with the appropriate regulatory experience with CGT products were screened and
identified for messaging. An anonymous link to the survey was provided. Individuals were asked
to share the anonymous link to the survey with other individuals in their professional network
who had the relevant experience and could contribute to the research.
3.5 Data Analysis
The survey was active in Qualtrics for approximately 15 weeks until at least 40
completed responses had been recorded. If a respondent answered a majority of the questions
(i.e., ≥ 19 answered questions), then the survey was counted as completed and the data were used
for analysis. Incomplete surveys (i.e., < 19 answered questions) were excluded from the analysis.
The survey data were collected and stored electronically in Qualtrics. The data were exported
into a spreadsheet software program for analysis. Survey results are reported in Chapter 4.
Statistical methods were used for analysis and interpretation of the data. The data were
analyzed using descriptive statistics, which included calculation of frequencies, as well as
calculation of the mean and the standard deviation, or the median and the interquartile range.
Counts varied from question to question because the survey used skip-logic and each respondent
encountered a different number of questions in the survey based on their answer choices, and a
respondent may not have answered every question. Therefore, counts are reported for each

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question with the results. The categorical data were graphed into vertical or horizontal bar charts.
Cross-tabulations were performed to sub-stratify the responses.
The survey contained Likert-style questions. The distribution of respondent views was
plotted in a bar graph to show the number of respondents with each view for each category of the
question. Additionally, a weighted score was calculated for each category to determine the
relative order of categories. For example, to calculate the weighted score for a question with the
options “agree”, “neither agree nor disagree”, “disagree”, and “do not know” or “not applicable”,
the number of respondents who selected “agree” was multiplied by the score of 1, the number of
respondents who selected “neither agree nor disagree” was multiplied by the score of 2, and the
number of respondents who selected “disagree” was multiplied by the score of 3; the number of
respondents who selected “do not know” or “not applicable” was multiplied by the score of 0.
The weighted scores for each category were summed and then divided by the number of
respondents who answered “agree”, “neither agree nor disagree”, or “disagree” to obtain the
overall weighted score. The overall weighted score for each category was used to determine the
relative order of categories. In this example, the minimum overall weighted score was 1.00 and
the maximum overall weighted score was 3.00. The category with the lowest overall weighted
score was determined to be the highest level of agreement and the category with the highest
overall weighted score was determined to be the lowest level of agreement. A similar calculation
was performed for Likert-style questions with different options, e.g., level of usefulness or level
of concern.
The survey contained rank-order questions. The distribution of respondent views was
plotted in a bar graph to show the number of respondents with each rank for each category of the
question. Additionally, a weighted rank score was calculated for each category to determine the

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relative ranking of categories. For example, to calculate the weighted rank score for a question
with six rank options (i.e., rank 1 for first, rank 2 for second, etc.), the number of respondents
who selected “rank 1” was multiplied by the score of 1, the number of respondents who selected
“rank 2” was multiplied by the score of 2, etc. The weighted rank scores for each category were
summed and then divided by the number of respondents to obtain the overall weighted rank
score. The overall weighted rank score for each category was used to determine the relative rank
order of categories. In this example, the minimum overall weighted rank score was 1.00 and the
maximum overall weighted rank score was 6.00. The category with the lowest overall weighted
rank score was determined to be the highest ranked category and the category with the highest
overall weighted rank score was determined to be the lowest ranked category.
Any responses to open-ended questions or free-text comment fields were analyzed for
trends or commonalities. Text responses were requested for certain questions to ask for the
respondent’s opinion or to provide the respondent with an opportunity to explain an answer
choice. The open-ended question allowed respondents to provide additional information that was
not described in the pre-defined answer choices of the survey and provided an opportunity to
learn unexpected information. Text responses were reviewed manually, and they were grouped
into categories. No edits or other changes were made to text responses (i.e., any typographical
errors were unfixed).

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Chapter 4. Results
4.1 Survey Participation
The Qualtrics mailer was used to distribute the survey to 92 potential participants using
individual links to the survey. Eight email invitations bounced (9%, 8/92). Of the 84 survey
invitations distributed, 28 people started the survey, yielding a 33% response rate (28/84), and
then 17 people finished the survey, yielding a 61% completion rate (17/28). Further, the survey
invitation was posted on LinkedIn group sites using an anonymous link and the invitation was
referred to colleagues through a snowball technique, which secured an additional 52 participants.
Combining all sources, Qualtrics recorded 69 responses, which consisted of 21
incomplete surveys (30%, 21/69) and 48 completed surveys (70%, 48/69). Of the incomplete
surveys, six people opened the survey but did not answer any questions (29%, 6/21) and 15
people answered at least one question (71%, 15/21). If a respondent answered a majority of the
questions (i.e., ≥ 19 questions), then the survey was used for analysis; three of the 21 incomplete
surveys had a majority of the questions answered and these data were used in the analysis.
Incomplete surveys with less than 19 answered questions were excluded. Altogether, the final
survey group included three incomplete surveys and 48 completed surveys. The number of
respondents for each question is provided in each figure below because not all questions were
answered by each respondent.
4.2 Demographic Profiles of Respondents
When asked about their current experience with medical products (Figure 12), most
respondents (71%, 36/51) had experience with advanced therapies, such as cell and gene
therapies (CGTs). Many (18%, 9/51) had experience with biological products (such as
recombinant proteins or vaccines). One respondent had experience with medical devices (such as

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combination products of a biologics-device or advanced therapy-device) (2%, 1/51) and another
one had experience with “other” and specified RNA-based therapies (2%, 1/51). Some
respondents (8%, 4/51) indicated that they had experience with small molecules, generic drugs,
or biosimilars and these were skipped to the end of the survey. Forty-seven respondents
proceeded with the remainder of the survey.
Figure 12: Distribution of Medical Product Experience
Question 1: Which of the following best describes the medical products with which you have the most
current experience? Choose one option. (n = 51)
When asked about their current or most recent type of organization (Figure 13), most
respondents (77%, 36/47) worked for a biotechnology, pharmaceutical, or medical device
company. One worked for an academic institution that sponsored INDs (2%, 1/47) and none
worked for a government institution that sponsored INDs (0%, 0/47). Some of the respondents
worked for a contract organization or consulting firm (17%, 8/47). Two indicated “other” (4%,
2/47) and specified that they worked as an independent consultant or previously worked for a
biotechnology company.

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Figure 13: Distribution of Type of Organization
Question 2: Which sector best describes your current or most recent organization? Choose one option.
(n = 47)
When asked about the size of their organization based on the number of employees
(Figure 14), roughly one-third (36%, 17/47) worked for small organizations of less than 100
employees and another roughly one-third (30%, 14/47) worked for small organizations with 101
to 500 employees. The remaining respondents worked for medium-sized organizations with 501
to 5000 employees (15%, 7/47) or for large organizations with more than 5000 employees (19%,
9/47).

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Figure 14: Distribution of Size of Organization
Question 3: What is the size of your overall organization based on the number of employees? Choose one
option. (n = 47)
The large majority of respondents worked in Regulatory Affairs (83%, 39/47) (Figure
15). The remaining few worked in CMC-related functions (6%, 3/47), research or translational
science (6%, 3/47), or related areas such as regulatory toxicology or CMC regulatory affairs,
which was designated as “other” (4%, 2/47). None worked in a clinical affairs or research role.
Figure 15: Distribution of Functional Area amongst Respondents
Question 4: Which department best describes your functional area? Choose one option. (n = 47)

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When asked about the length of experience that they had with biological products,
advanced therapies, or medical devices (Figure 16), none of the respondents had less than two
years of experience (0%, 0/47). Some had between two and five years of experience (9%, 4/47),
but most had six or more years of experience: 30% (14/47) had between six and ten years of
experience and 62% (29/47) had more than ten years of experience.
Figure 16: Distribution of Length of Experience amongst Respondents
Question 5: How many years of cumulative experience do you have with biological products, advanced
therapies (cell or gene therapies), or medical devices? Choose one option. (n = 47)
Most respondents dealt with products in development (Figure 17). Over one-third of the
products (38%, 18/47) were in a preclinical stage (i.e., before submission of an IND) and almost
half of the products (49%, 23/47) were in a clinical stage (i.e., after clearance of an IND and
before submission of a marketing application). None were in a marketing application review
(i.e., after submission of a marketing application and before regulatory action) (0%, 0/47), and
only a few (13%, 6/47) were commercialized (i.e., after approval of a marketing application).

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Figure 17: Distribution of Stage of Product Development
Question 6: What stage of development best describes your product? Choose one option. (n = 47)
When asked about experience with FDA-sponsor meetings for PDUFA-regulated
products with CBER, all respondents had such experience (100%, 47/47).
When asked how many FDA-meetings in which they had been involved with FDA CBER
(Figure 18), roughly two-thirds of respondents (66%, 31/47) had participated in more than three
meetings, less than a quarter (21%, 10/47) had participated in two or three meetings, and the
remaining 13% (6/47) had participated in a single meeting.
Figure 18: Distribution of Number of FDA-Sponsor Meetings
Question 8: How many FDA-sponsor meetings have you been involved with CBER? Choose one option.
(n = 47)

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When asked how long it had been since their most recent experience using the FDAsponsor meeting process with CBER (Figure 19), most respondents had an FDA meeting less
than one year ago (60%, 28/47) and the others had an FDA meeting between one and six years
ago (40%, 19/47).
Figure 19: Distribution of Experience with FDA-Sponsor Meetings
Question 9: How long ago was your most recent experience using the FDA-sponsor meeting process with
CBER? Choose one option. (n = 47)
4.3 Context Evaluation
The first stage of the CIPP evaluation framework is the context evaluation, where the
researcher assesses the needs of the intended beneficiaries and the potential problems for the
program to solve (Stufflebeam, 2003). Respondents were asked to what extent various resources
were useful when seeking technical information on the quality/CMC, non-clinical, and/or clinical
aspects of product development (Figure 20, Table 8). For the category “direct discussion/meeting
with FDA”, most respondents indicated that it was very useful (87%, 40/46) or somewhat useful
(11%, 5/46); one did not use it (2%, 1/46). For “FDA guidance documents”, 74% regarded them
as very useful (34/46) and the rest (26%, 12/46) as somewhat useful. For “FDA information
requests”, 47% (22/47) found them very useful, 32% (15/47) found them somewhat useful, and

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the remaining did not use them (21%, 10/47). For “dialogue with industry peers who have
relevant experience”, almost half viewed it as very useful (45%, 21/47), 40% (19/47) somewhat
useful, 4% (2/47) not useful, and 11% (5/47) did not use it. For “FDA website (e.g., package
inserts, approval letters, and summary basis for regulatory action)”, 43% (20/47) indicated very
useful, 45% (21/47) somewhat useful, 11% (5/47) not useful, and 2% (1/47) did not use it. For
“consultants”, less than one-third indicated that they were very useful (30%, 14/47), 38% (18/47)
somewhat useful, 13% (6/47) not useful, and 19% (9/47) did not use them. For “Advisory
Committee meetings and minutes”, 28% (13/47) indicated very useful, 43% (20/47) somewhat
useful, 15% (7/47) not useful, and 15% (7/47) did not use them. For “literature publications”,
20% (9/46) indicated very useful, 63% (29/46) somewhat useful, 7% (3/46) not useful, and 11%
(5/46) did not use them. For “conferences or seminars”, 17% (8/47) indicated very useful, almost
half as somewhat useful (49%, 23/47), 21% (10/47) not useful, and 13% (6/47) did not use them.
For “discussions with representatives from industry associations”, 13% (6/47) indicated very
useful, 38% (29/47) somewhat useful, 26% (12/47) not useful, and 23% (11/47) did not use
them.

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Figure 20: Distribution of Usefulness of Resources for Technical Information
Question 10: To what extent are these resources useful when seeking technical information on the
quality/CMC, non-clinical, and/or clinical aspects for product development?

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Table 8: Weighted Scores of Usefulness of Resources for Technical Information
Category
Weighted Score
VU Sum N Overall WS
(1)
SU
(2)
NU
(3)
DNU
(0)
Direct discussion/ meeting with
FDA 40 10 0 0 50 45 1.11
FDA guidance documents 34 24 0 0 58 46 1.26
FDA information requests 22 30 0 0 52 37 1.41
Dialogue with industry peers
who have relevant experience 21 38 6 0 65 42 1.55
FDA website 20 42 15 0 77 46 1.67
Consultants 14 36 18 0 68 38 1.79
Advisory Committee meetings
and minutes 13 40 21 0 74 40 1.85
Literature publications 9 58 9 0 76 41 1.85
Conferences/ seminars 8 46 30 0 84 41 2.05
Discussion with representatives
from industry associations 6 36 36 0 78 36 2.17
Abbreviations: DNU, did not use; N, number; NU, not useful; SU, somewhat useful; VU, very useful; WS, weighted
score.
When asked whether FDA-sponsor meetings with CBER offer more advantages than
other sources of information for product development, all respondents answered “yes” (100%,
47/47).
Respondents were asked to rank six potential benefits that might be associated with FDAsponsor meetings, as compared to other sources of information, from first (most beneficial) to
sixth (least beneficial) (Figure 21, Table 9). The option “reduce risk of potential setbacks” had
the closest weighted score to one (rank score = 1.30) and was selected most frequently as most
beneficial (1: 75%, 33/44; 2: 20%, 9/44; 3: 5%, 2/44; 4-6: none). The option “build a relationship
with the Agency reviewers” ranked second (rank score = 2.93) and was most frequently selected
second (1: 14%, 6/44; 2: 34%, 15/44; 3: 23%, 10/44; 4: 9%, 4/44; 5: 16%, 7/44; 6: 5%, 2/44).
The option “transparency to the regulatory review process” ranked third (rank score = 3.05) (1:
7%, 3/44; 2: 30%, 13/44; 3: 32%, 14/44; 4: 20%, 9/44; 5: 7%, 3/44; 6: 5%, 2/44). The option
“shorter development time” ranked fourth (rank score = 4.11) and the third and fifth ranks were

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most common (1: 0%, 0/44; 2: 7%, 3/44; 3: 30%, 13/44; 4: 20%, 9/44; 5: 32%, 14/44; 6: 11%,
5/44). The option “fewer studies required” ranked fifth (rank score = 4.41) and was frequently
selected fourth through sixth (1: 5%, 2/44; 2: 9%, 4/44; 3: 9%, 4/44; 4: 25%, 11/44; 5: 23%,
10/44; 6: 30%, 13/44). The option “lower development cost” had the closest weighted score to
six (rank score = 4.41) and was most frequently selected as least beneficial (1-2: 0%, 0/44; 3:
2%, 1/44; 4: 25%, 11/44; 5: 23%, 10/44; 6: 50%, 22/44).

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Figure 21: Distribution of Rank of Advantages of FDA-Sponsor Meetings
Question 12: What advantages do you think that FDA-sponsor meetings with CBER offer compared to
other sources of information (e.g., FDA guidance documents, conferences/seminars, etc.) for product
development? Please rank from most beneficial to least beneficial advantage.

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Table 9: Weighted Rank Scores of Advantages of FDA-Sponsor Meetings
Category
Weighted Rank Score
R1 Sum N Overall WRS
(1)
R2
(2)
R3
(3)
R4
(4)
R5
(5)
R6
(6)
Reduce risk of potential
setbacks 33 18 6 0 0 0 57 44 1.30
Build a relationship with the
Agency reviewers 6 30 30 16 35 12 129 44 2.93
Transparency to the regulatory
review process 3 26 42 36 15 12 134 44 3.05
Shorter development time 0 6 39 36 70 30 181 44 4.11
Fewer studies required 2 8 12 44 50 78 194 44 4.41
Lower development cost 0 0 3 44 50 132 229 44 5.20
Abbreviations: N, number; R, rank (i.e., R1 ranks first, R2 ranks second, etc.); WRS, weighted rank score.
Respondents were asked to rank five potential drivers for seeking feedback from FDA
from first (most beneficial) to fifth (least beneficial) (Figure 22, Table 10). The option “seek
Agency agreement on proposed study designs and methods to generate data” had the closest
weighted score to 1 (rank score = 1. 63) and was most frequently selected as most beneficial (1:
61%, 28/46; 2: 20%, 9/46; 3: 15%, 7/46; 4: 4% ,2/46; 5: 0%, 0/46). The option “resolve
questions or issues raised during product development” ranked second (rank score = 2.35) and
was frequently ranked second or third (1: 15%, 7/46; 2: 39%, 18/46; 3: 41%, 19/46; 4: 4%, 2/46;
5: 0%, 0/46). The option of seeking Agency feedback on interpretation of FDA guidance
documents or regulations ranked third (rank score = 3.20) and the fourth rank was most common
(1: 9%, 4/46; 2: 22%, 10/46; 3: 17%, 8/46; 4: 46%, 21/46; 5: 7%, 3/46). The option “resolve a
misalignment or disagreement between the sponsor and FDA” ranked fourth (rank score = 3.65)
and the fourth and fifth ranks were most common (1: 13%, 6/46; 2: 11%, 5/46; 3: 11%, 5/46; 4:
28%, 13/46; 5: 37%, 17/46). The option “fulfill a corporate goal or organizational expectation”
had the closest weighted score to five (rank score = 4.17) and was most frequently selected as
least beneficial (1: 2%, 1/46; 2: 9%, 4/46; 3: 15%, 7/46; 4: 17%, 8/46; 5: 57%, 26/46).

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Figure 22: Distribution of Rank of Drivers for FDA Feedback
Question 13: What were the drivers for seeking regulatory feedback from FDA CBER? Using drag and
drop, please rank from most beneficial to least beneficial driver.

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Table 10: Weighted Rank Scores of Drivers for FDA Feedback
Category
Weighted Rank Score
R1 Sum N Overall WRS
(1)
R2
(2)
R3
(3)
R4
(4)
R5
(5)
Seek Agency agreement on
proposed study designs and
methods to generate data
28 18 21 8 0 75 46 1.63
Resolve questions or issues
raised during product
development
7 36 57 8 0 108 46 2.35
Seek Agency feedback on issues
relating to the interpretation and
implementation of FDA
guidance documents and/or
regulations
4 20 24 84 15 147 46 3.20
Resolve a misalignment or
disagreement between the
sponsor and FDA
6 10 15 52 85 168 46 3.65
Fulfill a corporate goal or
internal organizational
expectation
1 8 21 32 130 192 46 4.17
Abbreviations: N, number; R, rank (i.e., R1 ranks first, R2 ranks second, etc.); WRS, weighted rank score.
4.4 Input Evaluation
The second stage of the CIPP evaluation framework is the input evaluation, where the
researcher assesses the resources of the program (Stufflebeam, 2003). First, respondents were
asked whether their organization was adequately resourced to request regulatory feedback from
FDA. Most respondents agreed that their organization was adequately resourced (91%, 43/47),
but a few disagreed (9%, 4/47). Respondents who disagreed were asked why. Three respondents
offered a comment that their organizations lacked a dedicated regulatory team or people with
regulatory experience or both.
Respondents were asked to rate their level of agreement with several statements about
their organization’s experience preparing for the FDA formal meeting process using a three-point
scale (Figure 23, Table 11). For the category “understood the meeting types and their purposes”,
most respondents strongly agreed (85%, 40/47), 11% (5/47) somewhat agreed, and 4% (2/47) did

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not agree. For the category “had the scientific and medical expertise”, over three-quarters
strongly agreed (79%, 37/47), 19% (9/47) somewhat agreed, and 2% (1/47) did not agree. For
the category “had a regulatory group”, over three-quarters strongly agreed (79%, 37/47), 13%
(6/47) somewhat agreed, and 9% (4/47) did not agree. For the category “requested a meeting at
the appropriate stage of development”, almost three-quarters strongly agreed (70%, 33/47),
roughly one-quarter somewhat agreed (28%, 13/47), and 2% (1/47) did not agree. For the
category “understood the required information for a meeting request/package”, almost threequarters strongly agreed (72%, 34/47), almost one-quarter somewhat agreed (23%, 11/47), and
4% (2/47) did not agree. For the category “requested a meeting with the appropriate supporting
data”, slightly more than half strongly agreed (57%, 27/47), roughly one-third (34%, 16/47)
somewhat agreed, and 9% (4/47) did not agree. For the category “pressured to meet with FDA”,
a few respondents strongly agreed (6%, 3/47), roughly one-quarter somewhat agreed (26%,
12/47), almost two-thirds did not agree (64%, 30/47), and 4% (2/47) did not know.

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Figure 23: Distribution of Agreement amongst Respondents on Organizational
Readiness
Question 15: Thinking about your organization's experience preparing for the formal meeting process,
please rank your agreement with the following statements.

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Table 11: Weighted Scores of Agreement amongst Respondents on Organizational
Readiness
Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
Understood the meeting types and their
purposes
40 10 6 0 56 47 1.19
Had the scientific and medical
expertise to prepare the meeting
request/package
37 18 3 0 58 47 1.23
Understood the required information
for a meeting request/package 34 22 0 0 56 45 1.24
Had a regulatory group to act as the
primary link with FDA 37 12 12 0 61 47 1.30
Requested a meeting at the appropriate
stage of development (neither
premature nor overdue)
33 26 3 0 62 47 1.32
Requested a meeting with the
appropriate supporting data and/or
study designs for the meeting package
27 32 12 0 71 47 1.51
Was pressured to meet with the FDA 3 24 90 0 117 45 2.60
Abbreviations: A, somewhat agree; DNA, do not agree; DNK, do not know; N, number, SA, strongly agree; WS,
weighted score.
Respondents were asked about resources within their organization that would improve its
readiness for an FDA meeting (Table 12). Most commonly identified was a need for better and
more experienced personnel. Other resources included better information and document
templates to support authoring the meeting request and package, improving communication
within an organization, and better management of time and planning.
Table 12: Respondent Opinions on Internal Organizational Resources
Question 16: What internal organizational resources do you feel would improve your organization's
readiness for an FDA-sponsor meeting? Please briefly explain.
Category Text Response
Personnel –
Expertise in
regulatory affairs,
Medical and technical writers, SMEs with fda meeting experience
Experienced staff and or consultants are key
Regulatory affairs experts

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Category Text Response
medical/ technical
writers, and/or
SMEs with
regulatory
experience
Involvement of the SMEs to play crucial role in explaining the technical
issues, and strategies to the agencies.
Project Management support
More scientists with actual FDA interaction experience.
People with relevant experience
technical writing
CMCRA dept/ representative, quality, CMC or clinical expert
Submissions experts - getting documents ready for submission and
interacting with FDA project managers and the FDA portal
More people with experience in FDA meetings
If we had a biostatistician that would have been helpful as we were going
in for a Type C on Comparability assessment. I acted as both the technical
SME and statistician. Its extremely helpful if you have individuals
whobare strong technical communicators and have experience across
interactions with multiple agencies.
most SMEs involved in the prep work had worked on regulatory filings
before and understood the timelines involved and importance to the
company
Dedicated medical writers
Highly experienced Medical Writers for FDA-sponsor meeting briefing
books
Larger regulatory team and technical writers for CMC and clinical
sections
Technical/medical writers to support writing the meeting package and
allow the Regulatory Team Lead to focus on strategy and other aspects of
meeting preparation.
Larger dedicated regulatory team and greater organizational knowledge of
FDA meetings. SMEs were not experienced with FDA meetings or knew
how to prepare for meeting.
A dedicated regulatory team that is in house and responsible for working
on submissions and can provide regulatory strategy for submissions. Our
company also lacked a general awareness of regulatory issues and which
would have helped prepare for FDA meeting.
more experienced CMC - development staff
Study plans/
supporting data
To maintain focus on the subject, to ask for feedback that is novel in your
approach, seek guidance on what sponsor does not already know. Avoid
seeking feedback for topics that you know what the FDA will provide.
Examples or templates on prior engagements to avoid redundant
questions.
Better planning because FDA advice was sought late in development and
too close to planned submission. Any disagreement would have lead to
delay or accepting risk of clinical hold.
Document
templates doc templates for reg submissions
Communication/
engagement
Earlier involvement of the Regulatory Affairs function with the technical
teams responsible for product development to provide regulatory input
earlier in development when it's easier to change aspects versus later in
development or not at all.

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Category Text Response
More alignment with cross functional SMEs for inclusion of content
details. (Extend of the details)
Training on Technical Writing and Understanding of FDA requirements
Education opportunities with the current landscape
I can’t stress enough the importance of planning these conversations with
the agency and thinking them through internally before meeting with the
agency.
Making sure all of the important areas and departments are aware of any
intended meetings and are onboard with an agency meeting and want to
meet with regulators
Timing
Better planning because FDA advice was sought late in development and
too close to planned submission. Any disagreement would have lead to
delay or accepting risk of clinical hold.
Not applicable anymore (no longer working in Biotech directly) but
generally, in past companies, drafting the meeting request alongside the
briefing document (rather than sequentially) was worthwhile most often.
SMEs dedicating time to work on regulatory filings
4.5 Process Evaluation
The third stage of the CIPP evaluation framework is the process evaluation. In this stage,
the researcher monitors the program activities to assess the program implementation
(Stufflebeam, 2003). Respondents were asked to rate their level of agreement with several
statements about their experience preparing for the meeting request (Figure 24). For the category
“meeting/WRO request included the information outlined in FDA guidance”, most respondents
strongly agreed (83%, 39/47), 15% (7/47) somewhat agreed, and 2% (1/47) did not know. For
the category “FDA evaluated meeting/WRO request within the timeframes”, roughly threequarters strongly agreed (76%, 35/46), 17% (8/46) somewhat agreed, and 7% (3/46) did not
know. For the category “my organization planned to request a meeting/WRO as part of a product
development strategy”, most respondents strongly agreed (81%, 38/47), 11% (5/47) somewhat
agreed, 4% (2/47) did not agree, and 4% (2/47) did not know. For the category “meeting was
scheduled within FDA’s target timeframe”, roughly two-thirds strongly agreed (66%, 31/47),
roughly one-quarter somewhat agreed (26%, 12/47), 2% (1/47) did not agree, and 6% (3/47) did

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not know. The four weighted scores were similar and clustered near the minimum weighted
score of 1.00 (Table 13), which indicated that the respondents had a high level of agreement with
each of the four statements.
Figure 24: Distribution of Respondent Views on Meeting Request
Question 17: Thinking about your experience with the meeting or written responses only (WRO) request,
please rank your agreement with the following statements:

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Table 13: Weighted Scores of Respondent Views on Meeting Request
Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
Meeting/WRO request included the
information outlined in FDA
guidance
39 14 0 0 53 46 1.15
FDA evaluated meeting/WRO
request within the timeframes in
FDA guidance
35 16 0 0 51 43 1.19
My organization planned to request a
meeting/WRO as part of a product
development strategy
38 10 6 0 54 45 1.20
Meeting was scheduled within the
FDA’s target timeframe for the
meeting type
31 24 3 0 58 44 1.32
Abbreviations: A, somewhat agree; DNA, do not agree; DNK, do not know; N, number; SA, strongly agree; WS,
weighted score.
Respondents were asked to rate their level of agreement with several statements about
their experience preparing the meeting package (Figure 25, Table 14). For the category
“considered FDA guidances and ICH guidelines”, most respondents strongly agreed (91%,
43/47) and 9% (4/47) somewhat agreed. For the category “meeting package was submitted
within the timeframe”, most respondents strongly agreed (85%, 40/47), 9% (4/47) somewhat
agreed, and 6% (3/47) did not know. For the category “key internal stakeholders were involved”,
most respondents strongly agreed (83%, 39/47), 15% (7/47) somewhat agreed, and one (2%,
1/47) did not agree. For the category “appropriate scientific or medical expertise was engaged”,
most respondents strongly agreed (81%, 38/47), 17% (8/47) somewhat agreed, and one (2%,
1/47) did not agree. For the category “authoring the meeting package helped think through
previously ill-defined topics”, roughly three-quarters strongly agreed (74%, 35/47) and roughly
one-quarter (26%, 12/47) somewhat agreed. For the category “my organization committed the
time and effort”, roughly two-thirds strongly agreed (64%, 30/47), roughly one-third (32%,
15/47) somewhat agreed, and 4% (2/47) did not agree. For the category “compiling the meeting

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package identified gaps”, roughly two-thirds strongly agreed (60%, 28/47), one-third (36%,
17/47) somewhat agreed, 2% (1/47) did not agree, and 2% (1/47) did not know. For the category
“started working on the meeting package before scheduled”, roughly three-quarters strongly
agreed (72%, 34/47), 9% (4/47) somewhat agreed, and 19% (9/47) did not agree. For the
category “list of final questions was substantially different”, roughly two-thirds did not agree
(68%, 32/47), roughly one-quarter (26%, 12/47) somewhat agreed, 4% (2/47) strongly agreed,
and 2% (1/47) did not know. For the category “my organization decided not to proceed with
meeting/WRO”, most respondents did not agree (87%, 41/47), a few strongly (6%, 3/47) or
somewhat (6%, 3/47) agreed.

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Figure 25: Distribution of Respondent Views on Meeting Package
Question 18: Thinking about your experience with the meeting package (sometimes called briefing
document or briefing book), please rank your agreement with the following statements:

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Table 14: Weighted Scores of Respondent Views on Meeting Package
Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
Considered FDA guidances and ICH
guidelines when developing the meeting
package
43 8 0 0 51 47 1.09
Meeting package was submitted within
the timeframe in FDA guidance 40 8 0 0 48 44 1.09
Key internal stakeholders were involved
in preparing the meeting package 39 14 3 0 56 47 1.19
Appropriate scientific or medical
expertise was engaged in preparing the
meeting package
38 16 3 0 57 47 1.21
Authoring the questions and supporting
data for the meeting package helped
think through previously ill-defined
topics
35 24 0 0 59 47 1.26
My organization committed the time
and effort to prepare the meeting
package
30 30 6 0 66 47 1.40
Compiling the meeting package
identified gaps in knowledge 28 34 3 0 65 46 1.41
Started working on the meeting package
before the meeting/WRO was scheduled 34 8 27 0 69 47 1.47
List of final questions in meeting
package was substantially different than
list of proposed questions in meeting
request
2 24 96 0 122 46 2.65
After writing the meeting package, my
organization decided not to proceed
with the meeting/WRO
3 6 123 0 132 47 2.81
Abbreviations: A, somewhat agree; DNA, do not agree; DNK, do not know; N, number; SA, strongly agree; WS,
weighted score.
Respondents were asked whether they received written response only (WRO), a
scheduled meeting, or were denied a meeting (Figure 26). Almost two-thirds of respondents
(62%, 29/47) received WRO, almost one-third (32%, 15/47) received a scheduled meeting, and
the remaining 6% (3/47) were denied a meeting. Based on the answers to this question,
respondents who were granted WRO or a meeting were presented with three questions, whereas
those who were denied a meeting were asked two different questions.

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Figure 26: Distribution of the Outcome of the Meeting Request
Question 19: Did you receive written response only (WRO), a scheduled meeting, or was the meeting
denied? (n = 47)
Respondents who were denied a meeting were asked for the reason FDA cited for the
denial. All respondents (100%, 3/3) indicated that their meeting was denied because FDA
determined that it was premature for the stage of development. Next, respondents were asked
whether they believed that the denied meeting resulted in a delay in progress of the product.
Two-thirds (67%, 2/3) indicated that a delay resulted from the meeting denial and one-third
(33%, 1/3) indicated that no delay occurred. Respondents were asked to briefly explain their
choice. One who answered “yes” wrote that the “Denied meeting resulted in delay in regulatory
submission and slow down in program” and the one who answered “no” wrote that “We
proceeded with product mfg process with changes and according to plans anyway”.
Respondents who answered that they received WRO (Figure 26) were asked three
questions. The first question asked respondents whether the written responses satisfactorily
answered the questions posed in the meeting package and addressed the concerns that prompted
the request for FDA feedback (Figure 27). Slightly over half (55%, 16/29) indicated that the
written responses were satisfactory and no further feedback was needed, whereas slightly over

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one-third (38%, 11/29) indicated that the written responses were unsatisfactory and further
feedback was still desired. The remainder (7%, 2/29) indicated “other” and explained that
“clarifications routinely sought” or that “Some feedback was vague and required followup (sic)”.
Figure 27: Respondent Satisfaction with Written Responses
Question 20a: After reviewing the FDA CBER’s written responses, did the responses satisfactorily
answer the questions in the meeting package and sufficiently address the concerns that prompted the
meeting? (n = 29)
The second question asked respondents to rate their level of agreement with four
statements about their experience with the written responses using a three-point scale (Figure 28,
Table 15). Most respondents (90%, 26/29) strongly agreed that they reviewed written responses
with key internal stakeholders within their organization, whereas 7% (2/29) somewhat agreed
and 3% (1/29) did not know. For the category “disagree with the Agency’s recommendations”,
one respondent strongly agreed (3%, 1/29), whereas roughly half somewhat agreed (52%, 15/29)
and roughly half did not agree (45%, 13/29). Almost half of respondents strongly agreed (7%,
2/29) or somewhat agreed (41%, 12/29) that a meeting was still needed, whereas 48% (14/29)
did not agree, and 3% (1/29) did not know. Most respondents (86%, 25/29) indicated that they

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did not follow-up with FDA to request a meeting, whereas a few strongly agreed (3%, 1/29) or
somewhat agreed (10%, 3/29).
Figure 28: Distribution of Respondent Views on Written Responses
Question 21a: Thinking about your experience with the written responses, please rank your agreement
with the following statements. My organization…
Table 15: Weighted Scores of Respondent Views on Written Responses
Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
Reviewed written responses with key
internal stakeholders 26 4 0 0 30 28 1.07
Disagreed with the Agency’s
recommendations 1 30 39 0 70 29 2.41
Believed a meeting was still needed 2 24 42 0 68 28 2.43
Followed-up with FDA CBER to
request a meeting 1 6 75 0 82 29 2.83
Abbreviations: A, somewhat agree; DNA, do not agree; DNK, do not know; N, number; SA, strongly agree; WS,
weighted score.

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Respondents were asked whether their organization submitted clarifying questions to
FDA after their review of the written responses (Figure 29). Almost half (48%, 14/29) indicated
that they did not submit clarifying questions and the remaining respondents indicated that they
did. Over one-third (38%, 11/29) indicated that the FDA responses to their clarifying questions
were helpful, 7% (2/29) indicated that the FDA responses were unhelpful, and 7% (2/29)
indicated that the FDA never responded.
Figure 29: Distribution of Clarifying Questions after receiving Written Responses
Question 22a: After review of the written responses, did your organization submit clarifying questions to
FDA CBER? (n = 29)
Respondents who answered that they were granted a meeting (Figure 26) were asked
three questions. The first question asked whether the preliminary written responses satisfactorily
answered the questions posed in the meeting package and addressed the concerns that prompted
the request for FDA feedback (Figure 30). One respondent (7%, 1/15) indicated “yes” and that
their organization cancelled the meeting, and 40% (6/15) indicated “no” and their organization
proceeded with the meeting. Almost half (47%, 7/15) indicated that their organization proceeded
with the meeting even though the preliminary responses were satisfactory. When asked to

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explain why, respondents wrote that they sought “relationship building”, wanted to gain
“additional information/details of CBER’s perspective on the questions raised”, or wanted the
“opportunity to have a dialog with FDA and discuss our plans in more detail.” One respondent
(7%, 1/15) selected “other” but wrote that “we kept the meeting for further discussion”.
Figure 30: Respondent Satisfaction with Preliminary Responses
Question 20b: After reviewing the FDA’s preliminary responses, did the responses satisfactorily answer
the questions in the meeting package and sufficiently address the concerns that prompted the meeting? (n
= 15)
In the second question, respondents were asked to rate their level of agreement with
several statements about their experience with the FDA meeting (Figure 31, Table 16). For the
category “prepared presentation materials before the meeting”, most respondents strongly agreed
(85%, 11/13), 8% (1/13) somewhat agreed, and 8% (1/13) did not know. For the category
“reviewed responses with internal stakeholders”, most respondents strongly agreed (83%, 10/12),
8% (1/12) somewhat agreed, and 8% (1/12) did not know. For the category “sponsor attendees
were appropriate”, most respondents strongly agreed (85%, 11/13) and 15% (2/13) somewhat
agreed. For the category “FDA attendees were appropriate”, roughly two-thirds strongly agreed

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(69%, 9/13) and 31% (4/13) somewhat agreed. For the category “internally reviewed before the
meeting”, roughly two-thirds strongly agreed (62%, 8/13) and roughly one-third somewhat
agreed (38%, 5/13). For the category “a mutual understanding of meeting outcomes was
achieved”, less than half strongly agreed (42%, 5/12) and the remainder somewhat agreed (58%,
7/12).
Respondents were asked to rate their level of agreement with several statements about
their experience with the meeting minutes (Figure 32, Table 16). For the category “FDA minutes
were an accurate summary”, roughly half strongly agreed (54%, 7/13), roughly one-third
somewhat agreed (31%, 4/13), and 15% (2/13) did not know. For the category “my organization
submitted its own minutes”, almost half strongly agreed (46%, 6/13), 23% (3/13) somewhat
agreed, 15% (2/13) did not agree, and 15% (2/13) did not know. For the category “my
organization had a difference of understanding”, one respondent strongly agreed (8%, 1/13), a
few somewhat agreed (15%, 2/13), almost two-thirds did not agree (62%, 8/13), and 15% (2/13)
did not know.

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Figure 31: Distribution of Respondent Views on Meeting Conduct
Question 21b: Thinking about your experience with the meeting conduct and meeting minutes, please
rank your agreement with the following statements:

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Figure 32: Distribution of Respondent Views on Meeting Minutes
Question 21b: Thinking about your experience with the meeting conduct and meeting minutes, please
rank your agreement with the following statements:
Table 16: Weighted Scores of Respondent Views on Meeting Conduct and Minutes
Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
Meeting Conduct
Prepared presentation materials and
internally reviewed questions/data before
the meeting
11 2 0 0 13 12 1.08
Reviewed preliminary responses with
internal stakeholders 10 2 0 0 12 11 1.09
Sponsor attendees were appropriate for
the discussion 11 4 0 0 15 13 1.15
FDA attendees were appropriate for the
discussion 9 8 0 0 17 13 1.31
Internally reviewed agenda, objectives,
and attendees before the meeting 8 10 0 0 18 13 1.38
By the end of the meeting, a mutual
understanding of meeting outcomes and
action items was achieved
5 14 0 0 19 12 1.58
Meeting Minutes
FDA minutes were an accurate and
sufficient summary of the meeting
discussion
7 8 0 0 15 11 1.36
My organization submitted its own
meeting minutes 6 6 6 1 18 11 1.64

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Category
Weighted Score
SA Sum N Overall WS
(1)
A
(2)
DNA
(3)
DNK
(0)
My organization had a difference of
understanding regarding the content of
the meeting minutes
1 4 24 0 29 11 2.64
Abbreviations: A, somewhat agree; DNA, do not agree; DNK, do not know, N, number; SA, strongly agree; WS,
weighted score.
In the third question, respondents were asked whether their organization submitted
clarifying questions to FDA after reviewing the meeting minutes (Figure 33). Most respondents
(85%, 11/13) did not, but one indicated “yes” and that the FDA clarification was helpful (8%,
1/13). A single respondent (8%, 1/13) did not know.
Figure 33: Clarifying Questions after receiving Meeting Minutes
Question 22b: After review of the meeting minutes, did your organization submit clarifying questions to
FDA CBER? (n = 13)
Respondents were asked to rank six possible changes to the FDA-sponsor meeting
process from the most beneficial to the least beneficial change (Figure 34, Table 17). The option
“greater detail in feedback and explanation of Agency’s thinking” had the closest weighted score
to 1 (rank score = 1.61) and was most frequently selected as most beneficial (1: 66%, 27/41; 2:

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22%, 9/41; 3: 5%, 2/41; 4: 2%, 1/41; 5: 2%, 1/41; 6: 2%, 1/41). The option “shorter length of
time between meeting request and meeting date” ranked second (rank score = 3.34) and was
most frequently selected second (1: 15%, 6/41; 2: 27%, 11/41; 3: 15%, 6/41; 4: 15%, 6/41; 5:
12%, 5/41; 6: 17%, 7/41). The option “more accessible documentation about the process” ranked
third (rank score = 3.80) and was frequently selected fourth or fifth (1: 7%, 3/41; 2: 15%, 6/41;
3: 15%, 6/41; 4: 27%, 11/41; 5: 27%, 11/41; 6: 10%, 4/41). The option “documentation how to
prepare the meeting request/package” ranked fourth (rank score = 3.85) and was frequently
selected third or fourth (1: 2%, 1/41; 2: 7%, 3/41; 3: 29%, 12/41; 4: 34%, 14/41; 5: 17%, 7/41; 6:
10%, 4/41). The option “greater clarity in documentation how to use the process” ranked fifth
(rank score = 4.17) (1: 2%, 1/41; 2: 10%, 4/41; 3: 22%, 9/41; 4: 20%, 8/41; 5: 27%, 11/41; 6:
20%, 8/41). The option “longer meeting time” ranked sixth (rank score = 4.22) and was most
frequently selected sixth (1: 7%, 3/41; 2: 20%, 8/41; 3: 15%, 6/41; 4: 2%, 1/41; 5: 15%, 6/41; 6:
41%, 17/41). Although the weighted rank scores could range from a minimum of 1.00 to a
maximum of 6.00, the scores ranged from 1.61 to 4.22.

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Figure 34: Distribution of Rank of Changes to Improve Meeting Process
Question 23: Would any of the following changes have made the FDA-sponsor meeting process easier to
use? Using drag and drop, please rank from best to worst change.

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Table 17: Weighted Rank Scores of Changes to Improve Meeting Process
Category
Weighted Rank Score
R1 Sum N Overall WRS
(1)
R2
(2)
R3
(3)
R4
(4)
R5
(5)
R6
(6)
Greater detail in feedback and
explanation of Agency’s thinking
on a topic
27 18 6 4 5 6 66 41 1.61
Shorter length of time between
submission of meeting request and
date of the meeting (or written
responses)
6 22 18 24 25 42 137 41 3.34
More accessible documentation
about the process
3 12 18 44 55 24 156 41 3.80
Instructional documentation on how
to prepare the meeting request and
meeting package
1 6 36 56 35 24 158 41 3.85
Greater clarity in documentation on
how to use the process 1 8 27 32 55 48 171 41 4.17
Longer meeting time 3 16 18 4 30 102 173 41 4.22
Abbreviations: N, number; R, rank (i.e., R1 ranks first, R2 ranks second, etc.); WRS, weighted rank score.
Respondents were asked about aspects of CBER’s policies and procedures governing
meetings that they would like to change to improve the FDA meeting process. Text responses
were grouped by category (Table 18). Respondents generally preferred face-to-face meetings
instead of written responses, wanted greater detail in the feedback or greater consistency in the
responses, and a shorter overall process, especially for Type C meetings. Less commonly,
respondents wanted a longer meeting time, more specialized meetings focused by discipline, the
ability to receive clarification (e.g., after receiving WRO), and improved staffing at CBER.
Table 18: Respondent Opinions on Improving FDA Meeting Procedures
Question 24: Given the opportunity to change FDA CBER’s policies and procedures governing meetings,
what do you feel would improve the procedural design or its implementation? Please briefly explain.
Category Text Response
Shorter process Make briefing book part a requirement for the meeting request for all meetings.
Shorter time lines.

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Category Text Response
Faster scheduling of meetings and shorter time between meeting request and the
meeting
i’m overall happy with the process, just wish it was shorter
Submission of briefing book/ questions at time of meeting inquiry may shorten
scheduling time of meeting. Would be nice to get responses, either meeting or
WRO in shorter timeframe than 75days for Type C.
Longer meeting
time, and
More specialized
meetings
Option for longer meetings broken up by specific functional areas (dedicated 30
minute discussion on clinical, 15 minutes on non-clinical, etc)
Face-to-face
meetings
Make face to face meetinfa (sic)
More actual meetings and less WRO.
Face to face meetings are most effective
Mechanism to request a face-to-face meeting when a Written Response was
granted
Supporting more meeting discussions instead of WRO—WRO are much less
valuable for complex programs or organizations with limited drug development
experience.
Face-to-face
meetings, and
Greater detail
and/or consistency
in responses
At this time the policies and procedures governing meetings are quite clear, I
would like to see less WRO, more meetings but FDA is working on that postCOVID. I would also like to see greater detail in their responses consistently,
sometimes we get that other times we do not.
Greater detail
and/or consistency
in responses
More explanation of the agency’s thinking in the response.
Not acceptable to not provide input on pre-IND meeting questions. I think this
has been an issue because of resources but the Agency has an obligation to
provide sponsors with responses to their questions within the pre-IND meeting
scope.
Consistency of responses from reviewers from product to product
The peocedural (sic) design is fine. The larger issue is the subjective nature of
the feedback. There are no defined rules (which is fine there should be
exceptions when technically justified). However holding a rare disease
development process to the same guidelines as a biosimilar isn't beneficial for
patients.
Good to get feedback no matter if positive or not because we were able to then
deal with the issues
More specialized
meetings
instead of multidisciplinary milestone meetings, CMC specific EOP meetings
would help for discussing more program related CMC issues in detail.
More frequent, brief interactions
Greater vlarity (sic) on the ability to have separate meetings based on didcipline
(sic)
Clarification (postWRO/ postmeeting)
It works pretty well. If clarifying information is needed after a WRO it would be
good to have a formal process for this
Clarification (postWRO/ postmeeting), and
CBER staffing
more responsiveness from FDA project managers, ability to have informal
conversation with FDA SME during follow-up questions
CBER staffing More resources at FDa (sic)

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Category Text Response
More staff to allow offered CBER engagements
Ability to request FDA attendees and have those requested attendees attend the
meeting even when the meeting date is flexible.
4.6 Product Evaluation
The fourth stage of the CIPP evaluation framework is the product evaluation, where the
researcher assesses whether the program was effective for its intended beneficiaries
(Stufflebeam, 2003). Respondents were asked whether their organization was able to receive its
milestone meeting (e.g., pre-IND, EOP1, EOP2, or pre-BLA) with FDA (Figure 35). Most
respondents (80%, 36/45) were able to receive one. One (2%, 1/45) was denied, and the
remaining respondents (18%, 8/45) did not know.
Figure 35: Ability to receive Milestone Meetings
Question 25: If requested, was your organization able to receive its milestone meeting(s) (i.e., pre-IND,
EOP1, EOP2, or pre-BLA) with FDA CBER? (n = 45)
Respondents were asked whether their organization was able to receive a non-milestone
meeting (e.g., a Type C) with FDA (Figure 36). Slightly over half indicated that they were able
to receive a non-milestone meeting: 44% (20/45) received a meeting and 7% (3/45) received
written responses only. A few (9%, 4/45) indicated that some or all non-milestone meeting

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requests were denied. One-third (33%, 15/45) indicated that their organization did not request a
non-milestone meeting. The remaining 7% (3/45) did not know.
Figure 36: Ability to receive Non-Milestone Meetings
Question 26: If requested, was your organization able to receive a non-milestone meeting(s) (e.g., Type
A, Type C, Type D, etc.) with FDA CBER? (n = 45)
Respondents were asked whether their organizations were able to receive an
interdisciplinary meeting and/or increased interactions with FDA CBER if granted Breakthrough
Therapy and/or RMAT designation (Figure 37). Roughly one-quarter (24%, 11/45) indicated that
they received an interdisciplinary meeting and increased interactions, while 7% (3/45) indicated
that they received such a meeting, but not the increased interactions. Amongst respondents who
had an interdisciplinary meeting, 79% (11/14) received increased interactions but 21% (3/14) did
not. None (0%, 0/45) indicated that their interdisciplinary meeting was denied. Over half (56%,
25/45) indicated that they did not have either Breakthrough Therapy or RMAT designation. The
remaining 13% (6/45) did not know.

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Figure 37: Ability to receive Interdisciplinary Meeting
Question 27: If you received Breakthrough Therapy and/or RMAT designation, was your organization
able to receive its interdisciplinary meeting and increased interactions with FDA CBER? (n = 45)
Respondents were asked whether they believed that the regulatory feedback received
from the meeting or written responses was effective (Figure 38). Most (87%, 39/45) indicated
“yes”, whereas 9% (4/45) indicated “no”, and 4% (2/45) did not know. Three respondents who
answered “no” identified a disconnect across disciplines as CMC feedback was not aligned with
clinical feedback, a misalignment on timing of process validation studies for a product in phase 3
clinical study, or a disagreement with feedback on a product intended for a rare disease.

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Figure 38: Respondent Opinion on Effectiveness of FDA Meeting
Question 28: Do you feel that the regulatory feedback received from the meeting or written responses was
effective? In other words, your organization formulated relevant questions and proposals that were
appropriate given the available data and stage of development for the WRO/meeting. (n = 45)
Respondents were asked to rank six benefits that the regulatory feedback offered their
organization from the most beneficial to the least beneficial (Figure 39, Table 19). The option
“reduced potential setbacks” had the closest weighted score to 1 (rank score = 1.41) and was
most frequently selected as most beneficial (1: 73%, 30/41; 2: 15%, 6/41; 3: 10%, 4/41; 4: 2%,
1/41; 5-6: 0%, 0/41). The option “provided transparency to the regulatory review process”
ranked second (rank score = 2.54) and was most frequently selected second (1: 15%, 6/41; 2:
39%, 16/41; 3: 29%, 12/41; 4: 15%, 6/41; 5: 0%, 0/41; 6: 2%, 1/41). The option “built a
relationship with the Agency reviewers” ranked third (rank score = 3.17) and was frequently
selected second (1: 7%, 3/41; 37%, 15/41; 3: 27%, 11/41; 4: 7%, 3/41; 5: 5%, 2/41; 6: 17%,
7/41). The option “fewer studies were required” ranked fourth (rank score = 4.32) and was
frequently selected fifth (1: 2%, 1/41; 2: 5%, 2/41; 3: 17%, 7/41; 4: 27%, 11/41; 5: 32%, 13/41;
6: 17%, 7/41). The option “shortened development time” was ranked fifth (rank score = 4.32)
and was frequently selected fifth (1: 2%, 1/41; 2: 5%, 2/41; 3: 15%, 6/41; 4: 29%, 12/41; 5: 34%,
14/41; 6: 15%, 6/41). The option “lowered development cost” was ranked sixth (rank score =
5.27) and was most frequently selected sixth (1-2: 0%, 0/41; 3: 2%, 1/41; 4: 20%, 8/41; 5: 29%,

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12/41; 6: 49%, 20/41). Although weighted rank scores could range from a minimum of 1.00 to a
maximum of 6.00, the scores had a wide range from 1.41 to 5.27.
Figure 39: Distribution of Ranking of Advantages from the FDA Feedback
Question 29: After receiving FDA feedback from the meeting or written responses, what advantages do
you think that the regulatory feedback offered for your organization's product development? Please rank
from most beneficial to least beneficial advantages.

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Table 19: Weighted Rank Scores of Advantages from the FDA Feedback
Category
Weighted Rank Score
R1 Sum N Overall WRS
(1)
R2
(2)
R3
(3)
R4
(4)
R5
(5)
R6
(6)
Reduced potential
setbacks 30 12 12 4 0 0 58 41 1.41
Provided transparency to
the regulatory review
process
6 32 36 24 0 6 104 41 2.54
Built a relationship with
the Agency reviewers 3 30 33 12 10 42 130 41 3.17
Fewer studies were
required 1 4 21 44 65 42 177 41 4.32
Shortened development
time 1 4 18 48 70 36 177 41 4.32
Lowered development cost 0 0 3 32 60 120 215 41 5.27
Abbreviations: N, number; R, rank (i.e., R1 ranks first, R2 ranks second, etc.); WRS, weighted rank score.
Previously, as part of the Context Evaluation section, respondents were asked to rank five
reasons for seeking feedback from FDA from most to least beneficial (Figure 22). In this
question, respondents were asked to rate their level of agreement with these same five reasons
based upon their experience with the regulatory feedback and rate whether that benefit was
obtained or not using a three-point scale (Figure 40, Table 20). For the category “obtained clarity
on issues related to interpretation of FDA guidances or regulations”, almost three-quarters (74%,
32/43) agreed, whereas 19% (8/43) neither agreed nor disagreed, and 7% (3/43) disagreed. For
the category “fulfilled corporate goal”, slightly over half (57%, 24/42) agreed, over one-third
(38%, 16/42) neither agreed nor disagreed, one (2%, 1/42) disagreed, and one (2%, 1/42) did not
know. For the category “satisfactorily resolved a misalignment or disagreement”, almost twothirds of respondents (62%, 18/29) agreed, whereas 31% (9/29) neither agreed nor disagreed, and
7% (2/29) disagreed. For the category “satisfactorily resolved issues raised during product
development”, almost two-thirds of respondents (64%, 28/44) agreed, 27% (12/44) neither
agreed nor disagreed, and 9% (4/44) disagreed. For the category “achieved FDA agreement on

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proposed study designs”, slightly over half (59%, 26/44) agreed, whereas 27% (12/44) neither
agreed nor disagreed, and 14% (6/44) disagreed.
Figure 40: Distribution of Respondent Views on Drivers of FDA Feedback
Question 30: Based upon your experience with the regulatory feedback received from the meeting or
written responses, please rank your agreement with the following statements:

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Table 20: Weighted Scores of Respondent Views on Drivers of FDA Feedback
Category
Weighted Score
A Sum N Overall WS
(1)
NAnD
(2)
D
(3)
DNK / NA
(0)
Obtained clarity on issues relating
to the interpretation and
implementation of FDA guidance
documents and/or regulations
32 16 9 0 57 43 1.33
Fulfilled corporate goal or
expectation 24 32 3 0 59 41 1.44
Satisfactorily resolved a
misalignment or disagreement
between the sponsor and FDA
18 18 6 0 42 29 1.45
Satisfactorily resolved questions
or issues raised during product
development
28 24 12 0 64 44 1.45
Achieved FDA agreement on
proposed study designs and
methods to generate data
26 24 18 0 68 44 1.55
Abbreviations: A, agree; D, disagree; DAnD, neither agree nor disagree; DNK / NA, do not know / not applicable;
N, number; WS, weighted score.
Respondents were asked whether their organization implemented the advice and
recommendations from FDA (Figure 41). Almost half (49%, 22/45) answered “yes” that their
organization implemented all advice and recommendations, and a similar number (44%, 20/45)
implemented some, but not all, of the advice or recommendations. One (2%, 1/45) indicated “no”
and the remaining 4% (2/45) did not know.

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Figure 41: Implementation of FDA Advice and Recommendations
Question 31: Did your organization implement FDA's advice and recommendations? (n = 45)
Respondents were then asked if they believed that the implemented regulatory advice and
recommendations had a positive impact on product development (Figure 42). Over three-quarters
(78%, 32/41) answered “yes”, while 7% (3/41) answered “no”, and 15% (6/41) answered
“maybe”. Respondents were asked to briefly explain their answer choice (Table 21).
Figure 42: Respondent Views of Impact of FDA Advice and Recommendations
Question 32: Do you feel that the implemented regulatory advice and recommendations had a significant
positive impact on product development? Please briefly explain your answer. (n = 41)

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Table 21: Summary of Respondent Views of Impact of FDA Advice and
Recommendations
Question 32: Do you feel that the implemented regulatory advice and recommendations had a significant
positive impact on product development? Please briefly explain your answer.
Answer Text Response
Yes
Understanding where FDA is on certain issues it is helpful to know how to frame the topic
in future submissions so we need to treat any advice like piece of data and apply it as
needed.
Clarity on expectations was key as well as the ability to better explain challenges.
Having early engagement with FDA has, from my experience de-risked the overall strategy
prior to implementing or executing regulatory or technical impedance on product
development.
Implemented advice lead to delays but submission approved.
Clarity for filing requirements
Clarity allowed the organization to focus on the most important issues and experiments
Many meetings leading up to and during BLA review that supported the eventual approval
The responses received were helpful but they did not answer any of the clinical questions.
Provided clarity on data expectations
reduced uncertainty for getting the IND approved
Allowed relatively smooth review of IND with few questions or changes to implement or
additional studies needed
Gained alignment of the regulatory filing requirements for a BLA
The advice for near-term studies was implemented and allowed our program to proceed as
planned and for the organization to hit our milestones, and the forward looking feedback
was considered for future use.
No
We followed all advice but still received a refusal to file because of issues the FDA never
raised during review
Delay in filing because of recommendations and making them work
Maybe
Potentially reduced contamination and criss (sic) contamination risks
We had to produce additional clinical batches and tighten some specifications
They were as expected
Implemented advice probably reduced risk of program setbacks, but no major surprises
A cross-tabulation was performed to explore any association between an organization
implementing FDA advice and recommendations (in Question 31) and whether the implemented
regulatory feedback had a positive impact on product development (in Question 32) (Table 22).
As expected, when an organization implemented the feedback, the feedback was most likely to
have a positive impact (86%, 19/22). Surprisingly, when an organization implemented the
feedback, a negative impact on product development occurred for 9% (2/22) of respondents. The
reasons for the negative impact are provided in Table 21 as these two respondents provided the

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two “no” text responses in that table, which included receiving a refuse to file (RTF) for issues
that the FDA did not raise in its feedback or a delay in a planned regulatory filing to allow time
to implement the recommendations. When an organization implemented some of the feedback,
two-thirds (65%, 13/20) reported a positive impact and roughly one-third (30%, 6/20) reported
“maybe” as a possible positive impact, but only one (5%, 1/20) reported a negative impact. The
reasons for this negative impact are not provided in Table 21, but this respondent wrote in an
earlier question that the organization did not understand the FDA feedback and felt that FDA
feedback was subjective but did not elaborate. Not enough respondents answered “no” in
Question 31 to allow investigation of not following FDA feedback.
Table 22: Cross-tabulation of Implementation of FDA Feedback against Outcome on
Product Development
Whether
implemented
feedback had a
positive impact
(Question 32)
Implementation of FDA Feedback (Question 31)
Yes, my organization
implemented all advice
and recommendations
My organization implemented some
of the advice and recommendations,
but not all of them
Total
N % N % N
Yes 19 86% 13 65% 32
No 2 9% 1 5% 3
Maybe 0 0% 6 30% 6
Blank 1 5% 0 0% 4
Total 22 100% 20 100% 45
Footnote: One respondent selected “no” for Question 31 and left Question 32 blank. Two respondents selected “do
not know” for Question 31 and left Question 32 blank. These three are not shown in the table.
Respondents were asked to rate their level of concern with four statements about
obtaining regulatory feedback from FDA in the future using a three-point scale (Figure 43, Table
23). For the category “delay in product development because unable to obtain advice”, almost
half were very concerned (42%, 18/43), 28% (12/43) somewhat concerned, and 30% (13/43) not
concerned. For the category “delay in product development because time needed to prepare for

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meeting”, some respondents were very concerned (19%, 8/42), whereas half were somewhat
concerned (50%, 21/42), and 31% (13/42) were not concerned. For the category “meeting
request will be denied”, some respondents were very concerned (19%, 8/43), whereas 40%
(17/43) were somewhat concerned and a similar percentage were not concerned (42%, 18/43).
For the category “unable to resolve a disagreement”, a few were very concerned (10%, 4/40),
slightly more than half were somewhat concerned (53%, 21/40), and the remainder were not
concerned (38%, 15/40).

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Figure 43: Distribution of Respondent Views on Concerns with obtaining FDA
Feedback
Question 33: Thinking about possible concerns with obtaining regulatory feedback from FDA in the
future, please rank your level of concern with the following statements.
Table 23: Weighted Scores of Respondent Views on Concerns with obtaining FDA
Feedback
Category
Weighted Score
VC Sum N Overall WS
(1)
SC
(2)
NC
(3)
NA
(0)
Delay in product development because
unable to obtain meaningful advice or
recommendations
18 24 39 0 81 43 1.88
Delay in product development because
of time needed to prepare for meeting
and wait for feedback
8 42 39 0 89 42 2.12
Meeting request will be denied 8 34 54 0 96 43 2.23
Unable to resolve a disagreement with
FDA 4 42 45 0 91 40 2.28
Abbreviations: N, number; NA, not applicable; NC, not concerned; SC, somewhat concerned; VC, very concerned;
WS, weighted score.

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Respondents were given the option to select “other”, provide a rating, and specify an
additional concern that were not captured in the four statements in Figure 43. These other
concerns are summarized in Table 24 for the six respondents who choose to provide an
additional concern.
Table 24: Summary of Respondent Views on Other Concerns with obtaining FDA
Feedback
Rating Statement of Concern
Very Concerned
unable to receive Type C meeting for similar topic again in new request
Loss of reviewers with subject matter expertise
Inexperienced FDA reviewers
Variation in responses between reviewers between different products
Somewhat
Concerned
Ability to have scientific dialogue with FDA early enough in development
when we need it vs WRO meetings
Blank (No rating
was selected) Understaffed so unable to meet requirements within timeframe required.
Respondents were asked to rank seven factors that would influence a decision whether to
use or recommend the use of FDA-sponsor meetings in the future from the most to the least
influential (Figure 44, Table 25). The option “development plans do not include the U.S.” had
the closest weighted score to 1 (rank score = 2.28) and was most frequently selected as the most
influential (1: 59%, 23/39; 2: 10%, 4/39; 3: 13%, 5/39; 4: 5%, 2/39; 5-6: 0%, 0/39; 7: 13%,
5/39). The option “benefits of regulatory advice outweigh the organizational time and effort”
ranked second (rank score = 3.26) and was most frequently selected second (1: 18%, 7/39; 2:
44%, 17/39; 3: 8%, 3/39; 4: 5%, 2/39; 5: 0%, 0/39; 6: 3%, 1/39; 7: 23%, 9/39). The option
“process is too long” ranked third (rank score = 3.49) and was most frequently selected third (1:
8%, 3/39; 2: 23%, 9/39; 3: 28%, 11/39; 4: 13%, 5/39; 5: 15%, 6/39; 6: 8%, 3/39; 7: 5%, 2/39).
The option “process is too complex” ranked fourth (rank score = 4.15) and was most commonly

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selected fourth (1: 10%, 4/39; 2: 0%, 0/39; 3: 18%, 7/39; 4: 38%, 14/39; 5: 15%, 6/39; 6: 13%,
5/39; 7: 8%, 3/39). The option “inaccurate meeting timelines” ranked fifth (rank score = 4.44) (1:
0%, 0/39; 2: 13%, 5/39; 3: 21%, 8/39; 4: 21%, 8/39; 5: 18%, 7/39; 6: 13%, 5/39; 7: 15%, 6/39).
The option “instructions about using the process are insufficient” ranked sixth (rank score =
4.85) but was most frequently selected fifth (1: 3%, 1/39; 2: 8%, 3/39; 3: 8%, 3/39; 4: 10%, 4/39;
5: 38%, 15/39; 6: 23%, 9/39; 7: 10%, 4/39). The option “additional training is required to
understand and use the process” ranked seventh (rank score = 5.54) but was most frequently
selected sixth (1: 3%, 1/39; 3%, 1/39; 3: 5%, 2/39; 4: 10%, 4/39; 5: 13%, 5/39; 6: 41%, 16/39; 7:
26%, 10/39).

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Figure 44: Ranking of Factors influencing Respondent’s Use of FDA Meetings
Question 34: Which of the following factors will influence your decision about whether you will use or
recommend the use of FDA-sponsor meetings with CBER in the future? Using drag and drop, please rank
the factors from most influential to least influential.

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Table 25: Weighted Rank Scores of Factors influencing Respondent’s Use of FDA
Meetings
Category
Weighted Rank Score
R1 Sum N Overall WRS
(1)
R2
(2)
R3
(3)
R4
(4)
R5
(5)
R6
(6)
R7
(7)
Development plans do not
include the U.S. 23 8 15 8 0 0 35 89 39 2.28
Benefits of regulatory advice
do not outweigh the
organizational time and
effort
7 34 9 8 0 6 63 127 39 3.26
Process is too long 3 18 33 20 30 18 14 136 39 3.49
Process is too complex 4 0 21 56 30 30 21 162 39 4.15
Meeting timelines are
inaccurate or unreliable 0 10 24 32 35 30 42 173 39 4.44
Instructions (e.g., FDA
guidance) about how to use
the process are insufficient
1 6 9 16 75 54 28 189 39 4.85
Additional training is
required to understand and
use the process
1 2 6 16 25 96 70 216 39 5.54
Abbreviations: N, number; R, rank (i.e., R1 ranks first, R2 ranks second, etc.); WRS, weighted rank score.
Respondents were asked to rate how well they believed that the FDA meeting process
met the needs of product development for their organization on a scale of 0 (not at all) to 10
(completely) (Figure 45). Most respondents rated the FDA meeting process favorably: 43%
(19/44) rated it an 8, 30% (13/44) rated a 9, and 9% (4/44) rated it a 10. The remaining ratings
were 5% (2/44) each for 4, 5, 6, and 7. The weighted average rating was 8.02.

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Figure 45: Overall Rating of Respondent Opinion on FDA-Sponsor Meeting
Question 35: On a scale of 0 to 10, how well did the FDA-sponsor formal meeting process meet the needs
of product development for your organization? (n = 44)
4.7 INTERACT Meeting
Based on a recommendation from the focus group, respondents were asked about any
experience with the INTERACT meeting given the recent introduction of this meeting type.
Respondents were asked whether their organization requested an INTERACT meeting (Figure
46). Almost one-third of respondents (32%, 14/44) had experience with the INTERACT meeting
while almost two-thirds (68%, 30/44) did not have such experience or did not know. Those who
answered “yes” (n = 14) were then asked additional questions about their experience.

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Figure 46: Distribution of Respondents who Requested an INTERACT Meeting
Question 36: Did your organization request an INTERACT meeting? Choose one option. (n = 44)
Respondents were asked which topics were included in the INTERACT meeting
request/package (Figure 47). Roughly three-quarters of meeting packages (79%, 11/14) included
CMC aspects and most (86%, 12/14) included non-clinical aspects. Slightly less than half (43%,
6/14) included clinical aspects and less than one quarter (21%, 3/14) included general regulatory
topics. Only four of the 14 meeting packages had a single topic (CMC, non-clinical, or clinical
only), whereas the remaining 10 had multiple topics (commonly CMC, non-clinical, and clinical
aspects), which reflected the multidisciplinary focus with which respondents used the
INTERACT meeting.
Figure 47: Distribution of Topics in the INTERACT Meeting Request
Question 36a: What topics were asked in the INTERACT meeting request/package? Select all that apply.
(n = 14)

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Respondents were asked to rate their level of agreement with seven statements about their
experience preparing the INTERACT meeting request and package using a three-point scale
(Figure 48). For the category “authoring questions helped think through ill-defined topics”, most
respondents (86%, 12/14) agreed, 7% (1/14) neither agreed nor disagreed, and 7% (1/14) did not
know. For the category “identified gaps in knowledge”, almost three-quarters of respondents
(71%, 10/14) agreed, almost one-quarter (21%, 3/14) neither agreed nor disagreed, while 7%
(1/14) did not know. For the category “had the scientific and medical expertise”, slightly over
two-thirds of respondents (69%, 9/13) agreed, almost one-quarter (23%, 3/13) neither agreed nor
disagreed, and 8% (1/13) did not know. For the category “had the regulatory expertise”, slightly
over three-quarters of respondents (77%, 10/13) agreed, 8% (1/13) neither agreed nor disagreed,
8% (1/13) disagreed, and 8% (1/14) did not know. For the category “understood the required
information for the meeting package”, three-quarters of respondents (79%, 11/14) agreed, 14%
(2/14) neither agreed nor disagreed, and 7% (1/14) disagreed. For the category “was pressured to
meet with FDA”, a few (14%, 2/14) agreed, about one-quarter (29%, 4/14) neither agreed nor
disagreed, half (50%, 7/14) disagreed, and 7% (1/14) did not know. For the category “struggled
to identify a product”, one (7%, 1/14) agreed, a few (14%, 2/14) neither agreed nor disagreed,
and over three-quarters (79%, 11/14) disagreed.

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Figure 48: Distribution of Respondent Views on Preparation of the INTERACT
Meeting Package
Question 36b: Thinking about your organization’s experience preparing the INTERACT meeting
request/package, please rank your agreement with the following statements. My organization…
Respondents were asked whether their INTERACT meeting request was granted or
denied. FDA granted the meeting for most (79%, 11/14) and denied almost one-quarter (21%,
3/14).
Respondents who answered that their INTERACT meeting request was granted were then
asked whether they believed the meeting helped to progress the product towards entry into a
clinical investigation (Figure 49). Most respondents (91%, 10/11) indicated that the meeting was

145
helpful and one (9%, 1/11) indicated that it was not. Eight respondents provided a brief
explanation for their answer choice (Table 26).
Figure 49: Respondent Opinion on Impact of INTERACT Meeting
Question 36d: In your opinion, did the INTERACT meeting help to progress the product towards entry
into the clinic? Please briefly explain your choice. (n = 11)
Table 26: Text Responses from Respondents about the INTERACT Meeting
Answer Text Response
Yes, the INTERACT
meeting was helpful
Expedited product development to FIH
Clarity on development path
Helped focus early work
Yes, required elements of nonclinical studies were defined.
Provided clarity on planned nonclinical development plan and study
outlines.
Great feedback for early development prior to IND enabling studies
Expertise provided
No, the INTERACT
meeting was not helpful time to meeting; broad/general feedback
Respondents who answered that their INTERACT meeting request was denied were then
asked for the reason FDA cited for the denial. FDA cited that the meeting was premature for the
stage of development for two of the three respondents, and the third respondent indicated “other”
and the FDA explained that the topics needed to be covered in a pre-IND meeting. The three
respondents were then asked for their opinion whether the denied INTERACT meeting resulted
in a delay in progress of their product towards entry into a clinical investigation. Two indicated

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that there was no delay and one did not know, but none provided an explanation for their answer
choice.
The 14 respondents were asked about their overall experience with the INTERACT
meeting process using a yes/no scale (Figure 50). For the category “do you intend to request a
pre-IND meeting”, most respondents indicated “yes” (86%, 12/14), 7% (1/14) indicated “no”,
and 7% (1/14) did not know. For the category “do you intend to request another INTERACT
meeting”, slightly over one quarter of respondents (29%, 4/14) indicated “yes”, 50% (7/14)
indicated “no”, and 21% (3/14) did not know. For the category “did you have prior interactions
with FDA”, slightly over one quarter of respondents (29%, 4/14) indicated “yes”, 57% (8/14)
indicated “no”, and 14% (2/14) did not know. For the category “do you intend to request a Type
C meeting as an alternative”, one (7%, 1/14) indicated “yes”, almost three-quarter (71%, 10/14)
indicated “no”, and 21% (3/14) did not know.
Figure 50: Distribution of Respondent Views on INTERACT Meeting
Question 36e: Thinking about your experience with the INTERACT meeting process, please rank your
agreement with the following statements.

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Last, respondents were asked whether they were satisfied with the INTERACT meeting
(Figure 51). Slightly over two-thirds (69%, 9/13) indicated that they were satisfied, but a quarter
(23%, 3/13) were dissatisfied, and 8% (1/13) did not know. Six respondents provided a brief
explanation for their answer choice (Table 27).
Figure 51: Respondent Satisfaction with INTERACT Meeting
Question 36f: Given your experience, were you satisfied with the INTERACT meeting process? Please
briefly explain your choice. (n = 13)
Table 27: Text Responses of Respondent Experience with the INTERACT Meeting
Process
Answer Text Response
Yes, I was satisfied with the
INTERACT meeting process
Clarity
Helpful input
confirmed development plans, provided insights
Expertise provided
No, I was dissatisfied with the
INTERACT meeting process
Wish we could submit the briefing book 30 days before meeting
rather than 75
Because meeting was denied
4.8 Final Question
The final survey question asked respondents if they had any comments that were not
captured in the earlier questions (Table 28).

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Table 28: Final Comments from Respondents
Question 37: Do you have any comments that were not captured above?
Text Responses
Overall, I think the meeting types and guidances are sufficient and if planning is done correctly they do
not need to be a burden during the development process. Organizations need to own the questions they
are asking and make sure they are correct. We need to guide organizations to ask questions at the right
time and with the right data sets in order to ensure FDA can answer. We cannot use meetings to drive
development in totality, there are things the industry needs to know and apply. By using the meetings
correctly, FDA and industry benefit because they are meaningful and it lessens concerns over resources
on both sides and keeps FDA wanting to interact with industry.
Ex-US agency interactions and FDA-ex-US combined interaction
Not all INTERACT meeting requests are granted. FDA had a staffing issue at that time
CBER is under resourced and I think this is creating issues.
FDA should attempt to grant more face to face meetings
Newer FDA guidances from past year or two should help and could have benefited us
With current company, FDA interactions H e (sic) been smooth but this has not always beeen (sic) the
case at previous companies where we had difficulty getting timely feedback even with RMAt (sic)
designation. Also, it can still be difficult to benchmark across different sponsor experienxes (sic)
I believe it would be useful to investigate whether the briefing booklet can be submitted an ECT format
to make finding and review of information easier on review staff and facilitate transition from pre-IND
meeting to submission

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Chapter 5. Discussion
5.1 Overview of Research
Advanced therapies, such as cell and gene therapies (CGTs), offer a novel approach to
treating serious illnesses compared with small molecule or biological products. Although the
FDA has established a regulatory framework for CGTs, developers may need help understanding
how to comply with these regulatory requirements. Sponsors may seek formal meetings with the
FDA to obtain feedback on product development plans at critical points in the regulatory
process. It has yet to be widely discussed in the literature whether the goals of this program are
being fully realized for these advanced therapies and where improvements to the design and use
of meetings may be identified. This research project used an electronic survey to measure
responses from regulatory professionals working in the industry who have experience developing
CGT products and interacting with the FDA. These results provide a systemic evaluation of the
FDA meeting process from the perspective of the individuals responsible for the development of
these therapeutics. However, the interpretation of these results depends upon an understanding of
the limitations of the study and the delimitations that restrict the scope of the study.
5.2 Considerations of Study Methodology
This research project used an online, electronic survey as a data collection tool. This
approach was selected based on a consideration of the research objectives, the target
respondents, and data collection needs. My sample of potential respondents was widely
distributed geographically, reflecting the fact that biopharmaceutical companies and their
employees are located throughout the country. I considered a survey to be the best approach to
gathering information. Other approaches, such as paper-based surveys, interviews, or focus
groups, lacked anonymity and confidentiality, could be complicated to organize and facilitate for

150
those living at a distance, and could be difficult to analyze (Mansell et al., 2004, Smithson, 2000,
Sue and Ritter, 2007). Further, traditional survey approaches, such as mailed paper surveys,
telephone surveys, or face-to-face surveys, would have been time consuming, could have higher
cost, and could have lower response rates than electronic surveys (Granello and Wheaton, 2004,
Sue and Ritter, 2007).
5.2.1 Limitations
This study had limitations that impacted the interpretation of the findings from the
survey. The survey participants were employed in the biopharmaceutical industry and
represented views from an industry perspective. The fact that the survey reached relevant
stakeholders in the industry appeared clear given that only two of the respondents worked in
academia and none worked in government. However, the study did not look at other viewpoints,
such as those of the regulators.
A concern at the outset of the study was that survey participants may be reluctant to share
their opinions or to participate in the study altogether because the information that they were
asked to give may be deemed proprietary. If the respondent was not forthcoming, those
responses would affect the validity and reliability of the survey results. I addressed this limitation
to some extent by avoiding questions that asked for proprietary or confidential information and
by providing assurances that the responses were anonymized with respect to both the names of
participants and their affiliated institutions. Such assurances may be adequate for a selfadministered survey (Schaefer and Dillman, 1998). Further, I created and distributed the webbased survey using Qualtrics. This survey administration method was selected so that the survey
would appear professional and trustworthy to lessen concerns for participation. I asked
respondents to focus on a particular situation within a recent time period when completing the

151
survey to increase the accuracy of their responses, which would improve the validity of the
measurement (Sue and Ritter, 2007). Also, I included “do not know”, “not applicable”, or similar
answer choices to give respondents the option to opt out of a question that was not seen to be
applicable. If a respondent was unfamiliar with a topic, then these options prevented the
respondent from choosing an answer choice for the sake of appearing informed, which would
impact the validity of the measurement (Sue and Ritter, 2007). The fact that many respondents
shared strongly stated views may be one indication that most felt comfortable with the measures
I introduced to allow free expression of views.
Results could also be limited if survey participants failed to complete the entire survey,
especially if the length of the survey was viewed to be too long. Failure to complete the entire
survey would result in a high drop-out rate, which would reduce the size of the dataset obtained
from later questions and provide an incomplete picture of the respondent’s views. Longer
surveys are known to be associated with lower participation and completion rates (Deutskens et
al., 2004, Galesic and Bosnjak, 2009, Marcus et al., 2007). This potential limitation was
addressed to some extent by restricting the number of questions to 37, though I recognized that
this would limit the depth and breadth of the survey. The completion rate was calculated as 61%,
which is consistent with a reported value of 65% in the literature (Göritz, 2006).
The number of questions and the types of questions can affect the quality of responses
(Crawford et al., 2001, Galesic and Bosnjak, 2009). The likelihood that the respondents could
answer most of the questions was addressed by asking initial questions regarding employment to
eliminate respondents without relevant experience. Skip-logic methods were used to avoid
asking irrelevant questions to respondents without appropriate experiences, and the number of
open-ended questions was limited so that text entries would not potentially retard survey

152
completion. Last, validating the survey through a focus group provided feedback that appeared
helpful to improve the navigability of the survey (van Teijlingen and Hundley, 2002).
At the outset of the study, I recognized that the number of participants might be small
because a limited number of companies have been developing CGT products and many are still
at an early stage of development. The number would therefore be further reduced if the
regulatory professionals may not yet have had relevant experience to participate or may consider
themselves too busy to add participation to an already demanding workload. A small sample size
would reduce the generalizability of the results. Nonetheless, the survey achieved 48 completed
responses, which I considered sufficient. This sample size is considered acceptable in social
science research (Hill, 1998), especially in a situation where the respondents are more
homogeneous in their backgrounds, research objectives are focused, and where saturation
appears to have been reached. Hennink and Kaiser assessed sample sizes needed to achieve
saturation for qualitative research methods and they concluded that saturation can be reached
with a sample size smaller than 25 (Hennink and Kaiser, 2022).
Obtaining a high response rate was also challenging for other reasons. I wrote the survey
invitation to stimulate the interest of the potential participant into making a worthwhile
contribution. The invitation included a descriptive title, introduced the purpose of the survey,
emphasized the important of the research, informed the approximate time to complete the survey,
assured anonymity and confidentiality, and provided a link to the survey for ease of responding.
The invitation thanked the reader in advance and my name was signed as a regulatory science
student with my affiliated academic institution. These elements are recommended to increase the
response rate (Crawford et al., 2001, Sue and Ritter, 2007). I also programmed Qualtrics to
follow-up with non-responders and send a reminder message. Follow-up is recommended to

153
increase the response rate (Crawford et al., 2001, Granello and Wheaton, 2004, Schaefer and
Dillman, 1998, Sue and Ritter, 2007). Third, I provided an incentive for participation by offering
a summary of the results. Participation was without financial compensation, although
respondents were offered the survey results as an incentive for their participation, which have
helped to increase the number of responses (Göritz, 2006). Non-material incentives are
recommended to increase the response rate and decrease the drop-out rate (Göritz, 2006). In my
survey, a response rate of 33% and a completion rate of 61% was achieved. The literature
indicates that a wide range of response rates can be expected in online surveys. Response rates
for web-based surveys are often reported to be approximately 30% (Kwak and Radler, 2002, Sue
and Ritter, 2007).
5.2.2 Delimitations
This study was delimited intentionally in certain ways to restrict the scope of the study.
Perhaps most importantly, it addressed a very specific aspect of regulatory activity, that of
meetings with the federal regulators. FDA-sponsor meetings are the single most important point
of contact for companies aspiring to commercialize their product because they provide an
opportunity for discussion of all technical and medical aspects of drug development to allow a
sponsor to modify study designs and collect data that may be more suitable for a future
marketing application. Other activities that contribute to development, such as guidances, were
explored only tangentially to allow for a focused research topic, which gave me the ability to be
more thorough. In my study, I organized the survey questions based on the four aspects of the
CIPP evaluation framework. This framework offered a systematic approach that was an
appropriate tool for this study as it examines planning, operation, and outcomes of a program and
focuses on stakeholders, which was important for my research objectives.

154
The study was delimited to industry professionals who had interacted with FDA and who
had experience primarily with CGT products, although some respondents had experience with
biological products. In those roles, they should have been involved with regulatory agency
interactions, IND applications, BLAs, or lifecycle management of biological or CGT products.
The fact that 47 respondents had an appropriate demographic profile suggested that the target
audience was reached successfully. That the respondents were mostly regulatory professionals is
not surprising given that these individuals are usually involved progressively across the full
breadth of product development, including preclinical development, clinical development, and
post-market activities. Further, they were most likely to be the individuals to prepare for and be
present at those meetings and thus have the deepest understanding of their strengths and
weaknesses. However, care must be taken to recognize that this is a singular perspective, and that
other individuals in different job functions internal or external to a company may not share the
same views.
As a second delimitation, the scope encompassed clinical, non-clinical, and quality
aspects of CGT product development, which are typically a focus for FDA meetings. Most of the
approved CGT products encountered challenges in one or more of these aspects, and many
products were granted an expedited program. Although FDA has made efforts to develop
mechanisms for enhanced interactions for novel products, it is unclear how useful industry
stakeholders have perceived these meetings.
Further, the study was delimited geographically to the United States and engaged
potential respondents who worked for organizations operating in the U.S. (e.g., sponsoring a
clinical trial in the U.S.). Although CGT products are developed in other regions, and the health
authorities in these other regions may offer scientific advice for sponsors, this study focused

155
specifically on the U.S. and within the CBER center of FDA, which is mainly responsible for the
oversight of these advanced therapies. If this study investigated other regions, then the findings
would be more generalizable across multiple regions. However, foreign authorities have different
regulatory frameworks and procedures, so the experiences of potential respondents with other
regulatory agencies might blur insights that I could gain regarding the U.S. system. Further, this
study focused on the U.S. because of the extensive history of CGT product development in the
country and the large number of active clinical trials (ARM, 2022). The U.S. has an established
regulatory framework that has resulted in approved CGT products since 2010, and FDA has
conducted formal meetings with sponsors since at least the 1980s (21CFR§312, 2022). The U.S.
system offered the appropriate combination of factors that allowed for the evaluation of FDAsponsor meetings in the development of CGT products, but the results from this study may not
generalize to other regions.
Finally, the study was delimited in time. The survey collected industry views between
December 2023 and March 2024. The views of respondents may change as the field matures. For
example, FDA meeting management underwent changes with the most recent PDUFA reauthorization (Chhina et al., 2022, FDA, 2021b, FDA, 2022b) and it may undergo further
modifications in future re-authorizations. Thus, the results presented here may become less
predictive over time.
5.3 Consideration of Results
The study evaluated the perceived barriers to successful communication and
interpretation of discussions with the Agency, as well as evaluated the nature, timing, and quality
of communications between the FDA and sponsors, and assessed the effect of formal meetings
on the efficiency of drug development and regulatory review. These insights may help guide

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sponsors as they engage and seek regulatory feedback from the FDA and help anticipate how to
best deal with FDA interactions as they advance their CGTs toward the goal of
commercialization.
5.3.1 Framework
This study sought to understand the biopharmaceutical industry’s views regarding formal
meetings with the FDA during the development of CGT products. The study used the CIPP
evaluation framework to structure the survey questions to probe areas in which improvements
could be needed. Using an evaluation framework to structure this survey was beneficial because
of the maturity of this regulatory program and the ability to examine the needs for the program,
examine how the program was operating, and evaluate the overall impact of the program (Van
Marris and King, 2007). The CIPP evaluation framework provided a comprehensive framework
for evaluations that can be usefully applied to the study of regulatory feedback obtained through
FDA meetings. This framework has been employed for over 50 years (Stufflebeam, 1966) in
various disciplines for program evaluation (Farley and Battles, 2009, Felix, 1979, Kahn et al.,
2014, Lippe and Carter, 2018, Nicholson, 1989). It offered a systematic approach by considering
several factors that could affect the design and implementation of a program.
5.3.2 Context
The first stage of the CIPP evaluation framework is the context evaluation. In this stage,
the researcher assesses the needs and assets of the intended beneficiaries and the potential
problems for the program to solve (Stufflebeam, 2003). Here, the context evaluation attempted to
determine the respondents’ expectations and needs when they consulted with FDA. To this end,
it explored the informational needs of developers and the motivation for seeking FDA feedback,
which is important to understand because deficiencies in regulatory filings could be mitigated

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through an awareness and use of the appropriate informational resources (Feigal et al., 2012,
Wonnacott et al., 2008).
Amongst the interesting observations that came out of this exploration were two that
seemed particularly important to highlight. First, respondents relied heavily on informational
sources from FDA for product development. Second, respondents utilized FDA meetings for
scientific advice over other sources of support.
5.3.2.1 Reliance on FDA
Industry has a strong history of relying on FDA as the primary source of information to
help direct their quality, non-clinical, and clinical aspects of product development. Amongst the
respondents in this research, direct discussion with FDA was identified as the most
advantageous. That is not to say that other methods to seek information from FDA were not also
important; still quite highly regarded were guidance documents and the Agency’s website (e.g.,
approval letters, summary basis for regulatory action, package inserts), as well as FDA
information requests, which are direct. These views are consistent with published literature from
FDA that recommend these sources (Husain et al., 2015, Wonnacott et al., 2008). Reliance on
FDA may not be unexpected because such information is not available as readily for CGT
products as for drugs. For example, CGT products are excluded from most ICH guidelines
(Drago et al., 2021). Although FDA has a policy of openness and makes documentation
accessible to the public to facilitate transparency, it also is restricted in what it can share because
of its obligation to protect the confidentiality of certain data and information in regulatory
dossiers (21CFR§10, 2022, 21CFR§20, 2024). Federal regulations disallow public disclosure of
manufacturing-related information, which primarily impacts CMC aspects of development, but
allows for release of information on product safety and effectiveness (21CFR§601, 2022). Any

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redaction of information deemed confidential limits the utility of those documents. Thus,
publicly available approval letters and SBRA documents contain numerous deletions. Despite
these redactions, respondents still found these documents useful for product development.
Apart from FDA, respondents indicated that dialogue with industry peers who had
relevant experience, as well as consultants and literature publications, were also useful sources of
information. These sources may become more important in the future. The biologic industry for
CGT products is relatively nascent and the field is expected to go through a period of maturation
(Lapteva et al., 2020). Deep expertise may still be hard to find, and a skilled workforce has been
cited as a challenge for growth of the field (Ho et al., 2022). Developers may benefit from the
sharing of scientific information in articles from professional journals or from other publications
and reducing a potential over-reliance on FDA.
5.3.2.2 Intended Use of Meetings
Most respondents indicated that the primary advantage of an FDA meeting was to reduce
the risk of potential setbacks in product development that might delay or compromise market
approval. For example, a sponsor might want to hold a pre-IND meeting to obtain CBER advice
that may prevent a clinical hold (Husain et al., 2015). In contrast, respondents placed a lower
emphasis on tangible, measurable benefits, such as shortening development time, lowering
development cost, or performing fewer studies, even though these benefits are frequently cited in
the literature as benefits of FDA meetings (DiMasi and Manocchia, 1997, Wonnacott et al.,
2008, Vu and Pariser, 2015). Interestingly, respondents tended to rank highly the benefits of
increasing the transparency of the regulatory review process and building a relationship with the
Agency reviewers. These observations suggest a desire to cultivate a partnership with the FDA
reviewers and possibly to educate FDA on the sponsor’s medicinal product.

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Respondents highlighted two principal reasons to seek regulatory feedback: to obtain
FDA agreement on proposed study designs and methods, and to resolve issues encountered
during development. For example, a sponsor might want to reduce uncertainties regarding the
adequacy of a pivotal study, so might request an EOP2 meeting to seek agreement and
suggestions on key features of the trial design. These might include, for example, suitability of
efficacy endpoints, a control group, appropriateness of statistical analysis, or adequacy of
product comparability plans after the manufacturing process changed (Feigal et al., 2012). This
feedback would allow the developers to learn from FDA’s extensive experience gained from its
review of many other regulatory applications (Fink, 2009, Holston, 1993). Surprisingly,
respondents indicated that regulatory compliance was not commonly the main motivation for a
meeting. Although respondents heavily relied on FDA sources of information, they did not often
use meetings to clarify their interpretation of FDA guidance documents or regulations. Further,
respondents indicated that meetings were not typically used to resolve disagreements, although
the regulations describe conflict resolution as a reason for holding a meeting (21CFR§312,
2022), which may suggest a hesitancy or fear of disagreeing with FDA that has been reported
elsewhere in interviews of industry individuals working in regulatory or clinical functions
(Berndt et al., 2006).
5.3.3 Input
The second stage of the CIPP evaluation framework is the input evaluation, during which
I attempted to assess the resources of the company or organization to support the program
associated with meetings (Stufflebeam, 2003). These organizational resources can include
sufficiency of personnel, technical expertise, data and information, and time. Identifying the

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inputs is important because constraints in these factors may affect the ability of an organization
to request or profit from regulatory feedback (Thomasson, 2021).
Although most respondents felt that their organizations were adequately resourced to
engage with FDA and request feedback, a closer examination of their experiences when
preparing for the meeting identified the importance of some resources that impacted their
readiness for this type of interaction. Three areas of weakness were identified in some
organizations as possible constraints: insufficient personnel who were inexperienced with
preparing regulatory submissions and interacting with FDA, lack of appropriate information and
data for the meeting package, and challenges related to strategic planning for the meeting at an
appropriate time in product development.
5.3.3.1 Regulatory Experience
Results suggested that most companies had the critical technical expertise amongst their
scientific, medical, and regulatory personnel to prepare for an FDA meeting. Nonetheless,
attention was often drawn to what might be seen as an area for improvement, that of assuring
sufficient access to medical and technical writers, as reflected for example by the following
comment:
Technical/medical writers to support writing the meeting package and allow the
Regulatory Team Lead to focus on strategy and other aspects of meeting
preparation.
The literature recommends that sponsor attendees should be scientists who are prepared to
discuss the submitted data because the discussion in an FDA meeting is typically from one
scientist to another and highly technical in nature (Grignolo, 2008). However, some respondents

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wanted the scientific and medical personnel to be more knowledgeable about regulatory
submissions and FDA interactions. Similar needs were identified in an assessment of the CGT
workforce that found technical roles were sometimes asking for knowledge of FDA guidances
and GMP regulations (Ho et al., 2022), suggesting that desired qualifications include some
familiarity with regulatory aspects. Future workforce development may include efforts to gain
this knowledge. One respondent noted:
Larger dedicated regulatory team and greater organizational knowledge of FDA
meetings. SMEs were not experienced with FDA meetings or knew how to prepare
for meeting.
5.3.3.2 Availability of Information
Providing sufficient detail in the meeting package has been identified previously as one
of the main factors for receiving substantive feedback from an FDA meeting (Salazar-Fontana,
2022, Winitsky, 2021, Grignolo, 2008). Effective meetings rely on a sponsor’s ability to
formulate relevant questions based on their available data and stage of development.
Respondents also noted this challenge. They responded that their organizations did not always
understand the information needed for the meeting package and that they sometimes requested
the meeting without the appropriate supporting data or study designs. One respondent
summarized this challenge as follows:
To maintain focus on the subject, to ask for feedback that is novel in your
approach, seek guidance on what sponsor does not already know. Avoid seeking
feedback for topics that you know what the FDA will provide. Examples or
templates on prior engagements to avoid redundant questions.

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5.3.3.3 Timing of the FDA Meeting
Another potential requirement identified here is knowing precisely when to engage with
FDA. Some respondents indicated that their organizations may not have requested a meeting at
the appropriate stage of development. Although meetings can be requested at any time during
development, certain meetings are intended to take place at unique points in the development
process and a sponsor must decide on the most appropriate time given the available data and the
desire to receive input on planned work. Timing of meetings during development is frequently
identified as an important consideration when planning an FDA interaction (DiMasi and
Manocchia, 1997, Feigal et al., 2012, Salazar-Fontana, 2022, Vu and Pariser, 2015, Grignolo,
2008), but organizations may struggle in practice to pick a suitable time. A respondent
acknowledged this challenge and its potential consequence:
Better planning because FDA advice was sought late in development and too
close to planned submission. Any disagreement would have lead to delay or
accepting risk of clinical hold.
5.3.4 Process
The third stage of the CIPP evaluation framework is process evaluation, in which the
researcher examines implementation by exploring specific program activities (Stufflebeam,
2003). This information is used to ensure that the program operates according to its design, to
refine the design of the program under operating conditions, and to revise procedures that could
not have been made during the creation of the program to assure its control (Stufflebeam, 1967,
Stufflebeam, 1971). I examined the program’s activities from the perspective of sponsors who

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have used the program to obtain regulatory feedback. It is important to understand the
experiences of regulatory professionals on the operational aspects of FDA meetings because
successfully navigating this process is considered critical for the development of novel advanced
therapies (Berndt et al., 2006, Feigal et al., 2012, Husain et al., 2015, Wonnacott et al., 2008, Vu
and Pariser, 2015).
Requesting and preparing for a meeting follows defined procedures and timetables as the
sponsor submits a written meeting request to the FDA, and, if granted a meeting, prepares a
meeting package that includes the purpose, a list of questions for discussion, and data to support
the discussion (FDA, 2017b). The timing and nature of each process step appeared to illuminate
potential areas for process understanding and improvements. These areas include the
responsiveness and reliability of industry and FDA resources, the industry preference for
meetings over written responses, and the desire for greater detail in the regulatory feedback.
5.3.4.1 Availability of Industry and FDA Resources
It can be challenging to schedule meetings between entities that have many other
obligations. It was not surprising, then, to find that CBER sometimes did not respond to meeting
requests or schedule a meeting within the PDUFA-specified timeframes. These results suggested
a continued difficulty for FDA to meet its PDUFA performance goals (FDA, 2020a, FDA,
2021a, Kish, 2020).
At the same time, sponsors appeared to face issues related to process timelines.
Respondents noted that their companies mostly started to work on the meeting package early,
which others have suggested to be good practice (Thomasson, 2021). They also noted that
meetings were identified as part of a product development strategy, which is consistent with the
literature (DiMasi and Manocchia, 1997, Feigal et al., 2012). Nonetheless, they indicated that

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some of scientific and medical functions outside of the core regulatory affairs department often
struggled to dedicate the time and effort needed for a well-prepared meeting package (and thus
were responsive but somewhat unreliable). FDA considers a well-prepared meeting package as
critical for a productive discussion (FDA, 2017b, Grignolo, 2008). Further, the interactions
across functional groups when authoring the meeting package was viewed as a productive
exercise to review development plans, so that the various functional groups could think through
ill-defined topics and identify gaps in knowledge. This exercise caused respondents to
consequently modify their list of questions in the meeting package. It seems likely that the
acknowledged problems with reliability and timelines are in some measure responsible for the
observations here that indicated some level of unpreparedness by requesting a meeting without
the appropriate supporting data for the questions and discussion. Improving the engagement of
all participants needed to prepare a submission might therefore be an area of challenge that
companies might anticipate. More effort might be expended to assure that all members of the
team understand their roles and have the support that they need to meet internal deadlines.
5.3.4.2 Preference for Meetings over Written Responses
When a company requests an FDA meeting, the Agency has three choices. It can deny a
meeting request, can provide written responses only (WRO) to the posed questions, or can grant
a scheduled meeting (FDA, 2017b). In this study, it seemed apparent that few meeting requests
for CGT products were denied. FDA does not publish metrics making it difficult to assess
whether this success rate is high or low compared to all companies making a meeting request or
compared to companies requesting a meeting for other drug types. Despite the recent growth of
the CGT field and given the resource constraints at CBER, the Agency may not be denying
meeting requests due to these factors and may be trying its best to provide feedback. One would

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expect fewer delays in development and fewer problems over time given the fact that CGT
products are known to have particularly complex challenges in development, which is welldocumented (Feigal et al., 2012, Husain et al., 2015, Lapteva et al., 2020, Salazar-Fontana,
2022).
WRO was the most common meeting format; only about one-third of meetings amongst
the respondents here were scheduled, either in-person or as a videoconference. The likelihood of
receiving WRO as opposed to a meeting is known to have increased compared to previous years,
in part because of logistical limitations imposed by the pandemic in 2020 (Sutter, 2022).
Consequently, some respondents showed a strong preference for scheduled meetings and one
stated that “Face to face meetings are most effective”. The Agency’s willingness to grant face-toface meetings may improve in the coming years as technology has improved at the Agency’s
White Oak campus (FDA, 2024).
Results here showed that respondents typically proceeded with a meeting even when
about half of them were satisfied with feedback given in the preliminary written responses. This
finding reinforces other evidence suggesting that sponsors highly value the dynamic interaction
made possible by a meeting with FDA. Respondents indicated that many of the best practices
identified by Grignolo (Grignolo, 2008) – preparing presentation materials for the meeting and
assuring that appropriate participants were in attendance, for example – had been followed in
their organizations. However, respondents indicated that a mutual understanding of the
discussion topics was not always achieved by the end of a meeting. Further, respondents
indicated that they sometimes disagreed with the FDA’s meeting minutes. These are areas where
some disagreement might be expected. At the same time, however, they are places in which

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miscommunication appears to be more likely so special attention might be paid to assuring the
clearest possible meeting of the minds.
Interactions based on a WRO seemed to be less satisfactory for respondents. More than a
third of those provided with WRO were unsatisfied with the responses and wanted additional
feedback. This outcome can prove frustrating for a sponsor because the written response
constitutes the only regulatory feedback. WRO may lead to unnecessary delays if the written
feedback is unclear or if the sponsor misinterprets it (Guthrie and Eshoo, 2023). Peter Marks has
stated that, in his opinion, some INDs for CGT products could quickly resolve deficiencies with
a scheduled meeting, but CBER struggled to hold this meeting format (Eglovitch, 2023). One
respondent noted the following:
Supporting more meeting discussions instead of WRO—WRO are much less
valuable for complex programs or organizations with limited drug development
experience.
It can be particularly frustrating if the sponsor disagrees with some of the Agency’s
recommendations. Although half of respondents in this position believed that a meeting was still
needed, most did not follow-up to request a further meeting. In part, they may recognize that no
good mechanism exists to do this; follow-up options include requesting a Type C or D meeting,
which are typically conducted through the WRO approach as well (FDA, 2017a, FDA, 2017b,
FDA, 2022b). Instead, half of the respondents submitted clarifying questions and often found the
response to be helpful. In comparison to respondents who were granted a meeting, respondents in
this survey who received WRO were about six times more likely to submit clarifying questions.
It is worth noting that this concern has been recognized. As part of the PDUFA re-authorization

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in September 2022, a follow-up opportunity was introduced for sponsors to ask clarifying
questions to confirm that they had an accurate understanding of the Agency’s responses after a
meeting or WRO (FDA, 2021b).
5.3.4.3 Greater Detail in Regulatory Feedback
Of all the changes that respondents would like to have from the current meeting process,
greater detail in the feedback from FDA was highly valued, including “explanation of the
agency’s thinking in the response”. Of course, providing more detail would require more time
and effort by FDA reviewers, and this would increase their workload at a time when, over the
past decade, the number of meeting requests has soared (FDA, 2015a, FDA, 2020a, FDA, 2021a,
Kish, 2020). One respondent suggested that resource constraints at FDA might limit their ability
to provide more feedback:
Not acceptable to not provide input on pre-IND meeting questions. I think this has
been an issue because of resources but the Agency has an obligation to provide
sponsors with responses to their questions within the pre-IND meeting scope.
The second most highly ranked process improvement was to shorten the length of time
between the meeting request and the meeting date or receipt of the written responses. This length
ranges from 30 days for Type A to 75 days for Type C (FDA, 2017a, FDA, 2017b, FDA, 2022b).
Although such a change is not known to have been proposed for meetings for PDUFA-regulated
products, or whether it is practical, a medical device consulting company called Emergo has
proposed shortening the timelines for FDA feedback and meetings for medical devices (Emergo,
2024). It is unclear if shortening the process would have a substantial beneficial impact on CGT
product development, whose times are typically measured in years.

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5.3.5 Product
The fourth stage of the CIPP evaluation framework focuses on product evaluation. In this
final stage, the researcher assesses whether the program was effective for its intended
beneficiaries (Stufflebeam, 2003). This evaluation can include assessing whether the program
reaches its target audience, assessing effectiveness by measuring the quality and significance of
outcomes, and assessing sustainability by identifying aspects of the program that should be
continued or remodeled (Stufflebeam, 2003). In this research study, I sought to determine
whether regulatory feedback through FDA-sponsor meetings yielded a perceived benefit for
product development, whether sponsors were satisfied with the program, and whether the
sponsors could identify any positive or negative outcomes of the program. These outcomes are
important to understand in order to validate a broadly accepted belief that consultations with
FDA produce safer and more effective study designs and increase the likelihood that an
application meets regulatory requirements (FDA, 2005, Feigal et al., 2012, Husain et al., 2015,
Wonnacott et al., 2008).
Although respondents generally thought that FDA-sponsor meetings were beneficial,
some issues were recognized. Among these are three areas of impact that might be highlighted.
These include the ability of FDA meetings to achieve some of the desired benefits and
objectives, the impact on product development from implementation of regulatory feedback, and
the concerns about future use of the program to obtain meaningful advice and recommendations.
5.3.5.1 Effectiveness of FDA-Sponsor Meetings
The effectiveness of FDA meetings can be assessed by examining the quality and
significance of the outcomes from these interactions. Almost all respondents indicated that the
regulatory feedback received from the FDA meeting was effective, though it can be measured in

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a few different ways. One measurement might be simply the ability to receive a requested
meeting. Almost all respondents were granted their requested milestone meetings. Because these
meetings occur at critical points in the development process, they are important for planning the
next stage of development with FDA (FDA, 2017a, FDA, 2017b, FDA, 2022b). Further, roughly
two-thirds of the respondents requested a non-milestone meeting and most of them were granted,
which suggests the need for additional regulatory feedback beyond the four traditional milestone
meetings. The former director, Wilson Bryan, of the Office of Tissues and Advanced Therapies,
has publicly said that developers are more likely to receive a meeting if their product has an
expedited pathway designation (Sutter, 2022). Of the roughly one-third of respondents who
indicated that their product was granted Breakthrough Therapy and/or RMAT designation, most
reported increased interactions with FDA, and none was denied this benefit of the designation.
Securing a meeting with FDA is only valuable if the meeting can achieve its anticipated
benefits. One benefit that is often desired would be a shortening of clinical development times, a
factor that can have significant financial and marketing benefits for the company (Berndt et al.,
2006, DiMasi and Manocchia, 1997). Earlier, FDA did not focus on the economics of drug
development (Woodcock, 1997). In a study conducted nearly three decades ago and prior to
PDUFA, DiMasi and Manocchia found an association between FDA meetings and shorter
clinical development time (DiMasi and Manocchia, 1997). However, this linkage seems more
tenuous today. In this study, respondents felt that the meeting reduced potential setbacks in their
development program but did not shorten development times or lower costs. This result is
perhaps not surprising in the face of FDA’s focus on safety and efficacy regardless of time or
cost. When Berndt and colleagues interviewed FDA reviewers, they concluded that those
reviewers were not concerned with time delays or added costs; they typically felt that they had

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the right and responsibility to ask the sponsor for additional studies and data without regard for
time or cost (Berndt et al., 2006).
Perhaps the most important measure of effectiveness would be the ability of the
respondents to achieve their objectives for having that meeting. In the first stage of the survey
that explored context evaluation, most respondents indicated that the principal objectives for
such meetings were to gain FDA agreement on study designs and to resolve issues raised during
product development. Based on respondents’ experiences, these objectives were confirmed to be
achieved about 60% of the time but not achieved about 10% of the time. Moreover, the objective
of FDA agreement on study designs, viewed as the most important objective for respondents,
here had the lowest score for agreement in the product evaluation, suggesting that this objective
was not successfully achieved as often as respondents desired. Failure to reach agreement on
such matters creates greater uncertainty. For example, FDA’s accelerated approval allows for
faster clinical development and approval of new therapies based on surrogate endpoints (FDA,
2014b, FDA, 2019b). A lack of agreement on these endpoints in CGT clinical study designs
could lead to significant problems at later stages of development. Peter Marks has noted that
accelerated approval is a necessary tool for CGT products for rare diseases, but CBER has not
always agreed on the endpoints before the start of these trials (Eglovitch, 2022).
5.3.5.2 Impact of Regulatory Feedback
The impact of FDA meetings can be assessed by examining the extent to which the
beneficiaries (i.e., industry sponsors) made changes to their development programs on the basis
of the advice. Almost all respondents identified that their organizations implemented at least
some of the Agency’s advice and recommendations. Some respondents believed that the
implemented feedback provided a lower risk of future setbacks in development:

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Having early engagement with FDA has, from my experience de-risked the
overall strategy prior to implementing or executing regulatory or technical
impedance on product development.
The advice for near-term studies was implemented and allowed our program to
proceed as planned and for the organization to hit our milestones, and the
forward looking feedback was considered for future use.
However, a few respondents felt that the feedback had a negative impact because of extra time
that was needed to implement the recommendations and thus lengthen the development path or
because issues not previously recognized by FDA caused a refuse-to-file determination when the
BLA was submitted.
5.3.5.3 Sustainability of FDA-Sponsor Meetings
The sustainability of FDA-sponsor meetings can be assessed by examining the extent to
which the program will continue to be valuable and used over time. Respondents expressed
concerns with four statements about obtaining regulatory feedback in the future. Their greatest
concern was the possibility that they will not be able to obtain meaningful feedback with a
consequent delay in development. Several respondents expressed concern about heightened
turnover amongst experienced FDA staff that might degrade the consistency of feedback, namely
“loss of reviews with subject matter expertise”. These same concerns are not new. They have
been recognized as far back as 2004 when industry complained about variability in
communication and feedback across divisions at FDA (although CBER was not identified as the
worst offender) and about the turnover of reviewers at FDA, which could lead to inconsistent
feedback (Berndt et al., 2006). Some of these concerns may be alleviated over the next few years

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because CBER has announced plans to increase staffing (Chhina et al., 2022, FDA, 2021b), but
any new reviewers or staff may take time to train and may not have sufficient background to
qualify as reviewers for advanced therapy products.
5.3.6 INTERACT
In the 1990s, most meetings occurred in late-stage development during Phase II or III
studies (DiMasi and Manocchia, 1997) and similar meetings in early-stage development are a
more recent opportunity. The PDUFA re-authorization in September 2022 introduced the
INTERACT meeting as a milestone meeting (FDA, 2021b), which reflects the common belief
that meetings can be a valuable resource for sponsors in early preclinical development. It was
built on an informal previous history of consultations with CBER for early interactions (FDA,
2018b, Marks, 2019), often called a pre-pre-IND meeting (Feigal et al., 2012). Even though the
program is relatively new, roughly one-third of respondents had INTERACT meeting
experience. The INTERACT meeting was intended to discuss CMC and
pharmacology/toxicology topics (FDA, 2022c, FDA, 2023b). Current practice reflects this intent
as a majority of INTERACT meeting packages included CMC or non-clinical topics and most
meeting packages contained multiple topics, which reflected an interdisciplinary focus.
Despite the recent creation of the INTERACT meeting, most respondents indicated that
they understood the information expected in a meeting package. As with other meeting
preparations, forming questions and organizing the supporting data helped their organizations to
think through ill-defined topics and find gaps in their knowledge. Most respondents indicated
that their organizations had the expertise to prepare for the meeting; none of the requests were
denied because of a deficient meeting package. These findings suggest that most companies have
the appropriate experienced personnel, even at an early stage of development, to manage an

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INTERACT meeting. Thus, access to expertise should not limit the ability to receive
constructive regulatory feedback. This is important because providing sufficient detail in the
meeting package is one of the main factors that can help to ensure substantive feedback
(Winitsky, 2021).
FDA granted most INTERACT meeting requests. Almost all respondents indicated that
the INTERACT meeting was helpful for their product development, and they were satisfied with
the process. These findings were further corroborated by the findings that the respondents did not
intend to request a Type C meeting to clarify feedback but rather planned to request a pre-IND
meeting after development had progressed further. Respondents typically praised the sharper
focus and more helpful feedback of the INTERACT meetings on development plans and
nonclinical studies. These benefits are described in the literature as useful for CGT products due
to the challenges of relevant animal studies (Feigal et al., 2012, Salazar-Fontana, 2022). Fewer
criticisms were provided, and these were in line with some criticisms seen for the other meetings
studied here – unhelpful feedback or delays in scheduling a meeting. These observations are
more positive than those identified by earlier research, in which industry rated early-stage
communication with FDA as lower in quality compared to Phase II (Berndt et al., 2006).
However, we might expect that the Agency has gained more experience in the discovery and
early preclinical stages of development for CGTs over the past two decades.
Notable, however, were findings that FDA denied roughly one-quarter of INTERACT
meeting requests because the Agency considered the request as either premature or too advanced
for the stage of development (Winitsky, 2021). These findings are cautionary for developers,
who should consider carefully when an INTERACT meeting should be staged and provide a
strong rationale for their request to increase the chances of receiving such a meeting. These

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concerns are shared by industry. For instance, Gilead Sciences requested FDA to clarify the
criteria for granting an INTERACT meeting because of a perceived “narrow window of time
where requesting an INTERACT meeting is appropriate” (Gilead Sciences, 2023). Further, the
Biotechnology Innovation Organization and Gilead Sciences asked FDA to provide examples or
describe situations that would be most appropriate for an INTERACT or a pre-IND meeting to
minimize the risk of a denial (BIO, 2023, Gilead Sciences, 2023).
5.4 Conclusion and Recommendations
FDA has approved approximately 30 CGT products, and the Agency expects the number
of INDs and BLAs will grow even higher over the next decade. Developers of CGT products
face challenges when trying to develop these inherently complex products. Assistance is
particularly important when the CGT is a candidate for an expedited development program that
could shorten the clinical development timelines (Drago et al., 2021, Salazar-Fontana, 2022). To
address these challenges, sponsors may seek formal meetings with FDA to obtain feedback on
product development plans at critical points in the development process.
This study explored the nature, timing, and quality of communications between FDA and
sponsors, whose format tended to take the form of written responses instead of face-to-face
meetings. Respondents generally agreed that the regulatory feedback from meetings or written
responses was effective given the stage of product development for the interaction. Overall, the
procedures appeared to be well-designed and well-implemented, and the goals of this program
are realistic and broadly helpful for CGT products, but modest improvements to the design and
use of meetings may be sensible. Four recommendations are proposed here that could potentially
improve interactions between sponsors and FDA without compromising the depth and usefulness
of Agency review or the safety and efficacy of new medicines.

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First, FDA could increase its outreach and guidance because industry heavily relies on
the Agency as a source of information. FDA can solicit industry for the most pertinent or
controversial topics that could be published in future guidance documents, as well as revise any
outdated guidance documents. More importantly, FDA should leverage its extensive experience
and repository of knowledge, which is recognized and valued (Woodcock, 1997). For instance,
FDA could publish its experience with INTERACT and pre-IND meetings of early preclinical
development products to aid developers, as well as experience with meetings held during the
critical Phase II or III development prior to a marketing application. For instance, it could
identify the most common pitfalls or informational deficiencies. The results would be useful to
understand trends and commonalities of previous applications. Such an analysis is not
unprecedented. In 2008, FDA reviewers published an analysis of CGT INDs placed on clinical
hold to identify common deficiencies (Wonnacott et al., 2008). The proposed analysis would
obviously require redaction to preserve the confidentiality of sponsor’s information, but still
offer sufficient detail to offer guidance. This information would be particularly helpful for CMC
issues because publicly available documentation related to the CMC deficiencies of approved
products on the FDA website is substantially redacted. Developers could avoid approaches or
studies previously found to be deficient, which may improve product safety and thus serve to
protect public health.
Second, respondents strongly advocated for greater engagement with FDA. To meet this
demand, FDA should continue to increase staffing and retain staff at CBER for review of CGT
applications. Sufficient well-qualified staff are foundational for effective and sustainable FDAsponsor meetings. Increased staff might allow CBER to provide a faster turnaround time when
responding to meeting requests, a greater capability to grant more face-to-face meetings instead

176
of written responses, and a better quality of feedback during such meetings. Although the
PDUFA re-authorization will allow CBER to increase hiring, it remains to be seen whether the
increased number of staff will be able to manage an increase in demand.
Third, some organizational resources within the companies themselves were identified as
potentially insufficient to permit efficient meeting preparation. Efficiencies could be gained if
leadership could be educated about the usefulness of individuals with specific skills, such as
medical writers and consultants who could work on preparation of meeting requests and
packages. It is also important that responsibilities of technical and medical staff be adjusted so
that they can dedicate the time and effort needed to prepare for meetings.
Fourth, FDA could reconsider the various timelines because they may not be optimal and
may be reasonably shortened. Some respondents sought a faster timeframe for receipt of written
responses or a scheduled meeting. Besides shortening the goal dates for meeting management in
future re-authorizations of PDUFA, other options for improvement may include submission of
the meeting package at the same time as the meeting request or a sponsor’s use of informal
communications in lieu of formal meetings.
5.5 Future Research
The survey used in this study could be extended for future use based on the observed
results. Although considerable thought was given to developing the survey questions in
consultation with a focus group, further refinement of the survey questions is possible to
investigate some of the key issues observed. For example, respondents were asked to identify
through ranking or level of agreement several possible objectives that were achieved or not.
Modification of these questions to better understand why they were not achieved, and what
factors contributed to that outcome, could provide more insight into the topic. Further, although

177
the survey considered industry perspectives of the FDA-sponsor meeting process, further
refinement is possible to probe industry perceptions of CBER. For example, the questions could
be modified to assess industry’s experience and satisfaction with informal interactions (e.g.,
telephone or email inquiries), the accessibility of FDA reviewers and leadership, the attitude of
CBER in understanding the scientific basis of novel CGT therapies, and the perception of FDA
reviewer and staff as well-qualified to provide scientific advice. Probing these topics could
identify further areas for improvement.

178
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190
Appendices
Appendix A. List of Acronyms and Abbreviations
A list of acronyms and abbreviations used in this thesis is provided in Table 29.
Table 29: List of Acronyms and Abbreviations
Acronym or Abbreviation Definition
AAV Adeno-associated virus
BLA Biologics License Application
BTD Breakthrough Therapy Designation
CAR Chimeric Antigen Receptor
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CFR Code of Federal Regulations
CGT Cell and gene therapy
CMC Chemistry, Manufacturing, and Controls
CR Complete response
EOP1 End-of-phase 1
EOP2 End-of-phase 2
FDA Food and Drug Administration
FDC Act Food, Drug, and Cosmetic Act
FT Fast Track
GMP Good Manufacturing Practice
HPC Hematopoietic Progenitor Cell
ICH International Council for Harmonisation
IND Investigational New Drug
INTERACT INitial Targeted Engagement for Regulatory Advice on CBER producTs
ODD Orphan Drug Designation
OTP Office of Therapeutic Products
PDUFA Prescription Drug User Fee Act
PHS Act Public Health Service Act
RMAT Regenerative Medicine Advanced Therapy
RTF Refuse-to-file
SBRA Summary Basis for Regulatory Action
U.S. United States
WRO Written response only

191
Appendix B. Data on Approved Cell and Gene Therapy Products
The data used for Figure 6 in Section 2.6, which shows the number of approved CGT products in
the U.S. by year (from January 2010 to December 2022), are provided below in Table 30. These
counts were obtained from the SBRA documents for each approved CGT product, which are
cited in the footnote.
Table 30: Data for Approved CGT Products in the U.S. by Year (2010 to 2022)
Year Number of Approved Products by Year
Somatic Cells Cord Blood Viral Vector Genetically-modified Cells
2010 1
2011 1 1
2012 1 2
2013 2
2014
2015 1
2016 1 2
2017 1 2
2018
2019 1 1
2020 1
2021 2 2
2022 2 3
Total 6 8 5 8
Source: Original table created by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA,
2012a, FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d,
FDA, 2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA,
2021d, FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

192
The data used for Figure 7 and Figure 8 in Section 2.6, which shows the percentage of regulatory
designations, type of BLA review, and type of approval of the 27 approved CGT products, are
provided below in Table 31. This information was obtained from the SBRA documents for each
approved CGT product, which are cited in the footnote.
Table 31: Data for Regulatory Designations and Approval of CGT Products
Name Active Substance Indication Date of
Approval Approval Regulatory
Designations
Somatic Cells
Provenge
Autologous
PBMCs activated
with GM-CSF
Metastatic
prostate cancer 29 Apr 2010 Regular None
Laviv Autologous
cultured fibroblasts
Improvement of
nasolabial fold
wrinkles
21 Jun 2011 Regular None
Gintuit
Allogeneic
cultured
keratinocytes
Mucogingival
conditions 09 Mar 2012 Regular None
MACI
Autologous
cultured
chondrocytes
Repair of
cartilage
defects
13 Dec 2016 Regular None
Stratagraft
Allogeneic
cultured
keratinocytes
Treatment of
thermal burns 15 Jun 2021 Regular ODD, RMAT, PR
Rethymic
Allogeneic
processed thymus
tissue
Immune
reconstitution
in congenital
athymia
08 Oct 2021 Regular ODD, BTD, RMAT,
PR
Viral Vectors
Imlygic
Genetically
modified oncolytic
Herpes simplex
virus
Melanoma 27 Oct 2015 Regular ODD
Luxturna
Recombinant
adeno-associated
virus
Retinal
dystrophy 19 Dec 2017 Regular ODD, BTD, PR
Zolgensma
Recombinant
adeno-associated
virus
Spinal muscular
atrophy 24 May 2019 Regular ODD, BTD, PR
Hemgenix
Recombinant
adeno-associated
virus
Hemophilia B 22 Nov 2022 Regular ODD, BTD, PR
ADSTILADRIN Recombinant
adenovirus Bladder cancer 16 Dec 2022 Regular BTD, PR
Genetically-modified Cells
Kymriah
Geneticallymodified
autologous T cell
immunotherapy
Acute
lymphoblastic
leukemia and
large B-cell
lymphoma
30 Aug 2017 Regular ODD, BTD, PR
Yescarta Geneticallymodified
Large B-cell
lymphoma 18 Oct 2017 Regular ODD, BTD, PR

193
Name Active Substance Indication Date of
Approval Approval Regulatory
Designations
autologous T cell
immunotherapy
Tecartus
Geneticallymodified
autologous T cell
immunotherapy
Mantle cell
leukemia 24 July 2020 Accelerated ODD, BTD, PR
Breyanzi
Geneticallymodified
autologous T cell
immunotherapy
Large B-cell
lymphoma 05 Feb 2021 Regular ODD, BTD, RMAT,
PR
Abecma
Geneticallymodified
autologous T cell
immunotherapy
Multiple
myeloma 26 Mar 2021 Regular ODD, BTD, PR
Carvykti
Geneticallymodified
autologous T cell
immunotherapy
Multiple
myeloma 28 Feb 2022 Regular ODD, BTD, PR
Zynteglo
Autologous
CD34+ enriched
cells genetically
modified to encode
beta-globin gene
Betathalassemia 17 Aug 2022 Regular FT, ODD, BTD, PR
Skysona
Autologous
CD34+ enriched
cells genetically
modified to encode
ALDP gene
Cerebral
adrenoleukodystrophy
16 Sep 2022 Accelerated FT, ODD, BTD, PR
Cord Blood
HEMACORD
Allogeneic cord
blood
hematopoietic
progenitor cells
Hematopoietic
and
immunologic
reconstitution
in patients with
disorders
affecting the
hematopoietic
system
10 Nov 2011 Regular None
HPC, Cord
Blood 24 May 2012 Regular None
DUCORD 04 Oct 2012 Regular None
ALLOCORD 30 May 2013 Regular None
HPC, Cord
Blood 17 Jun 2013 Regular None
HPC, Cord
Blood 28 Jan 2016 Regular None
CLEVECORD 01 Sep 2016 Regular None
HPC, Cord
Blood 21 Jun 2018 Regular None
Abbreviations: BTD, Breakthrough Therapy Designation; FT, fast track; HPC, hematopoietic progenitor cell; ODD,
Orphan Drug Designation; PR, priority review; RMAT, Regenerative Medicine Advanced Therapy.
Source: Original table by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA, 2012a,
FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d, FDA,
2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA, 2021d,
FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

194
The data used for Figure 9 in Section 2.6, which shows the percentage of regulatory actions,
advisory committee meetings, post-marketing requirements, and post-marketing commitments of
the 27 approved CGT products, are provided below in Table 33 and in Table 33. This
information was obtained from the SBRA documents for each approved CGT product, which are
cited in the footnotes.
Table 32: Data for Regulatory Review of Approved CGT Products
Name Active Substance Regulatory Actions Advisory
Committee Meeting
Somatic Cells
Provenge
Autologous PBMCs
activated with GMCSF
Original BLA submitted on 09 Nov 2006
and CR letter issued on 08 May 2007 due
to CMC and clinical issues. BLA resubmitted on 30 Oct 2009.
Yes
Laviv Autologous cultured
fibroblasts
Original BLA submitted on 06 Mar 2009
and CR letter issued on 18 Dec 2009.
BLA re-submitted on 22 Dec 2010.
Yes
Gintuit Allogeneic cultured
keratinocytes
Same product as Apligraf, approved
under a device Premarket Approval. Yes
MACI Autologous cultured
chondrocytes None No
Stratagraft Allogeneic cultured
keratinocytes None No
Rethymic Allogeneic processed
thymus tissue
Original BLA submitted on 05 Apr 2019
and CR letter issued on 04 Dec 2019.
BLA re-submitted on 09 Apr 2021.
No
Viral Vectors
Imlygic
Genetically modified
oncolytic Herpes
simplex virus
Major amendment to BLA submitted in
Nov 2014 for CMC information. Yes
Luxturna
Recombinant adenoassociated virus
BLA rolling submission started on 27 Apr
2016 and finished on 16 May 2017. Yes
Zolgensma None No
Hemgenix None No
ADSTILADRIN Recombinant
adenovirus
Original BLA submitted on 05 Sep 2019
and CR letter issued on 24 Apr 2020 due
to facility and CMC issues. BLA resubmitted on 30 Jun 2022.
No
Genetically-modified Cells
Kymriah Genetically-modified
autologous T cell
immunotherapy
None Yes
Yescarta Rolling submission of original BLA from
02 Dec 2016 to 31 Mar 2017. No

195
Name Active Substance Regulatory Actions Advisory
Committee Meeting
Tecartus None No
Breyanzi
Major amendment to BLA submitted on
05 May 2020 for CMC/manufacturing
facility information.
No
Abecma
Original BLA submitted on 30 Mar 2020
and RTF due to CMC-related issues.
Original BLA re-submitted on 27 Jul
2020.
No
Carvykti Major amendment to BLA submitted on
28 Oct 2021. No
Zynteglo
Autologous CD34+
cell-enriched
genetically modified
to encode beta-globin
gene
Major amendment to BLA submitted on
14 Jan 2022; BLA review extended by 3
months.
Yes
Skysona
Autologous CD34+
cell-enriched
genetically modified
to encode ALDP gene
Major amendment to BLA submitted on
13 Jan 2022; BLA review extended by 3
months.
Yes
Cord Blood
HEMACORD
Allogeneic cord blood
hematopoietic
progenitor cells
None Yes
HPC, Cord Blood Major amendment to BLA. No
DUCORD Major amendment to BLA with CMC
information. No
ALLOCORD
CR letter issued due to CMC and facilityrelated deficiencies. BLA amendment
submitted.
No
HPC, Cord Blood Major amendment to BLA. No
HPC, Cord Blood RTF issued due to CMC-related
deficiencies. BLA re-submitted. No
CLEVECORD Major amendment to BLA. No
HPC, Cord Blood RTF issued due to CMC-related
deficiencies. BLA re-submitted. No
Abbreviations: CMC, chemistry, manufacturing, and controls; CR, complete response; HPC, hematopoietic
progenitor cell; PMC, post-marketing commitment; PMR, post-marketing requirement; PR, priority review; RTF,
refuse-to-file; SBRA, Summary Basis for Regulatory Action.
Source: Original table by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA, 2012a,
FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d, FDA,
2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA, 2021d,
FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

196
Table 33: Data for Outcome of Approved CGT Products
Name Clinical Program Post-Marketing
Requirements
Post-Marketing
Commitments
Somatic Cells
Provenge
Fourteen clinical trials
conducted, including
three Phase 3 studies
(multicenter, randomized,
double-blinded, placebocontrolled)
One clinical PMR: Postmarketing study to assess the
risk of adverse events in
patients.
None
Laviv
Seven clinical trials
conducted, including two
Phase 3 studies
(multicenter, randomized,
double-blinded, vehiclecontrolled)
One clinical PMR: Postmarketing study to assess the
risk of adverse events in
patients.
None
Gintuit
Three clinical trials
(single- or multicenter,
randomized, controlled)
One clinical PMR: Conduct
post-marketing study to
evaluate safety and
effectiveness in pediatric
patients.
Five CMC-related PMCs (not
described in Approval Letter
or SBRA).
MACI
One Phase 3 study with
extension studies
(multicenter, open-label,
randomized)
One clinical PMR: Conduct a
pediatric study.
Three CMC-related PMCs:
two for analytical method
validations and release
specifications and one for
updating operating procedures.
Stratagraft
One Phase 1 study and
one Phase 3 study (openlabel, randomized)
One clinical PMR: Conduct
study to assess risk of
adventitious virus by
demonstrating clearance of
model viruses.
Two CMC-related PMCs to
develop and validate an
analytical method for identity
testing.
Rethymic
Seven clinical studies
conducted over a period
of 20 years (single-center,
open-label)
None
Two CMC-related PMCs:
develop a quantitative potency
assay and develop a new
container closure system.
Viral Vectors
Imlygic
One clinical study
(multicenter, open-label,
randomized)
Two clinical PMRs: Conduct
post-marketing observational
study to assess safety and
complete ongoing study to
evaluate biodistribution and
shedding of virus.
None
Luxturna
One Phase 1 study (dosefinding, safety) and one
Phase 3 study (efficacy
and safety) (multicenter,
open-label, randomized,
controlled)
None
Seven CMC-related PMCs
related to shipping validation,
analysis of lot release test
results, stability, release
testing, and cleaning
validation.

197
Name Clinical Program Post-Marketing
Requirements
Post-Marketing
Commitments
Zolgensma
One Phase 1 study (dosefinding, safety) and one
Phase 3 study (efficacy
and safety) (multicenter,
open-label, single-arm)
None Four CMC-related PMCs
related to analytical methods.
Hemgenix
One Phase 2b study
(safety) and one Phase 3
study (safety and
efficacy) (open-label,
multicenter)
Two clinical-related PMRs:
validate assay for clinical
samples and conduct postmarketing study to assess risk
of bleeding.
Six CMC-related PMCs
related to specifications,
release testing, and container
closure.
ADSTILADRIN
One Phase 1, one Phase 2,
and one Phase 3 study
(safety and efficacy)
(single-arm)
None
One clinical-related PMC:
Provide long-term data on
response for all subjects
enrolled in clinical trial.
Genetically-modified Cells
Kymriah
One clinical trial
(multicenter, open-label,
single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
One CMC-related PMC:
Conduct re-validation of
analytical method
(mycoplasma assay for release
of lentiviral vector).
Yescarta
One Phase 1/2 study
(multicenter, open-label,
single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
None
Tecartus
One Phase 1/2 study
(multicenter, open-label,
single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
Two clinical PMRs for
accelerated approval.
None
Breyanzi
One Phase 1/2 study
(multicenter, open-label,
single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
One CMC-related PMC:
Conduct validation of
analytical method and submit
validation report.
Abecma
One Phase 1 study (dosefinding, safety) and one
Phase 2 study (efficacy
and safety) (multicenter,
open-label, single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
One clinical PMC: Submit a
report containing data from
clinical trials to further
characterize the safety and
efficacy among
subpopulations.
One CMC-related PMC:
Conduct a comparability study
between analytical methods
and submit study report.

198
Name Clinical Program Post-Marketing
Requirements
Post-Marketing
Commitments
Carvykti
One Phase 1b/2 study
(multicenter, open-label,
single-arm)
One clinical PMR: Postmarketing observational
study to assess the long-term
safety including the risk of
secondary malignancies.
None
Zynteglo One Phase 1/2 study and
two Phase 3 studies.
One clinical PMR: Postmarketing observational
study to assess the long-term
safety.
One CMC PMR: Conduct
study on drug product
container closure.
Eight CMC-related PMCs
related to container closure
and assays.
Skysona One Phase 2/3 and one
Phase 3 study.
Two clinical PMRs related to
accelerated approval.
One additional clinical PMR
and two CMC-related PMRs
related to long-term safety
and suitability of drug
product container closure.
Nine CMC-related PMCs
related to container closure,
release assays, and stability.
Cord Blood
HEMACORD
No clinical trials
conducted to study the
efficacy or the safety due
to the minimal
manipulation of the
product and the previous
human experience with
HPC, Cord Blood (from
multiple cord blood
banks).
Two clinical PMRs (common
to all cord blood products):
Implement a safety outcome
monitoring and analysis plan.
Submit reports for each
serious infusion reaction.
None
HPC, Cord Blood
DUCORD
ALLOCORD
HPC, Cord Blood
HPC, Cord Blood
CLEVECORD
HPC, Cord Blood
Abbreviations: CMC, chemistry, manufacturing, and controls; CR, complete response; HPC, hematopoietic
progenitor cell; PMC, post-marketing commitment; PMR, post-marketing requirement; PR, priority review; RTF,
refuse-to-file; SBRA, Summary Basis for Regulatory Action.
Source: Original table by the author based on (FDA, 2010, FDA, 2011c, FDA, 2011b, FDA, 2012b, FDA, 2012a,
FDA, 2012c, FDA, 2013a, FDA, 2013b, FDA, 2015b, FDA, 2016c, FDA, 2016a, FDA, 2016b, FDA, 2017d, FDA,
2017f, FDA, 2017e, FDA, 2018e, FDA, 2019c, FDA, 2020d, FDA, 2021f, FDA, 2021g, FDA, 2021e, FDA, 2021d,
FDA, 2022g, FDA, 2022j, FDA, 2022i, FDA, 2022h, FDA, 2022f).

199
Appendix C. Data for PDUFA Meeting Management
The data used for Figure 10 in Section 2.7.3, which shows CBER and CDER meeting requests
by Fiscal Year (FY 2010 to FY 2021), are provided in Table 34. The table provides the number
of CBER and CDER meeting requests for Type A, Type B, Type B (EOP), and Type C meetings
by fiscal year (FY) from FY 2010 to FY 2021. Type B meetings are combined with the Type B
(EOP) meetings because Type B (EOP) meetings were created under PDUFA VI in 2018. The
overall mean is the average number of meetings from FY 2010 to FT 2021. These data were
obtained from the FDA in PDUFA performance reports or on its website, which are cited in the
footnote.
Table 34: Data for CBER and CDER Meeting Requests by Fiscal Year (FY 2010 to FY
2021)
Request Type Fiscal Year
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Type A Meeting
Requests 234 204 184 140 160 121 135 175 146 153 182 255
Type B Meeting
Requests 1305 1331 1322 1394 1467 1664 1738 1850 1609 1725 2438 2290
Type B(EOP)
Meeting Requests 0 0 0 0 0 0 0 0 343 343 350 339
Total Type B
Meeting Requests 1305 1331 1322 1394 1467 1664 1738 1850 1952 2068 2788 2629
Type C Meeting
Requests 718 715 785 932 995 1237 1372 1391 1403 1550 1716 1674
Total Meeting
Requests 2257 2250 2291 2466 2622 3022 3245 3416 3501 3771 4686 4558
Source: Original table created by the author with data obtained from (FDA, 2015a, FDA, 2020a, FDA, 2021a).

200
Appendix D. Finalized Survey

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216
Appendix E.Cross-Tabulations
A cross-tabulation was performed between Question 9 and Question 19 to explore any
association between time since last experience using an FDA-sponsor meeting (in Question 9)
and the outcome of the meeting request (in Question 19) (Table 35). Most recently (i.e., less than
one year ago from the time of the survey), 68% (19/28) respondents received WRO, 29% (8/28)
received a meeting, and one respondent (4%, 1/29) was denied a meeting. Moving further
backwards in time (i.e., from one to six years ago), 53% (10/19) of respondents received WRO,
37% (7/19) received a meeting, and two respondents (11%, 2/19) were denied a meeting. The
most recent experience was within the previous six years as none of the respondents last
experienced a meeting more than six years ago.
Table 35: Cross-tabulation of Time since FDA-Sponsor Meeting and Outcome of
Meeting Request
This table provides a cross-tabulation between the most recent experience using an FDA-sponsor meeting
(in Question 9) and outcome of the meeting request (in Question 19).
Outcome of Meeting
Request (Question 19)
Most recent experience using FDA-sponsor meeting
(Question 9)
< 1 year ago 1 to 6 years ago > 6 years ago Total
N % N % N % N
WRO 19 68% 10 53% 0 0% 29
Meeting
(in person face-to-face,
videoconference, or
teleconference)
8 29% 7 37% 0 0% 15
Meeting was denied 1 4% 2 11% 0 0% 3
Total 28 100% 19 100% 0 0% 47
As part of the context evaluation, respondents were asked to rank the expected
advantages from an FDA meeting (in Question 12) (Figure 21 and in Table 9), and in the product

217
evaluation, respondents were asked to rank the observed advantages after holding an FDA
meeting (in Question 29) (Figure 39 and in Table 19). A difference was calculated between the
weighted scores from Question 12 and the weighted scores from Question 29 because both
questions used the same list of potential advantages and the same scoring system (Table 36). The
greatest positive difference was the option “provided transparency to the regulatory review
process” (difference = +0.51) followed by “fewer studies required” (difference = +0.09), while
the greatest negative difference was the option “built a relationship with the Agency reviewers”
(difference = -0.24) followed by “shortened development time” (difference = -0.20) and
“reduced potential setbacks” (difference = -0.12).
Table 36: Calculation of Difference in Weighted Scores
Difference was calculated by subtracting to weighted score from Question 29 and the weighted score
from Question 12.
Category Weighted Score
from Question 12
Weighted Score
from Question 29 Difference
Reduced potential setbacks 1.30 1.41 -0.12
Provided transparency to the
regulatory review process 3.05 2.54 0.51
Built a relationship with the
Agency reviewers 2.93 3.17 -0.24
Fewer studies were required 4.41 4.32 0.09
Shortened development time 4.11 4.32 -0.20
Lowered development cost 5.20 5.24 -0.04
A tabulation was performed for the responses in Question 36a to identify the number of
INTERACT meeting requests/packages that were single topic or multiple topics (Table 37). Four
of the 14 meeting requests/packages had a single topic, whereas 10 had multiple topics.

218
Table 37: Frequency of INTERACT Meeting Topics
Topic Category N Percentage
Single Topic
CMC only 1 7%
Non-clinical only 2 14%
Clinical only 1 7%
Multiple Topics
CMC*Non-clinical 3 21%
CMC*Clinical 0 0%
CMC*Non-clinical*Clinical 4 29%
Non-clinical*Clinical 0 0%
CMC*Non-clinical*General Regulatory 2 14%
CMC*Non-clinical*Clinical*General
Regulatory 1 7%
Total 14 100%

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Asset Metadata

Creator Babcock, Eugene Christopher (author)

Core Title Evaluation of FDA-sponsor formal meetings on the development of cell and gene therapies: a survey of industry views

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2024-08

Publication Date 08/26/2024

Defense Date 08/13/2024

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

Tag cell and gene therapies,cell and gene therapy,CGT,CGTs,FDA,FDA meetings,FDA-sponsor formal meetings,FDA-sponsor meetings,Food and Drug Administration,OAI-PMH Harvest

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Bain, Susan (committee chair), Luong, Hai (committee member), Pacifici, Eunjoo (committee member), Richmond, Frances (committee member)

Creator Email ebabcock@usc.edu;eugenebabcock@gmail.com

Unique identifier UC113999JMC

Identifier etd-BabcockEug-13432.pdf (filename)

Legacy Identifier etd-BabcockEug-13432

Document Type Dissertation

Format theses (aat)

Rights Babcock, Eugene Christopher

Internet Media Type application/pdf

Type texts

Source 20240827-usctheses-batch-1202 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.

Repository Name University of Southern California Digital Library

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

Repository Email cisadmin@lib.usc.edu