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Experience with breakthrough therapy designation: an industry survey

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Experience with breakthrough therapy designation: an industry survey

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Content EXPERIENCE WITH BREAKTHROUGH THERAPY DESIGNATION: AN INDUSTRY SURVEY
by
Jennifer R. Wiley
A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE
May 2019
Copyright 2019 Jennifer R. Wiley
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DEDICATION
This work is dedicated to my parents, Stephanie and Jim, who have always encouraged my
endeavors, educational or otherwise. I would also like to dedicate this to my husband, Lee, and
son, Elliott, who provided lots of love and support while I pursued the completion of this work.

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ACKNOWLEDGEMENTS
I would like to thank my colleagues whose support and guidance have shaped who I am as a
Regulatory professional. Particularly, I would like to thank Jeff Fellows who has always been in
my corner and taught me many important lessons about staying true to myself while navigating
my career.
I would like to thank my thesis supervisors, Dr. Michael Jamieson and Dr. Frances Richmond, for
their guidance and encouragement while reviewing many drafts of this dissertation. I would also
like to thank my thesis committee members, Dr. Nancy Pire-Smerkanich and Dr. Mary Ellen
Cosenza, for their invaluable feedback on this work and assistance in locating survey participants.
I would like to thank my Smithies: Gigi Li, Annette Pollert, and Jennifer Truboff. Without their
encouragement and support I would not have applied to the DRSc program because working full
time and going to school sounded a bit crazy. They assured me a Smithie could do it and I
embarked on this journey.
In closing, I would also like to thank the other students in the 2014 Doctoral Cohort and the staff
of the Regulatory Science program for their support, both personally and professionally.

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TABLE OF CONTENTS
DEDICATION .................................................................................................................... 2
ACKNOWLEDGEMENTS ................................................................................................ 3
TABLE OF CONTENTS .................................................................................................... 4
LIST OF TABLES .............................................................................................................. 6
LIST OF FIGURES ............................................................................................................ 7
ABSTRACT ........................................................................................................................ 8
CHAPTER 1. OVERVIEW ............................................................................................ 9
1.1 Introduction .................................................................................................... 9
1.2 Statement of the Problem ............................................................................. 13
1.3 Purpose of the Study .................................................................................... 15
1.4 Importance of the Study ............................................................................... 16
1.5 Limitation, Delimitations, Assumptions ...................................................... 16
1.6 Organization of Thesis ................................................................................. 18
1.7 Definitions .................................................................................................... 19
CHAPTER 2. LITERATURE REVIEW ...................................................................... 20
2.1 Background to the Literature Review .......................................................... 20
2.2 History of United States Food and Drug Law .............................................. 21
2.3 Modern Day Drug Approval in the United States ........................................ 23
2.4 History of Expedited Development Pathways Prior to FDASIA ................. 26
2.4.1 Accelerated Approval ..................................................................... 28
2.4.2 Priority Review ............................................................................... 29
2.4.3 Fast Track Designation ................................................................... 30
2.5 Expedited Development Pathways Post-FDASIA ....................................... 33
2.5.1 Breakthrough Therapy Designation Pathway ................................. 33
2.5.2 Eligibility for BTD ......................................................................... 35
2.5.3 FDA Guidance and Application Reviews ....................................... 35
2.5.4 BTD Application Statistics ............................................................. 38
2.6 Comparison of Expedited Pathways and Usage by Industry ....................... 38
2.7 Academic Literature: Benefits of BTD ........................................................ 40

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2.8 Criticisms of BTD ........................................................................................ 44
2.8.1 Confirmation from Post-Marketing Evidence ................................ 45
2.8.2 FDA Resource Constraints ............................................................. 46
2.8.3 Inaccurate Public Perceptions of BTD ........................................... 46
2.8.4 Additional Considerations .............................................................. 47
2.9 Similar Mechanisms in Other Regulated Regions ....................................... 47
2.10 Methodology for Research ........................................................................... 48
CHAPTER 3. METHODOLOGY ............................................................................ 52
3.1 Introduction .................................................................................................. 52
3.2 Survey Development .................................................................................... 52
3.3 Focus Group ................................................................................................. 53
3.4 Dissemination of Survey .............................................................................. 54
CHAPTER 4. RESULTS .......................................................................................... 55
4.1 Participant Responses .................................................................................. 55
4.2 Profiles and Background of Participants ..................................................... 55
4.3 Information Publicly Available about BTD ................................................. 60
4.4 Deciding to Apply for BTD ......................................................................... 62
4.6 Company Size and Barriers to Applying for BTD ....................................... 69
4.7 Additional Thoughts on the BTD Pathway .................................................. 71
4.8 Experiences with Successful BTD Applications .......................................... 72
4.9 Experience with Unsuccessful BTD Applications ....................................... 75
CHAPTER 5. DISCUSSION .................................................................................... 80
5.1 Overview ...................................................................................................... 80
5.2 Methodological Considerations ................................................................... 80
5.3 Consideration of Results .............................................................................. 83
5.4 Utility of the Ramsey/Turnbull Framework ................................................. 90
5.5 Future Directions and Concluding Thoughts ............................................... 92
REFERENCES ................................................................................................................. 95
APPENDIX A: FINAL VERSION OF BTD SURVEY................................................. 102
APPENDIX B: FULL TEXT COMMENTS FROM BTD SURVEY ............................ 114
APPENDIX C: BTD SURVEY CROSS TABULATIONS ........................................... 122

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LIST OF TABLES
Table 1: Comparison of Expedited Development and Approval Pathways Before
2012 .......................................................................................................................... 32
Table 2: Percentage Use of Expedited Development and Approval Pathways to Gain
Market Access (2012-2017) ..................................................................................... 33
Table 3: Comparison of Expedited Pathways ......................................................................... 39
Table 4: Focus Group Participants .......................................................................................... 53
Table 5: Selected Responses Reflecting Challenges Associated with BTD Guidance
Document .................................................................................................................. 62
Table 6: Other Resources Used When Deciding to Apply for BTD ....................................... 63
Table 7: Select Recommendations for Additional BTD Resources ........................................ 64
Table 8: Should Additional Safety Monitoring Be Required for BTD Compounds? ............. 66
Table 9: Are Current Expedited Development Pathways Sufficient? ..................................... 68
Table 10: Ranking Company Size by BTD Pathway Benefit, n=36 ......................................... 70
Table 11: Common Barriers in Applying for BTD ................................................................... 70
Table 12: Select Comments on Additional Barriers to Applying for BTD ............................... 71
Table 13: Examples of Additional Thoughts on BTD as an Expedited Pathway ..................... 72
Table 14: Therapeutic Areas with Unsuccessful BTD Applications......................................... 75

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LIST OF FIGURES
Figure 1: Objectives of Regulation Per Ramsey Model ........................................................... 49
Figure 2: Ramsey Model Adjusted by Turnbull ....................................................................... 50
Figure 3: Distribution of Participants by Job Title ................................................................... 56
Figure 4: Participant Distribution by Company Size ................................................................ 57
Figure 5: Number of BTD Applications Submitted to FDA by Participants ............................ 58
Figure 6: Number of Successful BTD Applications ................................................................. 59
Figure 7: Number of Unsuccessful BTD Applications ............................................................. 60
Figure 8: Adequacy of Publicly Available Information Sources for BTD ............................... 61
Figure 9A: Level of Agreement at Time of First Marketing Approval ....................................... 65
Figure 9B: Level of Agreement at Time of First Marketing Approval ....................................... 67
Figure 10: Participant Perceptions of Current Expedited Development Pathways .................... 69
Figure 11: Drivers for Successful BTD Applications................................................................ 73
Figure 12: Use of Other Expedited Development Pathways in Addition to BTD ...................... 74
Figure 13: Drivers for Unsuccessful BTD Applications ............................................................ 76
Figure 14: FDA Rationale for Not Granting BTD in Unsuccessful Applications ...................... 77
Figure 15: Adequacy of FDA Feedback for Reapplication of an Unsuccessful
Application ............................................................................................................... 78
Figure 16: Framework Used to Assess BTD Expedited Development Pathway ........................ 84

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ABSTRACT
Breakthrough therapy designation (BTD) is the newest FDA mechanism intended to expedite the
drug development process for compounds that treat serious or life-threatening diseases. Much of
what is known about BTD is anecdotal and focused on outcomes rather than implementation.
This study was designed to investigate the views of regulatory affairs professionals in the
biopharmaceutical industry with respect to the usefulness of breakthrough therapy designation as
an expedited development pathway. A survey instrument was used to examine the perceived
effectiveness of the breakthrough therapy designation to satisfy three principal objectives of
regulation: 1) to ensure safety and effectiveness, 2) to facilitate efficiencies in research,
commercialization, and costs, and 3) to equalize the requirements and standards for industry. Data
analysis was conducted on responses from 48 participants from companies that varied in size.
Results showed that regulatory generalists perceive BTD to be a positive addition to the available
expedited pathways for drug development. Results also showed that participants perceive BTD as
satisfying the three principal objectives of regulation; however, there are potential areas of
improvement for the program, particularly with respect to interacting and receiving guidance
from FDA.

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CHAPTER 1. OVERVIEW
1.1 Introduction
The development of new drugs is a lengthy and expensive process. Estimates vary but suggest
that development times can be as long as 14 years and can cost more than a billion dollars
(DiMasi, Hansen, & Grabowski, 2003) (DiMasi, Grabowski, & Hansen, 2016) (Light &
Warburton, 2011). For drugs that are intended to treat serious and/or life-threatening conditions,
this slow development path has been of particular concern because it may deny patients timely
access to potentially life-saving treatments (Friends of Cancer Research, 2018). Thus, as early as
1988, the Food and Drug Administration (FDA) codified certain expedited development and
approval pathways (21 CFR 312 Subpart E) to speed the development of drugs for serious and/or
life-threatening conditions (FDA, 2014c). By FDA definition, a serious condition is one that, left
untreated, would progress from a less severe condition to a more serious one, as judged by its
impact on factors such as survival or day-to-day functioning (FDA, 2014b). This regulation also
acknowledges that patients and physicians are willing to accept more risk and side effects with
treatments that are developed for life-threatening and seriously debilitating diseases (FDA,
2014b).
Over time, the administrative pathways to facilitate the development of important new drugs were
expanded into a trio of routes: accelerated approval, priority review, and fast track designation
(FDA, 2014b). Accelerated approval and priority review help to expedite the FDA review and
approval process; whereas fast track designation helps to expedite drug development timelines.

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Accelerated approval allows for the approval of drugs that treat serious conditions with an unmet
medical need on the basis of a surrogate endpoint. A surrogate endpoint is a measure that is
thought to predict clinical benefit but is not in itself a measure of clinical benefit. A trial whose
outcome is based on a surrogate endpoint is typically much shorter than one that must prove a
more challenging improvement in clinical benefit, such as patient survival. Compounds that are
approved under this mechanism are required to confirm their clinical benefit in subsequent
clinical trial(s) as a condition of that approval. If the confirmatory trial(s) shows that the
compound does in fact provide an appropriate clinical benefit, the accelerated approval is
converted to a traditional approval (FDA, 2014b).
Priority review, allows products to receive a faster review by FDA, targeted at 6 months instead
of the standard 10 months typical for most New Drug Application (NDA) or Biologic License
Application (BLA) submissions. A compound is eligible for priority review if it demonstrates
significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention
of serious conditions when compared to standard of care (FDA, 2014b).
Fast track designation was the last of the expedited pathways to be implemented, in 1997 (FDA,
2014b). Fast track designation was designed for compounds that are intended to treat serious
conditions and fill an unmet medical need, so that they can be made available to patients earlier
than would otherwise be possible. Compounds that are designated for fast track designation
generally have a positive impact on such factors as survival and day-to-day functioning.
Compounds can also be designated for fast track designation if it is likely that the condition
would progress from a less severe condition to a more serious one if left untreated by the
compound. Fast track designation offers opportunities for more frequent interactions with FDA

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and allows for the possibility of priority review. Fast track designation also allows sponsors to
submit marketing applications over time as pieces of the application are ready as opposed to
submitting an entire marketing application at one time (FDA, 2014b).
Expedited development and approval pathways are intended to “ensure that therapies for serious
conditions are approved and available to patients as soon as it can be concluded that the therapies’
benefits justify their risks” (FDA, 2014b). The high percentage of novel compounds that have
used these expedited development and approval pathways suggests that these pathways may have
brought promising new drugs to market faster than others on a traditional development and
approval pathway (Kesselheim & Darrow, 2015). However, despite these efforts, additional
resources appeared to be needed for drugs with strong potential to remedy serious problems,
particularly in the area of cancer research (Friends of Cancer Research, 2018).
As early as 2010, the non-profit organization, Friends of Cancer Research (FOCR), began to hold
public meetings about the state of cancer research. They brought attention to the need for more
targeted therapies, including therapies that could target specific molecular pathways and methods
that could substratify patients most likely to respond to treatment. They also argued that
expedited development pathways are critical for drugs that show significant improvement over
currently available therapy early in development. FOCR and other attendees at that meeting
maintained that the “traditional multi-phase, sequential drug development process may not be
appropriate” in cases where new drugs show promising results (Friends of Cancer Research,
2018). On November 10, 2011, FOCR and the Brookings Institute co-hosted the fourth annual
Conference on Clinical Cancer Research, an event that brought together experts in cancer drug
development from academia, industry, federal health/ regulatory agencies, and patient advocacy

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groups. One of its panels specifically discussed potential approaches to speed the FDA approval
process for drugs that show large treatment effects early in development (Friends of Cancer
Research, 2018).
Following those public interest sessions, Congress passed the Food and Drug Safety Innovation
Act (FDASIA) that encouraged FDA to implement a new expedited development pathway,
Breakthrough Therapy Designation (BTD), for promising and important new drugs (Friends of
Cancer Research, 2018). In order to be granted BTD status, a drug
must be intended, alone or in combination with 1 or more other drugs, to
treat a serious or life-threatening disease or condition and preliminary
clinical evidence indicates that the drug may demonstrate substantial
improvement over existing therapies on 1 or more clinically significant
endpoints, such as substantial treatment effects observed early in clinical
development (FDA, 2014b).
A compound with BTD can receive intensive guidance from FDA on ways to expedite the
development plan for the compound. It is also eligible for shorter review timelines for almost all
standard program submissions to FDA, including marketing applications. FDA further proposed
to expedite the development of a compound by assisting the company, by assigning a cross-
disciplinary project lead for the review team and involving senior and experienced reviewers in
collaborative, cross-disciplinary discussions early in the development process. That cross-
disciplinary review team would then meet frequently with the sponsor as more information is
gathered about the compound (FDA, 2014b).
The additional attention provided by BTD appears to be working. In 2016, Shea identified that
median FDA reviews were 2.9 months shorter for compounds granted BTD compared to those
that were not. Shea also reported that the median pre-market development times for BTDs of 5.2

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years were considerably shorter than those of non-designees, of 7.4 years (Shea et al., 2016).
However, it is not clear to what extent these savings occurred as a result of the new BTD policies,
because compounds granted BTD would typically have been eligible for accelerated approval
under previously established programs where they would already have had a shorter development
pathway even without a BTD pathway in place (Poirier & Murphy, 2016).
BTD has been granted to over 200 development programs in the six-year period since the
program was enacted. Much of what is known about the relative success of BTD applications has
been published by FDA, whose counts of BTDs are collated on a quarterly basis. Most of the
available literature has focused on the comparative timelines of approvals or drug development
programs, and the types of products for which it is used and will be used in future (Kwok, Foster,
& Steinberg, 2015) (Shea et al., 2016) (Chizkov, 2015). Beyond these numbers, however, little
has yet been written about the perceived effectiveness and level of satisfaction of the program
amongst its stakeholders.
1.2 Statement of the Problem
Taken together, what is known to date suggests that BTD appears to be effective at accomplishing
its primary objective to expedite drug development. For example, in the oncology space, reports
suggest a reduction in average timelines of about 2 years (Shea et al., 2016). However, efforts to
shorten drug development timelines do not come without critics. Concerns have been expressed
about the ability of such short-term studies to assure long term drug safety particularly if more
comprehensive study data from confirmatory trials is slow to be provided (Kesselheim & Darrow,
2015). FDA has had a questionable track record of policing the timely conduct of confirmatory

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trials. Further, some have questioned the effect of the additional and difficult-to-satisfy demands
on FDA resources, and the possibilities of public misperceptions about therapeutic benefit and
risk for these products for which study is limited prior to marketing (Aggarwal & Topaloglu,
2014) (Kwok et al., 2015). Critics of the BTD program have also raised concerns about the ability
of manufacturing to keep pace with the accelerated clinical development programs, especially
since they limit the time available for the kinds of additional testing needed to design quality into
the product (Wechsler, 2015). Some have also expressed concern that the playing field may not
be level for such programs, and that smaller pharmaceutical organizations are underrepresented
among the grouping of companies receiving the designation (Kwok et al., 2015). Several authors
have questioned whether BTD adds any benefits to the current regulatory environment given that
many of the program benefits overlap with pathways that are already available to drug developers
(Kesselheim & Darrow, 2015) (Jae, 2014).
Much of the information that is available about the BTD program is anecdotal and is concerned
with outcomes rather than implementation. Little research to date appears to be directed at
understanding more systematically the views and concerns of stakeholders who now have had a
half-decade of experience with the program. One major stakeholder in this arena is of course the
manufacturers for whom this program can offer advantages. However, no published data has yet
examined industry perceptions related to the pathway and whether it is consistent with FDA’s
stated goals for regulation.
Three goals commonly assigned to regulation were summarized by Ramsey that included the
roles 1) to ensure safety and effectiveness, 2) to facilitate efficiencies in research,
commercialization, and costs, and 3) to equalize the requirements and standards for industry

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(Ramsey, 2013). Some of the concerns identified above suggest anecdotally that issues may exist
with regard to the effectiveness of BTD to achieve the identified goals, but opportunities still
exist to look more systematically at BTD through the lens of this triadic model.
1.3 Purpose of the Study
It is well known that companies are using the BTD pathway to bring promising products to
market. The primary purpose of this study was to explore industry perceptions related to success
of BTD at achieving the goals of regulations through the eyes of regulatory professionals. To
investigate this question, I used the Ramsey framework described above to examine if the BTD
expedited development pathway is effective at ensuring safety and effectiveness of the BTD
products, by facilitating efficiencies in research and commercialization and equalizing
requirements for large and small companies (Ramsey, 2013).
To this end, I developed a survey instrument that was critiqued by a focus group of regulatory
experts with experience either with expedited drug development or survey production. The survey
was then administered electronically to a selected group of participants possessing significant
experience with pharmaceutical development and regulatory submissions in product sectors
known to be associated with the BTD pathway. These individuals were identified not only
through personal contacts and membership lists from relevant professional meetings and advisory
groups, but also by searching FDA’s databases for approved drugs that have been granted BTD.

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1.4 Importance of the Study
Despite the number of BTDs granted in the last 6 years much remains to be known about the
views of regulatory professionals with regard to the usefulness of the BTD program. The
scholarly literature with respect to the policy effectiveness of BTD rests on metrics about the
number of products with BTD and the speed at which they have been commercialized. However,
policies have other objectives that can be sacrificed on the path to achieving a specific singular
outcome. Further it can be misleading to assign the increased speed of such designated products
to the BTD program if other expedited pathways could also explain that success. The results of
this survey will help us to understand whether industry views BTD as a useful expedited
development pathway that adds more than the previously available earlier expedited pathway
options. It will also provide insight into the success of this implementation – whether the
guidance that FDA has provided is sufficient for companies to gain maximum benefit from the
application and assistance programs. The results are also useful to regulators as they try to
understand what additional steps can or should be taken to improve the BTD process and
implementation. If specific areas appear to be suboptimal in achieving the goals of regulation,
those program elements may be modified to better meet the expectations of the other
stakeholders.
1.5 Limitation, Delimitations, Assumptions
Several potential features of this study face potential limitations. First is the availability of
relevant respondents and their knowledge related to BTD. It is unlikely that we can identify all
the individuals who would be appropriate for this survey since typically only positive outcomes

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from applying for BTD are publicized. Finding individuals who have applied for BTD and have
been denied is going to be challenging. Thus, we will aim to provide a sampling of appropriate
individuals across the United States who are in a position to use expedited pathways regardless of
whether they have been specifically associated with a successful BTD product. Using appropriate
early questions, we anticipate that we can stratify the population of respondents to see if
differences are present between those who have used and have not used the BTD pathway.
Nonetheless, there is an inherent risk of capturing a skewed subpopulation. As with any survey,
the quality of the data depends on who is willing to participate. Thus, even a carefully chosen
sample may fail to represent the views of Regulatory Affairs professionals as a whole. Letters of
invitation will be designed and personalized to the extent possible, but high survey response rates
may not be realistic.
This study is also limited in the number of publications that are available to conduct a thorough
literature review and thus have a clear picture of industry expectations in advance of the survey.
The lack of scholarly literature may affect my ability to identify key questions that will allow me
to obtain a comprehensive picture of the perceptions of industry on BTD and to compare my
findings with the existing literature. In order to reduce the problem of adequate support in
understanding the views of these stakeholders, a focus group will be used to critique the survey
and provide advice on the flow and nature of the questions.
The number of questions that can be included in a survey is another limitation. We are targeting
busy professionals and want to ensure that they can complete the survey within a reasonable
length of time. Because respondents for this survey will be regulatory affairs professionals at
more senior levels, they may be reluctant to participate in activities beyond their day-to-day job

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responsibilities. Thus, surveys must be kept short, but this limits the number of questions, and
thus our ability to explore fully certain areas of interest.
This survey is delimited in that it focuses on perceptions of Regulatory Affairs professionals
based in the United States. Further, it focuses on one pathway, the BTD pathway, although it may
give information about other expedited development pathways that are not mutually exclusive.
The survey is also delimited with respect to one particular respondent group, that of regulatory
personnel in industry. Other groups, such as other divisions in the same companies, or those in
government or academia, will not be represented here. Because BTD came into effect only in
2012, results are delimited to experiences gained in the first six years. These may not be
representative of views and experience going forward.
Several assumptions are made in any survey. Importantly, we will assume that survey
respondents understand the questions related to BTD, are answering questions honestly, and are
not delegating the survey to others who may lack the requisite experience.
1.6 Organization of Thesis
Chapter 1 introduces the problem being studied in this dissertation and summarizes the approach
that was taken to study the problem.
Chapter 2 reviews relevant literature to the problem. It summarizes the history of expedited
development pathways in the United States and what is presently published about BTD. It also
briefly summarizes similar programs in the European Union and Japan.

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Chapter 3 describes the methodology used to conduct the survey and includes all questions that
were developed and used to gather data.
Chapter 4 describes the results of the study based on the questions that were asked using the
survey instrument.
Chapter 5 interprets the results of the study and discusses implications for future research.
1.7 Definitions
Abbreviation Full Term
API Active Pharmaceutical Ingredient
BLA Biologic Licensing Application
BTD Breakthrough Therapy Designation
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CFR Code of Federal Regulations
FDA Food and Drug Administration
FDASIA Food and Drug Administration Safety Innovation Act
FD&C Federal Food, Drug, and Cosmetic Act
FOCR Friends of Cancer Research
FTC Federal Trade Commission
MAPP Manual of Policies and Procedures
NDA New Drug Application
PDUFA Prescription Drug User Fee Act
PMDA Pharmaceuticals and Medical Devices Agency
PRIME PRIority MEdicines

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CHAPTER 2. LITERATURE REVIEW
2.1 Background to the Literature Review
BTD is a relatively new expedited development pathway and it was essential to systematically
review publicly available materials to ascertain the current state of literature on BTD. The online
USC library was used to conduct a literature search of journal articles, books, and online
references. Key words searched were breakthrough therapy designation. In addition, Google and
the same key words were used to conduct a literature search to obtain references. Citations were
excluded from this review if they concerned solely a specific pharmaceutical compound (e.g.,
press release). Publications were also excluded if they were not in English.
Initially more than 23,000 citations were identified based on the key words above; however,
many of those citations were announcements of BTD being granted to a specific compound. The
following literature review is based on a survey of 150 sources that included the original citations,
as well as works cited in the original citations. The list was ultimately narrowed to approximately
80 bibliographic references. Of all materials, Dr. Aaron Kesselheim’s publications provided
comprehensive overviews of breakthrough therapy designation and potential concerns with the
program. The FDA website provided guidance documents, application statistics, and the current
thinking of the agency on this topic.

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2.2 History of United States Food and Drug Law
The history of modern drug oversight is marked by cautionary tales that changed the landscape
from a free market to one of the most regulated of commercial sectors. Before 1906, US
manufacturers could essentially sell whatever they wanted using any claims they wanted without
having to disclose the ingredients in a product or prove its safety and efficacy. The publication of
Upton Sinclair’s exposé, The Jungle, marked the beginning of change by opening the public’s
eyes to unsanitary conditions in meat-packing plants. These descriptions, as well as newspaper
articles exposing dangerous ingredients in medicines, led to the first of several acts by Congress
to regulate the food and drug industry (FDA, 2014c). On June 30, 1906, the Food and Drugs Act
and the Meat Inspection Act were passed by Congress to prohibit interstate commerce of
misbranded and adulterated food, drinks, and drugs. The relatively weak language of this Act,
however, was insufficient to counter the deceptive practices of many food and drug companies.
In 1911, the Supreme Court ruled that the 1906 Food and Drug Act did not prohibit false
therapeutic claims but only false and misleading statements about the ingredients or identity of a
drug (US v Johnson). In response to the Supreme Court ruling, the US Congress enacted the
Sherley Amendment in 1912. The amendment prohibited companies from labeling medicines
with false therapeutic claims, but again, weak language limited the usefulness of the Act by
restricting legal measures to the prosecution of companies that could be shown to commit those
acts deliberately. Deliberate fraud was very difficult to prove.
It was not until the middle of the 1930s that attention refocused on failures in the oversight of
medical products, again in response to a public health crisis. In this case, the precipitating event
was the deaths of 107 people, including many children, after ingesting a poisonous ingredient

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known as “elixir of sulfanilamide” in a medicine for streptococcal infections (FDA, 2014c). The
Federal Food, Drug, and Cosmetic (FD&C) Act of 1938 required that new drugs be shown safe
before marketing. To do this, drug developers were required to submit a New Drug Application
(NDA) to FDA for review and approval before introducing a drug product into interstate
commerce. In addition, the new law eliminated the requirement previously associated with the
Sherley Amendment that the prosecution had to prove intent to defraud in drug misbranding
cases. Amongst its other requirements, it mandated that safe tolerances be set for unavoidable
poisonous substances and added the remedy of court injunctions to the previous penalties of
seizures and prosecutions that could be levied against noncompliant companies.
The deficiencies of the 1938 Act came under scrutiny 25 years later, when another drug-related
tragedy caused Congress to develop additional new legislation. In this case, Thalidomide, a newly
marketed remedy for morning sickness marketed in the EU, was found to cause birth defects that
affected thousands of babies born in western Europe. Thalidomide was never approved for sale in
the United States, largely because an FDA reviewer, Dr. Frances Kelsey, expressed concerns
about the strength of the safety information provided by the manufacturer (FDA, 2006).
Nevertheless, the view that the US had narrowly missed the same tragedy led to strong support
for more rigorous drug oversight and drove public support for the passage of the Kefauver-Harris
Drug Amendments. Under the new law, a manufacturer was no longer allowed to sell a drug 60
days after submitting a market application to FDA if the time period passed without explicit
objections from the FDA, as had been the case previously. Instead the manufacturer was required
to prove the effectiveness of its product and FDA had to grant approval explicitly, based on the
safety and effectiveness profile of that product before marketing could begin. The Kefauver-

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Harris Amendments marked the first time that FDA had the authority to approve a drug on the
basis of safety and efficacy data, setting the stage for today’s assessments of the benefit: risk
profile of a compound. Additionally, the Amendments included a number of new elements,
notably formalizing good manufacturing requirements and introducing evidentiary standards of
well-controlled clinical trials (Hilts, 2003).
The Kefauver-Harris Amendments, like its predecessors, had a significant impact on the
pharmaceutical industry. By requiring more nonclinical and clinical studies of safety and
effectiveness, these amendments changed the business environment for manufacturers—greatly
increasing the costs and challenges for getting a product to market.
2.3 Modern Day Drug Approval in the United States
Today, as result of the Kefauver-Harris Amendments and numerous other amendments and
regulations that have followed, the drug development and approval process in the United States
typically takes many years and significant monetary and human capital investments by drug
developers. Estimates vary regarding the cost and time of drug development. Dimasi, in 2003,
estimated 14 years and $800 million dollars to complete the extensive animal and human testing
and review needed to bring a new drug from concept to the marketplace (DiMasi et al., 2003).
Thirteen years later, he published an updated estimate of $2.6 billion, a cost contested by some
who argue that the cost is closer to $1.3 billion dollars. They argue that the DiMasi figure is
misleading because it includes costs for drugs that failed to win approval and was calculated
using a small sample size (DiMasi et al., 2016) (Light & Warburton, 2011). Regardless of exact

24
figures, all reports agree that capital amounts above 1 billion dollars are not excessive when
capturing all the costs of bringing a new entity to the marketplace.
Where does that money go? Much of the expense is typically assigned to the animal and human
testing that must be carried out to satisfy regulatory and reimbursement requirements. A company
that develops a new molecular entity (commonly called the sponsor) must first conduct
nonclinical studies to gauge the safety of that product in a biological system and the effectiveness
of that product to treat a target condition. Typically, testing escalates from determining acute and
then chronic effects of the compound in cells and animals to conducting carcinogenicity and
reproductive toxicology studies in accordance with the nature of the compound, the types of
patients that will be treated, and the duration for which the drug will be given. A “typical”
nonclinical testing program to enable initial clinical trials can take up to 2 years to complete
(Attarchi, 2003).
Nonclinical studies establish foundational evidence to prove that a drug is sufficiently safe to
justify its use in clinical trials as required under the Kefauver-Harris Amendments. The rules
governing the conduct of nonclinical testing are outlined in a plethora of regulations and guidance
documents from the FDA that have evolved as scientific experience with different types of drugs
has matured (Preclinical safety evaluation of biopharmaceuticals: a science-based approach to
facilitating clinical trials, 2008). Permission to conduct that trial is then sought by submitting an
Investigational New Drug (IND) application to FDA. This IND contains all the information that
is known about the new active pharmaceutical ingredient (API) and final product. It includes
information about the API’s chemical or biological structure and how it is manufactured into a
drug product reliably and reproducibly. The nonclinical results are reviewed and the protocol for

25
the clinical trial is described. Based on the information, FDA will decide if the sponsor may
proceed with the clinical trial either as designed or with modifications ("United States Code",
2010). Sponsors may begin clinical trials thirty days after an initial IND submission provided
FDA deems that the sponsor has provided satisfactory information from its battery of nonclinical
tests, its ability to control the quality of its manufacturing, and its proposed clinical trial design
("United States Code", 2010).
A premarket program of clinical trials is typically organized as a sequence of study phases,
designated as phases 1 through 3. In phase 1, the new drug is given at varying doses to a small
number of healthy volunteers to evaluate the pharmacokinetic and adverse event profiles.
However, some drugs, such as those to treat cancer, often have a profile sufficiently toxic that
testing in volunteers would be unreasonable. These so-called “first-in-man” studies often involve
patients with the disease rather than healthy volunteers.
The results from the phase 1 trial are used to design well-controlled phase 2 trials which explore
the potential dose range and effectiveness of the drug in patients who have the disease of interest.
Phase 2 trials can take as little as a few months or as long as many years depending on the clinical
indication (FDA, 2018a). If positive results are obtained and the business case for pursuing
commercialization can be made, the drug enters phase 3 testing. This phase of testing seeks to
confirm the phase 2 results and obtain additional information on safety and effectiveness in the
disease population more broadly so that an overall benefit: risk assessment of the new entity can
be evaluated. Phase 3 clinical trials often involve thousands of patients and last from 1 to 4 years
depending on the indication (FDA, 2018a).

26
To seek market registration, the sponsor will submit a NDA/BLA to FDA. This NDA/BLA is a
substantive document that draws together all of the data gathered during the drug development
program and allows FDA to assess the benefits and risks associated with the proposed new
product.
2.4 History of Expedited Development Pathways Prior to FDASIA
The typically long timeframes and high costs of drug development are a problem not only for
industry but also for the FDA. FDA has a multi-faceted mission:
The Food and Drug Administration is responsible for protecting the public health by
ensuring the safety, efficacy, and security of human and veterinary drugs, biological
products, and medical devices; and by ensuring the safety of our nation's food supply,
cosmetics, and products that emit radiation.
FDA also has responsibility for regulating the manufacturing, marketing, and
distribution of tobacco products to protect the public health and to reduce tobacco use by
minors.
FDA is responsible for advancing the public health by helping to speed innovations that
make medical products more effective, safer, and more affordable and by helping the
public get the accurate, science-based information they need to use medical products and
foods to maintain and improve their health.
FDA also plays a significant role in the Nation's counterterrorism capability. FDA fulfills
this responsibility by ensuring the security of the food supply and by fostering
development of medical products to respond to deliberate and naturally emerging public
health threats (FDA, 2017a).
One part of the mission above that has received particular attention over the past decade is that of
“advancing the public health by helping to speed innovations.” If the FDA is to foster innovative
product development, most agree that it must look for ways to shorten drug development
timelines, especially for drugs that provide novel solutions to treat patients with life-threatening

27
illnesses. As early as 1988, political and societal pressure related to the AIDS crisis led FDA to
codify expedited development and approval pathways to speed the development of drugs intended
to treat serious and/or life-threatening conditions (FDA, 2014c). By FDA definition, a serious
condition is,
...a disease or condition associated with morbidity that has substantial impact
on day-to-day functioning. Short-lived and self-limiting morbidity will usually
not be sufficient, but the morbidity need not be irreversible if it is persistent or
recurrent. Whether a disease or condition is serious is a matter of clinical
judgment, based on its impact on such factors as survival, day-to-day
functioning, or the likelihood that the disease, if left untreated, will progress
from a less severe condition to a more serious one (FDA, 2014b).
According to FDA,
…The regulations call for earlier attention to drugs that have promise in
treating such conditions, including early consultation with Sponsors of such
products and efficient trial design, potentially relying on well-controlled
phase 2 studies for evidence of effectiveness (FDA, 2014b).
The regulations that are codified as part of, 21 CFR part 312 subpart E were put into place with
the tacit understanding that patients and physicians dealing with serious diseases are willing to
accept more risk with a drug whose safety or efficacy is less certain than other with less serious
conditions (Mathieu, 1993). For such serious conditions, patients are enthusiastic to see the
opportunity to have treatments that might save their lives or greatly improve their quality of life
(FDA, 2014b). The pathways that were implemented to speed drug development and approval
timelines in the last decade of the twentieth century are known as accelerated approval, priority
review, and fast track designation. Accelerated approval and priority review are intended to speed
approvals; fast track is intended to help speed compounds through their development program.

28
2.4.1 Accelerated Approval
The “accelerated approval” program is one of the FDA’s earliest efforts to expedite drug
availability. This program was established in 1992 after the passage of the Prescription Drug User
Fee Act and was implemented under Subpart H of FDA’s New Drug, Antibiotic, and Biological
Products regulation (21 CFR Parts 312, 314, 511, and 514). The accelerated approval pathway
facilitates the approval of drugs that treat serious conditions for an unmet medical need by
permitting the sponsor to use an outcome measure based on a surrogate endpoint. A surrogate
endpoint is a measure that is thought to predict clinical benefit but is not in itself a measure of
clinical benefit. Trials whose outcome is defined by a surrogate endpoint are typically much
shorter than they would be if a company had to demonstrate clinical benefit in that trial. Since
the introduction of the new pathway, the use of surrogate outcomes has at times been contentious
because such measures sometimes proved to be ineffective at predicting whether the patient’s
clinical condition improves in the longer term. For example, in 2016, FDA granted accelerated
approval to Exondys 51, the first drug approved to treat patients with Duchenne muscular
dystrophy. The approval was based on a surrogate endpoint of increased dystrophin in skeletal
muscle. The increase was observed in some patients participating in trials; however, the overall
clinical benefit (including increased motor function) could not be established by subsequent work
and longer follow-up (FDA, 2016a).
Compounds that are approved under the accelerated approval pathway still must eventually be
shown to provide the anticipated clinical benefit in clinical trials. If, for example, the
confirmatory trials for Exondys 51 fail to show that the compound provides clinical benefit as

29
more testing is carried out, the accelerated approval will not be converted to a traditional approval
and the product will be removed from the market.
2.4.2 Priority Review
The “priority review” program was established to support Prescription Drug User Fee Act
(PDUFA) legislation by the FDA in 1992 at the same time as accelerated approval was instituted.
The primary goal of PDUFA was to facilitate the collection of user fees from sponsors in order to
improve the review times associated with drug approvals. Under PDUFA, FDA was required to
justify the effective use of those fees, which it did by implementing a new two-tiered review
system that included Standard Review and Priority Review. Priority review was granted to
compounds that could demonstrate significant improvements in the safety or effectiveness of the
treatment, diagnosis, or prevention of serious conditions when compared to standard of care. FDA
provides the following as examples of demonstrating significant improvement:
 Evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;
 Elimination or substantial reduction of a treatment-limiting drug reaction;
 Documented enhancement of patient compliance that is expected to lead to an
improvement in serious outcomes; or
 Evidence of safety and effectiveness in a new subpopulation.
Under priority review, FDA committed to reviewing the drug in 6 months instead of the 10
months promised for standard review.

30
The performance goals set by FDA were evaluated and enforced by a “sunset” clause that
required PDUFA legislation to be reauthorized every five years, only if FDA could demonstrate
its effectiveness in meeting its goals. The priority review track has been retained throughout the
subsequent passage of later PDUFA II-VI legislation. In 2016, the types of compounds receiving
priority review included first-in-class compounds for which no other treatments existed, imaging
agents to help with cancer diagnoses, compounds that offered targeted oncology therapies based
on mutations in patient genes, and compounds that expanded the treatment scope of patients with
chronic diseases, such as hepatitis C (FDA, 2017b).
2.4.3 Fast Track Designation
The third expedited development pathway, “fast track designation”, was established a few years
later, in 1997, under section 112 of the Food and Drug Administration Modernization Act (FDA,
2014b). Like the accelerated approval program, fast track designation was designed to facilitate
the review of compounds intended to treat serious conditions and fill an unmet medical need. To
be designated as eligible for fast track status, compounds were required to show promise to
improve survival and day-to-day functioning or prevent the normally anticipated progression of a
serious condition. The ability to fill an unmet need was defined as providing a therapy where
none exists or providing a therapy which may have more benefit than an available therapy
through, for example, a superior effectiveness or adverse-event profile. Such products could also
address an important public health need or demonstrate better ability to detect a disease where
more accurate or timely diagnosis would improve treatment outcome.

31
Fast track designation comes with several benefits. These include more frequent meetings with
FDA to discuss the compound’s development plan and more frequent written communications
from FDA about strategic and operational issues related, for example, to the design of the
proposed clinical trials or the adequacy of their outcome measures and biomarkers. Fast track
products can gain access to accelerated approval and priority review programs as well, if certain
conditions are met, and they can take advantage of rolling BLA or NDA review, where the
sponsor can submit completed sections of their marketing application as they are ready, rather
than waiting for the entire marketing application to be completed (FDA, 2014b).
2.4.4 Use of the Pre-FDASIA Expedited Development and Approval Pathways
The expedited development and approval pathways that were available prior to the
implementation of FDASIA in 2012 all have slightly different qualifying criteria and benefits
associated with their use, as shown in Table 1. Interestingly, the pathways were not designed to
be mutually exclusive, so sponsors can benefit from more than one pathway. For example,
Exondys 51 was granted accelerated approval, priority review, and fast track designation (FDA,
2017b).

32
Table 1: Comparison of Expedited Development and Approval Pathways Before 2012
Fast Track
Designation
Accelerated Approval Priority Review
Qualifying
Criteria
A drug that is
intended to treat a
serious condition
and for which
nonclinical or
clinical data
demonstrate the
potential to address
an unmet medical
need
A drug that treats a serious
condition, generally provides a
meaningful advantage over
available therapies, and
demonstrates an effect on a
surrogate endpoint that is
reasonably likely to predict
clinical benefit or on a clinical
end point that is reasonably
likely to predict an effect on
“irreversible morbidity or
mortality” or other clinical
benefit
An application
(original or
efficacy
supplement)
for a drug that
treats a serious
condition and that
if approved would
provide a
significant
improvement in
safety or
effectiveness
Benefits Opportunities for
frequent
interactions with
FDA; possible
eligibility for
priority review;
rolling review
Approval based on an effect on a
surrogate or intermediate clinical
endpoint that is reasonably likely
to predict a drug’s clinical
benefit
Shorter period for
review of
marketing
application (6
months, as
compared with the
10-month standard
review)
Timing of
Submission
to Support
Request
With IND or after
(can be based on
preclinical data
only); ideally, no
later than pre-
NDA/BLA meeting
Discuss with review division
during development as
approaching pivotal trial

With original
NDA/BLA or
efficacy
submission
Adapted from (FDA, 2014b).
In 2017, the most recent year for which statistics are available, 28/46 (61%) of newly approved
drugs used one or more of the expedited pathways to help speed their development and/or
approval processes (FDA, 2018b). Tracing backward, in 2016, 2015, and 2014, the percentage of
novel drugs using one or more expedited development and/or approval pathways was 16/22
(73%), 27/45 (60%), and 27/41 (66%), respectively (FDA, 2017b), (FDA, 2016b), (FDA, 2015b).

33
Table 2 summarizes the percentage of compounds that have used each expedited development
pathway.
Table 2: Percentage Use of Expedited Development and Approval Pathways to Gain
Market Access (2012-2017)
Year
Overall Use
1

n (%)
Fast Track
n (%)
Priority Review
n (%)
Accelerated
Approval
n (%)
2017
(N=46)
28 (61) 18 (39) 28 (61) 6 (13)
2016
(N=22)
16 (73) 8 (36) 15 (68) 6 (27)
2015
(N=45)
27 (60) 14 (31) 24 (53) 6 (13)
2014
(N=41)
27 (66) 17 (41) 25 (61) 8 (20)
2013
(N=27)
13 (48) 10 (37) 10 (37) 4 (7)
2012
(N=39)
22 (56) 14 (36) 16 (41) 4 (10)
Adapted from (FDA, 2018b) (FDA, 2017b), (FDA, 2016b), (FDA, 2015b), (FDA, 2014d), (FDA, 2013)
1
A single product can be counted once in the overall usage column; however, the compounds can be
counted more than once depending on how many expedited development pathways were used in its
development.
From 1987-2014, priority review was the most common of the programs used across all
therapeutic classes while accelerated approval was the least common (Kesselheim et al., 2015).
2.5 Expedited Development Pathways Post-FDASIA
2.5.1 Breakthrough Therapy Designation Pathway
Despite the availability of three expedited development pathways, many patients and advocates in
the 21
st
century still complained about lengthy drug development timelines. New technological
advances in drug development, and particularly those associated with molecularly targeted
therapies paired with companion diagnostics, have helped physicians to personalize drugs for
subgroups of patients with particular genotypes or receptor susceptibilities (Yao, Meric-

34
Bernstam, Lee, & Eckhardt, 2013). The magnitude of these effects for some patients can
sometimes be seen as early as phase 1 trials (Sherman, Li, Shapley, Robb, & Woodcock, 2013).
For such therapies, patients and advocates have expressed strong views that a standard drug
development program is inappropriate because it delays access to life-saving treatments. These
concerns gained momentum when a well-known advocacy group, Friends of Cancer Research,
partnered with the Brookings Institution to co-host the fourth annual Conference on Clinical
Cancer Care Research in November 2011. One of the panels at the conference discussed potential
approaches to speed the FDA approval process for drugs that show large treatment effects early in
development (Sawyers, Haber, Horning, Ivy, & Selig, 2012). For such drugs, contributors
questioned why a development path with several sequential long trials should be necessary. The
panel proposed several pathways that might be taken for drugs that showed early promise, such as
relying on phase 2b clinical trial data to support a standard rather than accelerated approval or
proceeding directly from phase 1 to phase 3 clinical trials (Friends of Cancer Research, 2018)
(Horning et al., 2013).
Almost immediately thereafter, in March 2012, the “Advancing Breakthrough Therapies Act”
was introduced in the Senate and two months later, the “Breakthrough Therapy Act” was
introduced in the House of Representatives. On July 9, 2012, it was signed into law as an
amendment to the Food and Drug Administration Safety and Innovation Act (FDASIA) (Sawyers
et al., 2012). The new category of “Breakthrough Designation” had as its objective to increase
efficiency and simplify approvals for specific products by reducing requirements to those really
necessary to obtain marketing approval (Woodcock, 2014). Thus, it became added to the list of
programs already in place with significant new features to accelerate product approval.

35
2.5.2 Eligibility for BTD
To be eligible for BTD, compounds must show preliminary clinical evidence that a compound
offers a clear advantage over other available therapies on the basis of a clinically significant
endpoint(s) (FDA, 2014b). FDA defines a clinically significant endpoint as one that measures an
effect on irreversible morbidity or mortality or on symptoms that represent serious consequences
of the disease. Findings may also suggest an effect on an established surrogate endpoint, an
intermediate clinical endpoint likely to predict a clinical benefit, or a pharmacodynamic
biomarker(s) suggesting a clinically meaningful effect on the underlying disease. Eligible
products may also be given this designation if they can demonstrate a similar efficacy, but a
significantly improved safety profile compared to available therapy (FDA, 2014b).
2.5.3 FDA Guidance and Application Reviews
Two years after the breakthrough therapy designation was introduced, FDA published a final
guidance to serve as a resource for sponsors regarding the threshold criteria for applying for BTD
as well as other expedited development pathways (FDA, 2014b). The guidance defines the
specific features of BTD and amplifies the attributes considered important when applying for
BTD. FDA pointed to the opportunities provided by for BTD products to obtain intensive
interaction regarding developmental strategies as early as phase 1. Given the large benefit that
such products were expected to have, creative approaches might be recommended as part of their
regulatory or clinical strategy. For example, a sponsor might employ an adaptive trial design or
use interim data analyses to support an early marketing submission. In such a case, FDA would
like to engage with the sponsor as early as possible, to assure that the plan would be able to
furnish sufficient data to meet the requirements for approval. The guidance document also makes

36
it clear that the shortened timeline will place constraints on clinical and manufacturing groups,
and these groups may also profit from discussions with the extended FDA review team. In
addition to the intensive feedback during the development process, FDA also made a commitment
to involve senior managers and experienced reviewers in early cross-disciplinary reviews in order
to improve the quality and efficiency of their review process. As the development progresses, the
sponsor could submit its marketing application for rolling review and retain concurrent eligibility
for priority review (FDA, 2014b).
In 2014 and 2015, the Center for Drug Evaluation and Research (CDER) also published Manuals
of Policies and Procedures (MAPPs) related to good review practices for compounds with
breakthrough therapy designation (FDA, 2014a) (FDA, 2015a). These MAPPs further delineated
the types of support and benefits that compounds with BTD should expect to receive. As part of
the IND phase, BTD compounds would have a shorter review timeframe for most major
amendments. During the marketing application review phase, BTD compounds would be
assessed to determine if the application also qualifies for expedited review. If a compound were
to be eligible for expedited review, the FDA review team would try to complete the review and
author an action letter at least one month before the PDUFA goal date.
Sponsors can submit an application for BTD as soon as they have preliminary clinical evidence
indicating that their drug product may have substantial benefit over existing therapies (FDA,
2014b). Because many benefits could accelerate the clinical program at early stages, FDA prefers
to receive requests for BTD before the sponsor initiates trials intended to serve as the primary
source of efficacy data so that the sponsor can obtain all the benefits of the designation (FDA,

37
2014b). FDA might also suggest that a sponsor apply for the designation early in that clinical
program if the early clinical evidence is compelling (FDA, 2014b).
A BTD application is submitted to the applicable review division where reviewers make a
preliminary assessment. The request is then presented to CDER’s Medical Policy Council (with
participation by the Center for Biologics Evaluation and Research (CBER)) and an assessment is
made to determine if granting the designation is consistent with current FDA policy and direction.
Ultimately, the clinical review division makes the final decision regarding the product’s
suitability and interacts with the sponsor within 60 days of receipt of the initial application
(Conrad et al., 2017). According to Janet Woodcock, Director of CDER, this process has allowed
for consistent policy development and cross-organizational learning without being overly
intrusive in day-to-day FDA business. Further, it allows FDA to recognize policy issues related to
program implementation that might arise as requests are evaluated (Woodcock, 2014).
Not all drugs that apply for BTD are able to receive designation. An application may be denied if
clinical data fail to suggest a “substantial benefit” over existing therapy (FDA, 2014b).
Additionally, the value of various endpoints used to evaluate efficacy has been a significant area
of discussion among review teams. According to Woodcock, “a non-trivial percentage of denied
applications appear to represent the triumph of hope over clinical evidence” (Woodcock, 2014).
FDA intends to provide further guidance on how to apply the “substantial evidence” criterion to
BTD applications once “sufficient experience” is gained (Woodcock, 2014).

38
2.5.4 BTD Application Statistics
Several researchers have tried to assess the accomplishments of BTD and draw conclusions about
the future of the program (Shea et al., 2016) (Kwok, et al., 2015) (Poirier & Murphy, 2016). FDA
has also published what it sees as the appropriate metrics to judge the success of BTD
applications. The number of breakthrough therapy designations granted by FDA are reported
quarterly. As of September 2017, FDA had received 606 requests for breakthrough therapy
designation. Of these, 224 designations were granted. CDER had a slightly higher rate of granting
the designation (38%) compared to CBER (30%) (FDA, 2018c) (FDA, 2018d).
Further analyses of successful applications make it clear that certain therapeutic areas are more
likely to receive the designation than others; however, this information is not readily available on
the FDA website. The top three therapeutic areas to receive designations are oncology (47%),
infectious disease (26%), and pulmonary disease (16%) (Brookings Institution, 2015). It is not
clear whether this simply reflects the higher application numbers from those disease sectors or
whether the scientific basis for assessing clinical efficacy and safety in those sectors allows
earlier insight into clinical outcomes.
2.6 Comparison of Expedited Pathways and Usage by Industry
Table 3 compares the qualifying criteria and benefits of each expedited pathway.

39
Table 3: Comparison of Expedited Pathways
Fast Track
Designation
Breakthrough Therapy
Designation
Accelerated Approval Priority Review
Qualifying
Criteria
A drug that is intended
to treat a serious
condition
and for which
nonclinical or clinical
data demonstrate the
potential to address an
unmet medical need
A drug that is intended to treat
a serious condition and
that preliminary clinical
evidence indicates may
demonstrate substantial
improvement over available
therapies on a clinically
significant endpoint
A drug that treats a serious condition,
generally provides a meaningful
advantage over available therapies,
and demonstrates an effect on a
surrogate endpoint that is reasonably
likely to predict
clinical benefit or on a clinical end
point that is reasonably likely to
predict an effect on “irreversible
morbidity or mortality” or other
clinical benefit
An application
(original or
efficacy supplement)
for a drug that treats a
serious condition and
that if approved would
provide a significant
improvement in safety
or effectiveness
Benefits Opportunities for
frequent interactions
with FDA; possible
eligibility for priority
review; rolling review
All fast-track designation
features; intensive guidance
on an efficient drug
development program,
beginning as early as
phase 1; organizational
commitment involving
FDA senior managers
Approval based on an effect on a
surrogate or intermediate clinical
endpoint that is reasonably likely to
predict a drug’s clinical benefit
Shorter period for
review of marketing
application (6 months,
as compared with the
10-month standard
review)
Timing of
Submission to
Support
Request
With IND or after (can
be based on preclinical
data only); ideally, no
later than pre-
NDA/BLA meeting
With IND or after (once clinical
data are available); ideally, no
later than end-of-phase 2
meeting
Discuss with review division during
development as approaching pivotal
trial

With original
NDA/BLA or efficacy
submission
Adapted from (FDA, 2014b).

40
The totality of evidence so far available shows that accelerated pathways have played a
significant role in expediting drug development and commercializing promising therapeutic
candidates faster. For example, FDA reports that 66% of the 41 drugs approved in 2014 by
FDA’s Center for Drug Evaluation and Research used at least one of these four pathways, and
46% received at least two of the designations in combination (FDA, 2015b).
2.7 Academic Literature: Benefits of BTD
Academic studies to examine the impact of expedited development programs are appearing, albeit
slowly, in the literature. These typically support the effectiveness of BTD as a tool to reduce
development timelines including review timelines. For example, Park and colleagues examined
25 oncology approvals from November 1, 2013, through December 31, 2014. They observed that
timelines from phase 1 trial initiation to indication approval were twice as long for standard new
drugs as breakthrough therapy drugs (Park, Vegesna, Ray, & Tsang, 2015). Shea and colleagues
also reported shorter review times for novel anti-cancer drugs approved between January 1, 2013
to December 31, 2015. Drugs with BTD designations were approved a median of 2.9 months
before their PDUFA dates; those without the designation were approved a median of 0.2 months
before their PDUFA dates (Shea et al., 2016). However, the shorter review times are not without
the confounding factor of priority review. All of the BTD drugs had priority review, whereas only
three quarters of the non-BTD drugs had priority review. Shea also reported that pre-market
development time was considerably shorter for BTD designees (median 5.2 years) than non-
designees (7.4 years) (Shea et al., 2016).

41
A similar trend is apparent for compounds in disease sectors other than oncology. Poirier and
Murphy reported that breakthrough therapy status coupled with accelerated approval reduced
submission timelines for a meningococcal vaccine (Trumenda) by at least 18 months. Poirier and
Murphy also noted that many non-oncology drugs received approvals faster than their expected
PDUFA dates (Poirier & Murphy, 2016). However, they acknowledged that more comprehensive
studies were difficult to conduct because development timelines were not publicly disclosed.
As pointed out above, one challenge in trying to assess the impact of the BTD program is the
confounding possibility that the drugs are taking advantage of more than one of the expedited
programs open to them. Thus, it may not be possible to separate out the benefits that compounds
are receiving from BTD compared with benefits that would already come from obtaining priority
review and accelerated approval, pathways known to be associated with shorter review cycle
times. All compounds receiving BTD to date have also been granted Priority Review when their
marketing applications were filed.
Another metric on which the academic literature has focused is the success rate for first cycle and
final approvals. The data related to ultimate success rates are less compelling than those
associated with shortened development and review timelines. For example, Poirier reports that
non-oncology drugs designated as BTD and also granted priority review enjoyed a 91% success
rate (21/23) in first cycle approvals. However, a success rate of 88% is typical for non-oncology
drugs with priority review status even without BTD. These percentages exceed the benchmark of
76% for standard NMEs (Poirier & Murphy, 2016). Poirier states:
The trend is promising but too early to declare BTD as early indicator
subsequent approval... The FDASIA policy objectives of the BTD will be more

42
fully realized as more sponsors seek designation with early trial data and
benefit from the subsequent regulatory interactions (Poirier & Murphy,
2016).
Overall approval rates also appear higher with drugs granted priority review; however, as
previously discussed, the benefit of priority review is not limited to the BTD pathway. All of the
BTD drugs that have been approved received priority review compared to three quarters of drugs
without the designation. Use of the accelerated pathway was more varied; three quarters of BTD
products were reviewed under accelerated approval compared with less than one quarter of non-
designated products. Orphan designation was very common among both groups (Shea et al.,
2016). Shea concludes:
…BTD designation is helping to speed patient access to innovative new
cancer treatments. We also conclude that, owing to the large number of
accelerated approvals among BTD drugs [oncology], the FDA is more willing
to take measured risks in approving drugs that show early evidence of
substantial improvement over available therapy… the data presented here
provide preliminary evidence of the positive impact of the BTD in oncology
(Shea et al., 2016).
What is not clear, however, is whether FDA is more likely to grant priority review to a drug that
it already considers to be a strong candidate for approval. In such a case, it might be argued that
first-cycle success and overall success of marketing approval would likely have been higher even
without BTD designation or the use of another expedited development pathway.
It is not surprising that the focus on results associated with BTD have been on timelines, one of
the primary goals of the BTD program and an area of significant interest to industry. However,
BTD has also had an impact on other stakeholders. For example, financial investors, particularly
those involved with early stage startups with no proven development success, may use the
designation as a signal that the regulatory pathway and overall time to market may be shorter and

43
more certain, thus reducing the risk to their investment. Payers may also care about the
designation. A recent study found that
…Surveyed payers were unanimous that BTD will influence formulary
decisions for oncology drugs. Further, 40% said that BTD would result in
more favorable tier placement and 37% expected that such drugs would have
fewer prescribing controls. However, none of our surveyed payers considered
themselves yet very familiar with the BTD pathway (Duval & Cox, 2015).
Duval and colleagues found that payers were unanimous that BTD would influence formulary
decisions for oncology drugs with speculation that BTD would result in more favorable tier
placement as well as fewer pricing controls (Duval & Cox, 2015). However, that study also
reported that “none of the surveyed payers considered themselves to be that familiar with BTD”.
The Duval study also provided evidence that designation may affect the perceptions of
prescribers as well as payers. Health care providers, at least in oncology, appeared to be quite
familiar with BTD. One third of surveyed oncologists declared themselves to be very familiar
with BTD. Furthermore, almost all oncologists said that BTD will affect their prescribing
practices; nearly half agreed that an agent with accelerated approval based on phase 2 data and
BTD status will more likely be prescribed than such an agent without BTD (Duval & Cox, 2015).
Interestingly, a recent study observed that physicians tended to overestimate the minimum
evidence of efficacy required for new drugs and misinterpreted the term “breakthrough” and
believed those drugs were supported by stronger evidence than required by statute (Kesselheim et
al., 2016).

44
2.8 Criticisms of BTD
The BTD program is relatively new so critiques of BTD policies or practices are still rare. Most
literature has attempted to identify the weaknesses or concerns of expedited development
programs in general rather than BTD programs specifically. However, these concerns are
important to consider when trying to understand the management of the BTD program. Four main
areas of concern appear to emerge from these analyses.
2.3.1 Validity of Benefit: Risk Assessments
Concerns have been expressed that the relatively small number of patients to whom the drugs
have been given prior to approval do not provide sufficient data to assess benefit: risk adequately.
As a consequence, some of the products in these expedited pathways may ultimately prove to be
ineffective or even dangerous. There is some evidence that these concerns could be warranted.
Drugs approved under PDUFA legislation between 1992-2008 had an approximately 35% greater
chance of having a black box warning or being withdrawn from the market for safety reasons than
a cohort of drugs approved before PDUFA was enacted (Frank et al., 2014) (Kesselheim &
Darrow, 2015). Further, patients receiving orphan drugs approved for cancer indications had
about a 70% greater chance of causing serious adverse drug events during clinical testing than did
patients receiving a comparable cohort of nonorphan drugs (Kesselheim et al., 2015). Moreover, a
study of the 20 new molecular entities approved in 2008 showed that five (25%) drugs had
acquired new or expanded box warnings and four (20%) had additional warnings or precautions,
four years after approval (Moore & Furberg, 2014). However, it can be difficult to draw
conclusions form these types of studies. For example, some investigators have reported that drugs
receiving faster reviews have more drug-related adverse events after marketing (Olson, 2008)

45
(Lexchin, 2012) but others found no such relationship when using different methods to evaluate
the data (Grabowski, 2008) (Lexchin, 2012) (Olson, 2013). Such studies are complicated by the
fact that drugs in the cohorts that are being compared often have different indications and
mechanisms of action that can greatly confound the conclusions.
2.8.1 Confirmation from Post-Marketing Evidence
Because BTD approvals depend on minimal data, they are often predicated on commitments of
the manufacturer to conduct follow-up, confirmatory trials post-approval. The tendency to require
post-approval studies as part of the agreement for marketing approval has been growing.
Steenberg has reported that proportion of new molecular entities subject to post-approval studies
increased from ~36% in the late 1970s to ~80% in the early 2000s (Steenberg, 2006). However, a
substantial fraction of post approval studies are delayed or unfinished (Fain, Daubresse, &
Alexander, 2013). Moore’s study mentioned above showed that 60% of promised studies had not
yet been completed (Moore & Furberg, 2014), so the data needed to confirm the preliminary
safety and efficacy profile may not be available. It has been challenging for FDA to gather this
confirmatory data to establish safety and efficacy because FDA has limited power to force the
timely conduct of confirmatory post-approval trials. To date, FDA has not removed drugs from
the market or taken other remedial steps solely based on the absence of confirmatory trials
(Gardiner, 2010). A study of the 20 new molecular entities approved in 2008 showed that 4 years
after approval, five (25%) drugs had acquired new or expanded box warnings, four (20%) had
additional warnings or precautions, and 60% of promised studies had not yet been completed
(Moore & Furberg, 2014).

46
2.8.2 FDA Resource Constraints
Many have worried that FDA’s already limited resources will be strained if the Agency must
provide Priority Reviews and enriched interactions with sponsors during a product’s
investigational lifecycle. This may be a particular problem because some of the program benefits
are very similar to other programs that FDA administers (i.e., fast track) (Jae, 2014) (Kesselheim
& Darrow, 2015). FDA itself has indicated that the BTD program has been more popular than
expected (Eastman, 2014) and in 2015 instituted a preliminary request process to obtain BTD
advice. They have expressed the hope that that the numbers of BTD requests may be reduced if
sponsors fill out a short form with basic information on the compound and then engage as
necessary in an early, nonbinding teleconference with the appropriate review division. Building
on the argument are the suggestions by some that many drugs that have a BTD are not
particularly unique or essential clinically. For example, Kesselheim pointed out that four BTD
designated drugs approved in 2013 and 2014 had the same indication and several approved
therapies were already available (Kesselheim et al., 2015).
2.8.3 Inaccurate Public Perceptions of BTD
Expedited approval may give patients and health care providers the impression that a drug with
BTD is safer and more effective that it would be without such a designation. Critics of BTD also
point out that the lay public, including health care providers, do not truly understand what BTD
means and are therefore influenced “unfairly” to perceive higher benefit for drugs that receive
BTD. For example, a survey by Kesselheim and colleagues indicated that physicians demonstrate
limited understanding of the FDA approval process and the meaning of BTD (Kesselheim et al.,
2016). Other studies have report that consumers have high expectations that drugs with BTD will

47
be very effective with little understanding of what the BTD confers or means (Wechsler, 2015)
(Kesselheim et al., 2016). Given the small database upon which approval may have been granted,
such impressions may have dangerous implications.
2.8.4 Additional Considerations
Aside from these general concerns about expedited development programs, several authors have
questioned the value added by BTD given that many of its benefits overlap with pathways that
were already available to drug developers (Jae, 2014). Concerns have also been raised about the
ability of the manufacturers to assure an effective scale-up and quality management program for
products that are granted BTD under the shorter timelines to market that may follow expedited
approval (Wechsler, 2015).
2.9 Similar Mechanisms in Other Regulated Regions
The pressure to expedite drug development and approval timelines is not solely an issue in the
United States. This pressure exists in other regions of the world where programs are also being
developed to facilitate the development and approval process. The European Medicines Agency
launched a program similar to BTD, known as PRIority MEdicines (PRIME), in March 2016
(Kondo, 2017). Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) also introduced a
similar designation, termed the “Sakigake Designation”, in 2015 (Kondo, 2017). The success of
the PRIME and Sakigake Designation programs remains to be evaluated.
48
2.10 Methodology for Research
As the discussion above suggests, the mission and goals of the FDA have evolved over time.
Today, FDA is responsible for balancing the benefits of an individual’s use of a drug product
with the associated risk that it poses. The research that has been carried out in the past few years
with regard to expedited programs suggests both advantages and challenges with the programs.
However, what is not clear is how these programs are regarded by a largely silent but important
stakeholder, the pharmaceutical industry. Anecdotal evidence suggests that companies are
enthusiastic about these programs because of the opportunities that they provide to expedite their
drug development programs. Nonetheless, it is important after new programs are introduced to
assess whether they are fully effective at achieving their goals or whether over time they will
need revisions.
This study conducted here will aim to assess whether the BTD program has been effective in
helping FDA meet its stated mission. To do this in a systematic manner, a triadic framework
articulated by Ramsey in academic literature appears to be useful to evaluate the effectiveness of
the new expedited programs at meeting the three stated aims of regulatory programs (Ramsey,
2013). The model was first used to study the impact of a particular set of regulations in a different
sector, that of OTC drugs, but it appears to have more general applicability as discussed below.
Ramsey’s model is shown in Figure 1. Two elements, that of “ensuring safety and effectiveness”
and “facilitating efficiencies in research and commercialization”, come from the FDA mission
statement, discussed earlier. Ramsey’s model also incorporates a third element, that of equalizing
requirements for industry players, comes from the Federal Trade Commission’s (FTC) mission

49
statement; FTC also regulates medical products alongside the FDA but has as its primary goal to
assure a level playing field for businesses.
Figure 1: Objectives of Regulation Per Ramsey Model

Adapted from (Ramsey, 2013)
The model developed by Ramsey has been used for other studies that have evaluated the
effectiveness of other regulations to achieve their objectives (Turnbull, 2016). In a study
examining the regulation of cosmeceuticals, for example, Turnbull modified Ramsey’s model by
adding an explicit quality component to the first “safety and efficacy” element (Turnbull, 2016).
Turnbull argues that the addition of quality in Ramsey’s model does not greatly change the
original structure of the model because quality tends to be viewed as a component of the “safety”
umbrella. Since criticisms related to possible expedited pathways have sometimes been directed
Ensure Safety and
Effectiveness
Equalize
Requirements and
Standards for
Industry
Facilitiate
Efficiencies in
Research
Commercialization,
Costs

50
at its potentially negative effects on manufacturing quality, I have preserved the explicit
identification of quality in the framework (Figure 2).
Figure 2: Ramsey Model Adjusted by Turnbull

Adapted from (Turnbull, 2016).
When Ramsey and Turnbull examined the effectiveness of the regulations that they studied, they
examined each of these elements as separate parallel areas of concern. In this study, I will also
examine how industry sees the expedited programs in terms of these three regulatory aims. I wish
to explore the extent to which industry feels that the aims of the new programs are being met in
terms of the overall intents of regulations. However, I am also interested in exploring whether
FDA weighs these goals equally in the view of surveyed industry participants or whether
respondents perceive FDA as giving precedence to one aim over another.
Ensure Safety, Quality,
and Effectiveness
Equalize
Requirements and
Standards for
Industry
Facilitiate
Efficiencies in
Research
Commercialization,
Costs

51
By using a more comprehensive framework to which observations can be referenced, I hope that
the survey can put into context some of the criticisms of BTD that have been suggested by
academic researchers and others in the past. The model will ultimately help to organize the
questions that survey respondents will answer and assist with framing the views of BTD and
other expedited programs after several years of experience with the designation. Results of the
survey will inform policy developers about whether BTD has helped FDA to achieve its stated
goals. It will also help to make clear if BTD can be assessed using a standard framework such as
the one chosen here or if changes to the framework are needed to assess the BTD program
adequately.

52
CHAPTER 3. METHODOLOGY
3.1 Introduction
The purpose of this study was to evaluate the perceptions of regulatory affairs professionals
working in the biopharmaceutical industry regarding the BTD pathway. The survey directed its
focus specifically onto whether respondents felt that BTD achieves the common goals for FDA
regulation using the triadic framework articulated by Ramsey (Ramsey, 2013). The study also
explored how regulatory professionals are using the breakthrough therapy designation pathway
operationally and if that experience could be used to identify opportunities to enhance its use or
related FDA guidance. The study included 5 steps: literature review (see Chapter 2), development
of an industry survey instrument, critique of the survey instrument by an expert focus group,
dissemination of the developed survey, and analysis of the results and written conclusions.
3.2 Survey Development
The initial draft survey was developed using a web-based survey application tool, Qualtrics
(www.Qualtrics.com). The survey had approximately 23 general questions for all respondents and
approximately 10 subsequent questions about successful and/or unsuccessful BTD applications
that survey respondents could elect to answer. Question types included forced-choice questions
and open-ended questions where respondents could provide free text answers. A number of open
comment fields were included to elicit feedback from respondents on additional information that
could contribute to the research. Questions were grouped by subject matter into 3 areas around
the following themes: general questions about the respondent’s background, opinions related to

53
the ability of BTD to achieve policy objectives, and operational experience with products
applying for and achieving BTD.
3.3 Focus Group
A focus group was convened prior to finalizing and deploying the survey. The purpose of the
focus group was to provide critical feedback on the survey content based on the purpose of the
research. Participants were asked to comment on the organizational flow of the survey and the
overall content, clarity and format of its questions. Focus group members were also be asked to
identify any gaps in areas relevant to the survey topic. The focus group included 8 participants
from industry and academia. Participants were selected based on their knowledge of BTD,
clinical and regulatory experience in pursuing accelerated development pathways, and/or
experience with survey development. The focus group members are described in Table 4.
Table 4: Focus Group Participants
Participant Name Affiliation
Monique Carter Senior Regulatory Affairs Professional in Pharmaceutical Industry
Mary Ellen Cosenza USC Regulatory Science
Jeffery Fellows Independent Regulatory Affairs Consultant
Mike Jamieson USC Regulatory Science
Penny Ng Senior Regulatory Affairs Professional in Pharmaceutical Industry
Frances Richmond USC Regulatory Science
Nancy Pire-Smerkanich USC Regulatory Science
Tim Whitaker Clinical Development Expert in Pharmaceutical Industry

54
All participants were provided with an electronic copy of the survey prior to the focus group
meeting. The draft survey was reviewed and discussed at an online web conference for the
convenience and collaboration of the participants. The meeting was approximately 90 minutes in
duration and began with a short presentation of the intended research and purpose of the study.
Discussion of the survey questions and intended survey recipients immediately followed the
introduction. Each survey question was reviewed in sequence and analyzed for possible
improvements to content and clarity. Following the focus group, the survey was updated to
incorporate feedback from the group participants. The effective operation of the Qualtrics system
was validated by sending the survey to three individuals from the focus group to ensure that the
emails arrived properly, and the answers could be entered and analyzed appropriately.
3.4 Dissemination of Survey
The survey was deployed from June 8 to September 8, 2018, to 74 US-based regulatory affairs
professionals in the pharmaceutical and biologics industry. Efforts were made to identify a subset
of individuals who have direct experience applying for BTD at companies of varying sizes.
Individuals within the potential respondent pool were contacted prior to survey dissemination to
solicit their participation in the survey. Potential respondents were also asked to provide the
contact information of other individuals who might also be qualified to address the topic. The
recommended individuals were included in the initial distribution of the survey. No financial
compensation or incentive was offered to encourage participation. Email reminders were sent to
individuals who had not completed the survey 2-3 weeks after receipt. Interested respondents
were provided a summary of the results after the survey had been analyzed.

55
CHAPTER 4. RESULTS
4.1 Participant Responses
The survey was disseminated from June through early August 2018 to 74 individuals. The
individuals who received the survey were identified as having appropriate credentials to
participate through the researcher’s personal network, a search of a public social media platform,
or further recommendations from survey participants. The survey period closed on September 8,
2018. Forty-nine emails with personal links were opened and surveys were initiated, and 48
(98%) of the participants completed the survey.
4.2 Profiles and Background of Participants
Survey participants were prequalified as Regulatory Affairs professionals. Their self-reported
professional roles were typically at the level of either Vice President (9/48, 19%) or
Director/Senior Director (27/48, 56%). Three (3) were Managers/Senior Managers and one (1)
was a Specialist/Senior Specialist. The final eight (8) participants self-identified as Consultant (6)
or “Other” (2). The individuals who identified as “Other” provided titles of “Head of Regulatory
Affairs” and “Associate Director”. Figure 3 charts the distribution of job titles.

56
Figure 3: Distribution of Participants by Job Title

Survey participants were employed by organizations whose product lines varied. Many
companies developed multiple types of products as suggested by the 91 responses from 48 survey
participants. Most commonly, participants were employed by companies developing biologics
(38/91, 42%) or drugs (30/91, 33%); fewer companies were developing combination products
(14/91, 15%) or devices (9/91, 10%).
Amongst individuals who are not consultants, the distribution of participants working for
companies was fairly well-balanced across companies of different sizes (Figure 4). Twelve of 42
participants (29%) who answered this question were employed by small companies (<250
employees), 14 (33%) by mid-sized companies (250-15,000 employees), and 16 (38%) by large
companies (>15,000 employees).
2
6
9
27
3
1
0 5 10 15 20 25 30
Other
Consultant
Vice President
Director/Senior Director
Manager/Senior Manager
Specialist/Senior Specialist
n= 48

57
Figure 4: Participant Distribution by Company Size

Only one (1) survey participant indicated that s/he was not familiar with BTD and was directed to
the end of the survey. Participants were asked if their companies had filed a BTD application with
FDA. Thirty-four of the 36 respondents to this question (94%) answered “yes” and two answered
“no”. Twenty-two of 38 respondents (58%) identified that they participated as a team member on
a BTD application and 16/38 (42%) did not. Almost all of the self-identified “consultants” (5/6,
83%) had filed a BTD application on behalf of a company.
Across the subgroup of participants who had submitted a BTD application, a total of 52 BTD
submissions had been made. Ten participants (10/26, 38%) had submitted one or two
applications; four (4/26, 15%) had submitted three applications; and two (2/26, 8%) had
submitted 5 applications as illustrated in Figure 5.
12 12
2
16
0
2
4
6
8
10
12
14
16
18
< 250 employees 250-5,000
employees
5,001-15,000
employees
> 15,000
employees
n= 42

58
Figure 5: Number of BTD Applications Submitted to FDA by Participants

Eighteen of the 52 submitted applications were successful. Figure 6 illustrates that some
respondents had only unsuccessful applications (8/26, 30%), but others had one (10/26, 38%),
two (7/26, 27%), or three successes (1/26, 4%).
10 10
4
0
2
0
2
4
6
8
10
12
1 2 3 4 5
n= 26

59
Figure 6: Number of Successful BTD Applications

As illustrated in Figure 7, 8 respondents had a single unsuccessful application (8/26, 31%); six
had two unsuccessful applications (6/26, 23%); and two had 3 unsuccessful applications (2/26,
8%).
8
10
7
1
0
2
4
6
8
10
12
0 1 2 3
n= 26

60
Figure 7: Number of Unsuccessful BTD Applications

4.3 Information Publicly Available about BTD
Participants were asked to express their views about adequacy of information related to BTD
development and submission (e.g., guidance documents, statistics) that FDA disseminates. Most
commonly, participants found those sources of information to be adequate (Figure 8). However,
many comments provided by participants identified challenges associated with the specific
guidance document titled “Expedited Programs for Serious Conditions – Drugs and Biologics”
(May 2014) (Table 5 for select comments). The majority suggested that more clarity about data
requirements and FDA expectations would be helpful. Concerns were also expressed that the
guidance document had not been updated since it was initially published. Participants would like
an updated guidance with more examples from which to learn. Full-text comments are available
in Appendix B.
10
8
6
2
0
2
4
6
8
10
12
0 1 2 3
n= 26

61
Figure 8: Adequacy of Publicly Available Information Sources for BTD

24
15
1 1 1
15
10
12
1
4
18
9
10
2
3
0
5
10
15
20
25
30
Adequate Somewhat
adequate
Neither
adequate
nor
inadequate
Somewhat
inadequate
Inadequate No opinion
FDA Expedited Development Guidance Document
BTD Application Statistics from FDA Website
BTD Approval Statistics from FDA Website
n= 42

62
Table 5: Selected Responses Reflecting Challenges Associated with BTD Guidance
Document
As with most guidance it is understanding FDA’s threshold regarding “substantial
improvement over existing therapies” and also what constitutes clinically significant endpoints.
The latter very critical when treating very rare diseases without a lot of existing precedence in
regards to trial design and endpoints
The guidance is useful, but as a regulatory affairs professional any additional examples and
clarity is helpful. Additional examples of early stage compounds and the data companies
submit to acquire the BTD is helpful
Clear definition of “clinically significant endpoint”
It is unclear how much data is really adequate to seek BTD and qualitatively how good does
your data have to be over existing therapies to qualify for BTD. In cases where no existing
therapies exist and your product provides some symptoms relief but is not disease modifying,
again it is what data is adequate to support BTD
The determination of “substantial benefit over existing therapy” is subjective leaving the
sponsor to speculate whether or not the FDA bar has been met. The number of patients needed
to support the BTD request is also unclear, and in many cases too few patients treated is part of
the reason BTD is denied
Examples should be provided to better understand the FDA expectations
While the guidance describes type of data to be included (e.g., clinical), it gives no guidance on
the extent of data (patient numbers, endpoint, phase of trials). While I understand this will be
indication specific, for those indications most likely to be subject of a BTD request, the FDA
should provide some guidance on minimal extent of data to consider even before requesting the
preliminary teleconference with FDA
4.4 Deciding to Apply for BTD
Survey participants appeared to use a variety of sources when deciding to apply for BTD, as
reflected in the finding that the number of responses (159) exceeded the number of participants
(48). Participants indicated in descending order that they use the FDA website (41/159 responses,
26%), FDA preliminary BTD application feedback process (32/159 responses, 20%), colleagues
(28/159 responses, 18%), conferences, presentations, and webinars (27/159 responses, 17%), and
consultants (19/159 responses, 12%). Websites of patient advocacy organizations were also
chosen occasionally (6/159 responses, 4%), as were “Other” sources, listed in Table 6 (6/159
responses, 4%).

63
Table 6: Other Resources Used When Deciding to Apply for BTD
Previous experience
Patient advocacy organization, particularly for rare diseases—not just their website
Guidance document
Data driven event
Publication and newsfeeds
Analysis of internal experience – success/failure with BTD to understand expectations
Participants had mixed responses on whether additional resources were needed to guide the
decision to apply for BTD. Sixteen of 42 (38%) participants indicated that additional resources
were necessary, whereas 23 (55%) participants considered that no additional resources were
necessary and 3 (7%) had no opinion.
The 16 participants who felt that additional resources were needed (16/42, 38%) had suggestions
in three primary areas: 1) clarity around the nature or amount of evidence to support BTD
application; 2) case studies to assist with determining if, and when, to apply for BTD; and 3)
increased FDA interaction. Selected comments related to each area are presented in Table 7 and a
full listing can be found in Appendix B.

64
Table 7: Select Recommendations for Additional BTD Resources
Topic Area Recommendation from Participants
Clarity about
evidence
How to provide rationale for surrogate endpoints—what type of data is
required and how much data?
Clarity on what constitutes favorable preliminary evidence.
Clarification regarding use for drugs already approved for another
indication
Some clarity on minimum standards in the guidance. Initiating the pre-
BTD request has been helpful and FDA feedback has allowed for
better decision making on deciding whether or not, or when, to submit
Case studies Consultants that have experience with BTD, if FDA had more detailed
case studies of companies that have successfully applied for BTD and
why it was granted, and ultimately, were benefits of the company
realized due to BTD or would using other expedited pathways have
worked as well – especially for those companies that spent time
applying for BTD and didn’t receive the designation
For any indication, it’s helpful to understand what has previously
received and been denied designation. This process is limited by
FDA’s confidentiality within the IND process and willingness of
sponsors to share information. Recent information at conferences is
helpful, but needs to be incorporated into guidance, perhaps by broad
indication, oncology for instance
FDA interaction Perhaps more specific product examples to compare to. An interactive
Q&A to help you determine whether the BTD is a viable path for your
product on the FDA’s website
Additional Q&A or links to FDA public (conference) presentations on
topic may be useful. The clinical indication list of approved BTs is
helpful and some information on what the company studied in the
clinic is useful, and although specifics on the trials could be located on
clinicaltrials.gov, maybe some information on the types of
indications/results that could be more likely to interest FDA for
potential approval for public health reasons, it may spur innovation on
in a more novel or orphan indication
4.5 Amount of Data Available for BTD Compounds at Time of First Marketing Approval
Participants were asked a series of questions about the sufficiency of the data available for BTD
compounds that had been submitted at the time of first marketing approval (Figures 9A and 9B).
More than half of the participants agreed that “many BTD compounds have limited safety data”
(23/40, 57%); in contrast, eight (20%) participants disagreed and nine (22%) neither agreed nor

65
disagreed. Most (28/41, 68%) also agreed that “BTD compounds have limited long-term exposure
data to inform benefit-risk assessment”, but four (10%) disagreed and nine (22%) neither agreed
nor disagreed.
About half of participants (18/34, 53%) disagreed that “health professionals understand BTD
compounds may have limited safety databases”, whereas 8 (23%) agreed and 8 (23%) neither
agreed nor disagreed. Most participants (31/35, 89%) disagreed that “consumers understand that
BTD compounds may have limited safety databases”. In this instance, only two participants
agreed and two neither agreed nor disagreed (6% for each choice).
Figure 9A: Level of Agreement at Time of First Marketing Approval

23
9
8
28
9
4
8 8
18
2 2
31
0
5
10
15
20
25
30
35
Agree Neither agree nor disagree Disagree
Limited safety data
Limited long-term exposure data to inform benefit-risk assessment
Health professionals understand products may have limited safety databases
Consumers understand products may have limited safety databases
66
Approximately two-thirds (27/41, 66%) of participants agreed that “additional safety monitoring
requirements during the first few years after approval should be required”; nearly a quarter (9/41,
22%) neither agreed nor disagreed and only 5 (5/41, 12%) disagreed. However, when stratified by
experience with a BTD submission, those with BTD experience disagreed at a higher rate than
those without BTD experience that additional safety monitoring should be required (Table 8).
Table 8: Should Additional Safety Monitoring Be Required for BTD Compounds?
Response
BTD Experience
Yes No
Yes 11 11
Neutral 5 4
No 5 0
Total 21 15
Participants were relatively evenly split in response to the statement “Confirmatory trials
should be conducted after mark eting approval (similar to the accelerated approval pathway) to
confirm benefit: risk profile”; 35% (14/40) agreed; 38% (15/40) neither agreed nor disagreed;
and 28% (11/40) disagreed. Most disagreed that “Compounds that receive BTD do not have to
adhere to the same CMC review rigor as compounds that don’t have BTD at marketing
application stage” (disagreed: 28/38, 74%; agreed: 4/38, 10%; neutral: 5/38, 16%).
67
Figure 9B: Level of Agreement at Time of First Marketing Approval
Most participants did not believe that the BTD pathway introduced a concern for patient safety
(yes: 10/39, 26%; no: 29/39, 74%). Participants were evenly split on whether the BTD pathway
places a greater emphasis on efficacy data compared to safety data (yes: 21/40, 53%; no: 19/40,
48%).
Most participants agreed that “compounds that received BTD early in development typically
conduct fewer clinical trials to support ultimate approval” (agree: 25/40, 62%; neither agree nor
disagree: 10, 25%; disagree: 5, 13%) and “compounds that receive BTD conduct smaller trials to
support a first marketing approval than compounds that don’t have BTD” (agree: 24/41, 58%;
neither disagree nor agree: 13, 32%; disagree: 4, 10%). Most also agreed that “the current
expedited development pathways in the US encourage product innovation and research” (agree:
27
9
5
14
15
11
4
6
28
0
5
10
15
20
25
30
Agree Neither agree nor disagree Disagree
Additional safety monitoring should be required
Confirmatory trials should be conducted to confirm benefit: risk profile
CMC review rigor not as intense
68
28/40, 70%; neither agree nor disagree: 8, 20%; disagree: 4, 10%) and that “BTD is sufficiently
different from other expedited development pathways” (agree: 26/42, 62%; neither agree nor
disagree: 17, 44%; disagree: 9, 23%). However, only a third (13/39, 33%) felt that “the current
expedited development pathways are sufficient for bringing innovative products to market as
efficiently as possible”; more commonly participants neither agreed nor disagreed (17/39, 44%),
and a smaller proportion disagreed (9/39, 23%). Participants with BTD application experience
were more likely to choose that current pathways were sufficient than participants without BTD
application experience (Table 9). Figure 10 illustrates all responses received from participants to
this line of questioning.
Table 9: Are Current Expedited Development Pathways Sufficient?
Response BTD Experience
Yes No
Yes 8 3
Neutral 9 6
No 3 5
Total 22 15
69
Figure 10: Participant Perceptions of Current Expedited Development Pathways
Most participants identified that they would apply for BTD (32/42, 76%) rather than fast track
designation (10/42, 24%) if the pathways were mutually exclusive.
4.6 Company Size and Barriers to Applying for BTD
Participants were asked to rank the order in which companies of different sizes benefit from the
BTD pathway as illustrated in Table 10. Participants most commonly ranked large companies
(>15,000 employees) as deriving most benefit (22/36, 61%); medium sized companies were most
frequently identified as second or third ranked beneficiaries. Half of the participants (18/36, 50%)
ranked small companies (<250 employees) as the benefiting least from the availability of a BTD
pathway.
25
10
5
24
13
4
28
8
4
13
17
9
26
8 8
0
5
10
15
20
25
30
Agree Neither agree nor disagree Disagree
Conduct fewer clinical trials to support ultimate approval when BTD received early
Conduct smaller trials to support a first marketing approval when BTD received early
Expedited development pathways encourage product innovation and research
Current expedited development pathways are sufficient
BTD is sufficiently different from other expedited development pathways
70
Table 10: Ranking Company Size by BTD Pathway Benefit, n=36
Rank Order of Benefit Being Received (1=most;
4=least)
1

1 2 3 4
Size of
Company
by Number
of
Employees
< 250 9 3 6 18
250-5,000 2 10 19 5
5,001-15,000 3 18 10 5
>15,000 22 5 1 8
1
The top-ranked choice in each category is represented in bold font.
Participants were asked to indicate their level of agreement about different barriers to applying
for BTD. Table 11 lists the most commonly identified barriers.
Table 11: Common Barriers in Applying for BTD
Barrier
Number (%)
(n=42)
Meeting evidentiary threshold 33 (77%)
Internal resourcing 16 (38%)
Monetary constraints 14 (33%)
Application process 13 (31%)
Apart from the barriers listed in Table 11, 33 of 42 participants either could not identify further
barriers to applying for BTD or had no opinion (no additional barriers: 16/41, 38%; no opinion:
17/42, 41%). Nine (21%) participants indicated that there were additional barriers to applying for
BTD. When queried about the additional barriers, 11 comments were received that could be
grouped into three major categories: 1) inconsistent application of BTD “standards” across FDA
divisions; 2) resource constraints; and 3) lack of understanding of BTD and/or experience with
BTD. Selected comments are shown in Table 12 and a full listing of comments is provided in
Appendix B.
71
Table 12: Select Comments on Additional Barriers to Applying for BTD
Literature search developing case for seriousness. Meeting the clinical evidence requirements
in often small studies
The negative consequences for small companies that apply and don’t receive the designation. A
lot of time and effort goes into this process as it’s viewed as a very positive public relations
event, but with the high failure rate, either there is a misunderstanding on the part of companies
as to what is required or the outside influences (e.g., board of directors, Senior Management,)
to apply who don’t understand the requirements for success.
The perspective of the review division regarding the seriousness of the disease and their view
of the data. It is not consistent across divisions/reviewers.
Impact on technical development—applying for BTD early in clinical development means
many additional resources are needed to accelerate technical development and/or to negotiate
with FDA what might be able to be provided post-approval
Knowledge and experience in regulatory staff of company on BTD applications
FDA seems to have increased the standards for receiving BTD. FDA seems to require
randomized data which by the time the company has that information it is too late to receive
most of the benefits of BTD other than the press release and 1 month of earlier review
4.7 Additional Thoughts on the BTD Pathway
Eighteen participants elected to share additional thoughts on BTD as an expedited pathway.
These could be grouped into 6 major areas: 1) that BTD be granted earlier in clinical
development, potentially even before clinical phase; 2) that reasons for the high failure rate of
applications be clarified; 3) that review divisions be more consistent in granting applications; 4)
that the increased interactions with FDA be protected; 5) that more insight be provided into safety
and efficacy of BTD compounds; and 6) that more education be provided about the use and utility
of the BTD pre-application process. Selected comments are presented in Table 13 and the full list
of comments is provided in Appendix B.
72
Table 13: Examples of Additional Thoughts on BTD as an Expedited Pathway
Would be helpful for BTD to start earlier in the development process—before phase 1
Has FDA done anything to understand the high failure rate for the BTD pathway? It is a lot of time for
both industry and the Agency and it could be better use for other programs
It would be interesting to understand to what extent each Division and companies use the two-page
informal BTD request prior to submitting a formal request, how often companies submit BTD requests
for multiple patient populations, and how comfortable companies feel that their BTDs will not be
rescinded in the event that competitor products are approved in the same population
Multiple interactions with FDA and continued guidance on key elements of the development program
are the advantages of the program
Different Divisions within FDA have varying levels of experience with BTD. This leads to some
inconsistency in how it implemented. Some Divisions appear to take the “urgency” aspect more
seriously than others as evidenced by the time it takes to respond to sponsor requests, for example. There
also appears to be a major misperception by many in the “public” about BTD in that many believe
FDA’s evidentiary standards do not need to be met for BTD products
It seems as though the program maybe designed for smaller companies to get novel drugs or therapies
approved, but it seems as though the large global companies are the ones who have monetary resources
to conduct multiple trials and take “more shots on goal” to find an indication to be granted BTD, instead
of the little guy who it would benefit most, from the perspective of developing and sustaining innovative
drug development culture
4.8 Experiences with Successful BTD Applications
Eighteen participants elected to share information about a successful BTD application with which
they had been involved as a contributing member. Many of the successful applications were for
oncological (10/18, 56%) or antiviral (3/18, 17%) products. Products related to neurological,
gastroenterological, cardiovascular, dermatological, and rheumatological applications were also
successful (1/18 of each, 6%). Two of the successful applications were filed by consultants for
companies with >15,000 employees. Most companies in this group had submitted a pre-
application to FDA (11/18, 61% indicated yes; 7/18, 39% indicated no). No participants indicated
that FDA would not accept a pre-application.
A variety of factors were identified as driving the BTD application (Figure 11). These most
commonly were the development of strong clinical efficacy data (16/59, 27 %); the desire to
expedite the development timeline; and the potential for increased interactions with FDA (12/59,
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20%). Other factors included: shortened pre-approval timelines (9/59, 15%); a request from FDA
(4/59, 7%); and investor and commercial interest (3/59, 5%, and 4/59, 7%, respectively).
Figure 11: Drivers for Successful BTD Applications
Many of these BTD compounds took advantage of other expedited development pathways
(shown in Figure 12): nine (9/27, 33%) had priority review, nine (33%) had fast track
designation, and five (18%) had accelerated approval. Only four (15%) used no additional
expedited pathways.
0
11
9
4
0
4
3
12
16
0 5 10 15 20
Other
Potential for increased time with FDA
Shortened approval time
Request from FDA
Request from board of directors
Commercial interest
Investor interest
Expedite timeline
Strong clinical efficacy data
n= 59
74
Figure 12: Use of Other Expedited Development Pathways in Addition to BTD
Participants were asked to provide comments regarding the time that had been saved from first-
in-human trials to the submission of the first marketing application. A wide range of responses
were received varying from no saved time to three years.
One additional participant shared information related to a second successful BTD application.
This application was submitted to the renal division after a pre-submission application. The
participant suggested five factors that contributed to the decision to apply for the BTD: strong
clinical efficacy data; expediting the development timeline; a request from FDA; a shortened pre-
approval timeline; and the potential for increased interaction with FDA. No additional expedited
pathways were used for the development of this compound.
9
5
9
4
0
1
2
3
4
5
6
7
8
9
10
Fast track
designation
Accelerated
approval
Priority review No additional
expedited
pathways
n= 27
75
4.9 Experience with Unsuccessful BTD Applications
Fifteen participants elected to share additional information about unsuccessful BTD applications.
Table 14 lists the therapeutic areas in which participants submitted unsuccessful BTD
applications.
Table 14: Therapeutic Areas with Unsuccessful BTD Applications
Therapeutic Area Number of Participants Submitting
Unsuccessful Applications (N = 15)
Oncology and hematology 10 (67%)
Antiviral 2 (13%)
Metabolism and endocrinology 2 (13%)
Neurology 1 (7%)
Five of the unsuccessful applications were filed by consultants, two each for companies of
>15,000 employees and 250-15,000 employees respectively and one for a company with <250
employees. Slightly less than half of these applications had submitted a pre-application to FDA
for BTD (7/16, 44%, yes; 8/16, 50%, no). One individual indicated that FDA would not accept a
pre-application submission. In four cases (4/18, 22%), FDA requested that the BTD application
be withdrawn prior to denying the BTD request. In contrast, in 12 cases (12/18, 67%), FDA did
not request withdrawal of the BTD application prior to denying the BTD request.
The most frequently chosen drivers for submitting unsuccessful BTD applications were similar to
those discussed for successful applications: expediting development timeline (12/55, 22%) and
potential for increased interaction with FDA (12/55, 22%). These drivers were followed by:
strong clinical efficacy data and shortened preapproval development timeline (8/55 each, 14%),
investor and commercial interest (5/55, 9% and 6/55, 11%, respectively), request from board of
directors (3/55, 5%), and request from FDA (1/55, 2%). These data are illustrated in Figure 13.
76
Figure 13: Drivers for Unsuccessful BTD Applications
Most applications had been denied BTD because the product lacked substantial efficacy
improvement (13/21, 62%) as illustrated in Figure 14. Others were denied because they had
incomplete data (3/21, 14%), safety concerns (2/21, 9%), did not meet the bar for treating a
serious condition (2/21, 9%), and trial/analysis issues (1/21, 5%). No participants indicated that
“FDA rationale wasn’t clear”, or “FDA did not tell us”. Two participants chose “other” as an
option and indicated “no randomized data” and “insufficient comparator”.
0
12
8
1
3
6
5
12
8
0 2 4 6 8 10 12 14
Other:
Potential for increased time with FDA
Shortened pre-approval timeline
Request from FDA
Request from board of directors
Commercial interest
Investor interest
Expedite timeline
Strong clinical efficacy data
n= 55
77
Figure 14: FDA Rationale for Not Granting BTD in Unsuccessful Applications
When asked if FDA provided adequate information on which to develop a successful re-
application, participant feedback was mixed (Figure 15); more participants felt that FDA
provided “adequate” (4/21, 19%) or “somewhat adequate” (7/21, 33%) information than
“somewhat inadequate” (1/21, 5%) or “inadequate” (2/21, 9%).
0
0
2
2
3
1
13
0 2 4 6 8 10 12 14
FDA did not tell us
FDA rationale wasn't clear
Not a serious condition
Safety concern
Incomplete data
Trial/analysis issues
Lack of substantial efficacy
improvement
n= 21
78
Figure 15: Adequacy of FDA Feedback for Reapplication of an Unsuccessful
Application
Approximately 20% (3/15) of participants elected to re-apply based on the FDA feedback, and
two-thirds were successful. The one application that was not successful for a second time
indicated that the testing could not demonstrate “sufficient follow-up on efficacy in a single arm
study.”
Two consultants elected to share information on additional unsuccessful BTD applications. One
unsuccessful application was made to the Office of Hematology and Oncology Products and one
unsuccessful application was made to the Division of Antiviral Products. The applications were
submitted by the consultants for companies of <250 employees, and 250-5,000 employees,
respectively. One application had a pre-application to FDA. FDA did not request that either
application be withdrawn prior to denying the BTD application. The main driver for applying in
these instances was “expediting development timeline” (2/6, 33%). This driver was followed
4
7
2
1
2
0
1
2
3
4
5
6
7
8
Adequate Somewhat
adequate
Neither
adequate nor
inadequate
Somewhat
inadequate
Inadequate
n= 21
79
uniformly by “strong clinical efficacy data”, “investor interest”, “commercial interest”, and
“potential for increased interactions with FDA” (1/6 each, 17%). FDA identified that BTD was
denied because of “lack of substantial efficacy improvement” in both instances. The consultants
indicated that FDA provided “somewhat adequate” information regarding what would be needed
for a successful re-application. In one instance the company elected not to re-apply for BTD and
in the other instance “FDA requested data [that] has not been generated”.
One consultant provided information on a third unsuccessful BTD application that s/he filed for a
company with <250 employees. The application was filed to the Division of Antiviral Products
following a pre-application to FDA. The drivers for applying for BTD were split amongst
“expediting development timeline”, “shortened pre-approval development timeline”, and
“potential for increased interactions with FDA”. FDA did not request that the application be
withdrawn prior to the BTD application denial and cited “lack of substantial efficacy
improvement” as the reason for declining the BTD request. The consultant felt that FDA provided
“somewhat adequate” information regarding what would be needed for a successful re-
application for BTD. The company elected not to re-apply for BTD as “data [was] not available”.
80
CHAPTER 5. DISCUSSION
5.1 Overview
Expedited development pathways are intended to “ensure that therapies for serious conditions are
approved and available to patients as soon as it can be concluded that the therapies’ benefits
justify their risks” (FDA, 2014b). The high percentage of novel compounds that have used these
expedited development pathways reflects the fact that these pathways have brought promising
new drugs to market faster than others on a traditional development and approval pathway (Bujar
& Liberti, 2018) (Kesselheim & Darrow, 2015). The research results presented here extend these
observations on approval performance by exploring the views of regulatory affairs professionals
in the biopharmaceutical industry regarding their operational experience with the BTD
application process and the usefulness of BTD as an expedited pathway.
5.2 Methodological Considerations
5.2.1 Limitations
The results for this study were gathered using an online survey tool to gain information about
BTD from regulatory professionals employed by the biopharmaceutical industry. Use of an online
survey introduces methodological limitations that were appreciated before the survey was
launched. Perhaps the limitations that were of greatest concern related to validity and reliability
of the survey method and the availability of representative participants.
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5.2.1.1 Survey Methodology
This study employed an electronic survey tool to gather data. Survey tools are particularly useful
to gain input from a large, geographically dispersed group of individuals who can access the
survey at their convenience at any time of the day or night (Sue, 2007). However, the use of an
electronic survey tool can also introduce constraints on survey design related both to the number
of questions and the depth of views that could be explored (Galesic, 2007). This study employed
a focus group to evaluate the flow and content of its questions. Based on the focus group
feedback, the survey had an initial 21 questions that all participants were asked. After the last
general question, participants were asked if they would be willing to answer a series of questions
about a successful and/or unsuccessful BTD application with which they were involved. The
decision to orient the survey in this manner was based on feedback from the focus group that
busy professionals would be reluctant to complete a long survey and it would be preferable for
people to be able to opt out of the survey before sharing information about specific applications.
The focus group’s views are consistent with observations in methodological literature that long
surveys reduce participation (Galesic, 2009). However, by limiting the number of questions, not
all topics that the focus group thought would be interesting to question could be explored.
5.2.1.1. Availability of Representative Participants
Survey validity is well-known to be affected by the number and representativeness of its
participants (Sue, 2007). A larger sampling of participants is typically sought to assure that the
reported experiences reflect as accurately as possible the full views of the population that the
respondent pool attempts to represent. At the same time, surveys are constrained by logistical
82
considerations for recruiting participants (Sue, 2007). Regulatory professionals were selected as
recipients for this survey because their views on the BTD process have not been represented in
the literature and they are the most relevant individuals to provide feedback on how the BTD
application process is working from the industry-side. The logistical recruitment challenges of
finding regulatory professionals were of particular concern in this study because the numbers of
individuals with direct BTD experience is limited. As of September 30, 2018, there were 639
applications submitted to CDER for BTD (FDA, 2018d). Finding the responsible regulatory
professional who led each of the 639 CDER applications is challenging since the information is
not publicly available. Ultimately, participants were asked to participate in this survey based on
publicly available information about their roles and responsibilities, an assessment of the
likelihood that they may have worked on a program that would qualify for expedited
development, and the size of company by which they were employed. The fact that 60% of
participants had experience applying for BTD across companies of different sizes was viewed as
evidence that this targeted approach was reasonable. Since most participants were engaged in this
field, the topic appeared to be interesting to them, as reflected in the very large proportion of
participants who completed the survey after opening it (Fowler, 2008).
5.2.2 Delimitations
The BTD program is only 6 years old, and this is in itself a delimiting feature of the study. The
snapshot that it provides represents a special introductory period, and its finding may not reflect
the views of the industry in future years, especially if the program changes in response to initial
experience. Although BTD was introduced in 2012, other expedited development programs have
been in place for significantly longer (Kesselheim et al, 2015). The requirements for each of the
83
expedited development programs are slightly different and perceptions of the different expedited
pathways may differ. However, an exploration of these differences was considered to be outside
of the scope of the study, considering that the limitations on survey length might not permit a
deep study of all expedited routes. The study was also delimited to regulatory professionals, and
more particularly to regulatory professionals who have experience with regulatory submissions
for products that might be able to take advantage of expedited pathways. It would not reflect the
view of regulatory professionals who are engaged in other parts of the regulatory ecosystem, such
as those in promotion, regulatory intelligence, or animal testing, for example. Importantly, it does
not reflect the possible views of those in other parts of the company even when those parts are
affected by the BTD strategic decisions. For example, while clinical development timelines may
become more efficient it can be difficult for other components of a development program (e.g.,
CMC) to keep pace with the timeline which may limit the use of the efficiencies of the BTD
pathway (Wechsler, 2017).
5.3 Consideration of Results
This study used a triadic framework articulated by Ramsey in academic literature to evaluate the
effectiveness of BTD to meet the three stated aims of regulatory programs (Ramsey, 2013). The
framework has two elements enunciated in the FDA mission statement that reflect FDA’s goals to
ensure product safety, quality and effectiveness and at the same time facilitating innovation and
efficiencies that will increase access and decrease costs (Ramsey, 2013). A third element, that of
assuring a level playing field, was added from the mission statement of the Federal Trade
Commission (FTC), a second agency also concerned with the oversight of medical as well as
other health-related products (Ramsey, 2013) (Figure 16). By using this framework, a wider view
84
of the value and challenges with BTD was possible than might have been gained if the survey
looked only at BTD through the eyes of the FDA.
Figure 16: Framework Used to Assess BTD Expedited Development Pathway
5.3.1 Ensuring Safety, Quality, and Effectiveness
The first aim of the framework underlying this research was to explore whether personnel
involved in the development of BTD products viewed this expedited pathway as a threat to safety,
quality, and effectiveness of drug products. Because these individuals are closest to the data
associated with BTD products, they may be in a particularly useful position to weigh the benefits
and risks of the pathway. Results from the specific questions addressed by the respondents
painted a picture that was somewhat difficult to interpret. Although most participants appeared to
agree that BTD products are sufficiently safe for patients [given that the risk must be balanced by
Ensure Safety, Quality,
and Effectiveness
Equalize
Requirements and
Standards for
Industry
Facilitiate Efficiencies
and Decrease Costs

85
the benefits (Mussen, Salek, & Walker, 2009)] at the time of first marketing approval, most also
felt that additional post-marketing safety monitoring should be required. These responses may
seem contradictory and would be interesting to explore in more depth in future studies. For
example, participants might have different views of the safety of compounds receiving BTD in
phase 3 versus phase 1, or between approvals at relatively early versus late clinical stages or with
larger or smaller evidentiary datasets (Puthumana et al., 2018). It is also possible that the criterion
of whether more post-market studies are needed does not reflect a view that the products are less
safe (Weaver, 2008). Respondents might possibly consider that all products, and not just BTD
products, are reasonably safe at the time of market approval, but recognize that the clinical trial
data on which that approval is based can only go so far to identify rare adverse events or
problems even for the more intensively studied products (Weaver, 2008) (Moore and Furberg,
2014). NMEs that do not take advantage of expedited pathways often must make post-approval
commitments to study further the benefit: risk profile of the drug (Steenberg, 2006), suggesting
that post marketing data is valuable for many kinds of drugs and not just those in expedited
pathways (Kiri, 2012) (Puthumana et al., 2018) (Siebert, 2018).
This is reflected further by the finding that three-quarters of participants disagreed with the
statement that BTD compounds do not have the same rigor of CMC review as compounds
without BTD. From a quality perspective, it is well known that compounds that receive marketing
authority after obtaining BTD undergo the same rigorous review of analytic testing and
production than others entering the FDA review process without the benefit of BTD (Weschler,
2015). There is however some evidence that the shortened regulatory path puts great pressure on

86
the scale-up and manufacturing operations that may become a limiting feature and a potential
safety concern (Wechsler, 2015) (Dye et al, 2016).
However, the bigger concerns with product safety appear to be focused on the quality of clinical
data on which decisions are made. This study found that respondents do not perceive that
efficiency compromises safety for products entering the marketplace by the BTD pathway. This
finding could be considered conflicting with earlier literature reports that question the benefit:
risk ratio of compounds utilizing accelerated development pathways; however, many of those
surveys were done prior to 2012 when BTD was introduced therefore there was no direct
experience with BTD (Olson, 2008) (Lexchin, 2012). Nonetheless, even current literature appears
to provide evidence that might be considered to imply that the clinical trial data is too scanty to
assure the same level of safety (Puthumana et al., 2018). For example, authors of a recent analysis
of all BTD compounds approved for marketing from January 2012 through December 2017
concluded,
“This study…. Suggests that pivotal trials supporting these approvals commonly lacked
randomization, double-blinding, and control groups, used surrogate markers as primary
end points, and enrolled small numbers of patients. Furthermore, more than half were
based on a single pivotal trial… FDA-required post-marketing studies will be critical to
confirm the clinical benefit and safety of these promising, newly approved therapies
(Puthumana et al., 2018).”

However, potential future research could examine post-marketing commitments and whether they
differed amongst compounds granted BTD versus fast track versus compounds that use no
expedited development pathways.

87
At the same time that respondents personally appeared to believe that BTD products are safe, they
do not seem to believe that health care providers or consumers recognize BTD products are
marketed with a potentially more limited premarket dataset to inform their benefit: risk profiles.
This result is consistent with earlier literature (Duval and Cox, 2015) (Kesselheim et al., 2016).
For example, after surveying over 600 physicians, Kesselheim concludes,
“Physicians tended to overestimate the minimum evidence of efficacy required of new
drugs. Similarly, many misinterpreted the term breakthrough—believing these drugs
were supported by stronger evidence than required by the statute… the misconceptions
identified may lead physicians to overprescribe newly approved drugs—particularly
breakthrough therapies—and inadequately communicate how well these drugs works to
patients who will use them (Kesselheim et al., 2016).”
This area of ambiguity might be another area to be explored in future, given the increasing
recognition that stakeholder views are important when considering issues of product safety
(Kesselehim et al., 2016) (Krishnamurti et al, 2015).
5.3.2 Facilitating Efficiencies in Research, Commercialization, and Costs
The second goal of FDA, like that of many other agencies, is to encourage innovation and access
to useful medical products. This can be accomplished by, for example, 1) providing guidance
during developmental phases to avoid unnecessary or redundant activities (Lewis, 2011), 2)
reducing impediments to timely regulatory approvals (FDA, 2017c), and 3) implementing
strategies that reduce costs for medical product companies (Garber, 2014). All of these activities
help to accomplish FDA’s mission to bring promising agents to the market as quickly as possible.
For this reason, it seemed particularly important to ask questions about each of these elements.

88
First, are companies provided with sufficient resources regarding BTD? Most participants
suggested that adequate resources were available to assist with determinations regarding BTD
eligibility. However, some concern was expressed about the sufficiency of FDA’s expedited
development guidance: Expedited Programs for Serious Conditions – Drugs and Biologics (FDA,
2014b). One area of challenge appeared to be a lack of clarity about data requirements for BTD
submissions. This challenge suggests that the guidance FDA is providing related to BTD
submissions may not be sufficient for companies to gain maximum benefit from the program.
Notably, the guidance document has not been updated since it was first released in 2014 so the
last 6 years of experience with BTD are not reflected. For example, the guidance document
describes in general terms the criteria that companies are expected to meet to qualify for BTD but
includes no case studies or practical examples in specific therapeutic areas from which industry
can learn. Additionally, the guidance document discusses each expedited development or
approval pathway at a high level in a single document rather than having a more specific
guidance document for each individual expedited program.
Nonetheless it is clear that a valued positive contribution of the BTD approach is its ability to
both increase the efficiency of the developmental process and by extension, decrease its cost.
The respondents surveyed here appeared to confirm evidence from statistical analysis of BTD
applications by Shea and Poirier (Shea, 2016) (Poirier, 2016) that sponsors are conducting fewer
and smaller trials to support marketing applications for BTD compounds thereby introducing
some efficiencies in the process. This trend appears from the literature to have accelerated since
BTD was first introduced; recent analyses have found that many compounds are conducting a
single pivotal trial only to support licensure (Puthumana et al., 2018). Conversely, at the time that

89
BTD was first introduced, many compounds that received the designation were already in phase
3. For those compounds at such a late developmental stage, little advantage could be taken of the
BTD pathway to facilitate “efficient” development. As industry and FDA have gained experience
with BTD over the last 6 years, more compounds in earlier stages have received the designation;
the literature suggests that many products are approved based only on data from phase 2 trials
(Kern, 2016). Therefore, more opportunities exist for FDA to influence trial design in ways that
produce efficiencies and accelerated access to the product.
It is not surprising that the majority of participants in this study recognize that the current
expedited pathways encourage product innovation and research. At the same time, however, only
a third of participants think that the current expedited development pathways are enough. One
potential explanation for this finding is the relatively small number of products that have been
granted BTD and/or fast track designation when compared with the number of products that are
actively in development.
5.3.3. Equalizing the Requirements and Standards for Industry
The third aim forming the framework used to guide this study was the need to establish programs
that are fair and transparent to all involved parties, including companies of different sizes. The
results of the admittedly modest number of participants in this study suggest that the BTD
pathway has not been overtly discriminatory for companies of different sizes; small, medium and
large companies appeared to have had BTD applications accepted by FDA (cross tabulations in
Appendix C). In addition, responses suggested that perceived barriers to applying for BTD did
not vary significantly with company size. Nonetheless the respondents expressed the view that

90
large companies received more benefit than small companies from the BTD pathway which is
consistent with published literature (Kwok et al, 2015). Whether this survey misses an important
aspect of discrimination remains to be discovered.
In this study, participants from medium sized companies had a higher number of total
applications for BTD. This finding may simply reflect the relatively small sample size in this
exploratory study. Alternatively, it may be due to the tendency for medium size companies to
purchase smaller, more nimble and innovative companies that need additional capital to develop
novel products for serious diseases (Weisman, 2016). These compounds are particularly
promising to fuel the pipeline of bigger companies as their own products reach maturity
(Weisman, 2016). A specific case in point that illustrates this increasingly common trend (Kessel
& Frank, 2007) is that of Yescarta ® (axicabtogene ciloleucel), which was developed by a small
company, Kite Pharma, but acquired by Gilead just prior to FDA approval. In such a case, the
applications for BTD would tend to skew toward companies of larger sizes.
5.4 Utility of the Ramsey/Turnbull Framework
The Ramsey/Turnbull framework was initially selected for this study because it appeared to
capture best the stated goals of the BTD pathway. In retrospect, it appeared to be a good choice
for this exploratory work by providing a defined structure to explore the views of regulatory
affairs professionals employed by the pharmaceutical industry. By focusing on the three tenets of
the framework this research, it proved possible to evaluate the views of regulatory professionals
with respect to anecdotal concerns about the BTD program that had already been present in
literature. Ultimately, by using this framework I feel confident to conclude that industry

91
professionals perceive the BTD pathway as meeting the stated goals of regulation, but also as
having some operational aspects that could be improved.
One area that was highlighted as an area of some concern that did not fall easily into the
framework was related to inconsistencies amongst FDA review divisions. To understand this area
of potential concern, it may be advantageous to look at the perceptions of BTD in future by using
a complementary approach, such as by using an implementation framework. The study of
implementation as a formalized approach is relatively new, but its importance to evaluate how
effectively the processes associated with a complex program are working is becoming well
established (Bertram, Blase, & Fixsen, 2015). As more experience is gained with this relatively
new expedited pathway, it should be possible to look at the early experiences of practitioners who
can identify where potential hurdles or inconsistencies may exist.
A secondary aim of this study was to assess whether FDA weighed the goals of regulation equally
in the BTD program or if precedence was given to one aim over another. Results from this study
suggest that FDA is not weighing one aim of regulation to the detriment of others, at least as
reflected from the views of this single stakeholder. The fact that most felt that the BTD route had
a positive benefit: risk and good ability to improve access appears to suggest that at least two of
the main goals are being achieved. The goal that might deserve more investigation could be that
of the degree to which a level playing field is maintained as this study showed small differences
in perceptions amongst those who had BTD experience and those who did not.

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5.5 Future Directions and Concluding Thoughts
It is a key goal of both industry and regulators to bring promising drug products to consumers as
quickly as possible. This study provides insight into how a limited number of regulatory
generalists perceive the BTD expedited pathway to facilitate such efforts using a triadic
framework designed to evaluate the success of regulatory programs. This study revealed that
participants perceived the BTD pathway to meet the goals of regulation and to be a positive
addition to the expedited pathway armamentarium; however, this initial research is only a first
step to understand BTD from an industry-perspective.
As stated in the Ramsey framework, one of the goals of regulation is to ensure safety, quality and
effectiveness of drug products. While results from this study indicate that regulatory professionals
perceive BTD as ensuring that goal, future studies are needed to explore the implications of
products receiving BTD for healthcare professionals and the public. The views of the present
study and those expressed in other literature (Kesselheim et al., 2016) (Krishnamurti et al., 2015)
suggest that health care practitioners and the lay public may not understand what receiving BTD
means from a benefit: risk assessment perspective. For example, some have suggested that health
care practitioners overestimate the efficacy of BTD compared to non-BTD products (Kesselheim
et al., 2016). It is well known that health care practitioners make prescribing decisions by
weighing many variables in a complex way. It may be useful for future work to include an
analysis of the decision-making frameworks used by prescribers (Murshid & Mohaidin, 2017).
Such analyses might identify ways in which industry can communicate more effectively with
prescribers about the real attributes of approved compounds through its outward-facing
communications, such as, for example, advertising and promotion.

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Another potentially useful outcome of the current study was the identification of regulatory or
other changes or improvements that might make it easier to navigate processes associated with
accelerated access. For example, participants identified that FDA might provide greater clarity
with respect to meeting the evidentiary threshold for designation. The findings also point to a
need for updates to the existing guidance document and perhaps different types of training to
bridge gaps between industry and FDA. A future direction of research that might be useful,
particularly to FDA, would be to probe for more specific information about elements of
additional guidance that seem to be lacking or outdated. For example, more guidance with
explicit examples or case studies as well as templates for applications could help regulatory
professionals to improve their application success rate and reduce the time that FDA spends to
review unqualified applications.
It is well-known that experience with a process often changes the perception of individuals about
the usefulness or difficulty of that process (Ariely & Carmon, 2000). It would be useful to explore
a larger sample of regulatory professionals who have either experience or no experience with
BTD to see if both groups view the BTD pathway in the same way. The respondent sample in this
study was deliberately enriched with individuals who had direct experience with the BTD
pathway. It is not clear whether this experience has affected their views on the safety and
usefulness of this approach compared to others without such experience. However, this type of a
survey would require a more sophisticated method of assuring the right collection of research
participants. The current study did not have a large enough sample from which to draw definitive
conclusions about this particular topic. It would also be interesting to investigate and expand
certain aspects of this research by removing some of the other delimitations that were placed on

94
this exploratory study. For example, it would be interesting to see if a wider range of regulatory
specialists responsible for particular development activities, such as CMC, to have similar
viewpoints on specific elements on BTD. Beyond regulatory affairs, individuals in other parts of
the company, such as clinical development, commercial affairs or business development, may
have different perceptions of the BTD pathway.

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APPENDIX A: FINAL VERSION OF BTD SURVEY

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APPENDIX B: FULL TEXT COMMENTS FROM BTD SURVEY

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Topic: Challenges Associated with BTD Guidance Document
Better clarity on where there is flexibility on CMC data requirements for both small molecules and
biologics
Confusion between different programs—BTD, accelerated approval, fast track, priority. No information
on BTD for a sNDA
Assessing the best time in your product development to apply for BTD. With the large failure rate of
BTD submissions, understanding the gap between FDA expectation and industry interpretation of the
guidance.
Although the guidance describe and encourage enhanced interaction, the agency still has limited
bandwidth to provide thorough feedback during interactions which leads to ambiguity in the most
efficient path forward
There seems to be differences in the requirements needed to obtain BTD across divisions. As is seen I
many other aspects of FDA, different divisions interpret and apply guidances differently.
The guidance “Expedited Programs for Serious Conditions—Drugs and Biologics” only provides
information on the requirements to obtain BTD and a high-level view of the feature of BTD. There is
limited information in that guidance as to what Sponsors can expect with respect to Agency engagement
after BTD. A better source for the operational aspects of BTD is SOPP 8212 (Management of
Breakthrough Therapy-Designated Products: Sponsor Interactions and Status Assessment Including
Rescinding”
There is no template to follow for submitting a BTD application
As with most guidance it is understanding FDA’s threshold regarding “substantial improvement over
existing therapies” and also what constitutes clinically significant endpoints. The latter very critical
when treating very rare diseases without a lot of existing precedence in regards to trial design and
endpoints
With all of these special class designations, there is a misconception that less data is required. The same
standards apply. That said, the Agency, in my experience is quite willing to work with sponsors to
develop the drug in an expeditious way, keeping in mind that the data requirements drive everything
The guidance is useful, but as a regulatory affairs professional any additional examples and clarity is
helpful. Additional examples of early stage compounds and the data companies submit to acquire the
BTD is helpful
THere is variation in how the BTD is viewed depending on the Division and Disease. What worked for
one company may not work for another
Understanding how it will be applied to specific products

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Guidance is sufficiently informative the way it is written
Clear definition of “clinically significant endpoint”
The constantly changing clinical landscape—what might be BTD today may not be several months in
the future. Also, sometimes the “bar” that FDA applies isn’t always clear ahead of time (how many
patients are enough?)
It is unclear how much data is really adequate to seek BTD and qualitatively how good does your data
have to be over existing therapies to qualify for BTD. In cases where no existing therapies exist and your
product provides some symptoms relief but is not disease modifying, again it is what data is adequate to
support BTD
The guidance is adequate, it gives both sponsors and the agency room to be flexible
The determination of “substantial benefit over existing therapy” is subjective leaving the sponsor to
speculate whether or not the FDA bar has been met. The number of patients needed to support the BTD
request is also unclear, and in many cases too few patients treated is part of the reason BTD is denied
The guidance is useful as a starting point. This can be further supplemented by use of published SBAs. It
would be more useful if overall BTD application and approval statistics were provided as well as
Division specific subset information
It’s pretty straight forward. The form for the preliminary BTD application request could be more easily
acceptable but it’s still pretty easy to find
Examples should be provided to better understand the FDA expectations
Applying this broad guidance to each unique product
The guidance may be difficult for non-regulatory professionals to understand. Small businesses without
regulatory personnel may not take full advantage of all the programs that FDA has to expedite drug
development. The FAQ website provides additional helpful information and links
Guidance for Industry and MAPPs on BTD have not been updated since 2014/2015, although SOPs were
updated in 2016, FDA rulings and thoughts are changing more rapidly than written guidance, so more
recent updates on FDA current thinking should be provided to Industry
May not be detailed enough for small companies that don’t have a lot of FDA experience
While the guidance describes type of data to be included (e.g., clinical), it gives no guidance on the
extent of data (patient numbers, endpoint, phase of trials). While I understand this will be indication
specific, for those indications most likely to be subject of a BTD request, the FDA should provide some
guidance on minimal extent of data to consider even before requesting the preliminary teleconference
with FDA
It is not a standalone guidance

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I don’t feel that FDA follows it completely. I think they have become risk averse and they now seem to
wait until a company has randomized data before they grant BTD
No special challenges at this time
No major challenges. My company has had quite a lot of experience with BTD applications and
thorough knowledge sharing internally on each application has learned how best to apply the guidance
I would see the timelines and transparency becoming an issue for industry
The guidance is very helpful. The FDA template is useful, especially to a company filing for this
designation for the first time
It has not been updated since program implemented. Needs to be updated to reflect current practices and
lessons learned
Case by case basis. Expectations of details need direct guidance from the respective review team
There is no guidance to what the eligibility bar is for the BTD despite the understanding that data and
disease would dictate the so called “bar”

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Topic: Recommendations for Additional BTD Resources
Clarity on what constitutes favorable preliminary evidence. Clarification regarding use for drugs already
approved for another indication
Consultants that have experience with BTD, if FDA had more detailed case studies of companies that
have successfully applied for BTD and why it was granted, and ultimately, were benefits of the company
realized due to BTD or would using other expedited pathways have worked as well – especially for those
companies that spent time applying for BTD and didn’t receive the designation
Updated FDA guidance document
I see need a need for more clarity when data are limited
How to provide rationale for surrogate endpoints—what type of data is required and how much data?
Not sure
1) case studies of drugs gaining BTD after approval—e.g., of one such situation is the case studies done
at Aaadv for anti-cancer therapies
Some clarity on minimum standards in the guidance. Initiating the pre-BTD request has been helpful and
FDA feedback has allowed for better decision making on deciding whether or not, or when, to submit
Again, precedence would be helpful
For any indication, it’s helpful to understand what has previously received and been denied designation.
This process is limited by FDA’s confidentiality within the IND process and willingness of sponsors to
share information. Recent information at conferences is helpful, but needs to be incorporated into
guidance, perhaps by broad indication, oncology for instance
Perhaps more specific product examples to compare to. An interactive Q&A to help you determine
whether the BTD is a viable path for your product on the FDA’s website
Additional Q&A or links to FDA public (conference) presentations on topic may be useful. The clinical
indication list of approved BTs is helpful and some information on what the company studied in the
clinic is useful, and although specifics on the trials could be located on clinicaltrials.gov, maybe some
information on the types of indications/results that could be more likely to interest FDA for potential
approval for public health reasons, it may spur innovation on in a more novel or orphan indication
Webinars from FDA
Specific guidances for those indications most likely to be the subject of a BTD request
I would expect more involvement from the agency project manager

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Topic: Additional Barriers to Applying for BTD
Literature search developing case for seriousness. Meeting the clinical evidence requirements in often
small studies
The negative consequences for small companies that apply and don’t receive the designation. A lot of
time and effort goes into this process as it’s viewed as a very positive public relations event, but with the
high failure rate, either there is a misunderstanding on the part of companies as to what is required or the
outside influences (e.g., board of directors, Senior Management,) to apply who don’t understand the
requirements for success.
The perspective of the review division regarding the seriousness of the disease and their view of the data.
It is not consistent across divisions/reviewers.
Company experience in “regular” drug development is very important to understand the regulatory
context of an application based on BTD
Impact on technical development—applying for BTD early in clinical development means many
additional resources are needed to accelerate technical development and/or to negotiate with FDA what
might be able to be provided post-approval
Change my mind, evidence is a barrier both with respect to sponsors overestimating the value of their
data and underestimating, assuming BTD will not apply to their compound
Knowledge and experience in regulatory staff of company on BTD applications
N/A
The time it takes to develop the CMC information may take longer than other parts of development
I think the biggest barrier is generating sufficient evidence in light of there being no FDA guidance
concerning what sufficient evidence is. The logistics of the submission process itself are easy enough for
even small companies to handle
FDA seems to have increased the standards for receiving BTD. FDA seems to require randomized data
which by the time the company has that information it is too late to receive most of the benefits of BTD
other than the press release and 1 month of earlier review
Lack of knowledge or awareness of benefits. Internal company politics

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Topic: Time Savings Achieved by BTD Pathway
They have not gotten to marketing application submission yet, so I can’t say
7-9 months
0
We have applied late in the process so not much time
NDA not yet submitted
Hard to say, in the context of an orphan drug probably 2-3 years
4-6 months
4 months
I expect that this varies greatly. Perhaps statistics can be obtained from FDA or sponsors. Would need to
identify an appropriate comparison group to those products that have BTD. Maybe a historical group
from before the existence of BTD? For a product that had accelerated approval but not BTD versus a
product with BTD and accelerated approval, there could be some savings associated with prompt and
thorough interactions with FDA. Maybe a 10% reduction for BTD products. For those that don’t use
accelerated approval pathway, the savings may be greater in terms of percentage reduction in time from
FHD to marketing application
Varies per product so hard to determine
Two to three years
Several months if not a year or more
From 6 months to 2 years depending on the program
1-2 years
3 years as accelerated approval was possible and achieved

121
Topic: Additional Comments on BTD
We advise clients often on taking advantage of the various designation programs available. Historically,
we suggested to work in a step-wise fashion starting with fast track and then applying for breakthrough
once clinical data is available. However, most of use agree that fast track may not even worth the time as
benefits are small—and many clients have limited funding, so we have recently been recommending
they wait for some clinical data and given positive results, just apply for breakthrough therapy at that
time. I definitely think BTD is serving its purpose. I’m also curious to see, after a few more years pass,
how or if the EMA PRIME designation matches up with FDA breakthrough designation
Nope, I think I’ve said all I have to say on BTD
This program has been encouraging and successful to bring innovative medications to an unmet need
population. The FDA, DOHP, has been working in good partnership with research and academia to
apply the intent of BTD

122
APPENDIX C: BTD SURVEY CROSS TABULATIONS

123
What is the approximate size of the company by which you
are employed?
<250
employees
250-5,000
employees
5,001-
15,000
employees
>15,000
employees
Total
Of the breakthrough therapy
designation applications you
have been involved in the
submission, how many were
successful?
0
1 3 1 0 5
1
3 1 0 6 10
2
2 3 0 1 6
Total 6 7 1 7 21
Chi square 10.88*
Degrees of freedom 33
p-value 1
*The Chi square approximation may be inaccurate - expected frequency less than 5.

124

What is the approximate size of the
company by which you are employed?

(Number of employees)
<250
250-
5,000
5,001-
15,000
>15,000
Total
Please indicate your level of
agreement with the following
statements with respect to
barriers to applying for BTD -
Meeting evidentiary threshold
Agree
6 9 1 12 28
Neither agree nor
disagree 1 2 1 2 6
Disagree
3 0 0 0 3
Don't Know
0 0 0 0 0
Total 10 11 2 14 37

Please indicate your level of
agreement with the following
statements with respect to
barriers to applying for BTD -
Application process
Agree
2 2 0 1 5
Neither agree nor
disagree 1 2 1 1 5
Disagree
7 7 1 12 27
Don't Know
0 0 0 0 0
0 0 0 0 0
Total 10 11 2 14 37

Please indicate your level of
agreement with the following
statements with respect to
barriers to applying for BTD -
Internal resourcing
Agree
3 4 1 5 13
Neither agree nor
disagree 2 2 0 4 8
Disagree
5 5 1 5 16
Don't Know
0 0 0 0 0
Total 10 11 2 14 37

Please indicate your level of
agreement with the following
statements with respect to
barriers to applying for BTD -
Monetary constraints
Agree
1 2 0 1 4
Neither agree nor
disagree 2 1 0 2 5
Disagree
7 7 2 11 27
Don't Know
0 1 0 0 1
Total 10 11 2 14 37

Meeting Evidentiary Threshold:

Chi square 10.54*

Degrees of freedom 9

p-value 0.31

*The Chi square approximation may be inaccurate - expected frequency
less than 5.

125
Application Process:
Chi square 4.44*
Degrees of freedom 9
p-value 0.88
*The Chi square approximation may be inaccurate - expected frequency
less than 5.
Internal Resourcing:
Chi square 1.35*
Degrees of freedom 9
p-value 1.00
*The Chi square approximation may be inaccurate - expected frequency
less than 5.
Monetary Constraints:
Chi square 4.46*
Degrees of freedom 9
p-value 0.88
*The Chi square approximation may be inaccurate - expected frequency
less than 5.

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Asset Metadata

Creator Wiley, Jennifer Rose (author)

Core Title Experience with breakthrough therapy designation: an industry survey

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 02/20/2019

Defense Date 12/10/2018

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

Tag breakthrough therapy designation,BTD,drug development,expedited development pathways,FDA,OAI-PMH Harvest,regulatory affairs

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Cosenza, Mary Ellen (committee member), Jamieson, Michael (committee member), Pire-Smerkanich, Nancy (committee member)

Creator Email jennifer@meltingmosaic.org,jennifrw@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-124110

Unique identifier UC11676211

Identifier etd-WileyJenni-7094.pdf (filename),usctheses-c89-124110 (legacy record id)

Legacy Identifier etd-WileyJenni-7094.pdf

Dmrecord 124110

Document Type Dissertation

Format application/pdf (imt)

Rights Wiley, Jennifer Rose

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

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

Repository Name University of Southern California Digital Library

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