University of Southern California Dissertations and Theses

Effect of GDUFA legislation on the development and approval of generic drugs: a survey of industry views and experiences

(USC Thesis Other)

Effect of GDUFA legislation on the development and approval of generic drugs: a survey of industry views and experiences

PDF

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content

Effect of GDUFA Legislation on the Development and Approval of Generic Drugs:
A SURVEY OF INDUSTRY VIEWS AND EXPERIENCES.

by

Donatus Ako-Arrey

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 2020

Copyright 2020 Donatus Ako-Arrey

ii
DEDICATION………
I dedicate my thesis to my family, especially my parents Pa Joe and Mama Theresia
Arrey, my loving wife Violet, my sons Shawn and Tyler, and my siblings, Pam, Orock,
Denis and Manyi. I would like to thank them for their love, immense support and
relentless encouragement. Their belief in me gave me the strength to pursue my research
successfully.

iii
ACKNOWLEDGMENTS
First and foremost, I wholeheartedly thank God for giving me the strength to
complete this doctorate.
I give my sincerest appreciation to my dissertation advisor, mentor, and now
friend, Dr. Frances Richmond. I thank Dr. Richmond for believing in me and giving me
the opportunity to complete this DRSc program. Her magnificent supervision,
unconditional support, thoughtfulness, patience, motivation, and meticulous instruction
have had profound and long-lasting impacts on my life academically, professionally and
personally. I could not have had a better mentor and this work could not have been
possible without her thorough guidance and interest in my research. I would also like to
express my gratitude to the rest of my thesis committee, Dr. Daryl Davies, Dr. Benson
Kuo and Dr. Michael Hamrell for continuously permitting me to tap into their extensive
expertise that provided the fuel to keep me on track, and steer this thesis to fruition. I also
thank the dedicated staff from the USC Regulatory Science Department for their never-
ending and timely administrative interventions throughout my studies that facilitated the
achievements of my goals. I wish to acknowledge and express my sincere gratitude to the
many pharmaceutical industry colleagues, former FDA regulators, and consultants who
shared their knowledge and provided invaluable support, motivation, and inspiration.

iv
TABLE OF CONTENTS

DEDICATION……… ........................................................................................................ ii
ACKNOWLEDGEMENTS ............................................................................................... iii
TABLE OF CONTENTS ................................................................................................... iv
LIST OF TABLES… ........................................................................................................ vii
LIST OF FIGURES ........................................................................................................... ix
ABSTRACT………... ........................................................................................................ xi
CHAPTER 1. OVERVIEW ........................................................................................ 1
1.1 Introduction .................................................................................................... 1
1.2 Statement of the Problem ............................................................................... 5
1.3 Purpose of the Study ...................................................................................... 8
1.4 Importance of the Study ................................................................................. 9
1.5 Limitations, Delimitations, Assumptions ..................................................... 10
1.6 Organization of Thesis ................................................................................. 12
CHAPTER 2. LITERATURE REVIEW .................................................................. 14
2.1 Evolution of Generic Drug Regulations ....................................................... 14
2.2 The Generic Drug Approval Process ........................................................... 19
2.2.1 Gaining approvals for drugs that do not meet the generic
definition ........................................................................................ 26
2.3 Inefficiencies in the generic drug regulatory process .................................. 27
2.3.1 Competitive Strategies of Brandholders ......................................... 28
2.3.2 Regulatory Responses to Brandholder Tactics ............................... 38
2.3.3 Delayed Regulatory Reviews ......................................................... 41
2.4 Generic Drug User Fee Amendments (GDUFA) ......................................... 47
2.4.1 Evaluating GDUFA Initiatives ....................................................... 57
2.5 Monitoring and Evaluation Frameworks ..................................................... 59
2.5.1 Systems for Improved Access to Pharmaceuticals and Services .... 61
2.5.2 Global Strategy and Plan of Action on Public Health,
Innovation and Intellectual Property .............................................. 63
2.6 Transparency ................................................................................................ 66
2.7 Access .......................................................................................................... 71
2.8 Safety ........................................................................................................... 73
v
2.9 Research Approach ...................................................................................... 76
CHAPTER 3. METHODOLOGY ............................................................................ 78
3.1 Introduction .................................................................................................. 78
3.2 Survey Development .................................................................................... 78
3.3 Focus Group ................................................................................................. 79
3.4 Survey Delivery ........................................................................................... 82
3.5 Survey Analysis ........................................................................................... 83
CHAPTER 4. RESULTS .......................................................................................... 84
4.1 Analysis of Survey Results .......................................................................... 84
4.2 Profiles of Respondents ............................................................................... 84
4.3 Access .......................................................................................................... 92
4.4 Transparency .............................................................................................. 115
4.5 Safety ......................................................................................................... 130
4.6 GDUFA Performance Scorecard and Future Stakes .................................. 137
CHAPTER 5. DISCUSSION ................................................................................. 150
5.1 Overview .................................................................................................... 150
5.2 Methodological Considerations ................................................................. 151
5.2.1 Delimitations ................................................................................ 152
5.2.2 Limitations .................................................................................... 155
5.3 Consideration of Results ............................................................................ 160
5.3.1 Impact of GDUFA on Generic Drug Access ................................ 161
5.3.2 Impact of GDUFA on Transparency ............................................ 173
5.3.3 Impact of GDUFA on Safety ........................................................ 179
5.4 Conclusion and Future Directions .............................................................. 183
REFERENCES……… ................................................................................................... 186
APPENDIX A. FINAL VERSION OF QUALTRICS SURVEY ............................ 205
APPENDIX B. CROSS-TABULATION OF RESPONDENTS’ LEVEL OF
EXPERIENCE AND VIEWS ON CHALLENGES TO SUBMITTING A
HIGH QUALITY ANDA ............................................................................. 228
APPENDIX C. CROSS-TABULATION OF RESPONDENTS’ COMPANY
SIZE AND VIEWS ON CHALLENGES TO SUBMITTING A HIGH
QUALITY ANDA ........................................................................................ 230
APPENDIX D. CROSS-TABULATION OF NUMBER OF ANDAS
RESPONDENT’S COMPANY SUBMITTED AND VIEWS ON
CHALLENGES TO SUBMITTING A HIGH QUALITY ANDA .............. 232
vi
APPENDIX E. CROSS-TABULATION OF RESPONDENTS’ COMPANY
SIZE AND VIEWS RELATING TO THE CHALLENGES IN
DEVELOPING COMPLEX GENERIC DRUGS ........................................ 234
APPENDIX F. CROSS-TABULATION OF RESPONDENTS’ COMPANY
SIZE AND VIEWS ON THE OVERALL PERFORMANCE
ASSESSMENT OF GDUFA ........................................................................ 235

vii
LIST OF TABLES…

Table 1: Patent Certification Classification ...................................................................24
Table 2: GDUFA 1 Review Performance Goals ............................................................53
Table 3: GDUFA II Review Performance Goals ...........................................................54
Table 4: Focus Group Participants .................................................................................81
Table 5: Cross Tabulation of Number of ANDA Submitted Annually and
Company Size ..................................................................................................92
Table 6: Factors impeding access to generic drugs in the US? ......................................94
Table 7: Reasons for the lower numbers of generic drug launches. ..............................96
Table 8: Respondents’ View on the use of REMS to Limit Generic
Competition......................................................................................................98
Table 9: Leading Causes of the Increase in Issuance of Deficiency Letters to
ANDA Sponsor during FDA Review ............................................................100
Table 10: Additional Comments Regarding the Ability of Companies to Meet
Deadlines to Respond to FDA IRs and DRLs. ..............................................104
Table 11: Challenges to Submitting a Substantially Complete High Quality
ANDA ............................................................................................................110
Table 12: Challenges to Submitting a Substantially Complete High Quality ................113
Table 13: Impediments to the Successful Development of Complex Generics .............115
Table 14: Views on the Impact of GDUFA on Transparency .......................................116
Table 15: Comments on Impact of GDUFA on Transparency ......................................117
Table 16: Cross-Tabulation of Respondents’ Level of Pharmaceutical Industry
Experience and Views on Level of Transparency Exhibited by FDA
since GDUFA implementation ......................................................................118
Table 17: Level of Company-Initiated Interactions with OGD .....................................119
Table 18: Additional Comments Regarding Quality of Information Received
from Company Initiated Interactions with OGD ...........................................121
Table 19: Respondents’ View on FDA Guidance Development ...................................123
Table 20: Views on OGD Controlled Correspondence Process ....................................125
Table 21: Views on Formal Meetings between OGD and Sponsors of Generic
Drugs. .............................................................................................................128
viii
Table 22: Additional Comments Regarding FDA Consistency in ANDA Review
Process ...........................................................................................................130
Table 23: Additional Comments on Quality of FDA Compliance Inspections .............132
Table 24: Additional Comments Regarding Delays in ANDA Approval Due to
Slowness in FDA Site Inspection ..................................................................135
Table 25: GDUFA overall performance since its implementation in 2012 ...................139
Table 26: Cross-Tabulation of Level of experience of Respondent and their
Views on the effectiveness of the GDUFA user fees program. .....................141
Table 27: Additional Comments Regarding Quality of Generic Drugs .........................143
Table 28: Initiatives to Prioritize for GDUFA 3 ............................................................145
Table 29: Additional Comments on Initiatives to Prioritize in Future GDUFA III
Negotiations ...................................................................................................146
Table 30: Greatest success of the GDUFA program ......................................................147
Table 31: Greatest challenges of the GDUFA program .................................................148

ix
LIST OF FIGURES
Figure 1: Median approval time of generic drugs in the US (2000-2017) ......................42
Figure 2: Review cycles for ANDAs 2009 through July 2014 .......................................43
Figure 3: Backlog of unapproved ANDAs per month.....................................................51
Figure 4: SIAPS Pharmaceutical System Strengthening Approach ................................62
Figure 5: RBM results chain............................................................................................64
Figure 6: Total Number of FDA Inspections of Domestic and Foreign Drug
Establishments, Fiscal Year 2007 through June 30, 2016 ...............................75
Figure 7: Triadic framework of safety, access, and transparency ...................................77
Figure 8: Respondents’ Primary Job Function ................................................................85
Figure 9: Company Functional Roles of Respondents ....................................................87
Figure 10: Experience Level of Respondents within the Drug Industry ...........................88
Figure 11: Functional Roles of Respondents.....................................................................89
Figure 12: Size of Company Respondent is affiliated with ...............................................90
Figure 13: Number of ANDAs Submitted by Company Respondent is affiliated
with ..................................................................................................................91
Figure 14: Effect of Shorter FDA Timelines Imposed Since GDUFA on the
Ability of Companies to Respond to FDA IRs and DRLs. ............................102
Figure 15: Effect of Limited Resources on the Ability of Companies to Meet
Deadlines to Respond to FDA IRs and DRLs. ..............................................103
Figure 16: Frequency of Requests for Extension to FDA Information Requests or
Discipline Review Letters Response Deadlines ............................................107
Figure 17: Readiness of Generic Companies to Address the Increasing Number
of Deficiency Letters during ANDA Review ................................................108
Figure 18: Current State of Expertise in the Development of Complex Generics ..........112
Figure 19: Respondents View on Quality of Information Receive from Company
Initiated Interactions with OGD.....................................................................120
Figure 20: FDA Consistency in ANDA Review Process ................................................129
Figure 21: Quality of FDA Compliance Inspections .......................................................131
Figure 22: FDA Compliance Inspections ........................................................................132
Figure 23: Specific Concern Regarding FDA Compliance Inspections ..........................133
Figure 24: Effect of FDA Site Inspection Timing on ANDA Approvals........................134
x
Figure 25: Frequency of FDA compliance inspections ...................................................136
Figure 26: Effect of increased frequency of inspection on quality improvement ...........137
Figure 27: Quality of generic drugs better under the GDUFA System ...........................142

xi
ABSTRACT………...
The timely availability of generic drugs is a critical factor to improve
the affordability and access of medications, particularly as healthcare expenditures in the
US escalate at alarming rates. Nonetheless, the number of generic drugs approved yearly
has been modest when compared to the number of generic marketing applications
submitted to the FDA every year. Until recently, review times for such applications had
lengthened to periods of multiple years, resulting in a large backlog of applications whose
approval timelines are uncertain. To improve this situation, Congress passed the Generic
Drug User Fee Amendments (GDUFA) in 2012 (USFDA, 2012) to implement user fees
for generic drug applications. Such fees allowed the FDA to hire more reviewers and
improve review infrastructure. This research project explored systematically the views of
industry with regard to the success of the GDUFA user fee program to meet its primary
goals. A novel web-based survey tool was developed and disseminated to explore
experiences of generic drug industry professionals regarding GDUFA’s effectiveness in
improving the safety and access to generic drugs and the transparency of the regulatory
process. Results suggest that the passage and implementation of GDUFA in 2012, and its
successor, GDUFA II, in 2017 have resulted in reduction of the approval times for
generic drug applications. Further, better communication is typically reported between
generic drug sponsors and the FDA, and these interactions have fostered transparency.
However, respondents were also concerned that efficiency in the regulatory system for
generics was being jeopardized by inconsistencies between FDA reviewers and by the
submission of poor quality applications by ANDA sponsors.
1
OVERVIEW
1.1 Introduction
Generic drugs form the bedrock of accessible and inexpensive medical therapy.
Estimates suggest that nearly four billion generic prescriptions were dispensed in 2018,
accounting for more than 90 % of all prescriptions in the United States of America. The
availability of low-cost generics drugs saved the healthcare system $293billion in 2018
alone and $2 trillion over the last decade, according to the Association for Accessible
Medicines (2019). During the period 2011 – 2018, the market size for generic drugs in
the US grew at a rate of 12% per year, reaching a value of $ 315 Billion US dollars
(USD) in 2017. According to the market research firm, IMARC Group, that size is
expected to grow further at a rate of roughly 6.8% per year to reach approximately 474
billion USD by 2023 (IMARC, 2019).
Timely availability of generic drugs has a major influence on the affordability and
access to medications. Nonetheless, the number of generic drugs approved yearly has
been low when compared to the number of marketing authorizations submitted for
generic drugs every year. A substantial period of time, often in excess of three years, was
required prior to about 2015, from the filing of an abbreviated new drug application
(ANDA) to final FDA approval. This crucial marketing approval represents the last
hurdle to making the product available on a commercial scale. This evidence made it
clear that the FDA had inadequate resources to assure rapid reviews and approvals. In
2
fact, the review times were lengthening and the FDA had developed a large backlog of
ANDAs whose approval timelines were uncertain.
How did this situation develop? As early as 1962, the U.S. Congress recognized
that generic drugs would be essential to ensure that medicines would be available at a
reasonable cost. The Drug Price Competition and Patent Restoration Act (colloquially
called the Hatch-Waxman Act) of 1984 was designed as a compromise to promote
competition by encouraging the development of low-cost generic drugs and to encourage
research by granting certain competitive benefits to innovators. The Hatch-Waxman Act
opened the floodgates to a lucrative generic industry by reducing the cost and effort to
bring a new generic drug to market. (United States Congress, 1984)
It seems clear that the legislators and regulators of the 1980s did not anticipate the
massive growth of the generic industry that would put unmanageable pressures on the
FDA. It was in response to this pressure that the Generic Drug User Fee Amendments
(GDUFA) were passed by Congress and signed into law in 2012 (USFDA, 2012) as part
of the FDASIA legislation. This law was modeled after similar FDA user fee programs
that had proven so successful in other medical product sectors. The first such user fee
program was developed for novel drugs facing the same types of review delays in the
mid-1990s. The Prescription Drug User Fee Act (PDUFA) in 1992 provided additional
resources for the review of New Drug Applications (NDAs). This approach, which
required brand holder companies to pay substantial fees to supplement the resources of
FDA for reviews of NDAs and associated submissions, brought approval times down by
3
half from thirty months in 1992 to fifteen months by 1997, barely five years after
implementation of the PDUFA user fees program (Zelenay, 2005). More recently, new
drug applications (NDAs) have had a median approval time of 10 months, and more than
60% of these NDAS are approved after their first cycle of review (USFDA, 2017d).
The effectiveness of the PDUFA program, where NDAs were being reviewed in
less than one year, was in stark contrast to the experience faced by the generic industry.
Without supplemental funding from industry, a persistent financial shortfall prevented the
FDA Office of Generic Drugs (OGD) from hiring sufficient review personnel to fix the
drug lag issues. Thus, the generics drug sponsors entered into direct negotiations with the
FDA to craft and lobby for a new law, the Generic Drug User Fee Amendments
(GDUFA), introduced in 2012 (USFDA, 2012). As with FDA’s other user fee programs,
GDUFA is based on a relatively simple premise. Because generic drug companies are
eager to accelerate their access to market, they agreed to fund the FDA’s review of their
ANDAs by providing substantial user fees. These funds could then allow FDA to hire
additional staff and optimize its regulatory infrastructure and systems. In return for that
money, the regulators committed to a series of performance goals designed to achieve
specific incremental improvements in the speed and efficiency of the drug review
process. GDUFA levies a series of fees, including ANDA application, program and
establishment fees. The application fee is paid to the FDA upon submission of an original
ANDA, and then program fees are assessed annually on products with marketing
approvals and on approved manufacturing facilities. Like other user fee programs, the
4
generic user fees must be reauthorized every five years, so that Congress can assure that
the user fee program is achieving its objectives.
A primary goal of GDUFA has been to improve the predictability and timeliness
of the FDA’s application process. Its ambitious goal has been to reduce the median
review time of new generic drug applications from approximately 30 months, a period
typical for reviews prior to the implementation of GDUFA in 2012, to a target of 10
months for reviews approved in a single review cycle. Another goal of GDUFA,
however, was to address industry concerns that the review and approval process lacked
transparency. To address the concerns, GDUFA obligated the FDA to issue guidance
documents and hold public meetings or workshops covering a broad range of topics,
including agency–sponsor communication practices, and to facilitate in particular the
development of complex generics, whose management was particular complicated.
GDUFA I expired on September 30, 2017, and the second iteration, called
GDUFA II, was reauthorized and signed into law effective October 1, 2017. GDUFA II
continued the policies first implemented in 2012 that authorized the FDA to collect user
fees from generic drug companies (Prajapati & Patel, 2017). As part of the
reauthorization, significant changes were attempted to build on the experience with
GDUFA I. Perhaps the most important question that was asked as reauthorization was
considered was whether GDUFA I achieved its goals of reducing the review times of
generic applications. GDUFA’s performance was assessed by examining the annual
performance reports prepared by FDA’s Office of Planning to Congress, which detail the
5
funding, relevance, and performance of the user fee programs. From these documents, a
promising picture has emerged. For example, the FDA was able to act on 97% of FY2015
original ANDAs within 15 months of submission, exceeding the GDUFA goal to review
and act on 60% of FY2015 original ANDAs within that period. The trend for FY2016
was reported to be similar to that of 2015. As noted by Kathleen Uhl (2017), Director of
the Office of Generic Drugs (OGD) at the 2017 Annual GPhA conference, ANDAs were
“starting to see first cycle approvals”, with an increase of first cycle approvals to 9%
currently from 1.4% in 2014.
However, not all critics of GDUFA have been so enthusiastic about its success,
noting that the median review time for generic approvals, which was 30 months prior to
the implementation of GDUFA in 2012, in fact, rose to 36 months in 2013; 42 months in
2014; and was 42 months in 2015; 39.5 months in 2016; and 38 months in 2017. The
discrepancies above in the percentage of original ANDAs on which FDA acted within 15
months of submission in 2016 and the median review time for generic approvals for that
year derives from the terminology used to establish the GDUFA goals. The GDUFA
instructions to FDA were to “review and act on” applications within certain timeframes
but not necessarily to approve those submissions or carry out other favorable actions
within those same timeframes.
1.2 Statement of the Problem
Problems of regulatory efficiency and effectiveness have placed the generic
industry in a difficult position. If products cannot be approved in a timely way, the industry
6
cannot supply alternative medicines at lower costs to patients. In addition to the
detrimental impact that these delays have on patients and the healthcare system, the
generic industry is handicapped from replenishing its portfolio with timely new product
approvals. New product launches are critical for industry to gain the income needed to
make further investments. These problems have been compounded by the constantly
evolving strategies by brand-name companies to thwart competition from the generic
drug makers to delay generic introductions in other ways, such as introducing patent
barriers and paying generics companies to delay the introduction of competitive products.
According to Dureja (2010), an independent, consistent, transparent and robust regulatory
review system is indispensable to protect the public health and build confidence in the
marketed medicines. However, the US generic drug manufacturers found in the last
decade that they faced a number of challenges related to the lack of consistency,
predictability, and transparency of ANDA reviews. Further, the lengthy review times
have been seen to threaten access to affordable medications, and greatly complicate the
already complex task of launching a generic drug, where predictability is needed so that
appropriate planning can take place (Anderson, 2004; Rawson, 2000). GDUFA was
enacted to accelerate the review and approval process for generic drugs so that access to
generic versions of important new drugs would not be impeded unnecessarily. However,
the scorecard for its success is lopsided. The measure of its success largely comes from
reports of a single stakeholder, the FDA. The FDA monitors and reports annually to
Congress on the progress of GDUFA, but has had a narrow focus on metrics reflecting
the changes in certain approval timelines. FDA is strongly vested in assuring the
7
continuity of the GDUFA program so is incentivized to position the program as a
success. However, it is unclear whether the program has been successful at achieving all
of the goals that were enunciated for the program at its inception. Those who study
program implementation and evaluation from a best-practices point of view would
suggest that policy refinement should be guided by input from all of the stakeholders
affected by the policy.
Perhaps one of the most important stakeholders is the generic drug industry, both
because its constituents pay the user fees and are most vulnerable to any failures or
inadequacies in its implementation. However, the voice of this principal stakeholder
seems to be represented only modestly in considerations of GDUFA change. Most input
to the process appears to come from industry associations, and these have a fairly narrow
focus and skewed membership representing the largest generic drug companies. More
systematic evaluations of the effects of GDUFA from the point of view of individual
industries appear to be limited. Nonetheless, customer feedback is one of the most
important mechanisms to understand if customer expectations are met and determine
whether the standard of service is been delivered. The provision of any “service”, if
review and approval can be considered a service, should be aimed at satisfying identified
needs of the targeted customer (Rust & Zahorik, 1993). Given that the first iteration of
the GDUFA legislation is now over, the time seems appropriate to evaluate the successes
and shortcomings of the GDUFA program through the prism of the end-user – the generic
drug industry. While established procedures often exist to analyze the impact of new
regulatory proposals or publicly funded projects before they are adopted, little attention is
8
often paid to monitoring regulations after implementation or to evaluating the procedures
and practices that govern the regulatory process itself.
Following the implementation of GDUFA, many were skeptical about its abilities
to improve the timelines and transparency of the communication and review processes for
approving new generic drugs. Generic drug makers were also doubtful about the ability
of GDUFA to improve predictability, consistency, and transparency in generic drug
regulatory submission and review. The literature is not helpful in providing insight into
the current views and experience of the end-users on the success of GDUFA. This lack
of information led to the study proposed here, to explore the views of those in industry
who are positioned best to reflect on the experience that their organizations have had with
the regulatory approval and review processes since the enactment of GDUFA.
1.3 Purpose of the Study
The aim of this research project was to explore the regulatory environment for
generic drugs in the US as it relates to activities that encompass the development and
marketing authorization application review and approval of generic drug products. A
particular focus of the research was to evaluate the views of industry with regard to the
ability of the GDUFA user fee program to meet its primary goals. In the first part of this
study, I reviewed the literature to describe the evolution of the regulatory system
currently in place to regulate generic drugs. As part of this review, I examined the causes
of delayed generic entry. These include not only regulatory impediments, but also the
9
evolving strategies by brand-name companies to forestall competition and impact the
decisions made by generics companies as they strategize product commercialization.
The objective of the second phase of the research was to analyze the experience
and views of one stakeholder – industry -with regard to the ability of GDUFA to meet its
primary goals using a mixed-methods approach. A survey instrument was developed
using the knowledge gained from the literature review and a triadic framework built on
the expressed goals of the GDUFA legislation to assure product safety, improve timely
access and encourage regulatory transparency. In each of the three domains, subtopics
that were identified in the literature review were reflected in survey questions in order
that the survey was relatively comprehensive and systematic. The expertise of a focus
group of stakeholders from generic drug companies guided this phase of the study. Once
the recommendations of the focus group were incorporated into the survey, the survey
was disseminated to regulatory, research and development, and business professionals
who were judged to have experience with the GDUFA process and the submission of
ANDAs.
1.4 Importance of the Study
Much remains to be known about the monitoring and evaluation of FDA user fees
from the end-user perspective. By understanding the strengths and shortcomings of the
current GDUFA programs from the perspective of the end-user, it may be possible to
achieve a few important goals. First, it would help to build a picture of where progress
has been made and where it needs to go further. By knowing the experience of the
10
generic drug industry, it may be possible to identify additional areas for improvement
particularly in largely unstudied areas of transparency and communication, as well as in
improving timelines. An effective user fee program would not only assure that review
times are shortened but that the development process as a whole is improved by assuring
more frequent and effective communication during generic drug development and
application review. This type of improvement might increase the quality of the
submissions, decrease time wasted in the development of required scientific materials,
and increase the probability of final approval. Not only would such an outcome improve
the process for the generic drug industry but would also facilitate the work of the FDA,
so that fewer questions and clarifications on the submissions are needed and fewer review
cycles are necessary to complete the reviews. This research work may also contribute to
the assessment process itself, by exploring the usefulness of the adopted approach and
framework for capturing industry views. This approach might help those attempting to
review user fee programs more broadly in other FDA-regulated industries, and might
help to provide a basis for future international comparisons as the introduction of user
fees spreads globally.
1.5 Limitations, Delimitations, Assumptions
This research investigated the impact of FDA user fees for generic drug regulation
on drug development and approval in the United States of America. It did not examine
how other countries or regions are dealing with this problem, nor did it examine other
aspects of all FDA regulated activities within the scope of GDUFA, such as goals for
11
active pharmaceutical ingredients, drug master file (DMF) review or dispute resolution
procedure. Other important aspects central to generic drug regulation not directly
addressed here included activities associated with lifecycle maintenance of marketed
generic products and pharmacovigilance review, for example.
One challenging and potentially limiting aspect of this study was the ability to
sample a representative group of regulatory professionals with generic drug experience
covering the breadth of the generic drug industry. The selection of the participants was
accomplished by taking advantage of professional networks, industry consultants and
snowball referrals. This approach can potentially introduce some bias because the
participants may be likeminded individuals who may have been influenced by working
together or attending similar meetings or workshops organized by professional trade
associations. If the participants in the survey are not fully representative of all experts in
this field, the external validity of the study may be open to question. Furthermore, such
individuals are often too busy to participate in a survey study and this may impact the
response rate, which is well-known to be low in such open-access surveys. Some
individuals may be wary of providing information due to concerns about protecting
proprietary company information.
An appropriate survey tool is essential for the success of this analysis and the
strength of this survey may be compromised by my own inexperience. The use of a focus
group to critique the survey may be helpful but still may have limitations. The
effectiveness of the focus group may be diminished if the moderator finds it difficult to
12
keep the group focused on the survey without dwelling too long on only a few questions
or diverting the discussion into areas that are not germane to the topic. The ability to
develop a strong survey instrument is also challenged by the limited and often-anecdotal
information on this subject in the literature. Many of the resources used for the literature
review were not peer-reviewed and contained personal editorial comments, sometimes
very negative, towards regulatory authorities and the pharmaceutical industry. Thus,
these comments may present a skewed picture that may affect my approach to the
research, even subliminally.
I made a number of assumptions that may affect the feasibility and methodology
of this study. First, I assumed that all the individuals participating in the study put much
thought into the responses, answer the questions honestly, and express their own opinions
and experience based on their understanding of the subject matter. I also assumed the
participants who complete the survey had a sufficient understanding of the subject matter
to provide meaningful answers to the questions. Finally, I made the assumption that I will
use fair balance and objectivity throughout the conduct of the study by making
appropriate distinctions between what is fact and what is opinion. However, despite such
efforts, bias may persist to some degree and potentially limit the validity of the results.
1.6 Organization of Thesis
The thesis is organized into five chapters. Chapter 1 provides an introduction of
the study including the problem statement, the purpose, and importance of the study, and
the delimitations and limitations of the study. Chapter 2 provides an overview of the
13
generic drug regulatory system and examines the evolution and impact of GDUFA on the
development and approval of generic drugs. Chapter 3 describes the research
methodology used for this study. Chapter 4 will eventually report the results of the study.
Chapter 5 then will discuss the results, the researcher’s opinions drawn from the study,
and recommendations for future study.
14
LITERATURE REVIEW
2.1 Evolution of Generic Drug Regulations
Drugs have been important to human health management for many centuries, but
only in the last century have laws been formalized in the US to regulate their safety and
efficacy. Many of these laws were passed in reaction to public health disasters. Their
laudable goal, to protect consumer safety, was typically accomplished by increasing the
rigor of regulations imposed on pharmaceutical companies wishing to market a new drug
(Rägo & Santoso, 2008). However, those regulations also changed market forces in the
pharmaceutical sector.
As early as 1938, the Federal Food, Drug, and Cosmetic Act, which defined the
term “drug” formally and mandated premarket review of new drug safety, also helped to
protect the new drugs from competition. By increasing the amount of information that
would have to be provided to governmental authorities through a premarketing
submission called a New Drug Application (NDA), only those companies that could meet
this requirement could legally market a drug. This legislation took from the market many
products that could not meet FDA’s bar (Hilts, 2003). At the same time, new drug
protections through patents on chemical composition and manufacturing methods and
trademarks on brand names further restricted the ability of competing manufacturers to
market the same chemical entities as “generic” drugs. Restrictions on the entry of
pharmaceutical products caused much concern to those who were disenfranchised by it.
Nonetheless, generic drugs marketed in the US in the 25-year period after the FD&C Act
15
was enacted were often placed on the market without interference even though they
lacked FDA approval. The assumption was made that the agency’s approval of a brand
name drug under an NDA was sufficient to qualify generic versions as safe, and thus
should not be encumbered by the provisions for “new” drugs (Meyer, 1999). That free
ride for generic drug makers effectively ended in 1962 when the Food and Drug
Administration revised the Federal Food, Drug, and Cosmetic Act by passing the 1962
Drug Efficacy Amendment (Public Law 87-781), commonly called the Kefauver-Harris
Amendment.
The Drug Efficacy Amendments had a complicated political history, initiated in
large part by dissatisfaction with the state of drug pricing that legislators and the public
believed to be escalating too rapidly (Rägo & Santoso, 2008). However, a major public
health tragedy related to the drug, thalidomide, provided an additional and decisive
driving force by highlighting the rather shallow regulatory requirements for branded and
generic drugs alike. That tragedy unfolded soon after the marketing approval of
thalidomide in Europe to treat the nausea of morning sickness in pregnant women.
Thousands of European women receiving the drug in the first trimester subsequently gave
birth to children with serious birth defects (Rägo & Santoso, 2008). Relatively few
American babies were affected because thalidomide had been held back by the regulatory
review process by a dissatisfied reviewer and therefore never approved for marketing in
the US (Hilts, 2003). However, many considered the US experience with thalidomide to
be a close call or near miss.
16
The cry for change pressured the US Congress to increase the regulatory
requirements and oversight for pharmaceutical companies wishing to market a new drug.
As a key part of that change, the Drug Efficacy Amendment added a requirement that
drug manufacturers demonstrate both the safety and effectiveness of their drugs, typically
by providing increased scientific evidence from clinical trials that would now be under
rigorous oversight. However, the Act went a step further. It mandated that drugs
approved for marketing between 1938 and 1962 be reviewed for efficacy by evaluating
the drug’s postmarketing history, published clinical studies and expert views (Tabor,
2008). This review, called the Drug Efficacy Study Implementation (DESI) process,
permitted any manufacturer to market a duplicate of a DESI-reviewed drug originally
approved before 1962 as long as it could be shown that drug would be bioavailable,
manufactured correctly and labeled adequately (Lachman, Turco, & O’Donnell, 1990).
This information was required to be submitted in an ‘abbreviated’ new drug application,
containing the manufacturing and bioavailability information only.
In a final and notable change, the 1962 Drug Amendment gave FDA new
authority to require that drug manufacturers submit an NDA when attempting to
introduce a generic version of any post-1962 approved drug. This change made it more
difficult for generic drug manufacturers to market their products. It required new generic
drugs to perform the same costly clinical trials that were required for a new pioneer drug,
even if the active ingredients of the generic drug were identical to those in a branded drug
that had already a strong history of safe use in the marketplace for several years. In
addition, generic companies were forced to wait for the patent of the branded drug to
17
expire before they could even begin the testing required to satisfy the regulatory
requirements (Singh, 2010).
The new requirements were burdensome for generic manufacturers and slowed
the introduction of new generics to a trickle. The diminished flow of generic drugs had a
corollary effect, to cause drug-price inflation (Greene & Podolsky, 2012). This
consequence was clearly in conflict with efforts of the US Congress at that time to
contain drug costs. It also hindered the use of generic products by federal health and
welfare programs such as Medicaid and Medicare (Hornecker, 2009). Aware that the
1962 legislation was preventing generic competition, FDA in 1978 modified its policies
to allow for a new market authorization process called a “paper NDA”. Under this new
pathway, generic versions of brand name drugs could submit publicly available scientific
literature of well controlled studies and other bridging data in order to demonstrate the
drug’s safety and efficacy, thus avoiding the need to conduct expensive clinical trials
(Mossinghoff, 1999). However, because at that time an adequate repository of published
literature documenting safety and efficacy was available for only a few drugs, the paper
NDA approach had limited utility (Mossinghoff, 1999). As a result, generic versions
were available for only about 35 % of drugs on the market in the early 1980s. Further,
generic prescriptions accounted for just 15% of prescribed drugs (Rumore, 2009).
The legislation and FDA regulations discussed so far contributed only marginally
to the development of a robust generics industry, but their restrictions can be credited
with creating an escalation of political pressure that would foster the eventual passage of
18
a new regulatory pathway for generic drugs. The Drug Price Competition and Patent
Term Restoration Act, commonly known as the Hatch-Waxman Amendments (Public
Law 98-417), (United States Congress, 1984) was signed into law on September 24
th

1984 by President Ronald Reagan in order to address the challenges of generic drug
availability, by balancing the needs of two competing constituencies, the innovative drug
and generic companies. Its challenging goal was to put into place a compromise that
could promote competition by encouraging the development of low-cost generics drugs
but at the same time encourage research by granting certain competitive benefits to
innovators that would compensate for their lost revenues (Boehm et al., 2013). A key
concession for the generics industry was a new option to avoid lengthy human trials. The
Hatch-Waxman Amendments “established an abbreviated new drug application (ANDA)
process, provided for filing of generic drug applications 60 days later, and so created the
modern US generic drug industry” (Boehm et al., 2013). In the new approach, companies
merely had to prove that the generic drug under consideration had the same active
ingredients and a pharmacokinetic profile bioequivalent to that of a previously approved
branded product, called the Reference Listed Drug (RLD) (usually a brand name drug,
but sometimes another generic product if the brand name product was withdrawn). These
new rules allowed applicants to avoid the expensive and extensive preclinical and clinical
studies that had been required when the brand holder first had to establish safety and
effectiveness of the previously approved drug that the generic applicant intended to copy.
The Hatch-Waxman Amendments greatly accelerated the growth of a vigorous
generic drug industry, because it reduced the time and cost associated with the market
19
introduction of a generic drug. Since its passage, many top-selling drugs have lost patent
exclusivity and have been genericized. Nevertheless, a list published by the FDA on
June 27, 2017, still featured more than 200 approved pioneer drug products which are
now off-patent and off-exclusivity, for which the FDA has not yet approved a single
ANDA referencing that NDA drug product. These drugs exist on the market without
generic competition.
2.2 The Generic Drug Approval Process
The Hatch-Waxman Amendments have not been without critics. One of the
stated goals of the Act– to expedite FDA approval for generic applications– has been
particularly problematic for both the FDA and the generic drug industry. Their criticisms
concerned not only the particular details of the regulatory requirements but also the
challenges of meeting those requirements in a timely way. Understanding these problems
depends first on understanding the detailed nature of the new law.
The Hatch-Waxman Amendments provided the authority for the FDA to modify
the abbreviated path for generic drugs. Drugs that are eligible for this path have been
defined in regulations for marketing registration.
An abbreviated application for a new drug shall contain (i)
information to show that the conditions of use prescribed,
recommended, or suggested in the labeling proposed for the new drug
have been previously approved for a listed drug; (ii) active ingredient
of the new drug is the same as that of the listed drug; (iii) route of
administration, the dosage form, and the strength of the new drug are
the same as those of the listed drug; (iv) the new drug is bioequivalent
to the listed drug; (v) the labeling proposed for the new drug is the
20
same as the labeling approved for the listed drug except for changes
required because of differences approved under a suitability petition or
because the new drug and the listed drug are produced or distributed
by different manufacturers (Public Law 98-417), (United States
Congress, 1984).

The sponsor of the generic product must develop information relevant to the equivalence
and quality of the product in a submission called an Abbreviated New Drug Application
(“ANDA”) that is filed with the FDA. That application must present a compelling
argument that the generic drug has the same attributes of performance, quality, and safety
as the brand name drug that it attempts to reproduce. The Office of Generic Drugs
(OGD), part of FDA’s Center for Drug Evaluation and Research (CDER), is responsible
to assure that the generic drug has the same route of administration, dosage form, and
strength. Because the core safety and efficacy data for the active chemical entity have
been documented in the NDA of the RLD, the testing of the generic drug is less complex.
The developer instead must only demonstrate comparability by showing that the
proposed generic product is pharmaceutically equivalent to the RLD- it contains the same
active drug ingredient, in the same dosage strength, using the same dosage form and route
of administration as the RLD. The generic product must meet compendial or other
applicable standards of strength, quality, purity, and identity. To demonstrate the
comparability with the RDL, the testing regimen is relatively modest, usually involving
only a bioequivalence (BE) study to show a match with the bioavailability profile of the
reference drug.
BE studies are designed to demonstrate that the RLD and generic drugs have
closely comparable bioavailability. The design of the bioequivalence trial may vary from
21
one product to another depending on the complexity of the formulation. However, for
most products, these studies are conducted in twenty to thirty-five healthy male and
female adult volunteers under standardized conditions. Most employ a 2-way crossover
design, in which certain pharmacokinetic parameters- typically area under the
concentration-time curve (AUC), the peak concentration (Cmax), and the time to peak
concentration (tmax)- are measured after administration of either the test drug or the
reference drug (Midha & McKay, 2009). According to 21CFR320.23 of the FDA
regulations, a drug would be considered to be bioequivalent to an RLD if:
the rate [Cmax] and extent [AUC] of absorption of the drug do not
show a significant difference from the rate and extent of absorption of
the listed drug when administered under similar conditions in either a
single dose or multiple doses
OR
the extent of absorption [AUC] of the drug does not show a significant
difference compared the listed drug when administered under similar
experimental conditions in either a single dose or multiple doses and
the difference from the listed drug in the rate of absorption [Cmax] of
the drug is intentional, is reflected in its proposed labeling, is not
essential to the attainment of effective body drug concentrations on
chronic use, and is considered medically insignificant for the drug.
Statistically, the geometric mean ratio of the test to the reference drug for AUC and Cmax
must fall within 90% confidence of the upper and lower control limits of 80 and 125% of
RLD activity (USFDA, 2001). For some products whose absorption could be affected by
the concurrent ingestion of food, fasting and food studies may be required. Also, for
different dosage forms and sustained-release products, additional testing and expansion
of sample size are required, as outlined by Midha and McKay (2009).
22
The FDA believes that therapeutically equivalent generic drugs can be substituted
for a reference product if they have the same active ingredients entering the body at the
same rate, and thus will produce the same clinical response (Mossinghoff, 1999). This
position was, for example, explained in an FDA response dated July 23, 2010, to the
citizen petition FDA-2003-P-0273 (USFDA, 2010) submitted on behalf of Aventis
requesting that FDA withhold approval of any abbreviated new drug ANDA for a generic
version of Lovenox (enoxaparin sodium injection):
…the scientific premise underlying the Hatch-Waxman Amendments is
that when certain aspects of the drug products (e.g., active ingredient
(s), strength, dosage form, route of administration) are the same, the
products may be substituted for each other.

Within 60 days after receiving an ANDA application, FDA will decide whether
the application is sufficiently complete to permit a substantive review. At that time, it
will be classified according to whether or not it is eligible for priority review. FDA will
expedite the review of generic drug applications identified as eligible for expedited
review as outlined in CDER’s Manual of Policy and Procedures (MAPP) 5240.3, entitled
“Prioritization of the Review of Original ANDAs, Amendments, and Supplements”
(USFDA, 2017b). This category includes drugs for which fewer than three ANDAs have
been approved for the RDL provided there are no blocking patents. The FDA also
prioritizes ANDAs related to drug shortages, public health emergencies, or special review
programs, such as the President’s Emergency Plan for AIDS relief. Drugs in the
expedited category have a nominal review time of eight months. Drugs that do not fall
into the expedited category have a longer “standard” review time. In the past the review
23
time has taken more than a year and in some cases more than three years. FDA has
committed to making a determination about the approvability of an ANDA within 10
months of receiving the application under current GDUFA regulations. During the review
process FDA communicates with sponsors as they have questions and needs for further
information. This communication allows the company to gauge the agency’s progress
with the ANDA review and can give insight into the agency’s decision-making process.
One aspect of submissions through either the ANDA or 505(b)(2) route is the
need to provide the FDA with information about the way in which the submitting
company plans to assure its freedom to operate under patent rules that normally will
protect a new drug for some part of its lifetime. The relevant patents, which may cover
the molecule, its intended uses, and its production methods, are listed for the RLD in the
“Approved Drug Products with Therapeutic Equivalent Evaluations”, the publication
commonly known as the Orange Book that is updated monthly. Applications for a
generic version of an RLD, therefore, must contain one of the following four possible
certifications with respect to each listed patent as shown in Table 1.
24
Table 1: Patent Certification Classification
Patent Certification
Clauses
Regulation
Paragraph I The patent information relating to the innovator drug has
not been filed. FDA can approve ANDA once approval
requirements are met.
Paragraph II The patent has expired. FDA can approve ANDA once
approval requirements are met.
Paragraph III The patent will expire on a particular date and that the
generic drug will not go on the market until the patent
expires. FDA can approve ANDA when patent expires and
approval requirements are met.
Paragraph IV The patent is invalid or will not be infringed by the
manufacture, use, or sale of the drug for which approval is
being sought. Complex approval landscape. Patent holder
can sue when it receives notice. If NDA sponsor sues
within 45 days of notice, ANDA approval is stayed for 30
months. No lawsuit within 45 days of receipt of notice,
FDA can approve ANDA when ready

With increasing frequency, generic drug companies have been able to challenge the
exclusivity of patent-protected drugs even before their patents expire. Perhaps the most
contentious provision of the Hatch-Waxman Amendments is that defining the terms of
Paragraph IV (P-IV) patent certification or challenge. This provision allows generic
manufacturers to enter the market before a patent on an RLD expires by claiming non-
infringement or because the RLD’s patent is invalid. The law obligates the generic drug
company filing the ANDA containing a Paragraph IV certification to notify the patent
owner and NDA holder and to detail the legal and factual bases of the patent challenge
once the application has been formally accepted for filing and review. An often
25
predictable set of legal interactions then ensue. After the NDA holder receives that
paragraph IV notification, it has 45 days to file a patent infringement lawsuit against the
ANDA sponsor. Only if such a lawsuit is not filed can FDA proceed to review the drug.
If that review results in an approval, the generic version of the branded drug can be
marketed as soon as the approval has been granted (Jacobo-Rubio, Turner, & Williams,
2016). It is however typical that the brand-name firm will respond to the generic
company’s challenge with a suit claiming patent infringement (Grabowski et al., 2011;
Higgins & Graham, 2009). In such a case, the action automatically triggers a 30-month
stay on FDA actions with respect to the submitted ANDA. FDA can then only proceed
with its review of the ANDA after a successful first court ruling.
The outcome of the legal challenge before the court has significant economic
consequences for both the RLD and generics company. If the court rules in favor of the
NDA holder, the Para-IV certification fails and the FDA is unable to authorize generic
entry until the RLD’s period of market exclusivity ends. If, however, the court rules in
favor of the generic manufacturer, the FDA is released from its stay and can begin its
review.
The Hatch-Waxman Amendments attempted to entice generics manufacturers to seek
early market entry through patent challenges in another way, by adding additional
incentives. It guaranteed that the first generics manufacturer to win a patent challenge
would be given a market exclusivity of 180 days. During this time, the first challenger
would be the sole generic provider, thus occupying the position of a duopoly with the
26
original branded provider. As competition in the generics market has intensified, generics
manufacturers have become increasingly emboldened to seek opportunities for 180-day
exclusivity by challenging weak patents because of the significant profits that they can
promise. Because successful Paragraph IV challenges can significantly decrease the
effective patent life of a branded drug, early market access to the much cheaper generic
can force the RLD to reduce its price significantly and to sacrifice its monopolistic
market position.
2.2.1 Gaining approvals for drugs that do not meet the generic definition
Not all products that have the same active ingredient can use the generic pathway
for approval. If the proposed generic drug differs from the RLD in its route of
administration, dosage form, strength, or active ingredient, different options must be
explored. One option is to seek permission to market that new form of product by
arguing its suitability to the FDA by way of a “suitability petition” as described in 21
CFR 314.93. An ANDA suitability petition is a request for the FDA to make a
determination that a proposed change to an RLD does not raise any additional questions
of safety or efficacy and for permission to file an ANDA for a drug that differs from the
RLD with respect to that specific change. The use of a petition route is typically not
favored because it confers no specific competitive benefit to the company that files the
petition. Once a suitability petition is approved, any other drug developer can use the
approval to file for a generic form of that changed product (Karst, 2014).
27
An alternative regulatory option introduced by the Hatch-Waxman Amendments
is the use of a novel pathway, often called the “505(b)(2)” pathway, that was designed to
reduce the submission requirements for a drug product that differs from the RLD in its
route of administration, dosage form, or strength. The 505(b)(2) provision of the Act
permits an applicant to rely for approval on studies that the applicant did not conduct and
to which the applicant does not have a right of reference. An applicant may rely on such
studies either by submitting published literature that describes the study results of others
or by referencing the findings of safety and effectiveness that the FDA made for a
previously approved listed drug. For both the suitability petition and 505(b)(2) pathways,
the applicant must provide scientifically sound information demonstrating that the
differences to the RLD do not affect the safety or efficacy of the proposed drug product.
505(b)(2) applicants must also certify to relevant patents, which may cover the molecule,
its intended uses and/or its production methods.
2.3 Inefficiencies in the generic drug regulatory process
The original goal of the Hatch-Waxman Amendments was to accelerate the
patients’ access to affordable generic drugs of good quality. Yet impediments soon arose
that had the end-effect of reducing the speed with which these lower-priced generic drugs
could be marketed. These impediments had two primary forms: 1) evolving strategies by
brand-name companies to forestall competition, and 2) regulatory delays in generic drug
approval review.
28
2.3.1 Competitive Strategies of Brandholders
It is obvious why companies producing branded pharmaceuticals would not
welcome the changes made by the Hatch-Waxman Amendments. However, that Act
conferred onto the brandholder a powerful weapon that could help it to protect a new
molecule by using both patent and marketing exclusivities.
2.3.1.1 Patent Exclusivities:
Patent exclusivity has been the foundation by which investments in expensive
drug development programs can be justified. When the United States Patent and
Trademark Office (USPTO) approve patents submitted by brand holders, it normally
restricts competitive entry by generic drug makers. Issued patents can cover the active
ingredient (s), the product formulation and the indication or method of use of the branded
product. Nominally, patents are valid for a period of 20 years from the date on which the
patent application is filed (Grabowski et al., 2011). However, this 20-year period of
patent exclusivity is eroded by the long periods of clinical testing and regulatory review
required before the product can be commercialized. To encourage the development of
innovative drugs, the Hatch-Waxman Amendments offered pioneer companies the
opportunity to lengthen the active life of its drug patents by giving compensatory
extensions that essentially “gave back” some of the time expended in late-stage
development and review (Grabowski, 2007). The brand holder could request to receive a
one-year extension of its patent for every two years spent in the clinical testing phase
conducted under INDs, plus the full time required for regulatory review. However, limits
29
were placed on the total length of the extension to a period not exceeding five years.
Further, the residual patent life after the NDA has been approved could not exceed
fourteen years. The patent term could also be extended by another six months if the brand
name company performed tests to evaluate the drug’s pediatric health benefits. These
pediatric exclusivity provisions were born from the Best Pharmaceuticals for Children
Act (BCPA) (Public Law 107-109) (United States Congress, 2002) enacted on January 4,
2002, to incentivize industry to conduct pediatric studies of drugs.
2.3.1.2 Marketing Exclusivities:
In addition to patent protection, the Hatch-Waxman Amendments provides for
statutory periods of data and marketing exclusivity under certain conditions. One of the
most important of these exclusivities is the five-year period of regulatory protection
known as “New Chemical Exclusivity” (NCE) (21 CFR 314.108. This exclusivity can be
exercised regardless of the status of the underlying patent(s) but runs concurrently with
patent protection. Under this exclusivity, FDA cannot accept for review any generic drug
or 505B2 application for the same “new chemical” for five years from date of NDA
approval if the application does not contain a paragraph IV certification to a listed patent,
or four years if the application contains a paragraph IV certification to a listed patent
(USFDA, 2017a). A sponsor may also qualify for a three-year period of exclusivity for
an NDA application or supplement if such application contains reports of new clinical
studies conducted or sponsored by the sponsor and that was essential to approval of the
application or supplement. This can allow brand name companies to institutionalize
30
defensive strategies to combat generic intrusions into their market sector, described in
detail below.
2.3.1.3 Use of Patent “Stays”
Perhaps one of the most common strategies adopted by brandholders even before
the new generic incentives were introduced was the use of “evergreening” to extend the
period of brand protection by repeatedly filing new patent applications. Often the
brandholder would file a new patent claim to protect even insignificant changes, such as
manufacturing processes without impact on the therapeutic equivalence of the proposed
generic drug or reformulations that offered little or no therapeutic advantage, just prior to
the end of the life of already-listed patents (Noah, 2015). This would effectively “stay”
the entry of the generic product. If the generic company were to attempt a patent
challenge, the brandholder could then file a lawsuit against the generic company to
prevent it from violating these late listed patents, and thereby trigger an additional 30-
month stay on the approval of the generic drug (Jones et al., 2016; Rumore, 2009). By
using such a strategy repeatedly, the brandholder could obtain multiple 30-month “stays”
to keep generic competition at bay. This common practice eventually led to some
measure of legislative change to control evergreening, described in 2.3.2, below.
2.3.1.4 Authorized Generic Licensures
Another non-competitive tactic used by brandholder companies has been the
negotiation of “authorized” generic licensures. The brandholder does not want to lose its
exclusivity to the generic competitor that has successfully challenged its patent and thus
31
gained market approval. Its product then would become an “authorized generic” (AG),
i.e., a listed drug approved by the FDA as a brand-name drug, but marketed by a licensed
third party or the brandholder itself as the generic drug of record. Typically such a
product is marketed under the brandholder’ s initial NDA through a subsidiary, but as a
generic drug at generic prices with different labeling, packaging, NDC code, trade name,
and/or trademark (Fasanella & Pope, 2011). The underlying concern with an authorized
generics is that by competing with the generic drug that was entitled to a period of market
exclusivity, it undermines the anticipated financial benefits of the 180-day exclusivity
granted to the generic drugmaker for successfully challenging the innovator’s patent
(Oner & Polli, 2018). It also undercuts the expected drop in drug prices that the 180-day
exclusivity period was intended to provide (Oner & Polli, 2018; Berndt et al., 2007).
Authorized generic licensures can also reduce the incentives for the generic drug maker
to challenge the brand holder’s patent. The Federal Trade Commission (FTC) estimates
that the introduction of an authorized generic reduces the revenue for a first generic filer
on average by 40% to 52% during the 180 day exclusivity period, and by 53% to 62% in
the 30 months following that period (FTC, 2011). The reduction may be sufficiently
large that a generics company may find that a challenge to a patent is not worth pursuing,
especially considering the costly legal fees that the generic drug maker would have to
pay to defend against claims of patent infringement (Berndt et al., 2007).
Interestingly, Morgan Stanley noted that the effect on the generic segment of the
market when an authorized generic is introduced during the 180-day exclusivity is
estimated at fifty percent discount on the innovator’s price, compared to the thirty percent
32
discount with just one generic firm (Goodman, Nachman, & Chen, 2004). However, it
was not clear whether this observation, made more than a decade ago, still holds true for
more recent authorized generics. More recently, in 2011, the FTC analyzed the impact of
authorized generics on competition in the prescription drug marketplace. It reported that
generic drug prices were lowered by as much as 14 % when an authorized generic was
introduced during the 180-day exclusivity than it would have been if no authorized
generic were to compete with the brandholder (FTC, 2011). The FTC report also found
that authorized generics have a substantial negative effect on the revenues of competing
generic firms. The conclusion from the FTC report is that consumers benefit in the short
run from lower prices when an authorized generic is introduced during the 180-day
exclusivity, and the brandholder enjoys the continued profits from the additional revenue
stream; only the first ANDA filer loses out.
Attempts made by generic drug companies through either legal challenges or via
citizen petitions to prohibit the marketing of AGs during the 180-day exclusivity period
have been unsuccessful. Citizen petitions requesting that the FDA stop the practice of
authorized generics, filed by the two large generic drug manufacturers, Mylan and Teva
Pharmaceuticals, on February 17, 2004, and June 9, 2004 respectively, were both denied
by the FDA. The arguments and requests were different in these two petitions. Mylan
urged the FDA to treat authorized generics as any other generic drug- to prohibit the
marketing of a brandholder’ s generic until the first ANDA applicant that filed a
paragraph IV ANDA had fully exercised its 180-day period of exclusivity. Teva asked
the FDA to require that a brandholder submit and receive approval for a prior approval
33
supplemental new drug application before it could market or distribute its authorized
generic (Porter, 2005; Docket Nos. 2004P-0075/CP1 & 2004P-0261/CP1). A prior
approval supplement represents a more stringent pathway to market because it must
justify the introduction and then wait for six months for the FDA to approve that
supplement.
In denying both citizen petitions on July 2, 2004, the FDA stated in response to
Mylan’s request that
…under the Hatch-Waxman Amendments, it only has the authority to
regulate issues of public health, and that it does not regulate drug
prices and had no legal basis on which to prevent an innovator
company from marketing its approved NDA product at a price that is
competitive with that charged by a first generic applicant to the market.
Regarding Teva’s request, the FDA explained that the changes such as labeling
changes to add a distributor’s name required to market an authorized generic were
considered minor and that the FD&C Act allowed applicants to notify the FDA in their
annual reports of such minor changes (Docket Nos. 2004P-0075/CP1 & 2004P-
0261/CP1). Likewise, the U.S. District and Appeal Courts have sided with brand
manufacturers by asserting that the current statutes do not restrict the marketing of an AG
(Fasanella & Pope, 2011).
2.3.1.5 Pay-for-delay settlement agreements
A non-competitive tactic used by brandholder companies with the complicity of
generic drug companies has been negotiations in which patent challenges ended with
settlement agreements between the parties into Paragraph IV litigation (Toll, 2015). It is
34
clearly not in the best interest of the brandholder to lose its exclusivity to the singular
generic competitor that successfully gains market approval by successfully challenging
its patent. Equally, it can be expensive for a generic company to pay litigation costs
associated with a patent infringement suit, and manufacture and launch its new drug.
Thus, the generic company is often easily convinced to delay its market entry under its
own name if it receives money from the brandholder to compensate for the lost
opportunity that the ANDA exclusivity could provide (Toll, 2015). This arrangement
satisfies the economic interests of both the brandholder and generics company. The
brandholder does not want to lose its exclusivity to the generic competitor that is
challenging its patent to gain market approval. The generics company does not want to
expend a large amount of money for the costly legal fees that it would have to pay to
defend against claims of patent infringement if it can be compensated for the lost
earnings that the ANDA exclusivity would otherwise provide (Berndt et al., 2007). The
net effect is that generic drug makers are coerced into entering pay-for-delay settlements,
also known as reverse payments that often include “disguised” cash payments and other
side deals on the condition that the generic company delays its product entry. In some
settlements, brandholders have promised to retard the introduction of an authorized
generic (discussed in 2.3.1.4) that would compete with a true generic product. Since the
first reverse payment settlement was concluded in 1993 between Zeneca and Barr,
involving the cancer drug tamoxifen, the problematic practice has become common
phenomenon in the pharmaceutical sector (Holman, 2006; Hemphill, 2007). Such
arrangements are troubling for legislators and payers because they undermine the
35
expected drop in drug prices that the introduction of a generic was intended to provide.
This has compelled FTC to scrutinize these agreements and put serious efforts throughout
the years to attack them as violating the antitrust rules before different courts. However,
the issue remains unsettled thus far, with conflicting decisions from different Federal
Courts. Similarly, attempts by generic drug companies not directly benefiting from pay-
for-delay settlements either through legal challenges or via citizen petitions to prohibit
this have been unsuccessful (Toll, 2015). This has resulted in calls for the US Congress to
modify or eliminate the 180-day exclusivity period as a means of removing incentives
that give rise to the pay-for-delay settlement problem in the first place. However,
legislation options to address the pay-for-delay problem have so far fallen short of
enactment.
2.3.1.6 Exploitation of REMS program restrictions
A more recent creative tactic used by brandholders to counter generic competition
is by exploiting the FDA-mandated Risk Evaluation and Mitigation Strategies (REMS)
program. At first glance, REMS programs seem to have little to do with the competition
between branded and generic drugs. These programs were put in place to address
concerns that some drugs had benefit/risk profiles that could be improved if special
measures were taken to educate the consumers and healthcare practitioners about risks
that could be mitigated through educational initiatives. The Food and Drug
Administration Amendments Act (FDAAA) of 2007 required drug manufacturers to
submit and implement a formalized REMS program to safeguard the distribution of drugs
in such a category. FDA proposed a tiered approach to REMS whose degree of rigor
36
depended on the level of risk. The risk management plan might be as simple as
providing patients with a medication guide, or as complicated as developing a
demanding educational and certification program collectively called “Elements to
Assure Safe Use” (ETASU). This may involve special training for healthcare
professionals, certification of facilities providing the drug, and assessments of the
success of the REMS through such activities as surveys and analysis of drug
distribution patterns. The details of this program have been reviewed in detail
elsewhere (section 2.3.2). What is important for this discussion are the downstream
effects of implementing a REMS program because the program can be used to interfere
with generic entry.
Initially, the introduction of a risk mitigation program was applauded by many in
the medical world as an important tool to ensure that the benefits of a given medication
could outweigh associated serious but manageable risk. The REMS program has been
credited as sufficiently tilting the benefit-risk relationship for a number of now-approved
products that otherwise might not have been considered to be approvable. In many cases
the restrictions on product distribution prevented the distribution of the drugs to
individuals who were not on special registries or who had not passed certain clinical tests,
to keep the drug from patients for whom the product would not be safe or useful (Butler,
2016). However, this ability to restrict drug distribution was soon recognized by
brandholders as a valuable way to reduce generic competition; it could be used to prevent
a potential ANDA competitor from gaining access to samples of the RLD drug. Because
these samples are essential for mandatory bioequivalence studies, brand holders could
37
impede generic competition by blocking the development of test data needed for an
ANDA submission. Brand holders have typically justified their refusal to sell samples by
citing safety concerns, particularly that generic firms may not ensure the safe use of these
drugs, and that the brand holder could be held liable.
Generic drug companies have reported that some brandholders are using in a
different way to reduce generic entry. It is a statutory requirement that generic
companies, as well as the brandholder, participate in a shared REMS program if they are
to be on the market together. A single, shared system between the brandholder and its
generics competitor is required as an ETASU element for certain REMS, with the
purpose of the single, shared system being to reduce burden for stakeholders through the
use of a single portal to access REMS materials and other documentation. As of March 2,
2019, FDA’s database listed 58 approved REMS, fourteen of which must participate in
shared REMS systems (USFDA, 2019). However, for these eight drugs, brandholders can
effectively retard the marketing of generic drugs by delaying negotiation of the single
shared system with the competing generic firm(s). Brandholders defended the slow pace
of negotiations by claiming that negotiations over a single, shared system are complicated
and take time.
The extent to which REMS is serving as an anticompetitive tool is not well
understood nor is it clear whether this tool will persist in the future. The rules for REMS
could be modified in future in a way that could increase or decrease the usefulness of this
tool. The relevance of REMS programs in addressing and preventing drug-related safety
38
risks has been a subject of recent debate. Concerns have been raised regarding the
potential benefit, limitations, consequences, and burden to both patients and the health
care system associated with its implementation (Boudes, 2017). A 2013 report by the
Inspector General of the Department of Health and Human Services concluded, following
an extensive evaluation of REMSs launched between 2007 and 2011, that FDA lacked
data to determine whether the REMS program overall was improving drug safety.
Proponents of the program, including brandholder companies, argue that REMS
programs provide necessary drug safety precautions to protect patients and other
individuals who come into contact with higher-risk drugs. However, other stakeholders,
including many healthcare professionals, argue that the system is onerous and
cumbersome as currently configured, and may need reform (Bragg & Florence, 2010).
And reform may have also to address the program’s anticompetitive effects.
2.3.2 Regulatory Responses to Brandholder Tactics
To counter the hurdles placed in the approval path of generic drugs, generic
manufacturers needed assistance in the form of legislative, regulatory and judiciary
actions. Perhaps the first legislative response was that to mitigate the tactics of
“stacking” 30-month patent stays. An event that helped to trigger action on the part of
Congress was associated with Bristol-Myers. In this case, new patents for three of
Bristol-Myers products, BuSpar, Taxol, and Platinol, were listed in the Orange Book after
an ANDA was submitted for a competing generic version of those drugs. The way that
these new patents blocked generic entry was contested by the FTC in an antitrust lawsuit
that resulted in a settlement in 2003. However, the case served as a driver for the US
39
Congress to close the multiple 30-day stay loophole that was being used by innovative
drug companies to protect market exclusivity. The Medicare Prescription Drug,
Improvement, and Modernization Act (Public Law 108-173) (United States Congress,
2003) signed by President Bush on December 8, 2003 and often simply called by its
acronym MMA, limited the ability of innovative drug manufacturers to secure multiple
30- month stays on the same drug. Under the MMA it is no longer possible for an NDA
holder to obtain a 30-month stay of approval of an ANDA or 505(b)(2) based on later
listed patents, that is, those patents submitted to FDA on or after the date the ANDA or
505(b)(2) application was submitted. This effectively precludes multiple 30-month stays
for ANDAs and 505(b)(2) applications with paragraph IV certifications. Although late
listed patents cannot give rise to a 30-month stay, ANDA or 505(b)(2) filers are still
obligated to file a certification to the patent and must provide notice of a Paragraph IV
certification to the patent owner or NDA holder within 20 days of filing the paragraph IV
certification. However, multiple 30-month stays are still applicable in certain specific
cases. For example, it would not apply if a paragraph IV certified ANDA or 505(b)(2)
application, already subject to a 30-month stay resulting from litigation, also contains a
paragraph III certification to a different patent if the applicant subsequently converts this
paragraph III certification to a paragraph IV certification (see Table 1 for the
classification of patent certification).
MMA did not, however, address the issue of authorized generics as blocking
mechanisms. The FDA and courts are therefore still ill-equipped to stop the licensure of
authorized generics. Many generics manufacturers have therefore resorted to entering
40
into pay-for-delay or other settlements delaying the introduction of their generic product
to the market in return for the brand manufacturer’s agreement not to launch an AG
during the 180-day exclusivity period (Bokhari, Mariuzzo, & Polanski, 2016).
The third opportunity to delay the entry of some generics, that of using REMS to
limit drug availability for bioequivalence studies, has been under more scrutiny by FDA
with some effort to mitigate the negative effects of such restrictions. In 2014, the FDA
issued draft guidance titled “How to Obtain a Letter from FDA Stating that
Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable
REMS for RLD”. This guidance described a process for generic companies to request
samples for brand name drug products under a restricted REMS program. In this process,
FDA would provide a safety determination letter addressed to the RLD sponsor stating
that the BE study protocols of the ANDA applicant contain safety protections comparable
to applicable restrictions in the REMS for RLD. Thus, FDA will not consider it a
violation of the REMS if the RLD sponsor were to provide the ANDA applicant with
sufficient product to enable the necessary bioequivalence testing. However, as noted by
Nick Tantillo at the 2015 GPhA Fall Technical conference, such a letter places the
brandholder under no obligation to provide the sample in a timely manner or at all. A
number of lawsuits have been launched between generic drug makers, brandholders and
the FTC, but no definitive court opinion on the legal requirements to supply drug samples
to generics companies has been established yet. Similarly, legislative attempts to force
brandholders to provide samples for bioequivalence tests have so far failed. Thus, a
41
brandholder cannot be forced legally to supply samples to an ANDA applicant (Reichertz
& Ross, 2015).
2.3.3 Delayed Regulatory Reviews
Not all of the delays in generic product entry can be blamed on tactics ascribed to
the brandholder. Concerns have been expressed about the ability of the regulatory system
to assure efficient market approval of deserving generic drugs. US generic drug
manufacturers have faced a number of challenges related to the lack of consistency,
predictability, and transparency of ANDA reviews over the last decade (Dureja, 2010).
Chief among these areas of concern have been the unpredictable and lengthening
approval times for ANDAs (CMR, 2001) since the passage of the Hatch-Waxman
Amendments. In 1988, four years after the new law was introduced, the median review
time for an ANDA was 11.5 months. By 2012 it was 30 months with an average of three
to four review cycles before approval (Figure 1and Figure 2). In comparison, new drug
applications (NDAs) have had a median approval time of 10 months for more than a
decade now, more than 60% of which were approved after their first cycle of review
(USFDA, 2017d). The slowed review times were not just seen to be problematic because
they delayed patient access to less expensive medications. They also complicated the
already complex task of launching a generic drug, because effective planning for product
launch depends on knowing when the product can be reasonably expected to gain market
approval (Anderson, 2004; Rawson, 2000).
42
Figure 1: Median approval time of generic drugs in the US (2000-2017)

Source: From “Janet Woodcock, M.D. Testimony to the House Committee on Oversight and Government
Reform, February 4, 2016”. https://www.fda.gov/NewsEvents/Testimony/ucm485057.htm. In the
public domain and GDUFA Performance Reports FY2016a, FY2017c, and FY2018
18.9
18.4 18.4
17.3
16.3 16.3316.49
18.83
21.65
25.02
27.85
29.52
31.75
36
42 42
39.42
37.26
0
5
10
15
20
25
30
35
40
45
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
MONTHS
FISCAL YEAR
43
Figure 2: Review cycles for ANDAs 2009 through July 2014

Source: From “Janet Woodcock, M.D. Testimony to the House Committee on Oversight and Government
Reform, February 4, 2016”. https://www.fda.gov/NewsEvents/Testimony/ucm485057.htm. In the
public domain

At least two reasons have been suggested to explain the lengthening review times.
The FDA has suggested that longer review times are often required when the quality of
the submissions is poor. Deficiencies that require clarification slow down the application
review process and this may be a contributing factor to the low first-cycle approval rate
for ANDAs (McAuslane & Cone, 2006). The repeated interaction between FDA and
ANDA sponsors to clarify the content of submissions or to seek additional information is
often advanced by FDA as the main leading cause of long approval delays. To some
extent, the Agency has statistical evidence to support their assertions. At the 2016 Fall
Technical conference in Bethesda, MD, Johnny Young, Acting Director, Division of
Filing Review, Office of Generic Drugs at FDA, explained that 23.6% and 23.3% of
44
original ANDAs submitted in 2015 and 2016 respectively were issued a “refuse-to-
receive” action, meaning that they were rejected even before they were assigned a
reviewer. This designation is given when ANDAs have such major flaws or insufficient
content that a substantive review is not possible. The quality of a submission is not just
restricted to clarity of submitted documentation but to the scientific content related to the
drug product under review. Drug products whose development has been of high quality
have a superior basis from which to construct a high-quality submission (Walker, Cone,
& Collins, 2005).
The poor quality of submissions is not surprising for many who understand the
business model of some generics companies. In an industry where competition is fierce,
rushing to file an ANDA as quickly as possible is a high-stakes strategic move. The need
to file first in order to secure the exclusivity offered by the “180-day rule” adds further
pressure. When successful, the challenge will remove that patent as a barrier to generic
approval and provide market exclusivity as described earlier. The hypercompetitive
dynamics and strong financial incentives push bounty-hunting generic companies to file
ANDAs prematurely. Such an approach has predictable negative consequences. Even if a
rushed ANDA submission is accepted for review, that submission may be delayed as
poorly gathered or missing information must be queried subsequently by the reviewer. A
regulatory assessment of good quality cannot be expected from a submission that is
poorly presented, has discrepancies from one section to another, lacks sufficient relevant
data and fails to follow current guidance document(s) or recognized standards.
45
But is industry alone to be blamed for the slow rate of regulatory reviews? Some
responsibility for the lengthening review and approval times has also been assigned to the
regulators who control the distribution of resources that can dictate both the quality and
availability of reviewers for ANDA applications. Two concerns have been repeatedly
voiced that can impact the effectiveness of the review process. First is the concern about
the amount and quality of communication from the Agency. The importance of
communication and transparency has been identified by leaders from both industry and
FDA. Former FDA Commissioner Margaret A. Hamburg, testifying to the US House of
Representative Subcommittee on Energy and Commerce on February 9, 2012, noted that
…transparency means improving the FDA’s communications and
feedback with industry to expedite product access and enhance FDA’s
ability to protect Americans in our complex global supply environment.

According to Prasad and Pooja (2016), communication becomes even more
important when developing complex generics, where the multiple uncertainties and near-
total absence of FDA guidance make it essential to have meaningful and timely
interactions and advice from regulators. Without such guidance, ANDA applicants must
use their best judgment to develop a sound scientific approach. This can result in wrong
decisions. At the same time, the guidance that has been introduced has created problems
for applications caught in the very long review backlog at FDA, because those guidances
can “move the goalposts”. Even an application considered to be of high quality because
it complied with Agency thinking at the time of submission might later be found deficient
because it no longer complied with new guidance issued post-submission. Further,
46
applicants are quite commonly blindsided by new requirements that are still unspecified
in current guidance documents that become known only when FDA reviewers
communicate a deficiency. The queued applications then may be considered inadequate,
with the result of more review cycles and longer review times.
Why would the applicant not retrieve and update its application when new
guidance appears to add elements that are not contained in a submitted dossier?
Applicants are wary to jeopardize their application’s place in line even in instances when
they are aware of new expectations because the Agency discourages unsolicited
amendments while an application is under review. Industry advocates contend that
opaque and changing regulatory expectations can force applicants to perform or refine
development studies retroactively to comply with new or revised requirements. They
argue that applicants might submit better applications if clearer requirements were
communicated well in advance to all industry participants.
Another frequently cited obstacle to efficient regulatory review is a lack of
consistency in the ways that reviewers interpret and provide feedback regarding some
regulatory guidelines. In an efficient system, regulatory decisions should yield the same
outcome for the same issue each time (Breunig & Menezes, 2012). Instead, ANDAs are
frequently reviewed by reviewers who have different standards and expectations (GPhA,
2014). For example, companies with multiple, similar products or different applications
for the same product report that individual reviewers have asked different questions about
portions of the application or have requested that additional data be provided in different
47
ways (GPhA, 2014). Predictability would improve if regulatory decisions were clearer
and more consistent unless evidence was to exist that specific past decisions have led to
significant problems (Breunig & Menezes, 2012).
Regulatory inconsistency has not only been attributed to the review processes and
reviewer approaches at the FDA. Many generic drug makers also interpret FDA
regulations in an inconsistent way. The generic industry generally blames those
inconsistencies on regulatory language that they identify to be ambiguous, overly narrow
or overly too broad. Further, conflicting recommendations on the same topic may be
present in different guidance documents because the guidance documents were not
coordinated before issuance. When a regulation is unclear, its interpretation could vary
from one user to another. Additionally, without specific written guidance, companies
must rely on a controlled correspondence process put in place by the Agency to address
specific questions not covered in the guidance documents. This problem is particularly
acute for complex products because little guidance has been issued for these products, so
industry applicants have no way to know about some types of Agency expectations as
they develop their applications (Srinivasan, 2015).
2.4 Generic Drug User Fee Amendments (GDUFA)
The slow ANDA review processes have protected market monopolies for
expensive branded products at a time when the government has been trying to contain
the costs of drugs. They recently led Congress to consider the introduction of user fees
to defray some of the costs of expanded review capabilities at the FDA. The potential
48
application of user fees was not a new concept for the US regulatory system. As early as
the 1950s, the implementation of user fees was contemplated in many federal agencies,
including FDA (Woodcock & Junod, 2012). The US General Accounting Office (GAO)
report in 1971 floated the idea of supplementing FDA’s appropriated funds with user
fees (Shulman & Kaitin, 1996), but the idea garnered little support because FDA and the
Department of Health believed that FDA did not have the authority to charge user fees
(Zelenay, 2005). Ten years later, the Office of Management and Budget (OMB) urged
the implementation of user fees to resolve the disparity between the FDA resources and
the growing demand from a rapidly increasing number and complexity of NDAs
(Zelenay, 2005). However, the FDA remained opposed, arguing that a fee for services
was not a good idea for several reasons. First, FDA was concerned about the public
perception that FDA approvals would be influenced by a financial relationship with the
pharmaceutical industry. Further, concerns were expressed that user fees would prove a
disproportionate burden for small businesses and that the costs of the fees would
ultimately contribute to higher drug prices borne by consumers Shulman & Kaitin, 1996;
Zelenay, 2005). Opposition at the time also came from pharmaceutical trade associations
and lobby groups, especially the Pharmaceutical Research and Manufacturers of
America (PhRMA). Members of PhARMA were concerned that user fees would be
used to substitute for governmental funding through appropriations rather than
supplement review divisions with additional resources; the fees would then fail to
decrease FDA review times (Shulman & Kaitin, 1996; Zelenay, 2005).
49
The arguments against user fees became less persuasive as review times for
NDAs increased from about seven months in 1962, to thirty months by 1967, and over
thirty-two months by the early 1980s. These delays worried both the public and the
pharmaceutical industry. They argued that regulatory agencies elsewhere, and most
notably in Europe, were approving drugs more quickly (Zelenay, 2005). Many grumbled
that FDA’s “drug lag” was unethical, in that it deprived potentially effective treatments of
needy patients. The opposition of the pharmaceutical industry diminished in 1992 with
guarantees that the proposed user fee would not be used to alleviate the federal deficit but
would be dedicated to improving FDA’s review capabilities (Zelenay, 2005). Further,
industry was encouraged that the user fees would be tied to regulatory performance goals;
fees would sunset if FDA performance were to falter. This ultimately prompted
legislative action, in the form of the Prescription Drug User Fee Act (PDUFA) that was
signed into law by President Bush in the last quarter of 1992 (Shulman & Kaitin, 1996).
As the effectiveness of user fees for new pharmaceuticals became apparent, the
US Congress and FDA started to consider whether a system of user fees might assist
other FDA review divisions, including that for generic drugs. The generic drug makers
vigorously opposed the establishment of generic drug user fees for many years. They
expressed concern that fees for generic drug activities would create hardships and
discourage companies, especially small companies, from filing ANDAs. They further
argued that generic drugs had been responsible for remarkable reductions in health care
costs so that any benefits which might conceivably accrue to the generic industry would
be in the form of more general public health benefits rather than specific benefits to their
50
individual businesses (Boehm et al., 2013). But as review times and backlogs of
unapproved ANDAs grew (Figure 3), frustration rose in consumer and industry sectors.
The public and its representatives in Congress decried the delayed access to affordable
generic versions of life-saving drugs (Boehm et al., 2013). Further, generic drug makers
began to recognize the severity of financial loss that could be attributed directly to the
slow pace of approvals. Thus, Congress and the generic drug industry were forced to
reconsider their historic resistance to user fees so that the Office of Generic Drugs could
clear the submission backlog by increasing its staffing and regulatory infrastructure.
Hence the Generic Drug User Fee Amendments (GDUFA), (Public Law 112-144, Title
III) were signed by President Obama in 2012 as part of the FDASIA legislation. GDUFA
called for the implementation of user fees to underwrite the costs of better infrastructure
and additional review and facility-inspection staff in the OGD. In return for that funding,
the FDA agreed to review a majority of ANDAs within predetermined established
timelines.
51
Figure 3: Backlog of unapproved ANDAs per month

Source: Monthly Statistical Report of August 2013. Presented at the GPhA 2013 Fall Technical
Conference In the public domain (Gordon, 2013)

The FDA commitment letter of 2012 (USFDA, 2012) accompanying the GDUFA
legislation created specific performance goals requiring the FDA to review submissions
within a specified time limit. However, as specified by Dr. Kathleen Uhl, then Acting
Director, OGD GDUFA was not designed to focus only on timeline goals and matrices
(Uhl, 2014). Instead, she identified that it is an integral part of building a quality system
in three principal areas:
52
1) Access – To expedite the availability of low cost, high-quality generic drugs by
bringing greater predictability and timeliness to the review times for ANDAs,
amendments, and supplements.
2) Transparency – To enhance the FDA’s ability to protect Americans in the
complex global supply environment by requiring the identification of facilities
involved in the manufacture of generic drugs and associated active
pharmaceutical ingredients. Additionally, to increase interactions and
feedback with industry.
3) Safety – To ensure that generic industry participants are held to consistently
high-quality standards and are inspected biennially, using a risk-based
approach, with foreign and domestic parity.
Under GDUFA, like other user fee programs, FDA was required to meet
specific performance goals including the requirement to review a specified
percentage of submissions within a specified time frame, as shown in Table 2
below.

53
Table 2: GDUFA 1 Review Performance Goals

FY 2013 FY 2014 FY 2015 FY 2016 FY 2017
Original ANDA Expedited review of
paragraph IV and
maintain pre-GDUFA
productivity
60% in 15
months
75% in 15
months
90% in 10
months
Tier 1 first major
amendment
Maintain pre-GDUFA
productivity
60% in 10
months
75% in 10
months
90% in 10
months
Tier 1 minor
amendment (1
st
– 3
rd
)
Maintain pre-GDUFA
productivity
60% in 3
months*
75% in 3
months*
90% in 3
months*
Tier 1 minor
amendment (4
th
and
5
th
)
Maintain pre-GDUFA
productivity
60% in 6
months*
75% in 6
months*
90% in 6
months*
Tier 2 amendment Maintain pre-GDUFA
productivity
60% in 12
months
75% in 12
months
90% in 12
months
Prior approval
supplements
Maintain pre-GDUFA
productivity
60% in 6
months*
75% in 6
months*
90% in 6
months*
ANDA, amendment,
PAS in backlog on
October 1
st
, 2012
Act on 90% by end of FY2017

Controlled
correspondences
Maintain pre-GDUFA
levels
70% in 4
months
70% in 2
months
90% in 2
months
*10 months if inspection is required
Note: Performance goals in the chart means FDA should take a “first action” (as defined above) on a certain percentage of
applications, etc. within the timeframe listed; it does not mean FDA should approve applications, etc. within such timeframes.

GDUFA I expired on September 30, 2017; the second iteration referred to as
GDUFA II, was reauthorized on October 1, 2017 for an additional five-year period
ending in FY 2022. As part of the reauthorization, significant changes were attempted to
build on the experience with GDUFA I, and FDA was required to meet specific GDUFA
II performance goals shown in Table 3 below.

54
Table 3: GDUFA II Review Performance Goals
Submission Type GDUFA II Goal
Standard Original ANDAs
90% within 10 months of submission date
Priority Original ANDAs 90% within 8 months of submission date with
successful Pre-Submission Facility Correspondence
(PFC)
90% within 10 months of submission without
successful PFC
Standard and Priority
Minor ANDA Amendments
90% within 3 months of submission date
Priority Minor ANDA
Amendments
90% within 3 months
Standard Major ANDA
Amendments
90% within 8 months of submission date if preapproval
inspection not required
90% within 10 months of submission date if preapproval
inspection required.
Priority Major ANDA
Amendments
90% within 6 months of submission date if
preapproval inspection not required
90% within 8 months of submission date if
preapproval inspection required
90% within 10 months of submission date if
preapproval inspection required without successful
PFC
Standard Original PAS and
Major Amendments to the
PAS
90% within 6 months of submission date with
successful Pre-Submission Facility Correspondence
(PFC)
90% within 10 months of submission date without
successful PFC
Priority Original PAS and
Major Amendments to the
PAS
90% within 4 months of submission date if
preapproval inspection not required
90% within 8 months of submission date if
preapproval inspection required with successful PFC
90% within 10 months of submission date if
preapproval inspection required without successful
PFC
Standard and Priority Minor
PAS Amendments
90% within 3 months of submission date
55

Perhaps the most important question to be was asked as reauthorization was
considered was whether GDUFA I achieved its goals of reducing the review times of
generic applications.
Insight into GDUFA’s performance can be gained by examining the annual
performance reports prepared by the FDA’s Office of Planning to Congress, which detail
some of FDA’s accomplishments each year. These strategic reports enable Congress to
review on an ongoing basis the funding, relevance, and performance of the user fee
programs. In recent reports FDA provided evidence that the new funding to FDA through
GDUFA not only reduced the review times for new ANDAs but also eliminated the
backlog of submissions. At the 2017 Annual GPhA conference, Kathleen Uhl, then-
Director of OCG, boasted that FDA met and even exceeded some of their GDUFA I
goals. For example, the FDA was able to act on 97% of FY2015 original ANDAs within
15 months of submission, exceeding the GDUFA goal to review and act on 60% of
FY2015 original ANDAs within that period. The trend for FY2016 was reported to be
similar to that of 2015. Dr. Uhl remarked that ANDAs were “starting to see first cycle
approvals”, with an increase of first cycle approvals to 9% currently from 1.4% in 2014.
The current statistics for second cycle approval was 42%.
Others, however, did not appear to share the same optimistic view, based in part
on a more systematic analysis of approval times. In 2012, the median review time for
generic approvals was 30 months; in 2013, 36 months; in 2014, 42 months; in 2015, 42
months; in 2016, 39.5 months; and in 2017, 38 months (Gingery, 2018). Most of the
56
FDA’s attention had been focused on new submissions but older submissions continued
to languish. Generic reviews of applications are still estimated to take more than 30
months at the time of writing. The statistics even get worse with respect to the number of
first-cycle approvals – the first cycle review approval rate for ANDAs was still below
10% in 2016, and the average number of review cycles prior to an ANDA approval still
stood at four, compared to the more than 60% first-approval rate for NDAs and BLA
submissions over the same period (Uhl, 2017; USFDA, 2017d).
GPhA, the generic trade association, acknowledged improvements in Agency
communications and productivity. However, it also expressed concern that OGD’s
median times to approval had risen rather than fallen since GDUFA was passed, and that
a large gap still existed for rates of first cycle approvals for ANDAs compared to NDAs
(GPhA, 2015a). To some extent, the discrepancies between the views of the FDA and
industry appeared to derive from the terminology used to establish the GDUFA goals.
The GDUFA instructions to FDA were to “review and act on” applications within certain
timeframes but not necessarily to approve those submissions or carry out other favorable
actions within those same timeframes. In many cases, then, an action might take the form
of a tentative approval or complete response letter that extends the approval clock rather
than an approval. This trend raises questions about the extent to which such letters are
used by the Agency to meet the performance goals but postpone actual approvals.
Other concerns were also identified with the review system during the time of
GDUFA I, such as those with the quality of staffing. David Gortler (2016), a former FDA
57
medical officer, for example, commended FDA for its efforts to meet the targets for
hiring but questioned the quality of the new hires. The argument was made that new staff
who were not the best and brightest from academia and industry would hamper FDA’s
ability to carry out its mission. Further, a primary goal of GDUFA was to improve
clinical access to generic versions of important new drugs. However, no systematic
studies have evaluated the satisfaction of the generic industry with the performance of
GDUFA in this regard. GPhA comments in its white paper titled “Quality of ANDAs:
Perspectives and Forward Progress” (GPhA, 2015b) noted another shortcoming, that it
was still quite common for applicants to learn about specific new requirements that are
not specified in current guidance documents only when a deficiency is issued.
GDUFA II attempted to address some of the concerns that were identified during
the first GDUFA cycle. It set faster review goals for priority submissions, from the
standard ten months target action date from the date of the ANDA submission to eight
months for applications that qualify for priority review (Prajapati & Patel, 2017). As for
other GDUFA II performance goals and program enhancements commitments,
FDA will strive to approve approvable ANDAs in the first review cycle;
to approve potential first generics on the earliest lawful ANDA
approval date if known to FDA; and to tentatively approve first to file
Paragraph IV ANDAs so as to avoid forfeiture of 180-day exclusivity.
(USFDA, 2016b).

2.4.1 Evaluating GDUFA Initiatives
Although the FDA monitors and reports annually to Congress on the progress of
GDUFA, mostly with regard to its success at increasing approval timelines, it is unclear
58
the extent to which the programs are evaluated more systematically with regard to their
ability to achieve all of the goals that were enunciated for the program at its inception.
Further, most of the evaluations have come from government sources. However, those
who have studied program implementation from a best practices point of view would
suggest that policy refinement should depend on the input of all of the stakeholders
affected by the policy. Perhaps one of the most important stakeholders is the generic
industry, which is most affected both because they pay the user fees and because they are
most vulnerable to any failures or inadequacies in its implementation. However, the
voice of this principal stakeholder seems to be represented only modestly in
considerations of GDUFA change. Most input to the process appears to come from
industry associations, and these have a fairly narrow focus and skewed membership
representing the large generic companies. More systematic evaluations of the effects of
GDUFA from the point of view of individual industries appear to be limited.
To my knowledge, no research has yet been carried out to explore systematically
the satisfaction of the group that pays for those user fees and thus might be regarded as a
principal customer of this program. Customer feedback is one of the most important
mechanisms to understand if customer expectations are met and determine whether the
standard of service is been delivered. The provision of any “service”, if review and
approval can be considered a service, should be aimed at satisfying identified needs of
the targeted customer (Rust & Zahorik, 1993). Given that the first 5-year period of
GDUFA legislation is now over, the time seems appropriate to evaluate the successes and
59
shortcomings of the GDUFA program through the prism of the end-user – the generic
drug industry.
2.5 Monitoring and Evaluation Frameworks
Established procedures often exist to estimate the impact of new regulatory
proposals or public-funded projects before they are adopted. For example, every new
federal regulation must have a Regulatory Impact Assessment (RIA) and for FDA
regulations, a section titled “Economic and Small Business Impact” is present at the end
of the document. Comparatively little attention is paid to monitoring the outcomes of
regulations after they have been implemented or to evaluating the impacts of the
procedures and practices that govern the regulatory process itself. In the same manner
that governments need financial, human resource, and accountability systems, regulations
and regulatory programs also need good performance feedback systems (Coglianese,
2012). Regulations and regulatory programs once implemented are expected to trigger
changes in systems and entities that will lead to changes in outcomes, such as
improvement in an underlying problem (Coglianese, 2012). Setting up appropriate
monitoring and evaluation framework can, therefore, provide a structure within which it
is possible to systematically evaluate norms and best practices for performance. It also
provides insight into the degree of adherence to the standards/levels of performance
(Hafner et al., 2017).
Monitoring and evaluation (M&E) frameworks are usually considered to be
essential management tools to ensure that programs are implemented as planned and to
60
assess whether desired results are being achieved. These frameworks can be useful in
providing feedback on the progress of program activities, identification of
implementation challenges and guide program re-design. Thus, I looked for an M&E
framework that would be suitable to assess systematically whether the GDUFA
regulatory program is achieving the intended goals. Such an exploration can assess
independently what is working, what is not working, and what has been seen as
unintended outcomes or consequences. By knowing the views of stakeholders, programs
can be modified to better achieve organizational, technical, and/or institutional goals by
modifying the rules of the program (Hafner et al., 2017).
Every M&E framework has a set of indicators- variables that measure the
effectiveness and efficiency of the program by providing a descriptive snapshot that
benchmark the program with respect to underlying goals (Coglianese, 2012). Three types
of indicators typically are considered in an M&E framework: process, output and
outcome indicators. Process indicators measure progress in the processes of change, for
example, the establishment of expert advisory committees. Output indicators measure
products that come about as the result of processes, for example, publication of a strategy
document or the launch of a national program. Outcome indicators measure the ultimate
outcomes of an action (short, intermediate or long-term outcomes). These 3 types of
indicators can be further classified into two subsets: core indicators, considered the most
critical items to be analyzed in the implementation of the program and expanded
indicators, which are additional indicators that can enhance existing M&E activities
(WHO, 2008). How these are approached depends, however, on the structure of the
61
overarching framework to approach the analysis. Below, I will examine some of the more
mature frameworks being used to examine health delivery or regulatory/quality systems,
and then develop a novel fit-for-purpose framework from these options.
2.5.1 Systems for Improved Access to Pharmaceuticals and Services
One M&E framework that has gained prominence over that past few years is embedded
in the Systems for Improved Access to Pharmaceuticals and Services (SIAPS), advocated
by the US Agency for International Development (USAID) as part of efforts to
strengthen pharmaceutical systems that provide timely safe and quality pharmaceuticals
and healthcare services. SIAPS was designed to help build capacity for effective and
efficient management of pharmaceutical systems by working with stakeholders at local,
national, regional, and global levels (Hafner et al., 2017). Its ultimate goal is to improve
access to health products and services, ensuring that groups can obtain and use medicines
of assured quality. SIAPS framework has five interrelated health systems building blocks:
Governance, Human Resources, Information, Financing, and Service Delivery, with an
overlapping medical product building block depicting SIAPS’s focus on strengthening
pharmaceutical systems and services as illustrated in Figure 4 below.
62
Figure 4: SIAPS Pharmaceutical System Strengthening Approach

Source: Systems for Improved Access to Pharmaceuticals and Services (SIAPS, 2013). SIAPS Fact Sheet.
Retrieved from http://siapsprogram.org/wp-content/up loads/2013/09/SIAPS-Fact-Sheet_2013.pdf

This framework emphasizes the technical aspects of the program. An integral
aspect of the framework is the monitoring and evaluation of the program’s/project’s
performance in order to identify substantive areas of concern to which corrective
measures can be applied.
Some aspects of the SIAPS framework, and specifically its information and
service delivery components seem as though they could be useful for the work
anticipated in present research. USAID identifies that the framework is useful to
facilitate the harmonization of program activities with other key elements of the overall
63
pharmaceutical system, including regulatory approval processes. However, it is
essentially a health delivery approach, so that regulatory activities are only a peripheral
element in the SIAPS goal to strengthen health-care systems in low- and middle-income
countries where mechanisms to ensure access to safe essential medicines can often be
inadequate or under-resourced (SIAPS, 2012; United Nations, 2016). Thus, it may be less
appropriate for a more detailed study of a single aspect of drug management, that of
generic drug regulation.
2.5.2 Global Strategy and Plan of Action on Public Health, Innovation and
Intellectual Property
Another platform that has been used to monitor performance and progress of state
healthcare programs and activities has been part of what has been titled the Global
Strategy and Plan of Action on Public Health, Innovation and Intellectual Property
(GSPA-PHI). The WHO member states saw a need for a holistic approach to address the
lack of innovation and access to existing health products, including diagnostics, vaccines,
and medicines (WHO, 2004; Nannei, 2011). They sought a systematic and objective way
to assess projects, programs, and policies to determine their relevance and their ability to
fulfill their objectives efficiently and effectively (Frankel & Gage, 2007; WHO, 2008).
Notably, the approach, called Result-Based Management (RBM), attempted to shift the
assessment focus from how things are done (processes) to what is accomplished (results).
It became a monitoring and evaluation system to generate and utilize information on
program performance that could be used to assure accountability to external stakeholders.
It also became a vehicle to identify areas where skill-building and decision-making
64
interventions may be needed (Nannei, 2011; Vähämäki & Verger, 2019).
The RBM approach builds a “results chain” that depicts the logical relationship
expected between results at different programmatic levels. The results chain, shown in
Figure 5, is extended with the planning, monitoring and evaluation cycle (management
cycle) and the monitoring and evaluation plan for the particular program under
examination. All actors, defined as the people and organizations that contribute to the
results, must identify how their particular contributions affect the desired outcomes. Its
output and outcome indicators focus on longer-term impacts.
Figure 5: RBM results chain

This logic model starts with Inputs/Actions that lead to Outputs. These then
cascades into Short- and Long-term outcomes and then Impact. For a program or project
to achieve its goals, inputs such as money and staff time must result in outputs such as
stocks and delivery systems for drugs and other essential commodities, new or improved
services, or trained staff, for example. These outputs are often the result of specific
processes that are expected to generate short-term effects and ultimately longer-term
impact. This logical model has been used widely for project/program design,
implementation, and appraisal, as well as monitoring and evaluation (Broughton, 1996).
65
However, it has been criticized because it fails in its current configuration to focus on the
time allocated for strategy implementation, and this absence of the time dimension for
goal achievement may impact monitoring strategies. Second, it is a static tool that
presents a ‘snapshot’ of the project/program strategy. While this is not a problem if a
snapshot is indeed what is required, it is important to bear in mind that implementation
strategies and lessons learned are dynamic and constantly evolving (Crawford & Bryce,
2003).
Because most frameworks currently available to study drug development systems
are so broad and include regulatory processes as a singular element, they would be hard
to use as a basis for the type of research used here. The research proposed here will focus
on certain specific questions related to regulatory system implementation. Has it lived to
its expectations so far? How does it measure up to the precedent model, PDUFA? How
do industry stakeholders grade it five years after its implementation?
To assure a more systematic approach, I attempted to develop a simplified but fit-
for-purpose framework to explore systematically the effectiveness of GDUFA to achieve
its goals. Because the goals of GDUFA had been articulated so clearly at its inception, it
seemed sensible to return to those stated goals and use them as a structure within which
we could explore the success of GDUFA through the eyes of the generic drug industry.
Thus it will focus on GDUFA’s three stated purposes of improved Access, Transparency,
and Safety as outcome indicators. However, certain of the methods conceptualized in the
66
frameworks described above will be used to assist in developing the substructure of
survey questions.
2.6 Transparency
One of the goals of the Generic Drug User Fee Program was stated as
improving transparency between the FDA and industry by improving FDA’s
communications and feedback with industry during ANDA submission and review. The
term transparency has been described in many different ways in academic literature.
However, three particular definitions or concepts are useful to consider in the context of
this work. First is that of Horne (2012), who likens transparency to a window through
which “one can see clearly through with precise vision with uninterrupted detail of what
is on the other side”. Transparency defined in this way projects a positive image of
openness. Horne’s (2012) analogical description of transparency as a window would
seem appropriate when considering the drug submission, review and approval process-
industry on one side of the window is hoping for a clear vision of the thinking of
regulatory authorities on the other side of the window.
Second is Florini’s (2007) concept on transparency which goes beyond communication
and also considers its role in facilitating interaction. In her discussion of transparency
with regard to public involvement in decision-making processes, Florini defines
transparency as:
the degree to which information is available to outsiders that enables
them to have informed voice in decisions and/or to assess the decisions
made by insiders. (Florini, 2007)
67
This quote can be put into the context of the drug submission process by viewing
‘insiders’ in the drug review and approval process as decision-makers associated with FDA
and ‘outsiders’ as those in the pharmaceutical industry who may not participate in the
decision-making process but has a stake in its outcome. Florini (2007) further points out
that a key role of transparency in the field of public policy relates to its engagement in
policy evaluation. An efficient regulatory authority would be expected to solicit feedback
on how policies are working through a two-way flow of information, in this case, between
the Agency and generic drug makers.
As seems clear from the two definitions above, transparency requires ‘disclosure of
information’, generally for some purpose. Simply understanding how information is
disclosed is not enough; it is also important to explore the intent of the disclosed
information and the needs of the recipients in order to determine whether those intents are
met, if barriers exist, and whether instruments are in place to modify policy if its purposes
are not achieved (Robeyns, 2005). The instrumental nature of transparency is what makes
transparency critical in enhancing regulatory efficiency. Consistent with this line of
thinking, Solberg & Richmond’s (2012) definition of transparency is important for setting
a stage for this research in the specific context of the drug submission review and approval
processes.
Solberg & Richmond (2012) describe transparency in a more transactional way that
looks at transparency as a two-way interaction as well as a communication. It suggests
three dimensions to transparency- clarity, accessibility, and accountability- that are critical
to the drug registration processes. A transparent system, in this context, would ensure that
68
the decision-making process is more open by providing a clear guidance about the
regulatory process, ensuring that information on how to comply with the regulation is
readily accessible to stakeholders, and mandating that regulators attempt to be accountable
by explaining their actions and decisions to the end-users. In its Transparency Task Force
roadmap report published in January 2011, the FDA identified one more concept,
consistency, also considered an element of transparency. It posited that clarity and
consistency are pillars of an effective regulatory system (USFDA, 2011). Accordingly, any
framework on how to enhance transparency in the regulatory submission, review and
approval process should integrate the attributes of clarity, consistency, accessibility, and
accountability to bring about transparency effectively in a real context.
Transparency has been identified as a key specific goal of GDUFA, but a more
general focus on transparency appears to have a history that dates back far beyond the
enactment of GDUFA. President Barack Obama made transparency a priority in his
administration, by issuing a Memorandum on Transparency and Open Government on the
day after his first term inauguration on January 21, 2009. This Memorandum outlined his
administration’s commitment to creating an “unprecedented level of openness in
Government” by establishing a system of transparency, public participation, and
collaboration (USFDA, 2011). In June 2009, following the President’s lead, then FDA
Commissioner and Drug Administration, Dr. Margaret A. Hamburg, launched FDA’s
Transparency Initiative with the goal of developing recommendations for enhancing
transparency of FDA’s operations and decision-making processes. Some of these efforts
included the creation of a web portal, FDA Basics, with questions, answers, and videos
69
for the public, and an online program performance program, FDA-TRACK, with monthly
metrics on FDA offices (USFDA, 2011). Furthermore, to solicit public input on ways to
improve Agency transparency, the Task Force held two public meetings, launched an
online blog, held listening sessions with the pharmaceutical industry, and opened a
docket to which comments could be submitted (USFDA, 2011). Input from all of these
sources was used to inform the milestone report from the FDA Transparency Initiative
published in January 2011 that provided recommendations on “ways that FDA can
become more transparent to regulated industry in order to foster a more efficient and
cost-effective regulatory process” (USFDA, 2011).
However, it can be difficult to ensure that transparency objectives are met. For
example, the FDA-TRACK website launched by FDA was hoped to allow the public to
track the agency’s progress on a range of measures. However, it fell short of
expectations on issues such as assuring that the agency was hitting its targets for
completing reviews of product applications. The GPhA (2016) expressed concerns in
comments submitted in 2016 to Docket No. FDA-2016-D-0785 that the uncertainties and
near-total absence of FDA guidance in the area of complex biologics contributed to the
lack of transparency in an area where interaction and communication were critical. This
shortcoming drove requests for improvements in transparency to become a key metric in
the 2011 GDUFA negotiations with FDA.
Different dimensions of transparency were implicated as problems prior to the
enactment of GDUFA. Chief among the hurdles was lack of communication. The
70
importance of communication and transparency has been identified by leaders from both
industry and FDA. Former FDA Commissioner Margaret A. Hamburg, in a testimony to
the US House of Representative Subcommittee on Energy and Commerce on February 9,
2012, noted that:
Transparency means improving the FDA’s communications and
feedback with industry to expedite product access and enhance FDA’s
ability to protect Americans in our complex global supply environment.
Despite the Agency’s view that transparency has increased, some of that
transparency appears to be centered on communication of information about approval
timelines and trends as required by GDUFA performance goals. At least from the
anecdotal evidence so far available, there seems to be no clear roadmap for sponsors
about the nature and timeline of actions during the review of their application. GPhA
noted in comments to OGD following the Public Hearing on GDUFA Policy
Development (GPhA, 2014) that the current process of communicating status updates to
ANDA applicants has failed to generate consistency and predictability in the application
review process.
Another area where a perceived lack of transparency has been identified is in the
development process for FDA guidances (USFDA, 2011). Comments from industry note
that the formal mechanism for stakeholders to provide their views during the guidance
development process is not matched by a transparent procedure describing how the
Agency evaluates input on a draft guidance document from the different stakeholders
(USFDA, 2011). Industry comments further expressed concern that it was difficult to
71
know when an FDA guidance document will be issued. Many comments from industry
note that the process moves too slowly to provide meaning information in the ultra-
competitive generics business model where companies are in a race to be first to file
(USFDA, 2011).
Little has been written specifically about the role of FDA User Fees program in
achieving and enhancing transparency of drug registration processes. Since the passage of
GDUFA, more aggressive measures have been put into place to enhance transparency,
streamline the ANDA review process, and speed regulatory decisions. These measures
were expected to enhance regulatory efficiency, but systematic literature to confirm this
expectation has not been published.
2.7 Access
The US Congress and the FDA have made clear that providing greater access to
less costly medicines is an integral part of healthcare policies. Their goal is consistent
with the broadly promulgated international views that “equitable availability and
affordability of essential drugs as a key indicator for health care quality and their
availability is a pre-requisite to providing effective care” (WHO, 2004). Access to
essential medicines is a fundamental human right supported by international treaties
(United Nations, 2016). The generic pharmaceutical industry is, of course, a central
player in assuring such access, believing that …
…timely availability of generic drugs represents a major factor in
affordability and access to medications. Lack of access to lower-priced
generic drugs has direct cost implications for patients (GPhA, 2015c).
72

However, the methods to evaluate access are relatively ill-defined. According to
Andersen and colleagues (Aday & Andersen, 1974; Aday & Andersen, 1981), access up to
now…
..has been more of a political than an operational idea and has for
some time been an expressed or at least implicit goal of health policy,
but few attempts have been made to provide systematic conceptual or
empirical definitions of access that would permit policymakers and
consumers to actually monitor the effectiveness of various programs in
meeting that goal.
According to Paniz et al. (2010), there are no global fully standardized tools to
measure access nor is there a unique operational definition of it. Instruments used to
evaluate access are inconsistent, with a diversity of indicators and dimensions used to
assess outcomes. The WHO and the Management Science for Health (MSH) have taken a
lead to create a set of outcome indicators and methods to monitor and evaluate access to
medicine worldwide (Paniz et al., 2010). However, such models are most useful for
understanding the physical availability and affordability dimensions related to access but
are not so useful for measuring outcome effects on drug access as the results of
regulatory changes. For this purpose, information is needed on not only the quantitative
aspects of generic product introduction (statistics on the numbers and timelines of
introductions, for example) that can be found in government records but also more
qualitative information about the experience and satisfaction of stakeholders in their
efforts to secure more rapid accessibility.
73
2.8 Safety
It is not by chance that one of the principal objectives of GDUFA is to increase
safety of generic drugs by ensuring that foreign and domestic manufacturers of generic
drugs on the US market are held to consistently high-quality standards. At the time of
GDUFA I development, a perception existed that the Agency was challenged to assure
that generic drugs were uniformly safe. In particular, oversight of manufacturing was
perceived as inefficient. The problem was magnified over the past decade by the rapid
globalization of the supply chains for pharmaceutical products. According to Gardiner
Harris (2008a, 2008b), only 13 percent of the 1,154 facilities listed in FDA applications
in FY2007 as API manufacturing sites were located in the US; 43 percent of these
facilities located in China, and another 39 percent were in India. Testifying before the US
Congress in April 2008, Dr. Janet Woodcock, director of CDER conceded, “the F.D.A. of
the last century is not configured to regulate this century’s globalized pharmaceutical
industry” (Woo, Wolfgang, & Batista, 2008).
The FDA inspection scorecard for generic manufacturing facilities and
particularly for sites outside of the US was not favorable prior to the implementation of
GDUFA. As highlighted in a September 2010 GAO drug safety report, the FDA was far
below the mark in meeting this obligation. It was able to inspect just 11% of the 3,765
foreign establishments in their database in 2009, compared to the 40% of domestic
establishments that it inspected during that same year (Jaskot et al., 2011). GDUFA’s
authorization of additional resources was intended to expand FDA oversight of foreign
74
and domestic manufacturing facilities. Under GDUFA, FDA committed to undertake
various initiatives aimed at enhancing the quality and transparency of generic drugs.
GDUFA instituted a statutory requirement for manufacturing facilities and testing sites
involved in the manufacturing of finished drug products or active ingredients to self-
identify on an annual basis. This identification system was intended to allow FDA to
build an accurate inventory of all facilities involved in the manufacture of human generic
drugs and their ingredients that could facilitate surveillance inspections. The second
initiative was a commitment to conduct risk-adjusted biennial cGMP surveillance
inspections of API and drug product manufacturing facilities, with the goal of achieving
parity of inspection frequency between foreign and domestic establishments by FY 2017.
In addition to achieving risk-adjusted parity in the frequency of inspections, FDA also
committed to ensuring that domestic and foreign inspections are conducted with
“comparable depth and rigor” (USFDA, 2015).
The implementation of GDUFA represented a significant opportunity to improve
the safety of drugs in the global supply chain. In its 2016 GDUFA performance report,
FDA proclaimed that it had not only established and implemented a risk-based model to
promote equivalency when scheduling facility inspections but that it had exceeded its
goal of achieving parity of inspection frequency between foreign and domestic
companies. As shown in the figure below (Figure 6), by FY2014, the number of
inspections conducted at foreign manufacturing sites surpassed those conducted
domestically in the US.

75
Figure 6: Total Number of FDA Inspections of Domestic and Foreign Drug
Establishments, Fiscal Year 2007 through June 30, 2016

While the US FDA seems to be satisfied with improvements its inspection
program since the implementation of GDUFA, particularly with respect to inspection of
foreign drug manufacturing plants, it is not clear if this output measure is actually
reflected in outcomes, Safety outcomes are difficult to evaluate because they depend on
many factors. Thus, it would be useful to understand whether industry regards the
interventions under GDUFA to be effective in achieving the overall safety of products on
the US market. Increases in inspections are only one part of assuring that products are
safe. If for example modest increases in inspections are overwhelmed by increases in the
numbers of facilities, such a metric would be misleading. Value would be obtained by
76
examining industry feedback regarding their perceptions of the adequacy and
effectiveness of inspections and of other aspects that might be affecting the safety of low-
cost drugs in today’s market.
2.9 Research Approach
The goal of this study is to gain insight into the views and experiences of industry
with regard to the ability of GDUFA to meet its primary goals. A preliminary analysis of
metrics associated with generic approvals will be examined as a first step in the
development of a novel survey tool. A survey tool will then be framed with reference to a
triadic framework of safety, access, and transparency as described above and in Figure 7
below. In each of the three domains, subtopics that were identified in the literature review
have been identified in order that the survey questions are relatively comprehensive and
systematic. The survey will be distributed to regulatory and business professionals who
are judged to have experience with the GDUFA process and the submission of ANDAs.
77
Figure 7: Triadic framework of safety, access, and transparency

Transparency Access Safety
consistency Patent restrictions Inspectional
interactions
clarity Speed of review Sourcing options
accessibility Speed of approval Quality of review
accountability REMS restrictions Standards

Access
Safety Transparency
78
METHODOLOGY
3.1 Introduction
The exploratory study proposed here has two phases, each with its own objective. In the
first phase, documented in Chapter 2, a literature review examined the evolution and
impact of the generic drug user fee program on the development and approval of generic
drugs. As part of this overview, the types of impediments to generic product
development and commercialization were described critically, because these may impact
the eventual success of GDUFA in improving timely access to generic drugs. The second
phase of the study explored the views and experience of one principal stakeholder, the
generic drug industry, by using a novel web-based survey tool. Its questions were
designed to explore the views of experienced regulatory, research and development, and
business professionals in the generic drug industry regarding the efficiency of the generic
drugs review and approval process, and the effectiveness of GDUFA in meeting its
primary goals of enhancing safety, access of generic drugs and transparency in the drug
review and approval process.
3.2 Survey Development
A draft survey questionnaire of approximately about 40 questions, divided into five
blocks, and an open text field at the end for additional comments was initially developed
using the web-based survey tool, Qualtrics, as a platform. The first block of demographic
questions captured the respondent’s background, current involvement, and experience
79
with generic drug development and regulatory process. Questions in the next three blocks
explored each of the three domains of the proposed framework: 1) Enhancing access to
generic drugs; 2) Improving transparency between the FDA and industry, and; 3)
Improving drug quality and safety. The fifth and last block focused on questions specific
to the general performance of GDUFA. The survey questions were created in a variety of
formats including yes/no, multiple-choice, ranked order choice, rating scales measuring
agreement or preference and short answer text box questions. Additionally, open text
“comment” boxes in which respondents reflect on the additional detail related to their
assessments were provided to obtain further detailed opinions that might not be captured
by simple questions offering standardized choices. Open text comment boxes allow
respondents to write their responses without being influenced by the constraints of
predefined choices.
3.3 Focus Group
The survey for this research project was pilot-tested to ensure the removal of any
ambiguity in the questions, and further ensure that the items to which a question referred
would have a single-dimensional meaning. A focus group of eleven purposefully selected
stakeholders with different backgrounds in academia, generic and branded drug
companies, and regulatory consulting was convened on November 21, 2018. The group
was charged to critique the content of the survey instrument and provide suggestions and
alternative approaches to improve the capture of desired information in a concise and
structured format. Prior to the focus group meeting, an initial survey questionnaire,
80
together with the Abstract and Chapter 1 of this research, was circulated two weeks in
advance to focus group participants. This allowed the group to review and prepare their
feedback. The focus group was held at the University of Southern California’s Center for
Health Professionals, 1540 Alcazar St, Los Angeles, but a WebEx link was arranged for
those who had scheduling conflicts or geographic constraints, and the proceedings were
recorded. Three individuals were physically present at the meeting, and eight participated
via WebEx.
During the meeting that lasted 90 minutes and which I moderated, the focus group
discussed each question sequentially in an interactive manner and provided several ideas
to improve the survey. Typical suggestions from the participants included reducting the
granularity of the Likert scale-type questions from 7-point to 4 and 5 point scales,
removal of questions either because they were redundant and added little or no value to
the survey, or because questions were not well aligned with the survey focus or research
framework. Refinements and modifications of questions were also suggested, as was the
addition of a number of open text comment fields to solicit additional details on questions
with categorical responses. Potential areas of ambiguity and confusion related to
terminologies were addressed by either eliminating the terms or rephrasing the question.
Because not all respondents are familiar with all aspects of generic drug development and
its regulatory review and approval process, a suggestion was made to include an
additional response choice of “do not know” for certain questions. The survey questions
were modified according to the comments, corrections, and suggestions received from the
81
focus group participants, and a final survey consisting of 35 questions was locked in
Qualtrics. The final version of the survey is provided in Appendix A.
Table 4: Focus Group Participants
Name Title Institution
Frances Richmond, Ph.D. Professor and Director,
USC International Center
for Regulatory Science
University of Southern
California
Michael Jamieson, DRSc. Assistant Professor, USC
International Center for
Regulatory Science
University of Southern
California
Benson Kuo, Ph.D. Assistant Professor, USC
International Center for
Regulatory Science
University of Southern
California
Mr. Robert Pollock Senior Advisor and
Outside Director to the
Board of Directors
Lachman Consultant
Services, Inc.
Baohua Yue, Ph.D. Director, Product
Development and Pipeline
Strategy
Mallinckrodt
Pharmaceuticals
Samuel Akapo, Ph.D. Associate Director,
Analytical R&D
Impax Laboratories
Pius Okeyo, Ph.D. Principal Global
Regulatory Affairs, CMC
Upsher-Smith
Laboratories, LLC
Poonam Banker Associate Director,
Regulatory Affairs
Mallinckrodt
Pharmaceuticals
Cory Wohlbach Global Vice President
Biosimilar Regulatory
Affairs
Teva Pharmaceuticals
Sunni Miller (Churchill) Senior Director,
Regulatory Affairs
Gossamer Bio (formerly
of Teva Pharmaceuticals)
Nonyerem Onyewuenyi,
Ph.D.
Associate Director, US
Pipeline & Launch Mgmt,
Project Management
Sandoz Inc. (a Novartis
Division)

82
3.4 Survey Delivery
The final survey was validated prior to deployment by sending a trial run to three
administrative reviewers from the US Regulatory Science Faculty to verify that emails
arrived properly, survey answers were able to be recorded and analyzed properly and
problems in the instructions or design of the questionnaire were corrected. After this
validation step, the survey was disseminated to regulatory, research and development and
business professionals judged to have experience with the development, and regulatory
review and approval of generic drugs in the US. Also included as survey participants
were consultants who currently or previously worked with pharmaceutical companies.
This purposive sample was a subset of a larger population of experts in the field.
Potential respondents were identified from my personal contact database. These were
individuals who had become known to me through work, personal contacts, professional
social networking groups such as LinkedIn, attendees and speakers at conferences.
Potential participants were approached initially by telephone, email or LinkedIn to
identify their willingness to receive the survey and to clarify that they met the criteria for
inclusion into the surveyed population. To increase the potential participant pool, a
snowball technique was used. Individuals who had indicated their willingness to
participate in the survey were also asked to recommend other experts with similar work
experience that would possibly be interested in participating.
The final survey was emailed to participants on December 21, 2018, using the
web-based survey platform, Qualtrics (http://www.qualtrics.com). Potential respondents
83
were assured that their responses would be anonymous and that they would be able to
receive upon request a copy of the results after the survey was analyzed. No other
recompense was provided to respondents. The survey was open for six weeks and closed
on February 1, 2019. For the participants who did not complete the survey within the
first two weeks, a first pre-scheduled reminder email was sent via Qualtrics. The second
reminder was sent after one month, followed by personal emails and phone calls. Upon
completion of the survey, a thank you email was sent automatically using Qualtrics.
3.5 Survey Analysis
The survey results were collected, stored and analyzed using Qualtrics for any
patterns, trends or correlations in the topic areas covered by the survey. Most data were
subject only to simple descriptive statistics using percentages (%), means ( 𝑥𝑥 ̅) and
standard deviations (SD). Descriptive text, tables, and graphs were utilized to display the
data. Cross tabulation analyses were conducted to evaluate how demographic
information describing the respondents’ organizational association or job profile affected
their answers to the research questions. Open text and comment fields were examined for
their information content and a thematic analysis was performed to identify trends or
common elements. Non-respondents were not included in the analysis.
84
RESULTS
4.1 Analysis of Survey Results
The online survey was deployed between December 21, 2018, and February 5,
2019. One hundred and forty-two survey links were sent. Ninety-three respondents
opened the survey and responded to at least one question, and 74 participants completed
the survey; this corresponded to a response rate of 52% (74/142), and a completion rate
of 80% (74/93) respectively. Follow-up e-mails to potential respondents were important
in achieving a high completion rate. A number of individuals opened the survey but did
not answer every question. Hence, the number of respondents who answered each
question can vary in the results reported below. Some of the respondents who started the
survey but did not finish provided unsolicited explanation of their partial participation by
email or via LinkedIn despite the survey being anonymous. A reason given by five
participants who did not complete the survey was that, while taking the survey, they felt
that they did not have sufficient background or experience with generic drug
development to answer some of the more detailed questions. On average, for each
applicable question, about 10% of the respondents selected the “cannot answer” or “do
not know” answer choices.
4.2 Profiles of Respondents
The primary job function that the survey respondents most commonly self -
identified to hold was Director / Senior Director (31%, 27/88) (Figure 8), closely
85
followed by Manager /Senior Manager (28%, 25/88). Those with job titles of Vice
President (16%, 14/88), Consultant (11%, 10/88), Associate / Specialist (10%, 9/88), and
Scientist (2%, 2/88) also contributed to the respondent pool. No respondents had titles of
Chief Executive officer (CEO) or Chief Operating Officer (COO), and one respondent
selected the “other” answer choice, self-identifying as a Regulatory Attorney in the open
text box that was provided.
Figure 8: Respondents’ Primary Job Function
Q1 - Which of the following best describes your position? (n=88)

The largest share of respondents (34%, 48/143) at the time of the survey were associated
with companies that manufactured generic drugs, and a further 38 out of 143 (27%) were
associated with companies that manufactured innovative drugs (Figure 9). Several
86
respondents (15%, 22/143) reported working for manufacturers of drug substances /
active pharmaceutical ingredients, and a modest proportion of respondents (14%, 20/143)
represented consulting services for pharmaceutical companies. Respondents from the
medical device industry constituted only 5% (7/143) of the group. A few respondents
worked at contract development and manufacturing organizations (CDMOs) (3%, 4/143).
Additional types of organizations reported under the “others” category included contract
research organizations (CRO), a virtual biologics company and a law firm. The number
of responses for this question exceeded the number of individuals who completed the
survey because some respondents identified experiences in more than one area,
suggesting that they worked for companies that marketed more than one type of product
category.

87

Figure 9: Company Functional Roles of Respondents
Q2 - Which of the following best describes your company/organization? (n=143)

Respondents had different levels of experience within the pharmaceutical industry, from
less than 2 years (3%, 3/90) to greater than 20 years (17%, 15/90). However, most
respondents were in the intermediate parts of the range: 2-5 years (16%, 14/90), 6-10
years (27%, 24/90) and 11-20 years (38%, 34/90) as shown Figure 10.

88
Figure 10: Experience Level of Respondents within the Drug Industry
Q3 - Please indicate your level of experience within the generic drugs industry (n=90)
The majority (54%, 49/90) of the respondents reported working in Regulatory Affairs at
the time of the survey. The remaining 46% of respondents worked in diverse areas:
Product Development (13%, 12/90); Manufacturing/Operations (7%, 6/90); Sales and
Marketing (3%, 3/90); Management and Business Development (3%, 3/90); and Legal
services (1%, 1/90) as shown in Figure 11. None of the respondents identified a
functional role in Government Affairs. Of the 16 remaining respondents who identified
their functional roles as “other”, 8% (7/90) worked in Quality Assurance and 4% (4/90)
in Project Management. The other job functions reported under this category included
Clinical Affairs, Sales, and Drug Safety.

89
Figure 11: Functional Roles of Respondents
Q4 - What is your primary job function? (n=90)

The survey respondents were drawn from companies of different sizes benchmarked
according to the number of employees. Most commonly, individuals who responded to at
least one of the questions worked at large companies with more than 5000 employees
(42%, 37/89) (Figure 12). Another 30% (27/89) described their company as mid-sized,
employing between 500 and 5000 employees, while the remaining 28% (25/89) of
respondents self-identified as working for small companies of less than 500 employees.

90
Figure 12: Size of Company Respondent is affiliated with
Q5 - How would you characterize the size of your most recent company/organization?
(n=89)

To understand further the level of experience of survey respondents, they were asked to
indicate the number of original abbreviated new drug applications submitted to the U.S.
FDA annually by the company for which they worked or consulted. Most commonly, the
respondents (39%, 35/89) reported that the company with which they were affiliated
submitted more than ten ANDAs yearly. Thirty-one out of 89 respondents (35%)
indicated their company filed 1 to 5 applications annually, and a few (16%, 14/89)
respondents worked for companies that submitted between 6 to 10 ANDAs annually, as
shown in Figure 13.

91
Figure 13: Number of ANDAs Submitted by Company Respondent is affiliated
with
Q6 - Please indicate how many original Abbreviated New Drug Applications (ANDA)
the company for which you work or consult generally submits to the U.S. FDA annually.
(n=89)

Further, a cross-tabulation of data was performed to evaluate the relationship between
company size and the number of Abbreviated New Drug Applications submitted annually
(Table 5). Of the thirty-five respondents whose companies submitted more than 10
ANDA annually, nearly three quarters (71%, 25/35) identified their companies as large in
size, employing more than 5000 employees, 6 (17%) were from mid-sized companies of
between 500 and 5000 employees, and 4 (11%) worked for small companies of less than
500 employees.

92
Table 5: Cross Tabulation of Number of ANDA Submitted Annually and
Company Size
How would you characterize the size of
your most recent company / organization?

Small (<500
employees)
Mid-sized
(500 - 5,000
employees)
Large (>5,000)
employees)

Total
Please indicate how many
original Abbreviated New Drug
Applications (ANDA) the
company for which you work or
consult generally submits to the
U.S. FDA annually.
1 – 5
13 13 5 31
6 – 10
2 6 1 9
Over 10 4 6 25 35
Do not
know

6

2

5

13

Total 25 27 36 88

4.3 Access
The experiences, expectations, and satisfaction of stakeholders with respect to 1)
challenges to the development of generic drugs, 2) the review and approval process for
new applications and 3) the strategies used by brand-name companies to forestall those
applications were examined from several perspectives. First, respondents were asked to
rate the importance of eleven specific factors previously suggested impeding access to
generic drugs in the United States, using a four-point scale with weighting factors
assigned to each category as follows: very important (1), important (2), somewhat
important (3), and not important (4). All of the listed impediments except one were seen
as unimportant by less than 10 % of respondents; the one exception, the failure of
approved innovative drugs to be launched, was regarded as unimportant by only 16%
(13/80) as shown in Table 6. More than half of the respondents rated each one of the
93
listed impediments as very important or important. To simplify the distribution of the
multiple choices, each impediment was assigned a ranking of strength. According to this
ranking, the most important impediments, ranked with a score below two, were the
increasing scientific, clinical, and regulatory complexities in drug development (1.7);
brandholders extending brand protection (1.8); lack of incentives due to price erosion
(1.8); delays in FDA review and approval (1.9); and pay-for-delay settlements
agreements (1.9). This distribution replicates the relative numbers of individuals who
ranked the feature as “very important”. The remaining choices, including inconsistencies
in FDA review (2.0); anticompetitive use of REMS (2.0); new generic drugs approved
but not launched (2.2); insufficient FDA guidance (2.2); and lack of incentives due to
small market size, (2.3) were seen as very important by fewer participants but still ranked
at a strength suggesting that the options were considered important. Cross tabulations
were used to explore whether a relationship existed between the experience of
respondents or the size of the company and their views on what they thought may be
impeding generic drug access, but no large differences were seen. Even the strongest
relationship, that between the experience of the participants and the anticompetitive use
of REMS by brand holders as an important impediment, was still relatively unconvincing.

94
Table 6: Factors impeding access to generic drugs in the US?
Q7 - How important would you rate the following factors in impeding access to generic
drugs in the US? (n=80)
Question
Very
important
Important
Somewhat
important
Not
important
Cannot
answer
Mean
(SD)
1 2 3 4
Delays in FDA review and
approval of ANDAs
36%
(29/80)
41%
(33/80)
19%
(15/80)
4%
(3/80)
0%
(0/80)
1.9
(0.83)
Anticompetitive misuse of
restricted distribution REMS
by brandholders
30%
(24/80)
35%
(28/80)
23%
(18/80)
4%
(3/80)
9%
(7/80)
2.0
(0.86)
Brandholders extending the
period of brand protection by
repeatedly filing new patent
applications - Evergreening
43%
(34/80)
38%
(30/80)
15%
(12/80)
4%
(3/80)
1%
(1/80)
1.8
(0.83)
Pay-for-delay settlement
agreements between
brandholders and generic
companies
33%
(26/79)
41%
(32/79)
19%
(15/79)
5%
(4/79)
3%
(2/79)
2.0
(0.86)
Increasing scientific,
clinical, and regulatory
complexities in drug
development
48%
(38/80)
38%
(30/80)
10%
(8/80)
5%
(4/80)
0%
(0/80)
1.7
(0.84)
Insufficient regulatory FDA
guidance on the development
of generics
26%
(21/80)
35%
(28/80)
30%
(24/80)
8%
(6/80)
1%
1/80
2.2
(0.92)
Lack of incentives for
generics due to drug price
erosion over the last few
years
39%
(31/80)
36%
(29/80)
16%
(13/80)
4%
(3/80)
5%
(4/80)
1.8
(0.84)
Lack of incentives due to
small market size
25%
(20/80)
31%
(25/80)
28%
(22/80)
11%
(9/80)
5%
(4/80)
2.3
(0.98)
New generic drugs approved
but not being launched
26%
(21/80)
34%
(27/80)
29%
(23/80)
9%
(7/80)
3%
(2/80)
2.22
(0.94)
New innovative drugs
approved but not being
launched
23%
(18/80)
33%
(26/80)
28%
(22/80)
16%
(13/80)
1%
(1/80)
2.4
(1.01)
Inconsistencies in FDA
review
38%
(30/80)
31%
(25/80)
20%
(16/80)
9%
(7/80)
3%
(2/80)
2.0
(0.97)

Respondents were asked further to rank five potential reasons why new approved generic
drugs were not being launched, on a scale from most probable (1) to least probable (5).
95
As shown in Table 7, over half (51%, 39/76) of respondents ranked the most probable
reason as thin profit margins that restricted their abilities to compete against multiple or
larger competitors, with a mean ranking of 2.1. The second and third choices were
settlement deals between branded and generic companies to delay product launch and low
forecasted volumes; these were much less favored, with mean scores of 3.1 each.
However, for these two choices, individual responses varied, with 21% (16/79) ranking
the settlement deals as most important compared to 7% (5/76) ranking low forecasted
volumes as most important. Technical / Manufacturing challenges and strategic
corporate decisions on product launch timing had the highest mean scores (and thus the
lowest importance) of 3.2 and 3.4 respectively.

96
Table 7: Reasons for the lower numbers of generic drug launches.
Q8 - According to the FDA, more than half of approved generics have never been
launched or have a discontinued marketing status. Please rank the following potential
reasons from most (1) to least (5) probable for the lower numbers of generic drug
launches. (n=76)

Question
Rank Order Selected
Mean
(SD)
1 2 3 4 5
Technical / Manufacturing
challenges
9%
(7/76)
21%
(16/76)
25%
(19/76)
26%
(20/76)
18%
(14/76)
3.2
(1.23)
Thin profit margins – Can’t
compete against multiple or
larger competitors
51%
(39/76)
13%
(10/76)
16%
(12/76)
14%
(11/76)
5%
(4/76)
2.1
(1.31)
Low forecasted volumes
7%
(5/76)
32%
(24/76)
24%
(18/76)
20%
(15/76)
18%
(14/76)
3.1
(1.22)
Settlement deals with brand
holders for generics company to
delay launch of its product
21%
(16/76)
17%
(13/76)
17%
(13/76)
17%
(13/76)
28%
(21/76)
3.1
(1.51)
Strategic corporate decision on
product launch timing
12%
(9/76)
(17%)
(13/76)
18%
(14/76)
22%
(17/76)
30%
(23/76)
3.4
(1.38)

Responses were mixed when survey respondents were asked to rate their level of
agreement with four statements pertaining to the use of restricted distribution REMS to
limit generic competition using a three-point scale with weighting factors assigned to
each category as follows: agree (1), neither agree nor disagree (2), and disagree (3).
Many more (50%, 39/78) disagreed than agreed (26%, 20/78) that legitimate safety
justifications might exist in some cases for a refusal by branded drug companies to
provide drug samples for generic-drug bioequivalence testing (Table 8). The weighted
mean of 2.28 computed for this statement by converting the subjective opinions of
respondents to an ordinal scale ranging from 1 for agree to 3 for disagree is also indicates
97
that most respondents disagreed that legitimate safety justifications might exist. Opinions
were split more evenly when asked if access was facilitated when FDA issued letters to
brandholders to encourage access to samples (2.0). In these responses, 35% (27/78)
neither agreed nor disagreed, and about one-quarter of respondents separately either
disagreed (22%, 17/78) or agreed (23%, 18/78). Further, about a third of respondents
(35%, 27/77) agreed that intervention from FDA can create additional bureaucratic
hurdles to generic companies' efforts to acquire RLD samples rather than increasing
access; 29% (22/77) neither agreed nor disagreed and only 12% (9/77) disagreed. The
distribution of respondents’ choices resulting in weighted mean of 1.7. The statement that
attracted the most agreement from respondents with a mean score of 1.6 was suggesting
that the only way to resolve the abusive use of REMS to impede generic competition
would be a statutory solution. About half of the respondents (49%, 38/77) agreed and
only 12% (9/77) disagreed with this statement; however, 27% (21/77) neither agreed nor
disagreed with it. Notably, between 12% and 25 % of respondents could not offer an
answer for different choices.

98
Table 8: Respondents’ View on the use of REMS to Limit Generic Competition
Q9 - In regard to the use of restricted distribution REMS to impede or limit generic
competition, please indicate your level of agreement with the following statements.
(n=78)
Question
Agree
Neither
agree nor
disagree
Disagree
Cannot
answer
Mean
(SD)
1 2 3
In some cases there may be
legitimate safety justifications for a
temporary refusal by branded drug
companies to provide drug
samples.
26%
(20/78)
12%
(9/78)
50%
(39/78)
13%
(10/78)
2.3
(0.89)
Access to product samples has
been facilitated when FDA issues
letters to brandholders stating
ANDA sponsor's BE study
protocols contain safety
protections comparable to
applicable REMS for the RLD
23
(18/78)
35%
(27/78)
22%
(17/78)
21%
(16/78)
2.0
(0.75)
In some cases, intervention from
FDA can instead create additional
bureaucratic hurdles to generic
companies' efforts to acquire RLD
samples
35%
(27/77)
29%
(22/77)
12%
(9/77)
25%
(19/77)
1.7
(0.72)
The only way to solve this problem
is statutory solution
49%
(38/77)
27%
(21/77)
12%
(9/77)
12%
(9/77)
1.6
(0.71)

Respondents were asked to rate the importance of certain potential causes for the increase
in the number of deficiency letters issued by FDA to generic drug sponsors during
ANDA review since the implementation of GDUFA, using a four-point scale with
weighting factors assigned to each category as follows: very important (1), important (2),
somewhat important (3), and not important (4). When the weighted averages for all the
responses collected for this question were computed, the most important potential causes
for the increase in the number of FDA deficiency letters, ranked with a score at or below
99
2.0, were: inconsistencies in FDA reviews (1.7); challenges related to increasing
complexity in drug development (1.8); the lack of adequate expertise and / or training on
the part of new FDA reviewers (1.9); the strategic issuance of RTRs and CRLs by OGD
to assure they meet the GDUFA goal date (2.0); and the increased scrutiny in the FDA
review process (2.0). The scores reflected the relative numbers of individuals who ranked
the causes as “very important” and “important”. For example, the answer choice,
“inconsistencies in FDA reviews”, which had the lowest score when its weighted mean
was calculated, also was rated most commonly as “very important” by about half of the
respondents (49%, 39/79), and important by almost a third more (30%, 24/79). Only 4%
saw this reason as unimportant and only one individual could not answer. A listing of
other open text reasons provided by respondents is provided in Table 9 below. With the
exception of the “other” category, very few (1-6) respondents declined to answer this
question. Cross tabulations were used to gain insight into whether the size of the
company for which the respondent worked or the number of abbreviated new drugs
applications their company submitted annually, influenced the manner in which they
ranked the listed leading causes of the increase in the number of deficiency letters issued
during FDA review. The results from these analyses did not indicate any notable trends
between survey respondents’ company size or the number of ANDAs their companies
submitted and their views on the increasing number deficiencies issued by FDA during
ANDA review.

100
Table 9: Leading Causes of the Increase in Issuance of Deficiency Letters to
ANDA Sponsor during FDA Review
Q10 - A consequence of GDUFA has been an increase in the number of deficiency letters
that FDA issues to generic drug sponsors during ANDA review. Please give your opinion
on the importance of the following leading causes for the increase in deficiencies? (n=79)

Question
Very
important
Important
Somewhat
important
Not
important
Cannot
answer
Mean
(SD)
1 2 3 4
Increased scrutiny in the
FDA review process
28%
(22/79)
49%
(39/79)
18%
(14/79)
4%
(3/79)
1%
(1/79)
2.0
(0.78)
Declining quality of
ANDA submissions by
sponsors rushing to submit
to secure first to file or
first to market
opportunities
35%
(27/78)
32%
(25/78)
21%
(16/78)
12%
(9/78)
1%
(1/78)
2.1
(1.01)
Lack of clarity in FDA
regulatory requirements
27%
(21/79)
41%
(32/79)
22%
(17/79)
10%
(8/79)
1%
(1/79)
2.2
(0.93)
Lack of pre-submission
interaction and
communication with FDA
32%
(25/78)
40%
(31/78)
21%
(16/78)
8%
(6/78)
0%
(0/78)
2.0
(0.91)
Strategic issuance of
RTRs and CRLs by OGD
to assure they meet the
GDUFA goal date
32%
(25/77)
39%
(30/77)
16%
(12/77)
6%
(5/77)
6%
(5/77)
2.0
(0.89)
Lack of adequate expertise
and / or training on the
part of new FDA
reviewers
35%
(28/79)
33%
(26/79)
22%
(17/79)
3%
(2/79)
8%
(6/79)
1.9
(0.85)
Inconsistencies in FDA
reviews
49%
(39/79)
30%
(24/79)
13%
(10/79)
4%
(3/79)
4%
(3/79)
1.7
(0.84)
Challenges related to
increasing complexity in
drug development
43%
(34/79)
35%
(28/79)
19%
(15/79)
3%
(2/79)
0%
(0/79)
1.8
(0.83)
Others
33%
(6/18)
11%
(2/18)
0%
(0/18)
0%
(0/18)
56%
(10/18)
1.3
(0.43)

Respondents were asked about the ability of companies to respond adequately to requests
from the FDA given the shorter FDA timelines imposed since the 2012 implementation
101
of GDUFA (USFDA, 2012). Specifically, respondents gave feedback on the percentage
of information requests or discipline review letters converted by the FDA to complete
response letters because the company could not meet tight FDA response timelines. More
than a quarter of the respondents (29%, 23/79) indicated that less than 10% of the
complete response letters (CRLs) resulted because their company could not respond
adequately to information requests or discipline review letters within the specified
response timelines. Nonetheless, whereas a sizable minority (16%, 13/79) reported that
10–50% of CRLs they received resulted from failure to respond to FDA requests on time
(Figure 14). Only two out of the 79 respondents (3%) identified that more than 50% of
CRLs could be attributed to their company’s ability to respond to FDA deficiencies on
time.

102
Figure 14: Effect of Shorter FDA Timelines Imposed Since GDUFA on the
Ability of Companies to Respond to FDA IRs and DRLs.

Q11 - In the past five years, what percentage of complete response letters did the
company for which you work or consult receive because it could not meet the shorter
FDA timelines imposed since GDUFA for responding to information requests or
discipline review letters? (n=79)

When asked about the extent to which limited resources affected the ability of the
company for which they worked or consulted to meet the deadlines for responses to
information requests and discipline review letters set by FDA, most respondents
identified this factor as moderate (42%, 33/79) or minor (23%, 18/79). Slightly less than
a fifth (15%) of the respondents rated this factor as a major contributor. At the other
extreme, a fifth (20%) felt that resource limitations did not present a problem (Figure 15).

103
Figure 15: Effect of Limited Resources on the Ability of Companies to Meet
Deadlines to Respond to FDA IRs and DRLs.

Q12 - To what extent do limited resources affect the ability of the company for which
you work or consult to meet the deadlines for responses to information requests and
discipline review letters set by FDA? (n=79)

In an open text option to describe the ability of generic companies to meet FDA deadlines
to respond to deficiency letters, 28 respondents provided feedback that appeared to be
focused around four main overarching themes (Table 10): (i) Lack of resources and
expertise to adequately respond to FDA deficiency questions, (ii) FDA deadlines that are
unrealistic and often require additional research and development work to respond
adequately to FDA deficiencies, (iii) views that FDA response deadlines are reasonable,
placing the responsibility of companies to submit high-quality submission and to
prioritize work related to response to FDA-issued deficiencies, and (iv) lack of clarity and
consistency in regulatory requirements.

104
Table 10: Additional Comments Regarding the Ability of Companies to Meet
Deadlines to Respond to FDA IRs and DRLs.
Lack of Resources and Expertise on the part of Companies
This is a function of company size. Most times it depends on availability of resources
and expertise to quickly locate and assemble the information needed to provide a
comprehensive response to information requests.
It is generally not difficult to meet FDA deadlines, except when FDA requests
information on an unusually short timeframe, issues requests during times when most
team members are out of the office, or requests datasets that the team cannot easily
provide with current programming staff.
The deadlines often cause a shift in resourcing from other important projects to work
on providing the additional data FDA has requested.
For smaller companies it can be a major disruption and resource draw to respond to
information requests. The entire RA group will be called upon to respond, which can
delay other projects and initiatives. These individuals often work about 12 hours per
day to meet deadlines.
Some companies lack experience in responding when the ANDA represents the first
and only application ever filed with the FDA. Many companies may be virtual so
there may be difficulties in rallying the appropriate resources to prepare and submit a
response.

FDA Deadlines Unrealistic /Additional R&D Work Required to Respond
I think, in many instances, the FDA is becoming smarter to/and understands
complexities of drugs development. As such, much of their questioning can come in
the form of performing additional work to prove critical quality attributes and
therefore, take more time to determine past a given deadline.
Lack of planning and inability to schedule activity with contract manufacturing
provider.
The requested response timelines do not match up with the requests made in the DRL.
For example, a quality DRL may contain a request for a new stability study which
cannot be conducted and concluded in the 30 days the response is due by.
Sometimes they request seem to be easy changes, but they do not realize that such a
change requires 10-12 signatures on one document and they only give us 1 business
day + the weekend, so practically expecting us to work over the weekend to meet the
deadline. It doesn't seem fair.
FDA provides unrealistic deficiencies in an IR - for example complete a method
validation, or complete stability testing on split tablet within 10 days. These cannot be
completed in 10 days therefore a CR must be issued.
FDA has asked for responses to information request with a three day turnaround which
is very difficult. For several information requests the agency has allotted a 10 calendar
105
day response which again is difficult to do different experiments to comply data in
such a short timeframe.
Multiple times, I have noticed that FDA sets timelines, which are impractical to
respond based on the information requested.
CMO is sometime involved in finalizing responses to FDA deficiency letters causing
delay in response.

FDA Deadlines Reasonable / Companies Responsibility to Prioritize Work
Generally FDA timelines for some IR responses (ie. 5 days) are very challenging for
industry to manage on top of all of the priorities. However, FDA has been flexible in
providing due date extensions
I believe that overall the deadlines are defined adequately, but in a few cases the times
may not be fairly justified.
Limited resources can be successfully focused to meet timelines for responses to FDA
IRs.
No gap analysis at the time of submission and as such no action plan to be ready to
answer identified questionable points. Also probable change of market forecast,
therefore prioritization of one project over the other.
Companies don't understand the significance of a complete review of their internal
deficiencies, and thus provide unsatisfactory responses to 483 Observations.
US is a focus market, thus whilst the shorter deadlines are a major challenge for RA,
showing how hard we are working on to meet these deadlines in order to receive
product approvals helped to strengthen business partnership with internal stakeholders,
and we received additional resources to support our US RA activities.
More development and better understanding of the product prior to submission.
If too many then the company's system is overloaded and management must prioritize
responses to FDA based on the importance of the products for which action is
required.

Inconsistencies in Regulatory Expectations and Requirements
Lack of clarity in what FDA is requesting and FDA changing requirements with no
warning. Companies are learning FDA change in thinking when receiving deficiency
letters instead of through guidance and regulation
Lack of clarity or scientifically superfluous request from the FDA reviewer which
requires interactions with the FDA causing delay. This is mainly due to lack of
expertise on newer FDA review staff.
The Agency seems to strategically issue letters with short response time on Friday
afternoons and directly preceding holidays without adjustment of company response
106
times based on the number of business days available within the response timeline.
Major review issues come late in the review cycle for a company to address and then it
becomes a take it or leave it situation.
FDA at times will not give enough time to sponsors to reply to an information request
due to their own timelines in completing their review.
The response time should be standardized as a set number of days to provide carrots
and consistency.

The survey tried to establish how often companies requested extensions in the response
deadlines from the Office of Generic Drugs because they could not address numerous
information requests or discipline review letters within the short timelines imposed for
response under GDUFA. About half of the respondents who answered this question
(49%, 38/78) identified that they had requested an extension <10% of the time
(Figure 16). Of the remaining half, 31% (24/78) identified that their companies had
requested an extension in FDA response deadlines 10 – 50% of the time, and a small
minority (5%, 4/78) 50 – 90% of the time. A modest number of respondents (15%,
12/78) worked or consulted for companies that have never requested an extension to an
FDA deadline to respond to deficiencies.
107
Figure 16: Frequency of Requests for Extension to FDA Information Requests or
Discipline Review Letters Response Deadlines
Q13 - How often has the company for which you work or consult requested from OGD
extensions in the response deadlines because it cannot address the large number of
information requests or discipline review letters within the short timelines for response
under GDUFA? (n=78)

Respondents were offered additional statements with which to agree or disagree in order
to gain further insight into whether companies were adequately prepared to address the
increasing number of deficiency letters during ANDA review. The results shown in
Figure 17 suggested that most respondents regarded their companies as adequately
staffed with qualified regulatory affairs personnel to respond to the increasing number of
deficiency letters (73%, 47/64). At the same time, however, only a minority of
respondents thought other functional groups in their companies were staffed adequately
to respond to the increasing number of deficiency letters. Nearly half (45%, 29/65)
agreed that their companies needed additional regulatory affairs resources to respond to
the increased number of deficiency letters and a little more than half (55%, 36/65) agreed
108
that additional resources were needed for the other functional groups. Respondents also
confirm that the work needed to respond to FDA deficiency letters received by their
organizations had been outsourced to an outside 3
rd
party entity. A notable number of
respondents elected not to respond to this question.
Figure 17: Readiness of Generic Companies to Address the Increasing Number
of Deficiency Letters during ANDA Review

Q14 - Which one of the following statements is the most appropriate regarding the
readiness of the company for which you work or consult to address the increasing number
of deficiency letters during ANDA review? (n=65)

109
Respondents were asked to rank the impact of ten identified challenges on the efforts of a
company to submit a substantially complete ANDA of high quality using a three-point
scale with weighting factors assigned to each category as follows: strong impact (1),
some impact (2), and little impact (3). When the weighted averages for all the responses
collected for this question were computed, pressure from management to rush
submissions in order to secure the first-in-line position was ranked as having the
strongest impact on the efforts of companies to submit substantially complete
applications of high quality, with a weighted mean of 1.6. This value reflected the
relatively large number of individuals (57%, 44/77) who ranked this challenge as having
“strong impact” (Table 11). The other identified challenges had mean scores at or below
two, suggesting that they were considered by respondents as having some impact on the
efforts of companies to submit substantially complete applications of high quality.

110
Table 11: Challenges to Submitting a Substantially Complete High Quality
ANDA
Q15 - What level of impact do you believe the following challenges will have on the
efforts of a company to submit a substantially complete ANDA of high quality? (n=78)

Question
Strong
impact
Some
impact
Little
impact
Cannot
answer
Mean
(SD)
1 2 3
Disagreements between the R&D,
manufacturing and regulatory
functions on submission
requirements
47%
(35/75)
33%
(25/75)
19%
(14/75)
1%
(1/75)
1.9
(0.92)
Inadequate quality of submission
information or documentation from
external parties (raw
material/component supplies,
contract testing or manufacturing
sites)
45%
(35/78)
44%
(34/78)
9%
(7/78)
3%
(2/78)
1.7
(0.74)
Pressures from management to
secure a first-in-line position by
rushing submission
57%
(44/77)
35%
(27/77)
6%
(5/7)
1%
(1/77)
1.6
(0.77)
High turnover of key R&D staff
members
29%
(22/75)
49%
(37/75)
17%
(13/75)
4%
(3/75)
1.9
(0.76)
Insufficient qualified staffing of the
regulatory team
45%
(33/73)
38%
(28/73)
14%
(10/73)
3%
(2/73)
1.9
(0.92)
Challenges related to quality of
bioequivalence studies
49%
(37/75)
31%
(23/75)
19%
(14/75)
1%
(1/75)
1.8
(0.91)
Challenges related to quality of
manufactured product runs
40%
(30/75)
41%
(31/75)
17%
(13/75)
1%
(1/75)
1.9
(0.86)
Lack of understanding of new or
evolving regulatory submission
requirements
43%
(33/76)
34%
(26/76)
20%
(15/76)
3%
(2/76)
1.8
(0.87)
Failure to apply Quality by Design
(QbD) principles to the development
of the drug products
38%
(28/74)
31%
(23/74)
27%
(20/74)
4%
(3/74)
2.0
(0.95)
Interaction with FDA prior to
submission
35%
(27/78)
45%
(35/78)
18%
(14/78)
3%
(2/78)
1.9
(0.75)
Other
15%
(2/13)
0%
(0/13)
0%
(0/13)
85%
(11/13)
1.00
(0.00)

A further area of interest was the degree to which three demographic factors relating to
the background and experiences of the respondents- their level of industry experience, the
111
size of the company for which they worked, and the number of ANDAs the company
submitted annually- affected their views on challenges to submit a substantially complete
ANDA of high quality. The cross-tabulation results appear to suggest only marginal
associations between these demographic factors and the respondents’ views on challenges
to the efforts of companies to submit a substantially complete ANDA of high quality
(Appendices B, C, and D).
To evaluate whether companies were well prepared to prepare generic
submissions for complex drug products, respondents were asked to identify the current
state of expertise in the development of complex generics at the company for which they
worked or consulted (Figure 18). The two choices highlighted most frequently were “our
current staff has complex drug development expertise and we have successfully filed
multiple complex generic ANDAs” (36%, 28/77) and “we are interested in developing
complex generics, but are having difficulties hiring qualified staff with complex drug
product development expertise” (22%, 17/77). Relatively few (10%, 8/77) were not
planning to develop complex generics at their companies or had not filed a complex
generic ANDA but had hired new staff with complex generics expertise for ongoing
projects related to complex generics (10%,8/77). A small minority of respondents (4%,
3/77) indicated that their company was considering to rely on the expertise of outside
consultants. Seventeen percent of respondents (13/77) elected not to respond to this
question.

112
Figure 18: Current State of Expertise in the Development of Complex Generics

Q16 - Complex generics are drugs for which it is particularly difficult to establish
therapeutic equivalence to the reference listed drug. The designation is reserved for drug
products identified by the FDA as requiring extensive physicochemical characterization
or non-conventional bioequivalence studies to demonstrate sameness to the reference
listed drug. Which of the following choices identifies the current state of expertise in the
development of complex generics at the company for which you work or consult? (n=77)

Additionally, a cross-tabulation was performed suggested differences between large
companies and small companies with regard to the current state of expertise in the
development of complex generics. The modal value of responses for individuals from the
largest companies was that “our current staff has complex drug development expertise
113
and we have successfully filed multiple complex generic ANDAs”. Responses for
individuals from medium- and small-sized companies was that “we are interested in
developing complex generics, but are having difficulties hiring qualified staff with
complex drug product development expertise” (Table 12).

Table 12: Challenges to Submitting a Substantially Complete High Quality
How would you characterize the size of
your most recent
company/organization?
Small (<500
employees)
Mid-sized
(500 - 5,000
employees)
Large
(>5,000)
employees)

Total

Which of the
following
choices
identifies the
current state of
expertise in the
development of
complex
generics at the
company for
which you work
or consult?
Our current staff has complex drug
development expertise and we have
successfully filed multiple complex generic
ANDAs.
3 4 21 28
We have not filed any complex generic
ANDA,but have successfully hired new
staff with complex drug product
development expertise and are currently
working on complex generics projects.
3 4 1 8
We are interested in developing complex
generics, but are having difficulties hiring
qualified staff with complex drug product
development expertise.
3 11 3 17
We are evaluating available options with
regard to outside consultants with complex
drug development expertise
1 1 1 3
Our current staffing lacks complex drug
product development expertise and we are
currently not planning to develop complex
generics.
3 1 3 7
Cannot answer 6 3 4

13

Total 19 24 33 76

Respondents were given a list of potential barriers to the development of complex
generics and asked to rank these barriers using a scale from “Extremely important” to
114
“Not at all important”. The two most significant barriers identified by more than half of
the respondents as “extremely important” included “technical/clinical/regulatory
challenges” (62%, 49/79), and “lack of financial resources” (56%, 44/79). When scores
were computed by weighting the answers using a three-point scale with weighting factors
assigned to each category as follows: extremely important (1), somewhat important (2),
and not at all important (3), the listed potential barriers all had scores below 2.0
suggesting they were all considered by respondents as important (Table 13). According to
this ranking, technical, clinical and regulatory challenges still took precedence as the
most important impediment to companies considering development of complex generic
drugs (1.4). A difference was seen in the statement seen as 2
nd
placed most important
when the weighted mean ranking (2
nd
place ranking: “long development timeline”, 1.5),
was compared to the relative numbers of individuals who selected the “extremely
important” category (2
nd
place ranking: “lack of financial resources”). Further cross-
tabulation analyses performed to explore any correlation between the level of experience
of respondents, or the size of the company for which they worked (Appendix E) did not
appear to change their views relating to the challenges in developing complex generic
drugs.

115
Table 13: Impediments to the Successful Development of Complex Generics
Q17 - The successful development of a complex generic may be impeded by certain
barriers. From the list below, please indicate the level of importance these barriers
represent to the company for which you work or consult when considering the
development of complex generic drugs. (n=79)
Question
Extremely
important
Somewhat
important
Not at all
important
Cannot
answer
Mean
(SD)
1 2 3
Lack of financial resources
56%
(44/79)
28%
(22/79)
13%
(10/79)
4%
(3/79)
1.6
(0.71)
Lack of FDA guidance
49%
(39/79)
39%
(31/79)
10%
(8/79)
1%
(1/79)
1.6
(0.67)
Technical/Clinical/Regulatory
challenges
62%
(49/79)
33%
(26/79)
3%
(2/79)
3%
(2/79)
1.4
(0.54)
Finding/hiring knowledgeable
staff with complex drug
development experience
47%
(37/79)
43%
(34/79)
6%
(5/79)
4%
(3/79)
1.6
(0.61)
Development more expensive
than warranted by potential
market return
47%
(37/79)
32%
(25/79)
18%
(14/79)
4%
(3/79)
1.7
(0.76)
Long development timeline
49%
(38/78)
41%
(32/78)
4%
(3/78)
6%
(5/78)
1.5
(0.58)
Other
9%
(1/11)
18%
(2/11)
0%
(0/11)
73%
(8/11)
1.7
(0.47)

4.4 Transparency
Transparency in the regulatory process for generic drugs was examined by asking the
respondents about the consistency, predictability, communication, and availability of
guidance documents. First, respondents were given the opportunity to rate the impact of
GDUFA on the transparency of generic drug development and the FDA application
review process. Thirty-two out of 74 of the respondents (43%) characterized the level of
transparency exhibited by FDA as “improved” now relative to that prior to the
implementation of GDUFA; 18 (24%) felt that it had stayed the same, and 11 (15%) that
116
it had worsened (Table 14). When questioned about the effectiveness of their
communications with the Office of Generic Drugs (OGD) since the implementation of
GDUFA in 2012 (USFDA, 2012), responses were mixed. Most commonly, respondents
(38%, 28/74) believed that communication had improved, but 26% (19/74) believed that
it had stayed the same, and 16% (12/74) believed that it had worsened. Similarly when
responses in each ranking category were weighted using a three-point scale of improved
(1), stayed the same (2), and worsened (3), most respondents agreed that the level of
transparency exhibited by FDA now (1.7), and the effectiveness of their communications
with the Office of Generic Drugs (OGD) (1.7) had improved since the implementation of
GDUFA in 2012.
Table 14: Views on the Impact of GDUFA on Transparency
Q18 - Please indicate your position on the following questions regarding the impact of
GDUFA on transparency. (n=74)
Question
Improved
Stayed
the same
Worsened
Cannot
answer
Mean
(SD)
1 2 3
How would you characterize the
level of transparency exhibited by
FDA compared to the pre-
enactment of GDUFA?
43%
(32/74)
24%
(18/74)
15%
(11/74)
18%
(13/74)
1.7
(0.77)
Has the implementation of GDUFA
changed the effectiveness of your
communications with the Office of
Generic Drugs (OGD)?
38%
(28/74)
26%
(19/74)
16%
(12/74)
20%
(15/74)
1.7
(0.78)

Respondents provided the following additional assessments of the generic drugs
regulatory landscape related to transparency when given an opportunity to expand their
views in an open text option (Table 15).
117

Table 15: Comments on Impact of GDUFA on Transparency
QID78 - If you can, please provide any additional comments from your experience on the
impact of GDUFA on transparency.
Addition Comments on Impact of GDUFA on Transparency
Still have many concerns and questions about the questions being asked during
review- there is much inconsistency in reviewers.
GDUFA has provided clear ANDA timeline goals and timelines for controlled
correspondences. This transparency has helped industry with planning.
When GDUFA was first implemented, the level of communication was adversely
affected. PM's were unable to provide any details on the review status of pending
ANDAs. Subsequently, the level of communication increased but the level of detail
has diminished.
Overall, the transparency post GDUFA has had a positive impact on the industry.
I don't understand why the FDA is still utilizing the mail service to communicate
deficiencies and approvals. Sometimes a corresponding email notification is sent, but
not always. There are instances where your notification is delayed because the letter is
still in the mail. This can be critical for companies awaiting approvals to prepare
launch materials and can cost the generic company a lot of money.
General updates would be given but still no clarity on where files in the review
process and timing for comments.
Almost impossible to speak to FDA staff re: issue of significant importance- the
controlled correspondence system is not always a useful way to obtain clear and
concise answers because there is no potential for a dialog
GDUFA II is proving to be a game changer for the generic industry.
This comparison is GDUFA 1 to GDUFA 2.
I believe it has transparency has worsened. They give a generic answer to the status.
We cannot prepare for launch and twice I have received approval when it wasn't
expected. On the flip side, everything is going great and getting just IRs and then get
a Major CR when that is not expected. FDA reviews and reviews again and brings up
issues that weren't addressed the first time too late in the approval cycle.
Setting of target action dates is a vast improvement relative to business planning and
commercial readiness
FDA has limited the type of information that can be shared with applicants. It makes
it very difficult for organizations to understand where their applications stand and
whether an approval or CRL will be issued.
In my experience the FDA has become more defensive than ever and less transparent

118
By cross-tabulating the level of experience of the respondents against their assessment of
transparency, it was apparent that views on the level of FDA transparency were relatively
similar regardless of their level of experience in the pharmaceutical industry (Table 16).
However, a somewhat different picture was seen when the question “has the
implementation of GDUFA changed the effectiveness of your communications with the
Office of Generic Drugs (OGD)?” was cross-tabulated with the level of experience of
respondents. Respondents with more than 10 years of industry experience more typically
reported improvement in the effectiveness of communications between their companies
and the Office of Generic Drugs since implementation of GDUFA, compared to their less
experienced colleagues (Table 16).
Table 16: Cross-Tabulation of Respondents’ Level of Pharmaceutical Industry
Experience and Views on Level of Transparency Exhibited by FDA
since GDUFA implementation

Please indicate your level of experience within the
generic drugs industry
<2 years 2 – 5 years 6 – 10 years
11 – 20
years
>20 years

Total
P
l
e
a

How would you characterize the
level of transparency exhibited by
FDA compared to the pre-
enactment of GDUFA?
Improved 0 5 7 14 6 32
Stayed the
same
1 3 5 6 3 18
Worsen 0 0 3 4 4 11

Total 1 8 15 24 13 61
Has the implementation of
GDUFA changed the
effectiveness of your
communications with the Office
of Generic Drugs (OGD)?
Improved 0 3 7 11 7 28
Stayed
the same
1 5 5 8 0 19
Worsen 0 0 1 5 6 12
Total 1 8 13 24 13 59
119

Respondents were also asked to provide information relating to the level of contact that
their companies had experienced with reviewers, both during the development and review
processes. As evident in Table 17, interactions appeared to be somewhat more active
during development than during ANDA review. Sixty percent of respondents (32/53)
reported extensive formal interactions, including scheduled meetings and many
controlled correspondence exchanges, during the development phase of generic drugs
whereas only 40% identified having such interactions during ANDA review. In contrast,
more respondents reported extensive informal interactions by telephone or email during
ANDA review (64%, 35/56) than during drug development (36%, 20/56). The number of
respondents who reported only minimal or rare interactions was the same during
development compared to during ANDA review.
Table 17: Level of Company-Initiated Interactions with OGD
Q19 - How would you evaluate the level of company-initiated interaction between the
company for which you work or consult and the Office of Generic Drugs (OGD) in the
past two years? (n=65)
Question
During
development
During
review
Extensive formal interactions (including scheduled
meetings, many controlled correspondences)
60%
(32/53)
40%
(21/53)
Extensive informal interactions (frequent telephone or
email interactions)
36%
(20/56)
64%
(36/56)
Some formal interactions (possibility of meetings, some
controlled correspondences)
62%
(40/65)
39%
(25/65)
Some informal interactions (possibility of telephone or
email interactions)
44%
(23/52)
56%
(29/52)
Minimal interactions (rare occurrences of interactions)
50%
(12/24)
50%
(12/24)
No interactions
33%
5/15
67%
10/15
120

When asked to express their views on the quality of information received from OGD after
they initiated interactions, the majority of respondents rated the quality of information as
good (43%, 31/72) or satisfactory (43%, 31/72). Only a small proportion of the
respondents (7%, 5/72) rated the quality of information as excellent, and a similarly small
proportion rated it as “poor” as shown in Figure 19.
Figure 19: Respondents View on Quality of Information Receive from Company
Initiated Interactions with OGD
Q20 - How would you evaluate the quality of information received from the company
initiated interactions between the company for which you work or consult and the Office
of Generic Drugs? (n=72)

Respondents were offered the chance to share any additional comments with regard to the
quality of information received from OGD. Twelve respondents commented as shown in
Table 18 below.
121

Table 18: Additional Comments Regarding Quality of Information Received
from Company Initiated Interactions with OGD
Addition comments
If you can, please provide any additional comments regarding the quality of
information received from company initiated interactions between the company you're
associated with and the Office of Generic Drug.
GDUFA has not yielded much transparency as it’s still difficult to get the FDA to
return questions in a timely manner or even provide helpful clarifications.
In some cases, the expectations or quality required by the FDA regarding Controlled
Correspondences has not been clearly defined in the guidances and has resulted in
resubmittance on multiple occasions. I think this is a bigger problem for companies
outside the USA since English may not be their first language. The FDA seems very
particular in verbiage used in letters submitted. This may be more of an issue with the
company and not the FDA.
The Agency tends to reply in very vague terms instead of giving direct answers.
The feedback seems to vary greatly depending on who the RBPM is in both response
time and quality of information.
FDA often refers to the available guidance without providing any additional
information.
Very little, if any, actual guidance given by OGD beyond "it is a review issue".
Many responses during development would be that the items the company was looking
for guidance on were review issues and FDA would only provide feedback during
review. Lack of FDA granting meetings during review process for clarification on
deficiencies. Only written responses provided which were often insufficient.
The CC process produces less than adequate clarity and is cumbersome and not always
able to get actual answers to questions.
Lack of clear responses to controlled correspondences causing a multiple
correspondences to get clarity. FDA staff rejecting Controlled correspondences for
number of insignificant reasons.
We have submitted several requests for meeting and we never got a response. Or we
have asked for a meeting and a 30-min phone call was granted, which was mainly used
to read out questions and draft answers provided by FDA, however there was very
limited time for actual discussion. And they simply said goodbye at the end of the 30-
min, without finishing the discussion.
Many times the controlled correspondence answers from FDA do not address the
questions asked therefore, it is a cycle of us asking questions and not getting the
answers we need in development.

122
Respondents had mixed views on the FDA guidance development process. They were
asked to rate four specific statements related to guidance development from “always”
(assigned weighting of 1) to “rarely” (assigned weighting of 4) based on their most recent
or current experiences. According to this ranking, all four specific statements had a
weighted mean score greater than two, suggesting that most respondents considered all
options as sometimes occurring rather than always or frequently occurring. When asked
if FDA took feedback from stakeholders into consideration in the development of
guidance documents, 40% (29/72) identified that such feedback was taken frequently and
43% (31/72) that it happened sometimes. A similar distribution of answers was typical
for the statement that FDA guidance documents were written based on sound scientific
principles and / or reliable scientific evidence (frequently: 42%, 30/72; sometimes: 39%,
29/72). When asked if FDA’s new guidance-development priorities align with drug-
development priorities sought by industry, 32% (23/72) suggested that the alignment
occurred frequently and 53% (38/72) that it occurred sometimes. When asked if FDA
has accepted alternative approaches to guidance documents, provided they were
scientifically justified, 27% (19/72) respondents identified that this happened frequently
and a further 41% (29/71) that it happened sometimes (Table 19). In only a few cases
did the respondents identify the rate of occurrence as “rare” or “always” for any of the
four statements. The statement most often rated (17%, 12/71) as occurring rarely was that
relating to FDA acceptance of alternative approaches to those specified in guidance
documents, provided they could be scientifically justified.

123
Table 19: Respondents’ View on FDA Guidance Development
Q21 - Under GDUFA, FDA committed to enhance scientific and regulatory clarity for
generic drug developers by issuing relevant guidance documents. Please indicate your
views on the following statements regarding FDA guidance development. (n=72)

Question
Always Frequently
Sometime
s
Rarely Cannot
answer
Mean
(SD)
1 2 3 4
FDA takes feedback from
stakeholders into
consideration in the
development of guidance
documents.
4%
(3/72)
40%
(29/72)
43%
(31/72)
7%
(5/72)
6%
(4/72)
2.6
(0.69)
FDA sets priorities on its
new guidance development
in alignment with specific
drug development activities
sought by industry.
3%
(2/72)
32%
(23/72)
53%
(38/72)
3%
(2/72)
10%
(7/720
2.6
(0.60)
In situations where ANDA
sponsors have proposed
alternative approaches to
those specified in guidance
documents, FDA has
accepted such approaches,
provided they can be
scientifically justified.
3%
(2/71)
27%
(19/71)
41%
(29/71)
17%
(12/71)
13%
(9/71)
2.8
(0.77)
FDA guidance documents
are written based on sound
scientific principles and / or
reliable scientific evidence.
13%
(9/72)
42%
(30/72)
39%
(28/72)
1%
(1/72)
6%
(4/72)
2.3
(0.71)

The view of the respondents regarding the effectiveness of OGD’s controlled
correspondence process was probed by asking for their levels of agreement with regard to
certain statements about this process, using a five-point scale with weighting values
assigned to each category (strongly agree = 1, agree = 2, neither agree nor disagree = 3,
disagree = 4, and strongly disagree = 5). According to this ranking, the statement with
which the respondents most commonly agreed, ranked with a score of 2, was “OGD was
124
responding to controlled correspondences from sponsors within the GDUFA committed
timelines”. This score was consistent with the relative numbers of individuals who
strongly agreed with the statement. As shown in Table 20, the statement, “in my
company’s experience, OGD is responding to controlled correspondences from sponsors
within the GDUFA committed timelines”, elicited strong agreement from about one-
quarter of the respondents (23%, 17/73) and agreement from a further 42% (31/73). Only
4% disagreed with this statement and 16% neither agreed nor disagreed. The other
statements, all ranked with mean scores below 3, elicited less enthusiasm, but nonetheless
most commonly also evoked agreement. In response to the statement,” OGD responses to
controlled correspondences provide sufficient information and clarity regarding FDA’s
expectations and requirements”, somewhat less than half either strongly agreed (4%,
3/73) or agreed (40%, 29/73). Of the others, most neither agreed nor disagreed (26%,
19/73), and a small proportion disagreed (15%, 11/73). In response to the statement, “my
company is satisfied with the relevance of information provided by FDA in responses to
controlled correspondences”, only one (1%, /73) strongly agreed and 18 (25%, /73)
agreed. In contrast, 14% (10/73) disagreed and 3% (2/73) strongly disagreed. The most
common response, however, was neither agreement nor disagreement (41%, 30/73). For
the final statement, “…FDA has accepted approaches developed by sponsors, provided
the proposed approaches represent sound scientific judgment”, none strongly agreed but a
large proportion agreed (41%, 30/73). About a third neither agreed nor disagreed, and
about a tenth either disagreed (7%, 5/73) or strongly disagreed (3%, 2/73). For each of
the statements, 11-18% of the respondents selected “cannot answer”.
125
Table 20: Views on OGD Controlled Correspondence Process
Q22 - Please indicate your level of agreement with the following statements regarding the
Office of Generic Drugs controlled correspondence process for requesting information on
a specific element of generic drug product development. (n=73)

Question
Strongly
agree
Agree
Neither
agree nor
disagree
Disagree
Strongly
disagree
Cannot
answer
Mean
(SD)
1 2 3 4 5
In my company’s
experience, OGD is
responding to
controlled
correspondences from
sponsors within the
GDUFA committed
timelines.
23%
(17/73)
42%
(31/73)
16%
(12/73)
4%
(3/73)
0%
(0/73)
14%
(10/73)
2.0
(0.81)
OGD responses to
controlled
correspondences
provide sufficient
information and clarity
regarding FDA’s
expectations and
requirements.
4%
(3/73)
40%
(29/73)
26%
(19/73)
15%
(11/73)
4%
(3/73)
11%
(8/73)
2.7
(0.95)
My company is
satisfied with the
relevance of
information provided
by FDA in responses
to controlled
correspondences.
1%
(1/73)
25%
(18/73)
41%
(30/73)
14%
(10/73)
3%
(2/73)
16%
(12/73)
2.9
(0.80)
In my company’s
experience, when
there is no guidance
for a particular
situation, FDA has
accepted approaches
developed by
sponsors, provided the
proposed approaches
represent sound
scientific judgment.
0%
(0/73)
41%
(30/73)
32%
(23/73)
7%
(5/73)
3%
(2/73)
18%
(13/73)
2.6
(0.77)

126

Another similarly structured question explored views on formal meetings between OGD
and sponsors of generic drugs. As shown in Table 21, the statements with which
respondents mostly agreed, ranked with a score of two and below, were “meeting with
FDA prior to initiating clinical development significantly improves ANDA review
efficiency” (2.0); and “meetings with FDA have been helpful in navigating scientific and
technological challenges in the development of generic versions of complex drug
products” (2.0). This distribution reflects the relative numbers of individuals who ranked
the statements as “strongly agree” or “agree”. The statement, “meeting with FDA prior to
initiating clinical development significantly improves ANDA review efficiency” elicited
strongest agreement from most respondents (strongly agreed: 22%, 16/872; agreed: 46%,
33/72). Only one respondent of the 72 disagreed and no one indicated strong
disagreement with this statement, although 14% (10/72) did not comment. The statement,
“Meetings with FDA have been helpful in navigating scientific and technological
challenges in the development of generic versions of complex drug products”, elicited the
second most frequent agreement (strongly agreed: 15%, 11/72; agreed: 49%, 35/72), with
disagreement from only three individuals (4%, 3/72). Respondents agreed less strongly
with the remaining statements. The statement, “in case of divergence of view, generic
companies are fearful of disagreeing or pushing back on the Agency’s feedback” had a
score of 2.4 (strongly agreed: 17%, 12/72; agreed: 35%, 25/72; disagreed: 11%, 8/72 ;
strongly disagreed: 1%, 1/72). Similarly, the statement, “meeting with FDA after clinical
development but prior to ANDA submission significantly improves ANDA review
efficiency” also had a score of 2.4 (strongly agreed: 14%, 10/72; agreed: 33%, 24/72;
127
disagreed: 10%, 7/72). The statement, “the relevance of an FDA meeting to discuss the
development of a non-complex generic drug is diminished, due to availability of relevant
guidance documents” had a slightly lower score of 2.5 as did the statement, “FDA will
generally schedule meetings with sponsors within a timeframe favorable to incorporate
recommendations and/or guidance to the product development program” (2.4). For these
questions, between 10-25 % of the respondents neither agreed nor disagreed.

128
Table 21: Views on Formal Meetings between OGD and Sponsors of Generic
Drugs.
Q23 - Please indicate to what extent you agree or disagree with each of the following
statements in relation to formal meetings (pre-ANDA) and between the Office of Generic
Drugs and sponsors of generic drugs. (n=73)

Question
Strongly
agree
Agree
Neither
agree /
disagree
Disagree
Strongly
disagree
Cannot
answer
Mean
(SD)
1 2 3 4 5
FDA will generally schedule
meetings with sponsors within
a timeframe favorable to
incorporate recommendations
and / or guidance to the product
development program.
4%
(3/73)
44%
(32/73)
25%
(18/73)
3%
(2/73)
1%
(1/73)
23%
(17/73)
2.4
(0.72)
Meeting with FDA prior to
initiating clinical development
significantly improves ANDA
review efficiency.
22%
(16/72)
46%
(33/72)
17%
(12/72)
1%
(1/72)
0%
(0/72)
14%
10/72
2.0
(0.72)
Meeting with FDA after
clinical development but prior
to ANDA submission
significantly improves ANDA
review efficiency.
14%
(10/72)
33%
(24/72)
22%
(16/72)
10%
(7/72)
0%
(0/72)
21%
(15/72)
2.4
(0.91)
Meetings with FDA have been
helpful in navigating scientific
and technological challenges in
the development of generic
versions of complex drug
products.
15%
(11/72)
49%
(35/72)
10%
(7/72)
4%
(3/72)
0%
(0/72)
22%
(16/72)
2.0
(0.73)
The relevance of an FDA
meeting to discuss the
development of a non-complex
generic drug is diminished, due
to availability of relevant
guidance documents and / or
the controlled correspondence
process is sufficient to address
challenges for these types of
programs.
10%
(7/72)
38%
(27/72)
25%
(18/72)
11%
(8/72)
0%
(0/72)
17%
(12/72)
2.5
(0.86)
In case of divergence of view,
generic companies are fearful
of disagreeing or pushing back
on the Agency’s feedback.
17%
(12/71)
35%
(25/71)
20%
(14/71)
11%
(8/71)
1%
(1/71)
15%
(11/71)
2.4
(1.00)

129
To examine the extent of FDA’s compliance with consistency, respondents were asked
whether the current ANDA review processes provide consistent evaluations when
reviewed by different reviewers. Most respondents (64%, 47/74) believed that the ANDA
review process “sometimes” provided consistent evaluations when reviewed by different
reviewers (Figure 20). About one-fifth (20%, 15/74) claimed it was frequently consistent,
and no respondents thought that it was “always” consistent.
Figure 20: FDA Consistency in ANDA Review Process
Q24 - In your opinion, does the current ANDA review process provide consistent
evaluations when reviewed by different reviewers? (n=74)

Some respondents were forthcoming in their comments to amplify their views on this
issue. Most expressed views that the ANDA review process lacked consistency. A full
listing of respondents’ comments is provided in Table 22 below.
130
Table 22: Additional Comments Regarding FDA Consistency in ANDA Review
Process
Addition comments
There is not much consistency as questions have drastically differed for ANDAs; also
it appears many reviewers are requesting information not relevant or scientifically
justified for that particular drug.
Hard to answer, but I have heard in some instances it could be a problem. I believe the
problem is much more transparent when it comes to general GMP and PAI
inspections.
We see a ton of comments and requests that seem to be generated from inexperienced
reviewers who are unaware of the regulations, requirements guidance documents, ICH
etc. and waste a lot of time explaining and justifying why the requested information is
irrelevant or not required.
Review comments greatly varied between reviewers. Also new questions would be
sent in a deficiency following a complete response that was unrelated to topics in
complete response. Therefore, it was clear the review was not complete when the
complete response was issued.
Larger the number of reviewers the less likely that the CRLs are completely reviewed
by supervisors and/or the supervisor does not have sufficient time to go back to the
raw data to evaluate if the deficiencies are justified. Also there is a problem with
reviewers asking nice to know questions and not need to now questions.
I absolutely disagree with that. In my opinion ANDA reviews performed by different
reviewers with totally different backgrounds always brings a significant inconsistency
into the process and different quality submissions can be approved or rejected due to
such inconsistency. It is almost like you need to be lucky not just provide good quality
dossier.
When similar molecules are filed in different ANDAs we get different questions. You
would think there would be more consistency among the reviewers and the
deficiencies that are issued but it seems it is very reviewer dependent.

4.5 Safety
The implementation of GDUFA represented a significant opportunity to improve the
safety of drugs in the global supply chain. Survey questions, therefore, examined industry
perceptions regarding the adequacy and effectiveness of cGMP surveillance inspections
as well as other issues that might affect the quality and safety of generic drugs.
131
Respondents were first asked to rate the overall quality of FDA’s compliance inspection
program in terms of depth and rigor since the implementation of GDUFA. As shown in
Figure 21, less than 10% (5/71) viewed it as excellent but about two-thirds of the
respondents (66%, 47/71) viewed the quality of inspections was good, and about a
quarter (27%, 19/71) viewed it as satisfactory.
Figure 21: Quality of FDA Compliance Inspections
Q25 - How do you rate the quality of compliance inspections in terms of depth and rigor
since the implementation of GDUFA? (n=71)

Respondents were given the opportunity to expand on their views in an open text option;
their comments are listed in Table 23.

132
Table 23: Additional Comments on Quality of FDA Compliance Inspections
Addition comments regarding quality of FDA compliance inspection
Although, inconsistencies between different inspectors could result in slightly different
outcomes, the demands for quality and compliance are increasing.
Different investigators have stronger and weaker inspection skills. The FDA can
choose to send a more challenging investigator to a site or a less challenging
investigator if they are interested in getting a drug approved.
The quality of FDA compliance inspections is commensurate with the level of
experience the FDA Inspector(s) have. Inspections of firms in regions where more
facilities reside often have Inspectors with more experience and the rigor of the
inspection parallels that experience.

When asked if they had any concerns regarding FDA compliance inspections, most (81%,
59/73) said “no” but 19 % (14/73) said, “yes” (Figure 22).
Figure 22: FDA Compliance Inspections
Q26 - Do you have any concerns regarding FDA compliance inspections? (n=73)

133
A “display logic” technique was used to explore further the concerns of fourteen
respondents who had expressed concerns regarding FDA compliance inspections. As
shown in Figure 23, many respondents (28%, 10/36) were concerned about the lack of
consistency in inspections. A similar number were concerned about a perceived lack of
expertise of inspectors (25%, 9/36) and others were concerned about the scope of
inspection (19%, 7/36). The timing of inspections (11%, 4/36) and the quality of
inspection reports (11%, 4/36) ranked amongst the least serious concerns. The number of
responses to this question exceeded the number of individuals who responded to this
question suggesting that many of the respondents had concerns in more than one domain.

Figure 23: Specific Concern Regarding FDA Compliance Inspections
Q27 - What is your specific concern regarding FDA compliance inspections? Select all
that applies. (n=36)

134
Results suggest that the large majority of respondents (81%, 58/72) worked or consulted
for companies where ANDA approval has never been delayed because FDA site
inspections were slow to occur (Figure 24). The remaining 14 respondents (19%) who
answered this question identified at least one of their company’s ANDA approvals were
delayed by slow FDA site inspections.

Figure 24: Effect of FDA Site Inspection Timing on ANDA Approvals
Q28 - In the last two years has a delay occurred in approval of any ANDAs with which
you have been associated, because FDA site inspections were slow to occur? (n=72)

Additionally, respondents were provided with an open text box and asked to share any
additional comments regarding delays in approval of ANDAs with which they had been
associated, because FDA site inspections were slow to occur. Two respondents
commented as shown in Table 24 below.

135
Table 24: Additional Comments Regarding Delays in ANDA Approval Due to
Slowness in FDA Site Inspection
If an inspection occurs and there is one finding found, OGD can move the GDUFA
date and state it is from the inspection. This affects the review significantly.
Additionally, the Office of Compliance takes a long time to get their findings to the
review team.
Lack of resources by FDA.

Respondents were asked if the company for which they worked or consulted had
experienced an increase in frequency of FDA compliance inspections. Results were
mixed; about a quarter (26%, 19/73) who responded to this question had experienced an
increase in FDA compliance inspections whereas a third (34%, 25/73) did not
(Figure 25). The majority of the respondents (40%, 29/73) did not have sufficient
knowledge about the frequency of inspections to answer the question.

136
Figure 25: Frequency of FDA compliance inspections
Q29 - Has the company for which you work or consult experienced an increase in
frequency of FDA compliance inspections of the facilities used in manufacturing,
packaging and testing of its drug substances or products? (n=73)

A follow-up, “display logic”, question was directed at those respondents with increased
inspections to explore how that experience had altered generic companies’ perspective to
quality improvement. About half (54%, 13/24) identified a heightened sense of awareness
regarding quality improvement as a result of the more frequent inspections (Figure 26)
and a third (33%) reported an increase in activities related to quality improvement.
However, 8% (2/24) thought that no change occurred. One individual noted “other” as
the answer choice with the additional comment: “disruptive to normal business
practices”.

137
Figure 26: Effect of increased frequency of inspection on quality improvement
Q30 - Please identify how increased frequency in compliance inspections has altered the
company for which you work or consult’s perspective to quality improvement. (n=24)

4.6 GDUFA Performance Scorecard and Future Stakes
To explore the potential for a performance scorecard for the GDUFA user fees program,
survey respondents were presented with a series of options that might or might not be
appropriate metrics with which they could express agreement or disagreement with a
three-point scale (agree=1, neither agree nor disagree=2 and disagree=3). The weighted
mean scores computed for each statement were all 2 and below (Table 25), suggesting
that respondents mostly agreed with all statements. The statement, “GDUFA is executed
within the scope it was intended” elicited the strongest agreement (42%, 31/74). Thirty-
138
eight percent of respondents (28/74) neither agreed nor disagreed, and a smaller number
(7%, 5/74) disagreed. Fourteen percent (10/74) of respondents could not comment on this
statement. For the statement, “the measured progress of GDUFA is an incentive to bring
companies to the GDUFA”, 41% (30/74) of respondents agreed, 31% (23/74) neither
agreed nor disagreed and 7% (5/74) disagreed. For the statement, “under GDUFA, the
ANDA approval rate has improved to our company’s satisfaction”, 38% (28/74) agreed,
36% (27/74) neither agreed nor disagreed and 9% (7/74) disagreed. For the statement,
“GDUFA is executed with an appreciation for the hypercompetitive dynamics of the
generic drugs industry”, responses were more diverse. Although 21% (15/72) of
respondents agreed, 26% (19/72) disagreed, and 40% neither agreed nor disagreed. The
statement, “many generic drug programs associated with the user fees program are above
and beyond the GDUFA commitments”, evoked agreement in 20% (15/74), disagreement
in 8%, (6/74) and neither agreement nor disagreement in 42% (31/74). The percentage of
those who did not know the answer ranged from 13-30% (Table 25).

139
Table 25: GDUFA overall performance since its implementation in 2012
Q31 - Please indicate your level of agreement with the following statements (n=74)
Question
Agree
Neither
agree nor
disagree
Disagree
I don’t
know
Mean
(SD)
1 2 3
Under GDUFA, the ANDA approval
rate has improved to our company’s
satisfaction.
38%
(28/74)
36%
(27/74)
9%
(7/74)
16%
(12/74)
1.7
(067)
Many generic drug programs
associated with the user fees program
are above and beyond the GDUFA
commitments.
20%
(15/74)
42%
(31/74)
8%
(6/74)
30%
(22/74)
1.8
(0.61)
GDUFA is executed within the scope
it was intended.
42%
(31/74)
38%
(28/74)
7%
(5/74)
14%
(10/74)
1.6
(0.63)
GDUFA is executed with an
appreciation for the hypercompetitive
dynamics of the generic drugs
industry.
21%
(15/72)
40%
(29/72)
26%
(19/72)
13%
(9/72)
2.1
(0.73)
The measured progress of GDUFA is
an incentive to bring companies to the
GDUFA III negotiation table to
discuss further program expansion.
41%
(30/74)
31%
(23/74)
7%
(5/74)
22%
(16/74)
1.6
(0.65)

Further, the effect of a respondent’s level of experience or the size of the company with
which he/she is affiliated was examined against his/her assessment of the overall
effectiveness of GDUFA since its implementation in 2012 (USFDA, 2012). Respondents
with more than 10 years in the generic drug industry more frequently agreed with the
statement, “GDUFA is executed within the scope it was intended”, than did respondents
with less than 10 years of experience. A similar trend was observed with the statement,
“the measured progress of GDUFA is an incentive to bring companies to the GDUFA III
negotiation table to discuss further program expansion”. The more experienced
respondents disagreed more often than their less experienced colleagues that “GDUFA is
140
executed with an appreciation for the hypercompetitive dynamics of the generic drugs
industry” (Table 26). However, as shown in Appendix F, a cross-tabulation performed to
stratify views on the overall performance assessment of GDUFA based on the size of
company with which the respondent was affiliated did not produce any notable
relationship.

141
Table 26: Cross-Tabulation of Level of experience of Respondent and their
Views on the effectiveness of the GDUFA user fees program.

Please indicate your level of experience within
the generic drugs industry

˂2 years 2 - 5 years 6 - 10 years
11 - 20
years
˃20 years Total

Under GDUFA, the ANDA
approval rate has improved to
our company’s satisfaction.
Agree 0 4 5 11 8 28
Neither agree
nor disagree
0 3 9 12 3 27
Disagree 0 1 2 3 1 7
I don’t know 2 2 4 3 1 12
Total 2 10 20 29 13 74
Many generic drug programs
associated with the user fees
program are above and
beyond the GDUFA
commitments.
Agree 0 1 4 6 4 15
Neither agree
nor disagree
0 6 9 11 5 31
Disagree 0 0 0 5 1 6
I don’t know 2 3 7 7 3 22
Total 2 10 20 29 13 74
GDUFA is executed within
the scope it was intended.
Agree 0 5 6 16 4 31
Neither agree
nor disagree
0 3 9 8 8 28
Disagree 0 1 0 3 1 5
I don’t know 2 1 5 2 0 10
Total 2 10 20 29 13 74
GDUFA is executed with an
appreciation for the
hypercompetitive dynamics
of the generic drugs industry.
Agree 0 3 4 6 2 15
Neither agree
nor disagree
0 5 8 9 7 29
Disagree 0 1 3 11 4 19
I don’t know 2 1 4 2 0 9
Total 2 10 19 28 13 72
The measured progress of
GDUFA is an incentive to
bring companies to the
GDUFA III negotiation table
to discuss further program
expansion.
Agree 0 5 4 12 9 30
Neither agree
nor disagree
0 2 9 8 4 23
Disagree 0 1 0 4 0 5
I don’t know 2 2 7 5 0 16

Total 2 10 20 29 13 74

Respondents were split when asked if the overall quality of generic drugs had improved
under the GDUFA system. Nearly half of the individuals (34/74) who responded to this
142
question felt that the quality of generics drugs had improved (Figure 27). About 20%
(15/74) did not feel that the quality of generic drugs had improved under the GDUFA
system, and a third (25/74) could not answer the question.

Figure 27: Quality of generic drugs better under the GDUFA System
Q32 - With the current FDA decision making model, is the overall quality of generic
drugs better under the GDUFA system? (n=74)

Respondents were provided with an open text box and asked to share any additional
comments regarding the overall quality of generic drugs under the GDUFA system. Ten
respondents commented as shown in Table 27 below.
143
Table 27: Additional Comments Regarding Quality of Generic Drugs
Please provide any additional comments regarding your assessment of the overall
quality of generic drugs under the GDUFA system.
QbD, ICH and better technology have helped improve drug quality. GDUFA helps
facilitate getting the drugs to market sooner. The new inspection paradigm has put
more quality accountability on the site.
The quality of the applications seems to remain the same, but the review timeline has
been improved in most instances.
Beside the drastic increase in filling fees, there seems no difference under the GDUFA
system in the overall quality of generic drugs.
Implementation of the GDUFA system has helped improve the development, review
and approval of generic drugs. Further improvements are still needed, but I think FDA
is on the right track with the current Commissioner.
I feel more rush to submit from our end and more rush to review and make a decision
from the Agency's end. It doesn't necessary result in better quality.
The quality of the generic drugs has not changed, but the duration of review and
approval for a quality ANDA is significantly shorter now.
I have not seen any evidence that quality was improved nor diminished by GDUFA
If companies complete proper development, the GDUFA system works very well.
The review process follows a process and scheduled so it is easier to predict when an
action will be given by the FDA.

To solicit suggestions for any future GDUFA II negotiations, survey participants were
asked to rank their most preferred initiatives when negotiating user fees funding from a
menu of five proposed initiatives. The rankings as shown in Table 28 suggested that
initiatives targeted at improving review consistency were most important (1
st
place: 37%,
25/68; 2
nd
place: 37%). Initiatives targeted at enhancing guidance development for
complex generics were also quite popular (1
st
place: 37%, 25/68; 2
nd
place: 17%, 14/84)).
Third was initiatives targeted at improving the drug review timing; 25% (17/68) of the
respondents placed it in first place and another 25% ranked it in second place. The two
initiatives with the lowest rankings were those aimed at streamlining the post-marketing
144
lifecycle and pharmacovigilance surveillance programs and those targeted at achieving
parity in effectiveness and frequency of domestic and foreign facility inspections (ranked
1
st
place by 37%, 25/68 and 2
nd
place by 17%, 14/84). When rankings were evaluated
using another approach of determining the average ranking after each level of preference
was given a score with weighting factors assigned to each category [as follows:1
st
level
(1), 2
nd
level (2), 3
rd
level (3), 4
th
level (4), and 5
th
level (4)], and the weighted averages
for all the responses collected for this question were computed, the initiatives targeted at
improving review consistency (2.04) and initiatives targeted at enhancing guidance
development for complex generics (2.53) still emerged as the 1
st
and 2
nd
most important
initiatives to prioritize when negotiating user fees funding from a menu of five proposed
initiatives.
145
Table 28: Initiatives to Prioritize for GDUFA 3
Q33 - As part of future GDUFA III negotiations, please rank the following initiatives in
order of preference from most (1) to least (5) important initiative to prioritize user fees
funding for. To reposition the list, right click on the line you wish to move and then drag
it up or down. (n=68)
Question
Rank Order Selected
Mean
(SD)
1 2 3 4 5
Initiatives targeted at improving
review consistency - e.g.
increasing reviewer training
37%
25/68
37%
25/68
15%
10/68
9%
6/68
3%
(2/68)
2.0
(1.06)
Initiatives targeted at enhancing
guidance development for
complex generics
26%
(18/68)
21%
(14/68)
29%
(20/68)
21%
(14/68)
3%
(2/68)
2.5
(1.17)
Initiatives targeted at achieving
parity in effectiveness and
frequency of domestic and
foreign facility inspections
6%
(4/68)
13%
(9/68)
16%
(11/68)
32%
(22/68)
32%
(22/11)
3.7
(1.21)
Initiatives aimed at streamlining
post-marketing lifecycle and
pharmacovigilance surveillance
programs
6%
(4/68)
4%
(3/68)
13%
(9/68)
29%
(20/68)
47%
(32/68)
4.1
(1.14)
Initiatives targeted at improving
the drug review timing - e.g.
recruiting additional review
staff
25%
(17/68)
25%
(17/68)
26%
(18/68)
9%
(6/68)
15%
(10/68)
2.6
(1.34)

Given the option to provide additional comments in an open text format regarding
initiatives to prioritize as part of any future GDUFA III negotiations, four respondents
provided the comments shown in Table 29.
146
Table 29: Additional Comments on Initiatives to Prioritize in Future GDUFA
III Negotiations
I believe the biggest challenge for the FDA is clearly defining what are the
requirements and expectations for approving biogenerics. For simple small molecule
ANDA's not requiring BE studies timelines for approval could be accelerated.
Better division of funding sources to take into account the continued burden that fees
have on small and medium manufacturers.
Improvement on pre-submission FDA interaction and guidance. Product specific
guidances for complex products for CMC as well as clinical.
Note that my company is not a generic drug company but we have insight into this
sector through collaborations with others.

Respondents were asked in an open text format for their opinion regarding the greatest
successes of the GDUFA program (Table 30). The feedback provided by the respondents
appeared to be focused around the following main overarching themes: Increased
predictability in FDA review and approval timing; improvement in transparency and
communication between sponsors and the Office of Generic Drugs; and increase in level
of FDA guidance generic drugs manufacturers.

147
Table 30: Greatest success of the GDUFA program
Q34 - What in your opinion has been the greatest success of the GDUFA program?
Timelines are being met
Speed of review
Transparency of review timelines. Faster approval timelines.
Increasing awareness and commitment to product quality through QbD.
Improved timelines
Timely approval; communication
Improved response time.
Faster review timelines.
Knowledge of FDA action date for the filling(s).
The increased staffing at the Agency has increased the predictability of review timing of
pending applications making corporate planning easier.
Increased communication with FDA
Faster and more timely (on schedule) reviews and query responses.
More timely ANDA acceptance and predictability of timing for review letters
Some better certainty in review times but not necessarily approval time
Visibility to review and approval times.
Pre-ANDA meetings
Goal dates
Little more transparency and it cannot happen anymore that you need to wait 4 years to get
some feedback about your dossier.
Shorter Review Cycles.
Significant increase in approval numbers
Reducing review timing
Addressing the backlog and providing some structure of timing to an ANDA review.
My company does not file ANDAs but I have seen increase in guidance for industry for
generics.
Addressing the ANDA backlog
148
Reduced review timelines
Scientific initiatives.
Review and approval of Prior approval supplements
It has brought some level Of accountability to the FDA
Streamlines the overall generic review process and has justified FDA to add additional
resources in OGD. Also raising it to an Office level has helped

Similarly, respondents were asked to comment on the greatest challenges of the GDUFA
program (Table 31). The feedback provided by the respondents could be grouped around
the following main overarching themes: GDUFA goals still not being met;
inconsistencies in FDA expectations and requirements; lack of transparency in the Office
of Generic Drugs decisions; and lack of direct communication with OGD.
Table 31: Greatest challenges of the GDUFA program
Q35 - What have been the greatest challenges of the GDUFA program?
Inconsistent in review comments & many new inexperienced reviewers
Lack of transparency of OGD decisions
Since user fees are based on sites, the challenge is keeping an account of approved
facilities across all applications in the organization.
Based on the little experience, mid-cycle review meeting was not as productive as
we would have wished (the agency was not able to provide answers to the questions
that were provided in advance of the meeting)
Consistency in expectations and requirements, and allowing for more flexibility in
submissions based on scientific principles especially for biogenerics and complex
product formulations. RLD companies should not direct FDA policies.
Inconsistencies at the agency due to additional personal (possible lack of training or
supervision)
Bureaucracy
FDAs lack of transparency and poor communication.
Lack of transparency and consistent delay from OGD particularly from the
reviewers.
149
Inconsistent reviews have made it increasing difficult to offer guidance to the
company on requirements for filing acceptance and approval.
Inconsistency in reviews, lack of FDA guidance for complex products, changing
regulations and requirements without implementation prep
Cost to sponsors.
Inconsistent reviews. RTRs for non-significant issues that seem to be issued only to
lighten FDA’s workload allowing them to meet the Gouda timelines
Lack of direct communication with OGD and being able to discuss issues with FDA
staff at industry and national meetings
Meeting the actual goals of approved products instead of just working to meet the
metrics
The strict rules and timing policy we also need to meet otherwise Agency is not
obliged to meet their timelines.
Review Consistency
Consistency of review; review timelines being adhered to (FDA just creates more
deficiencies to meet their timing), lack of transparency about the application.
For industry, who pays and how much is still an open question. Generic business is
interwoven and suppliers/manufacturers can be seen as having a free ride under
certain situations.
Recruiting and training qualified and competent reviewers.
Communication with the PM's.
Communication and transparency. FDA perceptions of what was agreed versus
industry perceptions
The FDA uses deficiency letters to extend the reviews process because that cannot
actually meet the review timelines
Meeting the GDUFA goals

150
DISCUSSION
5.1 Overview
The timely introduction of new generic drugs is a crucial component of a cost-
effective healthcare system. The Generic Drug User Fee Act (GDUFA) has therefore
been seen as a progressive step to provide additional resources needed by the FDA to
accelerate reviews and approvals of new generic drugs. These resources permit the
Agency to hire more staff, upgrade data systems, provide industry guidance regarding
ways to enhance drug development and improve procedures and standards, all with the
goal of expediting the review of new generic drugs. Several recent reports by the FDA’s
Office of Generic Drugs and others credit GDUFA with the Agency’s success in reducing
ANDA review times, eliminating the huge backlog of generic drug applications, and
enhancing transparency between the FDA and the generic drug industry. Despite these
reports, questions persist regarding GDUFA’s impact on the time and effort required to
develop and market new generic drugs. The research conducted here was undertaken to
provide an independent assessment of the FDA’s progress toward meeting its
commitments under GDUFA, based on the views and experiences of one important
stakeholder, the generic drug industry. The research evaluated the broader impact of the
user fee initiatives on the overall drug development process and review, which will have
implications for new drug availability in the United States.

151
5.2 Methodological Considerations
Social science researchers clearly recognize that the medium used to collect data
in any research study has the potential to affect the data gathered in that study (Babbie,
2016). Thus, the design of the investigational plan is a key consideration when deciding
the tools that will be used to explore the questions of interest. An online survey was
selected as a suitable way to collect data for this research because it provided a tool that
can transcend geographic boundaries; it permitted us to obtain input from a broad pool of
respondents located throughout the United States of America and in some cases at
international locations. This geographic reach would be difficult, expensive and time-
consuming to attain with face-to-face interview methods. Interviews by telephone might
be an alternative option to face-to-face interviews, but research shows that respondents
are becoming averse to telephone interviews in response to the increasing number of
telemarketing and sales calls to which they have been subjected (Draugalis, Coons, &
Plaza, 2008). Also, face-to-face or telephone interviews have to be tape-recorded,
transcribed, coded and collated into recurrent themes, and this can be a time-consuming
process (Wyatt, 2000). Additionally, interviewer bias and time pressures on respondents
can affect the depth and quality of the data (Holbrook, Green & Krosnick, 2003; Duffy et
al., 2005). Web administration of surveys is faster (Taylor, 2000; Yun & Trumbo, 2000)
and cheaper (Miller et al., 1996; Fisher, Margolis & Resnick, 1996; Couper, 2000). Its
popularity as a tool has grown as the technologies become more sophisticated and the
respondents become more comfortable with internet interfaces (Fox, 2001; Nie, Hillygus
& Erbring, 2002). Surveys also permit respondents to participate anonymously at greater
152
arm’s length to the researcher, so they may be less likely to be influenced by the cues or
opinions of the interviewer, as is often pointed out by the methodological literature
(Buchanan & Bryman, 2007). Web-based respondents have also been shown to make
fewer errors in responding to questions. In addition, most internet-based platforms
allowing branching in the presentation of question groupings based on precedent
responses. Data can be automatically coded and stored without data re-entry by a
researcher, and encryption can be used to protect the confidentiality of particularly
sensitive responses (Hayslett & Wildermuth, 2004). The use of an internet platform and
email system to distribute the survey also has advantages compared to traditional
methods such as paper surveys distributed by mail or web-based surveys announced by
mail. A study comparing these three methods suggests that web surveys were returned
more quickly. Further, the use of e-mail notices and reminders were more effective for
securing responses to web-based surveys than paper notices (Hayslett & Wildermuth,
2004).

5.2.1 Delimitations
Although survey methods allow substantial opportunities to reach an intended
audience, the actual effectiveness of that outreach depends on the nature of the sampling
plan (Creswell & Creswell, 2017; Jansen, 2010). It was clear from the outset that an
exploratory survey such as this would require certain delimitations so that results would
not be confounded by too many variables. Originally, one of the delimitations placed on
this study was to restrict the respondent pool to include only regulatory and marketing
153
professionals currently or previously working in companies that manufacture or distribute
generic drug products in the United States. These individuals are most likely to
understand and appreciate the implications of the GDUFA regulations on the generic
drug industry. However, based on recommendations from experts who reviewed the
preliminary survey draft, the inclusion criteria were expanded to individuals in roles that
closely interact with Regulatory Affairs and Marketing, such as Legal Affairs and
Product Development. Given the cross-functional nature of today’s work environment,
most respondents from ancillary functions will have insights regarding the challenges
experienced in the development and regulatory review process for generic drugs. The
survey was also sent to individuals currently or previously working in other medical
product industries in the U.S. beyond those specifically developing generic drugs. Unlike
the past when medical products companies specialized in developing and marketing a
narrow range of products, companies today often market multiple medical product types
including prescription drugs, generic drugs, medical devices and/or others at the same
time. A broader approach ran the risk of smearing the response patterns by merging
subpopulations with different viewpoints. To address this question, cross-tabulations
based on job functions were carried out to see if discernible differences existed in the
responses to questions. The fact that the responses of individuals in different job
functions appeared similar suggests that respondents in these other job functions did not
hold views that were obviously different from the originally envisioned job functions.
Indeed, their inclusion may strengthen the survey by bringing together a broader
154
representation of views from affected industry professionals, thereby maximizing
representativeness and minimizing systematic omissions or biases (Rea & Parker, 2014).
Surveys of other important stakeholders, such as consumers, FDA regulators or
researchers in academia, could have provided different views, but these views were not
explored in this research. This delimitation may potentially restrict the external validity
of the study. To strengthen the external validity, a future direction of this research would
be to expand the respondent pool to include other stakeholders who might provide
valuable insights that generic industry professionals might not have considered.
The topic of the survey is perhaps the primary delimitation. Because the survey
focused on GDUFA and its influence on the generic drug landscape, it did not attempt to
solicit views on other programs, and most notably the FDA user fees programs for other
product lines such as prescription, biosimilar or animal drugs, or medical devices. Other
FDA user fee programs associated with those products have guidelines, regulations, and
commitments that may be different and instructive to this topic. Because of this
delimitation, the findings from this research might not generalize to FDA user fee
programs for other types of medical products. Being cautious in this regard is important
because the FDA Office of Biopharmaceutics, the Office of Pharmaceutical Quality and
the office responsible for planning and executing FDA inspections are same for both
generic and innovative drugs. Thus, the temptation may exist to broaden the
interpretation of views learned here related to FDA transparency and compliance
oversight to product types other than generic drugs. However, the programs that govern
155
user fees, approval processes and quality oversight for prescription drugs differ
significantly from those for generic drugs. Programs for innovative drugs have been in
place for a longer time, have fewer submissions with which to deal, and higher user fees
than is characteristic for the generic drug program.
Further, the constantly evolving regulatory landscape for generic drugs affects the
currency of the literature review. The research conducted here took place across two
generic user fees iterations, GDUFA I and GDUFA II. This dissertation is therefore
limited to a snapshot in time during a period of significant and rapid change in the
generic drug regulatory environment. The views of the generic drug industry may change
as the regulatory environment undergoes further evolution going forward.
5.2.2 Limitations
The potential effects of study design and survey methodology have been
considered above, but other conditions affecting the trial can also limit the validity of the
results and must be acknowledged. The findings from the survey must be viewed
through the prism of these limitations (Creswell & Creswell, 2017). First, the
development of a survey tool was challenged by the relative paucity of literature relating
to the subject of generic drug user fees. In particular, baseline information on industry
views was very difficult to find. Only limited insight beyond anecdotal information is
currently available on this topic and many of the resources drawn from for this research
came from non-peer reviewed sources, such as magazines, blogs, the web, and reports.
Commonly, these writings contained personal and often inflammatory opinions from
156
authors that might be unsubstantiated by methodologically rigorous data. Relying on this
sparse literature as the theoretical foundation to create a survey questionnaire made it
difficult to assure that the depth and nature of its questions were sufficiently
comprehensive.
Because the literature on this subject is scanty and addresses a relatively recent
change in policy, it was necessary to use sources beyond the usual published scholarly
literature. The restricted body of literature may be viewed as a potential limitation, but it
also illustrates a need for systematic research to extend the current body of knowledge on
GDUFA and the generic drug regulatory process. I felt in this situation that the inclusion
of non-refereed content was important. The quality of research, published or not, is
distributed along overlapping continua, and it is evident that not all unpublished studies
are of poor quality, and not all published studies are of high quality despite being peer-
reviewed (Conn et al., 2003). As identified by others, the exclusion of “grey” literature
can admit into discussion only a portion of available evidence. If the views that are
expressed more informally are not taken into account, systematic error may be introduced
that favors only those who are adept at writing scholarly papers, and this could threaten
validity, for example by misestimating effect sizes or giving a stronger voice to
individuals with a particular academic viewpoint (Moher et al., 2000; McAuley et al.,
2000). In some social science fields, it is now recognized as important to seek and
include grey literature when it meets predefined criteria (Balshem et al., 2013).
157
Another potential limitation in survey research relates to the ability of the
questions in the survey instrument to probe the views and experiences of the audience
sufficiently; failure to have an adequate range and depth of survey questions can
challenge the internal, or face, validity of the survey results (Marshall & Rossman, 2014).
It is well documented that question complexity, as reflected by syntax, word length, and
frequency, and sentence length will also affect the readability of survey questions and
could have an impact on the survey results (Sahlqvist et al., 2011; Lenzner, 2014). It is
also difficult to know whether the survey participants answer the questions from the point
of view of the company or from their own personal experiences unless the questions are
worded appropriately. For this reason, a focus group was used to critique the survey
questions. The use of a focus group has been suggested to improve the “face” validity of
the survey questions (Nassar-McMillan et al., 2010; Elser, 2016). The use of experts
with significant but diverse experiences ensured that the research questions were
considered from different points of view. Those expert contributions certainly assisted in
finding areas where questions were confusing or inappropriate.
An exploratory study is limited in its scope, especially when the survey questions
use formats that allow only simple yes or no answers or graded levels for satisfaction or
agreement. Likert scale-type questions are known to insert a level of ambiguity by
offering a neutral choice of “neither agree nor disagree” that could reflect either no
opinion or a neutral opinion (Garland, 1991; Hartley, 2014). Multiple choice questions
risk the introduction of bias especially if the answer choices are not comprehensive
(Dialsingh, 2008). Thus, the survey included open text “comment” boxes in which
158
respondents reflect on their experiences and views give an opportunity to obtain detailed
opinions that might not be captured by simple multiple-choice or scaled-choice questions.
Nonetheless, it is always possible that the survey will fail to identify important areas that
would have added more clarity. In the future, follow-up interviewing methods may be
useful to understand certain areas more deeply and to gain insight into why some
respondents did not complete all of the questions in the survey, for example. For instance,
it may be useful to identify specific findings that need additional explanation or locate
individuals who gave extreme or unexpected results and then sample those respondents
through interviews to refine and further explain select statistical results.
Another challenge associated with electronic surveys is its external validity- the
ability to assure the representativeness of potential respondents so that data collected in
the study can be generalized to other contexts and to all experts in the field
(Bhattacherjee, 2012). An online survey does create risks. The respondents will be those
who self-select to have time and inclination to take the survey, so it may be biased toward
only a particular, perhaps unrepresentative, subset of those solicited to participate
(Braithwaite et al., 2003). It is a particular challenge to identify and assure the
engagement of busy professionals (Bhattacherjee, 2012). For this study, it was clear that
the respondent pool would be a specialized group of individuals with a set of experiences
not common to regulatory professionals more generally, so a purposeful sample appeared
to be the most appropriate sampling design (Hulley, 2007). This purposive sample was
then expanded using a “snowballing” approach, reputed to be particularly effective in
assessing hard-to-reach populations (Atkinson & Flint, 2001). However, snowball
159
methods, in which individuals recommend others with like interests or backgrounds, have
also been criticized because the new additions may share similar views to their
“recruiter”, diminishing the likelihood that the sample will be drawn randomly from the
target population (Atkinson & Flint, 2001; Sadler et al., 2010). I, therefore, attempted to
assure that the survey respondents came from companies of different sizes, worked for
companies that marketed more than one type of product category, and had different levels
of experience within the pharmaceutical industry, spanning from less than 2 years to
greater than 20 years of experience. This heterogeneity is important to assure some
degree of generalizability to the overall study population. However, when reviewing the
findings from the survey, the highly specialized experiences and skillsets of the
respondents, many of whom are interacting professionally with one another, could
present a bias that does not represent the views of those outside of this group (Sue &
Ritter, 2012).
Perhaps the area of greatest concern when dealing with an electronic survey is
that of obtaining a reasonable response rate (Sheehan, 2001). External validity of the
study can be challenged if the respondent group is too small. Short surveys are known to
elicit higher response rates; a lengthy and difficult survey can be uninviting even for
highly motivated respondents and can result in a low completion rate (Kost & de Rosa,
2018; Bhattacherjee, 2012). The survey for this study consisted of 35 questions and took
respondents on average less than 20 minutes to complete. To increase the response rate
further, the survey was held open for six weeks and participants who did not complete
were sent reminder emails. Nevertheless, security constraints imposed by companies on
160
their electronic communications blocked many surveys from the e-mail “inbox” of the
potential recipients. Some respondents identified that they later found the email with the
attached survey tool in a “spam” folder, but others may have missed the email because
they did not check for it there. Thus, it is not possible to know whether many potential
respondents were unresponsive because the survey did not arrive as intended.
Nevertheless, the response rate of 52% was relatively good compared to the average
response rate of 24% – 40% for electronic surveys generally considered sufficient to
deduce analyzable data (Sheehan, 2001; Medina, 2015). The fact that the survey was
anonymous may have helped to increase the response rate by reassuring the respondents
that they could express their views honestly. The importance of the research topic to the
respondents may also influence the response rate (Cook, Heath & Thompson, 2000;
Sheehan, 2001; Medina, 2015).
5.3 Consideration of Results
The passage of GDUFA in 2012 (USFDA, 2012)constituted perhaps the biggest
change in generic drug regulation since the Hatch-Waxman Act in the 1990s. The aim of
this research project was to appraise the effect of GDUFA legislation on the regulatory
environment for generic drugs in the US. It uses a triadic framework of safety, access,
and transparency, enunciated in the 2012 GDUFA Commitment Letter (USFDA, 2012)
accompanying the implementation of GDUFA, as areas that congress wanted to be
improved by the legislation. In each of the three domains, subtopics identified in the
literature review were explored to identify whether gains in those areas are in fact
161
occurring, through the views and experience of a principal stakeholder, the generic drug
industry.
5.3.1 Impact of GDUFA on Generic Drug Access
5.3.1.1 Efficiency of Regulatory Approval
Following the implementation of GDUFA, many were skeptical as to whether the
new law would improve access to new generic drugs by accelerating the timeline to
approve these products. However, results from this research seem to prove those skeptics
wrong. The fact that fewer than 10% of respondents disagreed with the statement, “under
GDUFA, the ANDA approval rate has improved to our company’s satisfaction”, suggests
that the legislation is having a positive effect on approvals. These survey findings are
consistent with data from more recent GDUFA performance reports showing that the
FDA not only met but exceeded its performance goals related to the timeliness of reviews
(Berndt, Conti & Murphy, 2018; Woo et al., 2018). Under GDUFA, for instance, FDA
committed to review and act by the end of September 30, 2017 on 90 percent of all
ANDAs that were pending on October 1, 2012 (the so-called “backlog” applications).
According to the 2017 GDUFA performance report (USFDA, 2017c), FDA exceeded
expectations by acting on 98 percent of the 2,866 applications comprising that backlog.
Furthermore, it took action within 15 months on 497 out of 502 (97%) of original ANDA
applications submitted in 2015, exceeding the GDUFA goal of 60%. It also exceeded its
performance goal for 2016 by taking action within 15 months on all of the 680
162
applications submitted in 2016 (100% actions taken versus 75% GDUFA goal). For
applications submitted in FY 2017, FDA took action on 99% within 10 months.
Some would argue that looking at first actions on submissions is misleading if
those first actions do not relate well to product approvals. GDUFA explicitly instructed
the FDA to “review and act on” applications within certain timeframes but not
necessarily to approve those submissions or carry out other favorable actions within those
timeframes (GDUFA II Commitment Letter). Nevertheless, ANDA approval rates seem
also to have improved since the implementation of GDUFA. In 2017, FDA had the
largest number of generic drug approvals and tentative approvals in the history of the
generic drug program (USFDA, 2017c). More importantly, as indicated in the GDUFA II
Quarterly Performance Activity Report (USFDA, 2019), the current median approval
time for applications dropped to 24.43 months in the second quarter of FY2019. FDA
identified two reasons that might account for the quicker generic drug approvals. First
was the increase in the number of qualified FDA staff who could dedicate their efforts to
application review. Second was the submission of more complete applications by
sponsors. In part, those improvements may be attributed to an increased level of
interaction between FDA staff and industry sponsors before the ANDAs are submitted
(Craddock, 2018). All of these improvements seem to have had an effect on increasing
the confidence of industry with respect to FDA’s commitments under GDUFA. The
findings here that respondents rarely disagreed with the statements that “the measured
progress of GDUFA is an incentive to bring companies to the GDUFA III negotiation
table” and “GDUFA is executed within the scope for which it was intended” seem to
163
provide compelling evidence that GDUFA has, at least in some respects, been successful
in gaining the respect of the generic stakeholders.
The speed with which FDA reviews the ANDA submissions is only one, albeit
important, dimension of access. Another important factor, recognized by respondents
here, is the price erosion for some drugs over the last few years. Price erosion diminishes
the incentive for some generic companies to produce certain types of products. Other
factors relate to the competitive nature of the market itself. Some drugs are too complex
to make inexpensively. Others have a reference product held by aggressive brandholders
determined to keep generic competition at bay by using a number of anticompetitive
tactics, discussed below.
5.3.1.2 Impediments related to complexity of novel generics
Even ten years ago, generic drugs typically had simple forms and straightforward
production pathways. However, innovator companies have recently taken advantage of
technological advances to produce more complex drugs and drugs with more specialized
delivery systems. Generic products can be introduced when these products lose their
patent protection. The development of such generics, however, can be limited if generic
companies do not have the technical and regulatory capabilities to deal with these more
complicated drugs. Only about one-third of respondents in this survey had filed one or
more complex generic ANDAs. Many found it difficult to hire staff with suitable
expertise for the more complicated products. Others did not answer questions related to
complex generics, possibly because they saw it as irrelevant for their organization. This
164
might signal that many companies, and particularly smaller companies, are still at early
stages of considering whether to develop more complex generics. It might also reflect a
sensitivity to share what they considered to be confidential information.
Generic versions of a few complex generics have been approved by the FDA as
therapeutically equivalent to the innovator products. Yet, misinformation and myths
persist regarding the ability of FDA personnel to understand and review bioequivalence
for these products (Schellekens et al., 2011; Bates et al., 2016). In agreement with
previous literature, technical, clinical, and regulatory challenges all ranked as important
barriers to the development of complex generics by most survey respondents. However,
different types of challenges may be more or less important for individual complex
generics. For some, pharmaceutical equivalence is difficult to establish because
physicochemical composition is difficult to determine (Srinivasan, 2015). For others,
pharmaceutical equivalence to the reference listed drug is difficult to replicate using a
simple bioequivalence study (Lionberger, 2014; Srinivasan, 2015). Some products have
complex biochemical constituents (e.g., low molecular weight heparin, peptides, iron
carbohydrate complexes, natural source products), whereas others have formulations that
are difficult to replicate (e.g., liposomal, abuse-deterrent generics, parenteral
microspheres, iron colloids), and/or the inclusion of a device for drug delivery (e.g., DPI,
MDI, nasal sprays, and transdermal systems) (Srinivasan, 2015; Prasad & Pooja, 2016).
For many complex drug preparations, an ANDA regulatory pathway may not
exist (Srinivasan, 2015). However, even complex generics that can take advantage of the
165
ANDA pathway face significant hurdles. Not only did half of the survey respondents
view the development of complex generics as more expensive than warranted by
potential market return. An even greater proportion identified that they lacked the
requisite financial resources to produce the drugs. This is not surprising given ample
evidence that the development of some complex generics can require new manufacturing
infrastructure and complex production processes that add time and cost compared to
those of simpler generic drugs (Prasad & Pooja, 2016). The survey results also underlined
the difficulties faced by companies when trying to hire staff who understand how to
develop complex generics.
Although the findings from the survey regarding the development of complex
generics may not come as a surprise, they still do not fully answer a question that is
persistent in the literature. How can we reconcile the fact that a copycat version of a new
drug product, which in most cases requires very modest clinical data compared to the
new drug, will be more challenging to develop or will take the FDA a longer time to
review and approve than the innovative drug itself? One part of the answer may lie in
differences between NDA and ANDA processes and regulatory management. Many
pharmaceutical professionals attribute the relative regulatory success of the NDA process
in the US to the frequency and quality of communication between the Agency and
sponsors (Prasad & Pooja, 2016). The resources provided by the six iterations of the
PDUFA since it was first authorized in 1992 have greatly improved predictability and
timeliness in the NDA review and approval process as a result of enhanced FDA’s
guidance, communications, and feedback with industry (Barlas, 2017). The findings from
166
this study suggest that the frequency and quality of communication between the Office of
Generic Drugs and manufacturers of generic drugs have also been improving. However,
these improvements have not been on the same scale when compared to the substantial
interactions and formalized ongoing communications that occur between NDA sponsors
and the FDA before and during the NDA review process (Milne & Kaitin, 2012). About
half of the respondents surveyed here identified the lack of FDA guidance as an
important impediment to the development of complex generics. Synergies can be gained
by lessons learned from PDUFA and branded drugs industry in designing a road map for
the regulation of complex generics (Hussaarts et al., 2017). In order to achieve success, it
will be necessary for the generic industry and FDA to collaborate on implementing high-
quality communication tools (Lee, et al., 2016). The Office of Generic Drugs seems to be
moving in that direction and now has provisions to grant pre-ANDA meetings for
complex generics in conjunction with the regulatory science program established under
GDUFA (Lionberger, 2015; Honig & Zhang, 2019). However, as echoed during the
Association for Accessible Medicines’ 2019 Rx+Biosims conference, those meeting
requests are being granted only in some cases; they appear to be limited to products with
unique regulatory or scientific issues or products that have no commercialized generic
options.
The changing world of generic approvals may require a culture change. Instead
of waiting for regulators to provide policy and guidance, some have advocated a stronger
role for industry in gathering and analyzing data as it becomes available, helping to draft
legislation and guidance documents, and providing input to questions that regulatory
167
agencies may have as they formulate their perspectives on complex drug development.
Regulatory intelligence and policy intervention are relatively new activities for regulatory
affairs departments in generic companies. It will be necessary to engage key stakeholders
from academia, regulatory bodies, and the drug industry to establish the scientific and
regulatory criteria for the review and approval of complex generics (Lionberger, 2019).
Industry, in particular, has valuable experience that it can offer when alternatives are
suggested (Miller & Cocchetto, 1997). The generic industry can look to the kind of
cooperative interactions with regulators that have been so instrumental in shaping the
global regulatory landscape for branded products, as it becomes a more active player in
this environment (Versteegh & Tracey, 1999; Gummerus et al., 2016).
5.3.1.3 Products with Restricted Access
A second type of product that can be difficult to introduce under a generic label is
that which is subject to a restricted access program such as a REMS program. It seems
clear from this research that industry professionals regard the anti-competitive misuse of
restricted access programs as a major factor impeding the commercialization of certain
types of drugs. Their views are consistent with previous reports claiming that REMS-
restricted distribution programs can prevent companies from securing a sufficient supply
of the reference listed drug samples for equivalence testing. A 2014 study sponsored by
the Generic Pharmaceutical Association (GPhA; now called the AAM) estimated that
misuse of REMS and other restricted distribution programs costs the United States $5.4
billion annually (Brill, 2014). Brand holder companies have typically justified their
refusal to sell samples by citing safety concerns for which the brand holder could be held
168
liable (Tucker, Well & Sheer, 2013). However, many respondents from generic
companies studied here do not accept these arguments as valid. Half of the respondents
disagreed that a legitimate safety justification can be made for denying access to drug
samples for generic drug testing. At the same time, however, about a quarter had a
different view, that denials based on safety justifications might sometimes be valid. The
FDA has attempted to address this issue by providing certain generic companies with a
letter, directed to the RLD holder, to confirm that the proposed bioequivalence testing
protocol of that generic company can fit safely within the parameters of the applicable
ETASU. However, as demonstrated from the results of this survey, and corroborated by
literature, the measures appear to fall short. Even recent measures taken by the FDA to
publish the list of brand holders that refuse to provide samples in an effort to “shame”
them appear to have been unsuccessful in many cases (Yadin, 2018). In some instances,
respondents even felt that the intervention from FDA has created additional bureaucratic
hurdles to the efforts of generic companies to acquire RLD samples. Instead, some
advance the opinion that the problem cannot be solved by policies alone and may require
a legislative mandate requiring the RLD holder to provide the needed samples (Reichertz
& Ross, 2015).
There is another way in which the REMS system can impede access to a generic
product - specifically when that drug product is subject to a shared REMS program.
Under such shared programs, the generic and RLD must enter into a single, shared
agreement to ensure compliance to the ETASU. Innovator companies often complicate
and delay the negotiations for establishing the shared system with generic drug
169
companies (Gottlieb, 2018a); some have even implemented restricted distribution
systems that have not been mandated by FDA (Gottlieb, 2018a). For example, Turing
Pharmaceuticals employed a restricted distribution system requiring that prescriptions be
filled from a single specialty pharmacy that could refuse to sell the product to generic
drug developers (Karas et al., 2018). It then comes as no surprise that a majority of
respondents in this survey considered that a statutory solution would be required to
resolve the use of REMS to impede generic competition. Their view appears to be shared
by many in the US Congress, who have worked over the past few years to implement
certain reforms in the REMS regulations. The most prominent of these reforms include
the “Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act” and
the “Fair Access for Safe and Timely Generics (FAST) Act” introduced in the US
Congress in 2017 with broad bipartisan support. Under the CREATES Act (United States
Congress, 2019), a drug company can bring a civil action against an innovator drug
company if the company refuses to make available enough samples of a product for
biosimilar or generic testing. The FAST Generics Act seeks to require RLD holders of
non-REMS drugs to provide drug samples to generic manufacturers at a market-based
price like that offered to third parties in the open market (United States Congress, 2017).
These bills are slowly making their way through the multiple review and approval
processes in Congress. CREATES was passed by the Full House of Representatives in
May 2019. The Senate HELP Committee and the Senate Judiciary Committee also
passed their own versions of CREATES, yet neither have yet passed the full Senate as it
is wrapped up in a much larger package with multiple Senate holds [Action on
170
Legislation, H.R. 965, 116th Cong. (2019-2020)]. Certainly, the legislative option
remains an uphill task because it can be so difficult to balance the interests of brand
holder and generic pharmaceutical companies (Karas et al., 2018). The generic drug
industry and other stakeholders have generally supported congressional efforts to prevent
the use of restricted distribution programs from delaying generic entry. The brand holder
companies firmly oppose such legislation. Testifying to the Senate Judiciary
Subcommittee on Antitrust, Competition, Policy, and Consumer Rights in June 2016, a
representative from those companies reiterated the argument that many safety concerns
could arise as a result of certain legislative attempts to make it easier for generic
companies to obtain samples (U.S. Senate, 2016).
5.3.1.4 Products Restricted by Patent System
Another impediment to generic entry, commonly captured in previous studies or
anecdotal reports and corroborated here, is the prevalence of patent and exclusivity game-
playing by brand-holder drug companies to delay or prevent the introduction of generic
drugs. Two strategies recognized in the literature, pay-to-delay patent settlements
(Holman, 2006; Vokinger et al., 2017) and patent evergreening (Noah, 2015), were
investigated in this survey. That these approaches still exert significant power is evident
from the responses of industry participants here. Seven out of ten survey respondents
rated pay-for-delay patent settlement agreements as either a very important or important
factor impeding access to generic drugs. These arrangements, characterized by payments
to generic manufacturers to delay the introduction of generics, rely on the complicity of
171
the potential generic entrant. Although the practice of pay-for-delay is controversial and
has been litigated extensively (Holman, 2006; Hemphil, 2007), existing literature
suggests such settlements continue to be popular among drug companies.
Innovator drug companies also delay competition through “evergreening”, an
approach in which additional patents relating to product and process improvements are
introduced to extend the exclusivity period, or new product generations are launched to
secure additional protections (Dutfield, 2017). Results from this survey reinforce much
other evidence that evergreening is still used to impede generic drug access. For example,
a study involving drugs listed in the Orange Book between 2005 and 2015, conducted by
Robin Feldman, revealed that patent evergreening is not only pervasive but is also
growing across time (Feldman, 2018). The study paints an image of an innovative
pharmaceutical system trying to create “competition-free zones” to push the generic
competition further into the future. Feldman identified that branded pharmaceutical
companies increasingly recycle and repurpose old drugs rather than create new ones.
According to his study, seventy-eight percent of the drugs associated with new patents in
the FDA’s records between 2005 and 2015 were existing rather than new drugs.
Compounding this problem is the finding that many of the additional patents were of
questionable validity. Nevertheless, the prohibitive cost of litigating these questionable
patents discourages potential competitors from pursuing the development of affordable
generic drugs, especially if the litigation costs are likely to exceed the potential return on
investment (Feldman & Frondorf, 2016).
172
Evergreening is particularly common among blockbuster drugs. The fact that
more than 70% of the roughly 100 best-selling drugs had their protection extended at
least once, and almost 50% had it extended more than once, illustrates the common use of
patent extensions as an anticompetitive tactic. Manufacturers of blockbuster drugs have
the most to lose when exclusivity ends, and the most to gain by extending the lifetime of
the drug, even by just a few months (Feldman, 2018). Looking more widely at both
blockbuster and non-blockbuster drugs, Feldman further identified that almost 40%
erected additional barriers to entry by having additional patents or exclusivities. As he
states, “once a company starts down this road, there is a tendency to keep returning to the
well” (Feldman, 2018). About 80% of companies added more than one patent, some
added 4 or more protections and some even added more than 20. That the trend may be
growing is suggested by findings that the number of drugs with a patent extension almost
doubled during the 10 years from 2005 and 2015 (Feldman, 2018).
The combined effects of all of these competing factors have the unintended public
health consequence of increasing drug prices. Although different solutions have been
proposed to resolve these issues, most stakeholders appear to believe that the most
effective way to reduce prescription drug costs is to prevent innovative pharmaceutical
companies from taking advantage of the anti-competitive opportunities presented by the
patent and regulatory systems (Roehr, 2017; Vokinger et al., 2017). Restrictions on such
behaviors will require not only political will but also legislative action, in the opinion of
most respondents here.
173
5.3.2 Impact of GDUFA on Transparency
The ability to gain marketing approval efficiently is a key concern for generic
companies that currently operate in an environment where only about 10 percent of
submissions are accepted on the first action by the FDA. One reason that has been
advanced for the delays and denials has been what some have perceived as a lack of
review consistency during the ANDA review process. Prior to the implementation of
GDUFA, industry complained about inadequacies in the transparency and consistency of
the ANDA review process. Seven years after its implementation, FDA appears to believe
that transparency has improved (2018 performance report). Their views seem to be
supported by the results from this survey because nearly half of the respondents
characterized the level of transparency as “improved” compared to the situation prior to
the implementation of GDUFA. Furthermore, almost the same number of respondents
identified that the effectiveness of communications with the Office of Generic Drugs had
improved; only a small percentage opined that it had stayed the same or worsened.
Commenting on the impact of transparency, one respondent noted that “the overall
transparency post-GDUFA has had a positive impact on the industry”. According to
another respondent,
… when GDUFA was first implemented the level of communication was
adversely affected. PM's were unable to provide any details on the
review status of pending ANDAs. Subsequently, the level of
communication increased but the level of detail has diminished.
Results from the survey also suggest increased efficiency and transparency in the
FDA guidance development process. Respondents more commonly agreed than disagreed
174
that FDA’s new guidance-development priorities align with drug-development priorities
sought by industry and that FDA guidance documents were written based on sound
scientific principles and/or reliable scientific evidence. Respondents also indicated that
FDA was taking their feedback into consideration in the development of guidance
documents. The qualitative insights in the current FDA guidance development program
identified by the respondents are consistent with a blog by Kristen Booth, which reported
that FDA has focused increasingly on guidance development for generic drug
products. While only two generic-related guidance documents were issued in 2015, and
seven in 2016, there was a surge to 15 guidance documents issued in 2017.
regarding ANDAs and/or generic drug products, not including product-specific guidances
(Booth, 2018). Even more noteworthy according to the 2017 GDUFA performance report
is the fact that the Agency posted 108 new draft guidances and 86 revised draft product-
specific guidances in 2017 with recommendations on how to demonstrate therapeutic
equivalence to specific reference-listed drugs. A similar trend was observed in 2018 with
the issuance of 16 non-product specific guidances for industry documents and multiple
product-specific guidances (USFDA, 2018). Perhaps the reason that FDA is focused on
guidance development relates not only to the fact that it committed under GDUFA to
advance scientific efforts to develop new generic drugs but also because guidance
documents are critical to support industry efforts to comply with the law and to submit
substantially complete applications.
However, the responses to questions about the consistency of the review process
create a somewhat different picture. Consistency can be an important indicator of
175
efficiency and effectiveness in the regulatory system. Many within the generic drug
industry express the opinion that the FDA has not done enough to improve the
consistency of ANDA reviews. According to most respondents here, the ANDA review
process only sometimes provided consistent evaluations from different reviewers; only
one in five stated that FDA review was frequently consistent, and none found it to be
always consistent. It was striking that more than one in three respondents identified
inconsistencies to be the most important impediment to generic drug entry in the US.
Further, half of the respondents regarded such inconsistencies as the most important
cause for the increased number of FDA deficiency letters issued to ANDA sponsors. One
respondent opined that
…ANDA reviews performed by different reviewers with totally different
backgrounds always brings a significant inconsistency into the process
and different quality submissions can be approved or rejected due to
such inconsistency. It is almost like you need to be lucky, not just
provide good quality dossier.

Other respondents noted that many reviewers requested information that they
regarded as irrelevant or scientifically unjustified for that particular drug. One respondent
commented that inconsistencies extended beyond reviews to FDA inspections. Different
inspectors could reach different conclusions during FDA compliance inspections.
The views regarding inconsistency are not unique to this survey. Similar
observations have been made by others (DiMasi, Milne & Tabarrok, 2014) and have also
been acknowledged by FDA itself, as one of the leading causes in the delay of ANDA
review (Food and Drug Administration Safety and Innovation Act of 2012, Section 1131,
176
(United States Congress, 2012)) (USFDA, 2011). Further, concerns about consistencies
are not limited to a specific review division. In a recent report to the US Congress, the
Government Accountability Office (GAO) identified inconsistencies in the FDA’s review
of applications in multiple offices. Examples are also described in the literature where
companies with multiple, similar products or in some cases different applications for the
same product report that different reviewers ask different questions or request additional,
different data when reviewing the application (GPhA, 2014).
A consistent standard of review across staff and disciplines would allow a more
efficient, transparent and predictable process for all parties, who could then expect
regulatory decisions to yield the same outcome on repeated review (Breunig & Menezes,
2012). Now that FDA has made substantial progress with regard to the speed of its
reviews, it might be encouraged to develop a stronger framework to ensure application
consistency. When respondents in this survey were asked for suggestions on initiatives to
prioritize during future GDUFA III negotiations, more than one in three identified that
initiatives to improve review consistency were most important to their companies. The
Agency seems to be responsive to these concerns. Former FDA Commissioner Scott
Gottlieb announced a framework designed to enhance clarity, predictability, efficiency,
and consistency of premarket reviews on February 5, 2018 (Gottlieb, 2018b). Similarly,
Peter Stein (2018), the Director of Office of New Drugs, recently admitted that FDA’s
reviews had inconsistencies during the Biopharma Congress IV, sponsored by Prevision
Policy and the Friends of Cancer Research, on Nov. 14, 2018. At that time, he outlined
policies that help to reduce the extent of the inconsistencies. Stein said that certain
177
centralized activities within the OND, such as better project management and targeted
policy development, will increase consistency, but he also asked industry to call out FDA
when it does not give consistent advice or a similar regulatory interpretation. In Stein’s
(2018) words,
I think industry has a role in flagging where we are clearly
inconsistent. I think that's where there's a legitimate scientific question
and really clear information to suggest that there's really been a
disconnect between how things have been done before or how things
are done in one division versus another, I think flagging that is
perfectly legitimate.

The FDA Office of Pharmaceutical Quality (OPQ) has also launched a pilot study to
explore the effectiveness of a standardized question-based review format that emphasizes
the critical aspects of quality that manufacturers should address in both NDAs and
ANDAs. This structured format for summarizing quality information can enhance
quality, transparency, and consistency of assessments; reduce review documentation
time; and facilitate team-based review and communication (OPQ White Paper).
Clearly, enhancing the consistency of FDA review is important, but may not be
the only area that could benefit from improvement. The results of this study revealed that
a significant portion of deficiencies identified during FDA review might be linked to the
poor quality of ANDA submissions. Thirty-five percent of respondents rated as “very
important” and another 32% rated as “important’ the declining quality of ANDA
submissions by sponsors rushing to be first to file or first to market. As explained in
Chapter 2, rushing to file as soon as possible is a high-stakes strategic move, fueled
178
particularly by the “180-day rule”. This rule gives 180-day marketing exclusivity to the
first applicant filing a generic drug application containing a Paragraph IV certification if
that applicant is sued by the brand holder company and successfully wins that suit.
Because generic drug strategy often relies on early market access, Bob Pollock, a former
OGD deputy director, explained that manufacturers often submit a “placeholder” ANDA
that does not represent what they consider to be a good final product so that they can get
a date stamp on the submission. They recognize that the desired “quality target product
profile” or conditions of marketing may be inadequate, but hope to fix the inadequacies
later (Pollock, 2013). As an illustration, he cites the example of a generic drug
manufacturer submitting an application with information about an API or packaging
component from a source that will not be the one used when the company carries out its
commercial manufacturing. The regulatory challenges induced by this hypercompetitive
environment can lead to submissions of poor quality that require multiple review cycles,
and delay access to generic drugs, perhaps by years, if the deficiencies cannot be
addressed without additional research and development (Woo et al., 2018). For instance,
some respondents in the survey noted that FDA deficiency letters may contain requests
for new stability studies, new bioequivalence studies or further work to prove critical
quality attributes of the drug product. The necessary data will take more time to collect
than the review time typically spans. This issue of poor submission quality, noted by
Director of OGD Kathleen Uhl, at the 2017 Annual GPhA conference, remains a serious
subject of concern for FDA reviewers. The FDA Guidance for Industry titled “ANDA
Submissions – Refuse-to-Receive Standards” identifies certain recurrent deficiencies that
179
in FDA’s experience have led the FDA to refuse to receive (RTR) an ANDA. Some of
the deficiencies include: applications with failing stability data; applications that do not
justify levels of inactive ingredients that acceptable levels; applications that do not
provide validation or verification reports for analytical test methods; and applications that
have inadequate or failing dissolution or bioequivalence data. FDA has recently laid
down clear steps for the submission of substantially complete applications in the
Guidances for Industry titled “ANDA Submissions — Content and Format of
Abbreviated New Drug Applications” and “Good ANDA Submission Practices”.
Nevertheless, ANDA applicants continue to struggle with preparing and submitting high-
quality applications. Of the 1,044 ANDA applications in FY18, the RTR rate stood at
12.2%, and only 10 percent of applicants received first-cycle approval (Woo et al., 2018).
5.3.3 Impact of GDUFA on Safety
The impact of pharmaceutical quality on drug safety cannot be overemphasized,
so changes to drug regulations can often be used as opportunities to consider more
broadly whether improvements can be made to drug safety. GDUFA gave FDA the
opportunity to evaluate its approaches to the inspections associated with drug approvals,
and as importantly, to increase the resources for such inspections. As the results from the
survey demonstrate, industry respondents mostly believe that the FDA is taking its
GDUFA compliance obligations seriously. Not only did two out of three respondents
report that the depth and rigor of compliance inspections had improved since the
implementation of GDUFA, but they also identified that ANDA approvals had not been
delayed by slow site inspections in the companies for which they worked or consulted.
180
This is good news for all stakeholders, including patients, industry and the FDA, because
the discussions leading to the enactment of GDUFA were carried out in an environment
perceived not only to delay the introduction of new generic drugs but also to risk the
safety of the public because GMP facility inspections were insufficient. Prior to GDUFA,
FDA inspected domestic facilities about once every 2 years, but only had resources to
conduct inspections of human foreign drug manufacturers about once every 7 to 13 years
(GAO, 2016; Vivian, 2008). Thus, FDA committed as a performance goal to achieving
risk-adjusted parity in the frequency of inspections between foreign and domestic
establishments by FY 2017, and ensuring that domestic and foreign inspections would be
conducted with “comparable depth and rigor”.
This survey provides certain findings suggesting that the FDA’s commitment to
heightened compliance oversight and enforcement has had a positive effect beyond that
on product approval times. The majority of survey respondents identified that the
increased frequency in compliance inspections had enhanced the attention paid by their
companies to quality improvements. Their views are consonant with FDA’s 2017 annual
GDUFA report to the US Congress suggesting that the heightened inspections have had
an impact and are especially important to assure the quality of internationally-sourced
products. The responses suggest that drug manufacturers are becoming more attuned to
quality standards. Their attention to quality is particularly important to assure that drugs
do not fall into short supply because of manufacturing nonconformities detected during
FDA inspections (Kweder & Dill, 2013). Significant violations of the current good
manufacturing practice regulations identified during compliance inspections can prompt
181
FDA to issue a warning letter or additional regulatory actions up to and including
injunctions from commercial drug distribution or suspension of ANDA approvals. Drug
shortages have serious effects on the ability of patients to access their medications, so
proactive attention to manufacturing and quality issues is an important public safety goal
for both the FDA and drug manufacturers (Kweder & Dill, 2013; Nonzee & Luu, 2019).
The fact that survey respondents identified an increase in the frequency of FDA
compliance inspections is consistent with claims made by the FDA in the successive
GDUFA performance reports that it had exceeded its commitment to ensuring
consistency and frequency of inspections for domestic and foreign facilities. However, as
the review times shortened, some critics have worried that FDA could sacrifice its
diligence to ensure safety on the altar of speed (Darrow, Avorn & Kesselheim, 2017;
DiMasi, Milne & Tabarrok, 2014). The increase in the frequency of compliance
inspections and the improvement in the conduct of the inspections may provide some
assurance to those critics that public health has not been compromised by the more rapid
administrative activities.
While the FDA would appear to be on the right track when it comes to
compliance inspection and enforcement, it still has work to do if it is to satisfy all of its
critics in the generic drug industry. In the present survey, a few respondents expressed
concerns about inconsistencies in inspections and a perceived lack of expertise of
inspectors. Complaints about inconsistencies in FDA compliance inspection programs are
not new. For example, Jaskot et al. (2011) noted that inconsistent availability and
182
communication of information regarding the status and outcomes of FDA inspections
could affect the transparency and predictability of reviews. FDA itself acknowledged
certain shortcomings in the quality of inspections during the GDUFA negotiations but
blamed it on the inadequate resources provided to manage an increase in both the number
of ANDAs and the number of facilities supporting those applications that must be
inspected (Jaskot et al., 2011). FDA is not the only regulatory agency to have difficulties
in meeting inspectional obligations, especially in the face of surging growth in overseas
drug facilities. In an effort to enhance its inspection program, beginning November 1,
2017, the FDA entered into Mutual Recognition Agreement (MRA) arrangements with
European Union drug regulatory authorities The MRA enables the U.S. and EU
regulators to rely on the inspectional data obtained by the inspections of pharmaceutical
manufacturing facilities by one of the agencies belonging to the group. Stressing the
benefit of the MRA, former FDA Commissioner Scott Gottlieb stated that,
..at a time in which medical product manufacturing is truly a global
enterprise, there is much to be gained by partnering with regulatory
counterparts to reduce duplicative efforts and maximize global
resources while realizing the greatest bang for our collective
inspectional buck (Gottlieb, 2017).

However, the most active pharmaceutical ingredient is coming from China and India,
which are not covered by the MRA.
183
5.4 Conclusion and Future Directions
Prior to 2012, the FDA typically took more than 30 months, and sometimes up to
60 months, to review an Abbreviated New Drug Application (ANDA). The FDA and
industry reached a consensus and were able to convince a skeptical US Congress that
speeding up the review and approval of generic drug applications would likely require
greater resources. Thus, was born the Generic Drug User Fee Act with the laudable goal
of clearing the enormous backlog of applications, speeding new application reviews, and
improving the quality and safety of generic drugs.
The research underpinning this thesis has examined in greater depth the elements
that determine the effectiveness of the regulatory processes for generic drugs. Evidence
from the research seems to suggest a system in evolution. Respondents saw the passage
and implementation of the Generic Drug User Fee Act in 2012, and its successor,
GDUFA II, in 2017 as achieving their objectives to reduce the approval times for generic
drug applications. Another important finding from this research was the evidence that
increased communication is now occurring between generic drug sponsors and the FDA,
and that these interactions have fostered transparency. However, respondents were also
concerned that efficiency in the regulatory system for generics was being jeopardized by
inconsistencies between FDA reviewers and by the submission of poor quality
applications by ANDA sponsors. At the end of the day, problems in the development and
regulatory approval of generic drugs stem from both “drug development on the clock” on
the part of applicants and “regulatory review on the clock” on the part of the FDA.
184
Industry and FDA share the goal of achieving an ANDA review process that is capable of
providing a first-cycle approval rate consistent with other FDA programs such as NDAs
and BLAs. In order to improve ANDA quality, both sides must recognize the deficiencies
and focus on concrete steps that can ensure improvements. Insight from this research also
underlines the need for statutory changes that can minimize the game playing by brand
holder drug manufacturers. Achieving a legislative solution to this issue will be difficult
in the current political landscape, but it is central to ensuring patients have affordable
access to vital drugs.
The snapshot of views collected in this study provides an initial gauge and a
baseline that will assist in defining future frameworks for FDA user fee programs. The
survey represents the views of industry taking into consideration only the first iteration of
GDUFA and the first full year out of the five years that constitute the second iteration,
GDUFA II. It would be useful to repeat this survey after future GDUFA iterations
because changes to the scope and structure of GDUFA will no doubt cause the landscape
to shift. Measuring the shift at time points in the future would serve to benchmark the
effectiveness of FDA user fee programs in enhancing regulatory efficiencies. Another
worthwhile avenue for further research is to obtain the regulators' point of view on the
issue of ANDA review inconsistency. An interview with the regulators would give
additional insights regarding their perceptions of how transparency and consistency could
be improved. Furthermore, periodic surveys of the same or similar questions would allow
changes to be seen over the baseline documented here. The challenges, complexities and
185
the dynamic nature of GDUFA and generic drug development will continue to provide a
fertile landscape for research.
186
REFERENCES………
Aday, L. A. & Andersen, R. (1974) ‘A framework for the study of access of medical
care’. Health Services Research, 9(3), pp. 208-220.
Aday, L. A. & Andersen, R. M. (1981) ‘Equity of access to medical care: A conceptual
and empirical overview’. Medical Care Research and Review, 19(12), pp. 4-27.
Anderson, C. (2004) An evaluation of harmonization in the regulatory environment and
its impact on patients’ access to new medicines. Unpublished Doctor of Philosophy,
Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Association for Accessible Medicines. (2019) 2019 Generic drug and biosimilars access
and savings in the U.S report. Available from:
https://accessiblemeds.org/sites/default/files/2019-09/AAM-2019-Generic-Biosimilars-
Access-and-Savings-US-Report-WEB.pdf [Accessed 1st September 2019].
Atkinson, R. & Flint, J. (2001) ‘Accessing hidden and hard-to-reach populations:
Snowball research strategies’. Social Research Update, 33(1), pp. 1-4.
Babbie, E. R. (2016) The practice of social research. Boston, MA: Cengage Learning.
Balshem, H., Stevens, A., Ansari, M., Norris, S., Kansagara, D., Shamliyan, T., Chou, R.,
Chung, M., Moher, D., & Dickersin, K. (2008) ‘Finding grey literature evidence and
assessing for outcome and analysis reporting biases when comparing medical
interventions: AHRQ and the effective health care program’. In: Methods guide for
effectiveness and comparative effectiveness reviews [Internet]. Rockville (MD): Agency
for Healthcare Research and Quality (US). Available from:
https://www.ncbi.nlm.nih.gov/books/NBK174882/ - [Accessed 1st May 2019].
Barlas, S. (2017) ‘Drug companies breathe easier as PDUFA VI heads for approval’.
Pharmacy and Therapeutics, 42(6), p. 357.
Bates, R., Mathur, A., Lever, H. M., Thakur, D., Graedon, J., Cooperman, T., ... & Fox,
E. R. (2016). Generics substitution, bioequivalence standards, and international oversight:
complex issues facing the FDA. Trends in pharmacological sciences, 37(3), 184-191.
Berndt, E. R., Conti, R. M. & Murphy, S. J. (2018) ‘The generic drug user fee
amendments: An economic perspective’. Journal of Law and Biosimilars, 5(1), pp. 103-
141.
187
Berndt, E. R., Mortimer, R., Bhattacharjya, A., Parece, A. & Tuttle, E. (2007)
‘Authorized generic drugs, price competition, and consumers' welfare’. Health Affairs,
26(3), pp.790-799.
Bhattacherjee, A. (2012). Social science research: Principles, methods, and practices. usf
Open Access Textbooks.
Boehm, G., Yao, L., Han, L. & Zheng, Q. (2013) ‘Development of the generic drug
industry in the US after the Hatch-Waxman Act of 1984’. Acta Pharmaceutica Sinica B,
3(5), pp. 297-311.
Bokhari, F. A. S., Mariuzzo, F. & Polanski, A. (2016, March 31) Entry limiting
agreements for pharmaceuticals: pay-to-delay and authorized generic deals. Available
from: https://ssrn.com/abstract=2626508 [Accessed 3rd November 2017].
Booth, K. (2018) ‘FDA Steps up its Game on Generic Drugs: The story behind the recent
focus on generic products’. The Weinberg Group. Available from:
https://weinberggroup.com/blog/fda-increases-focus-generic-drug-regulation/ - [Accessed
31st May 2019].
Boudes, P. F. (2017) ‘Risk Evaluation and Mitigation Strategies (REMSs): Are they
improving drug safety? A critical review of REMSs requiring Elements To Assure Safe
Use (ETASU)’. Drugs Research and Development, 17(2), pp. 245-254.
Bragg, J. L. & Florence, M. P. (2010) ‘Life with a REMS: Challenges and opportunities’.
J. Health Care L. & Pol'y, 13(2).
Braithwaite, D., Emery, J., De Lusignan, S. & Sutton, S. (2003) ‘Using the internet to
conduct surveys of health professionals: A valid alternative?’ Family Practice, 20(5), pp.
545-551.
Breunig, R. & Menezes, F. M. (2012) ‘Testing regulatory consistency’. Contemporary
Economic Policy, 30(1), p. 15.
Brill, A. (2014) Lost prescription drug savings from use of REMS programs to delay
generic market entry. Available from: http://www.matrixglobaladvisors.com/REMS
[Accessed 15th August 2017].
Broughton, B. (1996) Project planning, monitoring & evaluation training course: session
guides & notes. ACFOA, Canberra.
188
Buchanan, D. A. & A. Bryman (2007) ‘Contextualizing methods choice in organizational
research’. Organizational Research Methods, 10(3), pp. 483-501.
Butler, H. N. (2016) REMS-Restricted drug distribution programs and the antitrust
economics of refusals to deal with potential general competitors. Florida Law Review,
67(3): 977 Available from: http://scholarship.law.ufl.edu/flr/vol67/iss3/1
CMR International Institute for Regulatory Science (2001) Asia Update: Key issues in
the registration of pharmaceuticals, R&D Briefing No. 32B. [Online] Surrey: CMR
International. Available from: http://www.cmr.org/institute
Coglianese, C. (2012) Measuring regulatory performance: evaluating the impact of
regulation and regulatory policy. OECD, Expert Paper No. 1, August 2012. Available
from: https://www.oecd.org/gov/regulatory-policy/1_coglianese%20web.pdf - [Accessed
25th September 2017].
Conn, V. S., Valentine, J. C., Cooper, H. M. & Rantz, M. J. (2003). ‘Grey literature in
meta-analyses’. Nursing research, 52(4), pp. 256-261.
Cook, C., Heath, F. & Thompson, R. L. (2000) ‘A meta-analysis of response rates in
web-or internet-based surveys’. Educational and psychological measurement, 60(6), pp.
821-836.
Couper, M. P. (2000) ‘Web surveys: A review of issues and approaches’. Public opinion
quarterly, 64(4), pp. 464-494.
Craddock, K. (2018). ‘Improving generic drug approval at the FDA’. Michigan Journal
Environmental & Administrative Law, 7(2), p. 421.
Crawford, P. & Bryce, P. (2003) ‘Project monitoring and evaluation: a method for
enhancing the efficiency and effectiveness of aid project implementation’. International
Journal of Project Management, 21(5), pp. 363-373.
Creswell, J. W. & Creswell, J. D. (2017) Research design: Qualitative, quantitative, and
mixed methods approaches. Thousand Oaks, CA, Sage publications.
Darrow, J. J., Avorn, J. & Kesselheim, A. S. (2017). Speed, safety, and industry
funding—from PDUFA I to PDUFA VI. New England Journal of Medicine, 377,
pp.2278-2286.
189
Dialsingh, I. (2008) Face-to-face interviewing. In: Lavrakas, P. J. (Eds.), Encyclopedia
of survey research methods. Thousand Oaks, CA, Sage Publications.
DiMasi, J. A., Milne, C. P. & Tabarrok, A. (2014) ‘An FDA report card: Wide variance
in performance found among agency’s drug review divisions’. The Manhattan Institute
(7). Available from: https://media4.manhattan-institute.org/pdf/fda_07.pdf [Accessed
12th July 2019].
Draugalis, J. R., Coons, S. J. & Plaza, C. M. (2008) ‘Best practices for survey research
reports: A synopsis for authors and reviewers’. American Journal of Pharmacologic
Education, 72(1), p. 11.
Duffy, B., Smith, K., Terhanian, G. & Bremer, J. (2005) ‘Comparing data from online
and face-to-face surveys’. International Journal of Market Research, 47(6), pp. 615-639.
Dureja, H. (2010) New drug approval process: Regulatory view. Available from:
http://www.pharmainfo.net/reviews/new-drug-approval-process-regulatory-view
[Accessed 4th April 2016].
Dutfield, G. (2017) ‘Healthcare innovation and patent law’s ‘pharmaceutical privilege’:
Is there a pharmaceutical privilege? And if so, should we remove it?’ Health Economics,
Policy and Law, 12(4), pp. 453-470.
Elser, C. (2016) Validation master plans: Progress of implementation within the
pharmaceutical industry. School of Pharmacy. University of Southern California.
Fasanella, D. & Pope, N. D. (2011) ‘Authorized generic drugs-A look at this hotly
debated class of medications from the perspectives of generic drug companies, industry
trade organizations, and patients’. US Pharmacist, 65, p. 32.
Feldman, R. (2018) ‘May your drug price be evergreen’. Journal of Law and Bioscience,
5(3), pp. 590-647.
Feldman, R. & Frondorf, E. (2016) ‘Drug wars: A new generation of generic
pharmaceutical delay’. Harvard Journal on Legislation, 53, pp. 499 -561.
Fisher, B., Margolis, M. & Resnick, D. (1996) ‘Breaking ground on the virtual frontier:
Surveying civic life on the internet’. The American Sociologist, 27(1), pp. 11-29.
190
Florini, A. (2007) The Right to Know: Transparency for an Open World. New York:
Columbia University Press.
Fox, S. (2001) Wired seniors. The Pew Internet and American Life Project. Available
from: https://www.pewresearch.org/internet/2001/09/09/wired-seniors/ [Accessed 6
th

January 2017].
Frankel, N. & Gage, A. (2007) M&E fundamentals: a self-guided minicourse. [EPUB
edition]. Available from:
http://www.endvawnow.org/uploads/browser/files/M_E%20Fundamentals.pdf -
[Accessed 23rd April 2017].
FTC. (2011) Authorized Generic Drugs: Short-Term Effects and Long-Term Impact.
Available from https://www.ftc.gov/sites/default/files/documents/reports/authorized-
generic-drugs-short-term-effects-and-long-term-impact-report-federal-trade-
commission/authorized-generic-drugs-short-term-effects-and-long-term-impact-report-
federal-trade-commission.pdf [Accessed 15th November 2017].
Garland, R. (1991) ‘The mid-point on a rating scale: Is it desirable’. Marketing bulletin,
2(1), pp. 66-70.
GAO. (2016). Drug Safety, FDA Has Improved Its Foreign Drug Inspection Program,
But Needs to Assess the Effectiveness and Staffing of Its Foreign Offices: Report to the
Committee on Energy and Commerce (GAO-17-143). U.S. Government Accountability
Office.
Gingery, D. (2018) NDA median approval times still rising, but what does it mean? “The
Pink Sheet” Daily. Retrieved from Pink Sheet Pharma Intelligence. Available from:
https://pink.pharmaintelligence.informa.com/PS122756/ANDA-Median-Approval-
Times-Still-Rising-But-What-Does-It-Mean [Accessed 6th February 2019].
Goodman, M., Nachman, G. & Chen, L. (2004) Quantifying the impact from authorized
generics. Morgan Stanley Equity Research North America.
Gordon, J. (2013) GDUFA updates: In the beginning…. GPhA Fall Technical Meeting,
29-30 October 2013, Bethesda, MD.

191
Gortler, D. (2016) 7 ways to make the FDA great again, from a former agency official.
Available from: https://www.statnews.com/2016/12/06/fda-drug-approvals-improvement/
[Accessed 20th August 2017].
Gottlieb, S. (2017) FDA takes unprecedented step toward more efficient global
pharmaceutical manufacturing inspections [Press release]. 31st October. Available from:
https://www.fda.gov/news-events/press-announcements/fda-takes-unprecedented-step-
toward-more-efficient-global-pharmaceutical-manufacturing-inspections - [Accessed
17th February 2018].
Gottlieb, S. (2018a) FDA statement on new policies to reduce the ability of brand drug
makers to use REMS programs as a way to block timely generic drug entry, helping
promote competition and access. Retrieved from https://www.fda.gov/news-events/press-
announcements/statement-fda-commissioner-scott-gottlieb-md-new-policies-reduce-
ability-brand-drug-makers-use-rems [Accessed 17th July 2018].
Gottlieb, S. (2018b). FDA in Brief: To advance efficient development and review of
combination products, the FDA outlines principles to promote a more predictable
premarket review pathway. Retrieved from https://www.fda.gov/news-events/fda-
brief/fda-brief-advance-efficient-development-and-review-combination-products-fda-
outlines-principles [Accessed 20th May 2019].
GPhA. (2014) Comments of the Generic Pharmaceutical Association regarding Docket
No. FDA-2014-N-1168 following the Public Hearing on GDUFA Policy Development.
Available from:
https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%2
0Sheet/76/49/GPhA%20GDUFA%20Part%2015%20hearing%20comment%20101314.p
df [Accessed 2nd November 2016].
GPhA. (2015a) Statement by Ralph G. Neas, President and CEO, GPhA, on the June
15th FDA Public Meeting on GDUFA [Press Release]. Available from:
https://www.pharmacytimes.com/news/statement-by-ralph-g-neas-president-and-ceo-
gpha-on-the-june-15th-fda-public-meeting-on-gdufa [Accessed 3rd November 2016].
GPhA. (2015b) Quality of ANDAs: Perspectives and Forward Progress. Available from:
http://www.gphaonline.org/media/cms/Quality_of_ANDA_Submissions_-_03-13-
2015_1.pdf [Accessed 20th February 2017].
GPhA. (2015c) Comments of the Generic Pharmaceutical Association regarding Docket
FDA-2012-N-0882-0002: Generic Drug User Fees; Public Meeting; scheduled for June
15
th
, 2015 to discuss GDUFA I and GDUFA II. Available from:
https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%2
192
0Sheet%20DAILY/2015/August/GPhA%20GDUFA%20renewal%20comment%20CLE
AN%2081315.pdf [Accessed 23rd November 2016].
GPhA. (2016) Comments of the Generic Pharmaceutical Association regarding Docket
No. FDA-2016-D-0785, General Principles for Evaluating the Abuse Deterrence of
Generic Solid Oral Opioid Drug Products. Available from:
https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%2
0Sheet%20DAILY/2016/May/GPhA%20comments%20on%20generic%20abuse%20dete
rrent%20opioids%20draft%20guidance.pdf [Accessed 17th April 2017].
Grabowski, H. (2007) ‘Competition between Generic and Branded Drugs.’ In Sloan, F.
A. and Hsieh, C.-R. (eds). Pharmaceutical Innovation: Incentives, Competition, and
Cost-Benefit Analysis in International Perspective. Cambridge: Cambridge University
Press, pp. 153–173.
Grabowski, H. G., Kyle, M., Mortimer, R., Long, G. & Kirson, N. (2011) ‘Evolving
brand-name and generic drug competition may warrant a revision of the Hatch-Waxman
Act’. Health Affairs, 30(11), pp. 2157-2166.
Greene, J. A. & Podolsky, S. H. (2012) ‘Reform, regulation, and pharmaceuticals--the
Kefauver-Harris Amendments at 50’. New England Journal of Medicine, 367(16), pp.
1481-1483.
Gummerus, A., Airaksinen, M., Bengtström, M. & Juppo, A. (2016). Outsourcing of
Regulatory Affairs Tasks in Pharmaceutical Companies—Why and What?. Journal of
Pharmaceutical Innovation, 11(1), pp.46-52.
Hafner, T., Walkowiak, H., Lee, D. & Aboagye-Nyame, F. (2017) ‘Defining
pharmaceutical systems strengthening: concepts to enable measurement’. Health Policy
Plan, 32(4), pp. 572-584.
Harris, G. (2008a) ‘The safety gap’. New York Times Magazine, p. MM8. Available
from: https://www.nytimes.com/2008/11/16/magazine/16letters-t-
THESAFETYGAP_LETTERS.html [Accessed 10th November 2017].
Harris, G. (2008b) ‘US identifies tainted heparin in 11 countries’. New York Times, p. A1.
Available from: https://www.nytimes.com/2008/04/22/business/worldbusiness/22iht-
heparin.1.12221431.html [Accessed 10th November 2017].
Hartley, J. (2014) ‘Some thoughts on Likert-type scales’. International Journal of
Clinical and Health Psychology, 14(1), pp. 83-86.
193
Hayslett, M. M. & Wildemuth, B. M. (2004) ‘Pixels or pencils? The relative
effectiveness of web-based versus paper surveys’. Library & Information Science
Research, 26(1), pp. 73-93.
Hemphill, C. S. (2007) ‘Drug patent settlements between rivals: A survey’. Columbia
Academic Commons. Retrieved from:
https://academiccommons.columbia.edu/doi/10.7916/D85H7NSK [Accessed 11th
February 2018].
Higgins, M. J. & Graham, S. J. H. (2009) ‘Balancing innovation and access: Patent
challenges tip the scales’. Science, 326, p. 2.
Hilts, P. J. (2003) Protecting America's Health: The FDA, Business, and One Hundred
Years of Regulation. New York: Alfred A. Knopf.
Holbrook, A. L., Green, M. C. & Krosnick, J. A. (2003) ‘Telephone versus face-to-face
interviewing of national probability samples with long questionnaires: Comparisons of
respondent satisficing and social desirability response bias’. Public Opinion Quarterly,
67(1), pp. 79-125.
Holman, C. M. (2006) ‘Do reverse payment settlements violate the antitrust laws’. Santa
Clara High Technology Law Journal, 23, pp. 489-587.
Honig, P. & Zhang, L. (2019) ‘Regulation and innovation: Role of regulatory science in
facilitating pharmaceutical innovation’. Clinical Pharmacology & Therapeutics, 105(4),
pp. 778-781.
Horne, C. (2012) ‘Transparency: A concept analysis’. Nursing Science Quarterly, 25(4),
pp. 326-331.
Hornecker, J. R. (2009) ‘Generic drugs: History, approval process, and current
challenges’. US Pharmacist, 34(6), pp. 26-30.
Hulley, S. B. (2007) Designing Clinical Research. Lippincott Williams & Wilkins.
Hussaarts, L., Mühlebach, S., Shah, V. P., McNeil, S., Borchard, G., Flühmann, B.,
Weinstein, V., Neervannan, S., Griffiths, E., Jiang, W., Wolff-Holz, E., Crommelin, D. J.
A. & de Vlieger, J. S. B. (2017) ‘Equivalence of complex drug products: Advances in and
challenges for current regulatory frameworks’. Annals of the New York Academy of
Sciences, 1407(1), pp. 39-49.
194
IMARC (2019) US Generic drug market: Industry trends, share, size, growth,
opportunity and forecast 2019-2024. Available from: https://www.imarcgroup.com/us-
generics-market - [Accessed 8th September 2019].
Jacobo-Rubio, R., Turner, J. L. & Williams, J. W. (2016) Generic entry, pay-for-delay
Settlements, and the distribution of surplus in the US pharmaceutical industry. Available
from: https://www.nhh.no/globalassets/departments/business-and-management-
science/seminars/2016-spring/250516-paper.pdf - [Accessed 19th September 2017].
Jansen, H. (2010). ‘The logic of qualitative survey research and its position in the field of
social research methods’. Forum Qualitative Sozialforschung / Forum: Qualitative Social
Research, 11(2), Art 11. Available from: http://www.qualitative-
research.net/index.php/fqs/article/view/1450/2946 - [Accessed 21st April 2019].
Jaskot, D., Johnston, G., Coates, M. E. M., Mayr, C., Moutvic, T., Ramsburg, L. & Stec,
R. (2011) ‘Globalizing the FDA: Achieving safety, access, and transparency through a
comprehensive generic drug user fee program’. Journal of Generic Medicines: The
Business Journal for the Generic Medicines Sector, 8(4), pp. 198-203.
Jones, G. H., Carrier, M. A., Silver, R. T. & Kantarjian, H. (2016) ‘Strategies that delay
or prevent the timely availability of affordable generic drugs in the United States’. Blood,
127(11), pp. 1398-1402.
Karas, L., Shermock, K. M., Proctor, C., Socal, M. & Anderson, G. F. (2018) ‘Limited
distribution networks stifle competition in the generic and biosimilar drug industries’.
American Journal of Managed Care, 24(4), e122-e127. Available from:
http://www.webaddressgoes.here - [Accessed 16th July 2019].
Karst, K. R. (2014) ‘Letting the devil ride: Thirty years of ANDA suitability petitions
under the Hatch-Waxman Act’. William Mitchell Law Review, 40(4), pp. 1259-1306.
Kost, R. G. & de Rosa, J.C. (2018) ‘Impact of survey length and compensation on
validity, reliability, and sample characteristics for ultrashort-, short-, and long-research
Participant perception surveys’. Journal of Clinical and Translational Science, 2(1), pp.
31-37.
Kweder, S. L. & Dill, S. (2013) ‘Drug shortages: the cycle of quantity and quality’.
Clinical Pharmacology & Therapeutics, 93(3), pp. 245-251.
Lachman, L., Turco, S. & O’Donnell, J. T. (1990) ‘Generic drugs - A look back and a
look ahead’. Journal of Pharmacy Practice, 3(3), pp. 192-202.
195
Lee, C. Y., Chen, X., Romanelli, R. J. & Segal, J. B. (2016) ‘Forces influencing generic
drug development in the United States: A narrative review’. Journal of Pharmaceutical
Policy and Practice, 9, 26. Available from:
https://joppp.biomedcentral.com/articles/10.1186/s40545-016-0079-1 - [Accessed 24th
September 2018].
Lenzner, T. (2014) ‘Are readability formulas valid tools for assessing survey question
difficulty?’ Sociological Methods & Research, 43(4), pp. 677-698.
Lionberger, R. (2014) Developing New Bioequivalence Approaches for Complex
Products. GphA Fall Technical Meeting, 27-29 October 2014, Bethesda, MD .
Lionberger, R. (2015) GDUFA Regulatory Science Update. GPhA 2015 Annual Meeting,
9-11 February 2015, Miami Beach, Florida.
Lionberger, R. A. (2019) ‘Innovation for generic drugs: Science and research under the
generic drug user fee amendments of 2012’. Clinical Pharmacology & Therapeutics,
105(4), pp. 878-885.
Marshall, C. & G. B. Rossman (2014) Designing Qualitative Research. Thousand Oaks,
CA, Sage publications.
McAuley, L., Pham, B., Tugwell, P. & Moher, D. (2000) ‘Does the inclusion of grey
literature influence estimates of intervention effectiveness reported in meta-analyses?’
The Lancet, 356(9237), pp. 1228-1231.
McAuslane, N. & Cone, M. (2006) Building Quality into Regulatory Activities: What
does it Mean? Epsom, UK: CMR International.
Medina, C. (2015) Incentivizing Quality in the Manufacture of Pharmaceuticals:
Manufacturers' Views on Quality Ratings. School of Pharmacy. University of Southern
California.
Meyer, G. F. (1999) ‘History and regulatory issues of generic drugs’. Transplantation
Proceedings, 31(3A Suppl):10S-12S.
Midha, K. K. & McKay, G. (2009) ‘Bioequivalence; its history, practice, and future’.
American Association of Pharmaceutical Scientists Journal, 11(4), pp. 664-670.
196
Miller, J., Daly, J., Wood, M., Brooks, A. & Roper M. (1996) ‘Electronic bulletin board
distributed questionnaires for exploratory research’. Journal of Information Science,
22(2), pp. 107-115.
Miller, L. L. & Cocchetto, D. M. (1997) ‘The regulatory affairs professional in the “Hot
Seat” in the drug development process’. Drug Information Journal, 31(3), pp. 805-823.
Milne, C. P. & Kaitin, K. I. (2012) ‘FDA review divisions: Performance levels and the
impact on drug sponsors’. Clinical Pharmacology & Therapeutics, 91(3), pp. 393-404.
Moher, D., Cook, D. J., Eastwood, S., Olkin, I., Rennie, D. & Stroup, D. F. (2000)
‘Improving the quality of reports of meta-analyses of randomised controlled trials: the
QUOROM statement’. QUOROM Group. British Journal of Surgery 87, (11), pp. 1448-
1454.
Mossinghoff, G. J. (1999) ‘Overview of the Hatch-Waxman Act and its impact on the
drug development process’. Food and Drug Law Journal, 54(2), pp. 187-194.
Nannei, C. (2011). Monitoring and evaluation framework for the Global Strategy and
Plan of Action on Public Health, Innovation and Intellectual Property. Available from:
https://www.who.int/phi/implementation/ME_framework_and_implementation_final.pdf
?ua=1 [Accessed 1st February 2017].
Nassar-McMillan, S. C., Wyer, M., Oliver-Hoyo, M. & Ryder-Burge, A. (2010) ‘Using
focus groups in preliminary instrument development: Expected and unexpected lessons
learned’. The Qualitative Report, 15(6), pp. 1629-1642.
Nie, N. H., Hillygus, D. S. & Erbring, L., (Eds.) (2002) Internet use, interpersonal
relations, and sociability. The Internet in Everyday Life. Malden, MA: Blackwell.
Noah, L. (2015) ‘Product hopping 2.0: Getting the FDA to yank your original license
beats stacking patents’. Marquette Intellectual Property Law Review, 19, p. 161.
Nonzee, N. J. & Luu, T. H. (2019) ‘The drug shortage crisis in the United States: Impact
on cancer pharmaceutical safety’. Cancer Policy: Pharmaceutical Safety, Springer: pp.
75-92.
Oner, G. Z. & Polli, J. E. (2018) ‘Authorized generic drugs: An overview’. AAPS
PharmSciTech, 19(6), pp. 2450-2458.
197
Paniz, V. M., Fassa, A. G., Maia, M. F., Domingues, M. R. & Bertoldi, A. D. (2010)
‘Measuring access to medicines: A review of quantitative methods used in household
surveys’. BMC Health Services Research, 10, p. 146
Pollock, B. (2013) Time to Tighten Your Belts and Pay Attention to Quality. Available
from: https://www.lachmanconsultants.com/2013/10/time-to-tighten-your-belts-and-pay-
attention-to-quality/ [Accessed 24th July 2019].
Porter, B. (2005) ‘Stopping the practice of authorized generics: Maylan's effort to close
the gaping black hole in the Hatch-Waxman Act’. Journal of Contemporary Health Law
& Policy, 22(1), pp. 176 - 209.
Prajapati, J. & Patel, D. (2017) ‘Generic Drug User Fee Act II: The positive features for
generic drug industry’. Journal of Generic Medicines, 13(4), pp. 206-213.
Prasad, V. & Pooja, K. (2016) ‘Complex generics: Opportunities & challenges’.
International Journal of Drug Regulatory Affairs, 4(3), pp. 1-10.
Rägo, L. & Santoso, B. (2008) Drug regulation: history, present and future. In: Van
Boxtel, C. J., Santoso, B., Edwards, I. R. (eds). Drug benefits and risks: international
textbook of clinical pharmacology. revised 2nd ed. IOS Press and Uppsala Monitoring
Centre; pp. 65–77.
Rawson, N. S. B. (2000) ‘Time required for approval of new drugs in Canada, Australia,
Sweden, the United Kingdom and the United States in 1996–1998’. Canadian Medical
Association Journal, 162(4), pp. 501-504.
Rea, L. M. & Parker, R. A. (2014) Designing and Conducting Survey Research: A
Comprehensive Guide. John Wiley & Sons.
Reichertz, P. & Ross, C. (2015) New FDA Draft Guidance on REMS and Bioequivalence
Studies: Does New Procedure Secure ANDA Applicants the Right to Obtain Samples?
Available from: https://www.fdalawblog.com/2015/01/articles/legislation/new-fda-draft-
guidance-on-rems-and-bioequivalence-studies-does-new-procedure-secure-anda-
applicants-the-right-to-obtain-samples/ [Accessed 2nd June 2017].
Robeyns, I. (2005) ‘The capability approach: A theoretical survey’. Journal of Human
Development, 6(1), pp. 93-117.
Roehr, B. (2017) ‘Ban evergreening and restricting generics to reduce drug prices, says
US academy’. British Medical Journal, 359, j5624.
198
Rumore, M. M. (2009) ‘The Hatch-Waxman Act–25 years later: Keeping the
pharmaceutical scale balanced’. Pharmacy Times. Available from
http://www.pharmacytimes.com/publications/supplement/2009/genericsupplement0809/g
eneric-hatchwaxman-0809 [Accessed 6th December 2016].
Rust, R. T. & Zahorik, A. J. (1993) ‘Customer satisfaction, customer retention, and
market share’. Journal of Retailing, 69(2), pp. 193-215.
Sadler, G. R., Lee, H. C., Lim, R. S. & Fullerton, J. (2010) ‘Recruitment of hard-to-reach
population subgroups via adaptations of the snowball sampling strategy’. Nursing &
Health Sciences, 12(3), pp. 369-374.
Sahlqvist, S., Song, Y., Bull, F., Adams, E., Preston, J., Ogilvie, D. & iConnect
consortium. (2011) ‘Effect of questionnaire length, personalisation and reminder type on
response rate to a complex postal survey: randomised controlled trial’. BMC Medical
Research Methodology, 11, 62. Available from:
https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/1471-2288-11-62 -
[Accessed 20th April 2019].
Schellekens, H., Klinger, E., Mühlebach, S., Brin, J. F., Storm, G. & Crommelin, D. J.
(2011) ‘The therapeutic equivalence of complex drugs’. Regulatory Toxicology and
Pharmacology, 59(1), pp. 176-183.
Sheehan, K. B. (2001) ‘E-mail survey response rates: A review’. Journal of Computer-
Mediated Communication, 6(2). Available from:
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1083-6101.2001.tb00117.x - [Accessed
14th April 2019].
Shulman, S. R. & Kaitin, K. I. (1996) ‘The Prescription Drug User Fee Act of 1992. A 5-
year experiment for industry and the FDA’. Pharmacoeconomics, 9(2), pp. 121-133.
SIAPS. (2012). Monitoring and Evaluation Plan. Submitted to the US Agency for
International Development by the Systems for Improved Access to Pharmaceuticals and
Services (SIAPS) Program. Arlington, VA: Management Sciences for Health. Available
from: http://siapsprogram.org/publication/altview/siaps-monitoring-and-evaluation-plan-
2012/english/
SIAPS. (2013). SIAPS fact sheet. Systems for Improved Access to Pharmaceuticals and
Services. Available from: http://siapsprogram.org/wp-content/up loads/2013/09/SIAPS-
Fact-Sheet_2013.pdf
199
Singh, D. P. (2010) ‘Generic drug access in global scenario’. Journal of Pharmaceutical
Sciences and Research, 2(2), pp. 90 - 98.
Solberg, M. & Richmond, F. J. R. (2012) ‘Transparency in drug submission processes of
3 Asian countries’. Drug Information Journal, 46(2), pp. 216-225.
Srinivasan, A. (2015) Complex Generics: Maximizing FDA Approval Prospects.
Available from
https://www.parexel.com/files/6714/3076/9385/ComplexGenerics_WPApril2015_final.p
df [Accessed 29th January 2017].
Stein, P. (2018) Four rules for being a consistent US FDA reviewer. BIOPHARMA
CONGRESS IV, 14 November, 2018, Washington D.C.
Stem, C., Margoluis, R., Salafsky, N. & Brown, M. (2005) ‘Monitoring and evaluation in
conservation: A review of trends and approaches’. Conservation Biology, 19(2), pp. 295-
309.
Sue, V. M. & Ritter, L. A. (2012) Conducting Online Surveys. Thousand Oaks, CA, Sage.
Tabor, E. (2008) ‘Generic drug approvals in the US prior to the Hatch-Waxman Act’.
RAPS Regulatory Focus. September 2008. Available from: https://www.raps.org/news-
and-articles/news-articles/2008/9/perspective-generic-drug-approvals-in-the-us-prio -
[Accessed 16th February 2016].
Tantillo, N. (2015) Restricted Access Programs and their Impact on ANDAs and Patient
Access. GPhA 2015 Fall Technical Conference, 2 - 4 November, 2015 Bethesda, MD.
Taylor, H. (2000) ‘Does internet research work? Comparing electronic survey results
with telephone survey’. International Journal of Market Research 42(1), pp. 51-63.
Toll, T. (2015) ‘Pharmaceutical reverse payment settlement agreements and a proposal
for clarifying the application of antitrust law rule of reason analysis to these agreements’.
Houston Journal of Health Law & Policy, 15, pp. 281-318.
Tucker, D. S., Well, G. & Sheer, M. (2013) ‘REMS: The next pharmaceutical
enforcement priority’. Antitrust, 28, pp. 74 -82.
200
Uhl, K. (2014) GDUFA Goal Dates: It’s Not Just About the Numbers – Building a
Quality System. GPhA 2014 Fall Technical Conference, 28 October 2014, Bethesda,
Maryland.
Uhl, K. (2017) FDA Office of Generic Drugs (OGD) Keynote Address - GDUFA: Past,
Present and Future. AAM (formerly GPhA) 2017 Annual Meeting, 14 February 2017,
Orlando, Florida.
United Nations (2016). Promoting innovation and access to health technologies Report of
the Secretary-General. A Report of the Secretary-General. New York, NY: United
Nations. Available from: http://www.politico.eu/wp-content/uploads/2016/09/HLP-
Report-FINAL-Sept-2016.pdf [Accessed 2nd February 2017].
U.S. Senate. (2016) Written Testimony of Peter Safir Senior Counsel, Covington &
Burling LLP to U.S. Senate Committee on the Judiciary Subcommittee on Antitrust,
Competition Policy and Consumer Rights Hearing on the CREATES Act of 2016 (S.
3056).
United States Congress. (1962) Drug Amendments of 1962 (Kefauver Harris Amendment)
of 1962. Public Law No. 87-781.Stat. 76. Available from:
https://www.govinfo.gov/content/pkg/STATUTE-76/pdf/STATUTE-76-
Pg780.pdf#page=9 - [Accessed 29th July 2015].
United States Congress. (1984) Drug Price Competition and Patent Term Restoration Act
of 1984. Public Law No. 98-417.Stat. 98 Available from:
https://www.govinfo.gov/content/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf -
[Accessed 26th July 2015].
United States Congress. (2002) Best Pharmaceuticals for Children Act of 2002. Public
Law No. 107-109.Stat. 1408. Available from:
https://uscode.house.gov/statutes/pl/107/109.pdf - [Accessed 31st August 2016].
United States Congress. (2003) Medicare Prescription Drug, Improvement, and
Modernization Act of 2003. Public Law No. 108-173.Stat. 117. Available from:
https://www.govinfo.gov/content/pkg/PLAW-108publ173/pdf/PLAW-108publ173.pdf -
[Accessed 29th January 2016].
United States Congress. (2012) Food and Drug Administration Safety and Innovation Act
of 2012. Public Law No. 112-144. Stat. 126. Available from:
https://www.congress.gov/112/plaws/publ144/PLAW-112publ144.pdf - [Accessed 2nd
August 2015].
201
United States Congress. (2017) FAST Generics Act of 2017. H.R.2051. Available from:
https://www.congress.gov/bill/115th-congress/house-bill/2051/text - [Accessed 1st
August 2019].
United States Congress. (2019) CREATES Act of 2019. H.R. 965. Available from:
https://www.congress.gov/bill/116th-congress/house-bill/965/text - [Accessed 1st August
2019].
U. S. Food and Drug Administration. (2001) Guidance for industry: ANDA submissions –
Statistical approaches to establishing bioequivalence. Available from:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/statistical-
approaches-establishing-bioequivalence
U. S. Food and Drug Administration. (2010) FDA response to Citizen Petition Docket
No. FDA-2003-P-0273. Available from: https://www.fda.gov/media/78975/download -
[Accessed 15th August 2016].
U. S. Food and Drug Administration. (2011) FDA transparency initiative: improving
transparency to regulated industry - Task Force Report 2011. Available from:
http://wayback.archive-
it.org/7993/20171101192958/https://www.fda.gov/AboutFDA/Transparency/Transparenc
yInitiative/ucm273856.htm - [Accessed 23rd November 2015].
U. S. Food and Drug Administration. (2012) Human generic drug performance goals and
procedures fiscal years 2013 through 2017 (GDUFA Commitment Letter). Available
from: https://www.fda.gov/industry/generic-drug-user-fee-amendments/commitment-
letter - [Accessed 14th November 2015].
U. S. Food and Drug Administration (2015) FY 2015 GDUFA performance report, Office
of Generic Drugs/FDA. Available from: https://www.fda.gov/media/97128/download -
[Accessed 3rd April 2017].
U. S. Food and Drug Administration (2016a) FY 2016 GDUFA performance report,
Office of Generics Drug/FDA. Available from:
https://www.fda.gov/media/102779/download - [Accessed 3rd October 2017].
U. S. Food and Drug Administration (2016b) GDUFA Reauthorization Performance
Goals and Program Enhancements Fiscal Years 2018 -2022 (GDUFA II Commitment
Letter). Available from: https://www.fda.gov/media/101052/download - [Accessed 21st
October 2017].
202
U. S. Food and Drug Administration (2017a) CDER conversation: Patents and
exclusivities for generic drug products. Available from: https://www.fda.gov/drugs/news-
events-human-drugs/cder-conversation-patents-and-exclusivities-generic-drug-products -
[Accessed 4th April 2018].
U. S. Food and Drug Administration (2017b) CDER manual of policies and procedures,
MAPP 5240. 3 Rev. 4. Prioritization of the Review of Original ANDAs, Amendments, and
Supplements. Available from:
https://www.fda.gov/files/about%20fda/published/Prioritization-of-the-Review-of-
Original-ANDAs--Amendments--and-Supplements.pdf - [Accessed 20th January 2018].
U. S. Food and Drug Administration (2017c) FY 2017 GDUFA performance report.
Available from: https://www.fda.gov/media/113302/download - [Accessed 6th May
2019].
U. S. Food and Drug Administration (2017d) FY 2017 PDUFA Performance Report.
Available from: https://www.fda.gov/about-fda/user-fee-performance-reports/pdufa-
performance-reports - [Accessed 6th May 2019].
U. S. Food and Drug Administration (2018) FY 2018 GDUFA performance report.
Available from: https://www.fda.gov/media/130572/download - [Accessed 6th May
2019].
U. S. Food and Drug Administration (2019) Activities report of the generic drugs
program (FY 2019) – GDUFA II quarterly performance. Available from:
https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/activities-report-
generic-drugs-program-fy-2019-monthly-performance - [Accessed 27th July 2018].
Vähämäki, J. & Verger, C. (2019) ‘Learning from Results-Based Management
evaluations and reviews’. OECD Development Co-operation Working Papers, No. 53,
OECD Publishing, Paris. Available from: https://www.oecd-
ilibrary.org/docserver/3fda0081-
en.pdf?expires=1574804824&id=id&accname=guest&checksum=13BC32AFE85707F9
A2C136CEB775FB7A – [Accessed 12
th
July 2019]
Versteegh, L.R. & Tracey, L.M. (1999). Bringing information on evolving FDA
standards to bear on ongoing drug development programs. Drug information
journal, 33(3), pp.955-963.
203
Vivian, J. C. (2008) FDA Inspection of Foreign Drug Companies. US Pharmacist, 33 (6),
pp. 53-57. Available from: FDA Inspection of Foreign Drug Companies - [Accessed 5th
July 2019].
Vokinger, K. N., Kesselheim, A. S., Avorn, J. & Sarpatwari, A. (2017) ‘Strategies that
delay market entry of generic drugs’. JAMA Internal Medicine, 177(11), pp. 1665-1669.
Walker, S., Cone, M. & Collins, J. (2005) Assessing the regulatory environment and its
impact on and its impact on patients access to new medicines. R&D Briefing No. 46.
Surrey: CMR International Institute for Regulatory.
Woo, J., Wolfgang, S. & Batista, H. (2008) ‘The effect of globalization of drug
manufacturing, production, and sourcing and challenges for American drug safety’.
Clinical Pharmacology & Therapeutics, 83(3), pp. 494-497.
Woo, J., Luan, J. J., Li Z., Grosser S, Peters J. & Chazin H. (2018) Abbreviated new drug
applications: Generic Drug User Fee Amendments Act analysis of application quality
metrics’. Therapeutic Innovation & Regulatory Science, 53(5), pp. 696-700.
Woodcock, J. & Junod, S. (2012) PDUFA Lays the Foundation: Launching into the Era
of User Fee Acts. PDUFA & the Expression of FDA User Fees: Lessons from
Negotiators, edited by the Food and Drug Law Institute, pp.1-26.
World Health Organization (WHO). (2004). Equitable access to essential medicines: a
framework for collective action . Geneva: World Health Organization. Available from:
https://apps.who.int/medicinedocs/pdf/s4962e/s4962e.pdf [Accessed 1st February 2017].
World Health Organization (WHO). (2008). Monitoring And Evaluation Toolkit
Hiv/Aids, Tuberculosis And Malaria. Available from:
https://www.who.int/malaria/publications/atoz/a85537/en/ [Accessed 1st February 2017].
Wu, J. & Juhaeri J. (2016) ‘The US Food and Drug Administration's risk evaluation and
mitigation strategy (REMS) program - Current status and future direction’. Clinical
Therapeutics, 38(12), pp. 2526-2532.
Wyatt, J. C. (2000) When to use web-based surveys. BMJ Group BMA House, Tavistock
Square, London, WC1H 9JR.
Yadin, S. (2018) ‘Shaming big pharma’. Yale Journal on Regulation Bulletin, 36: p. 131.
204
Yun, G. & Trumbo, C. (2000) ‘Comparative response to a survey executed by post, e-
mail, and web form’. 2000. Journal of Computer-Mediated Communication, 6, pp. 1-26.
Zelenay Jr, J. L. (2005) ‘The prescription drug user fee act: is a faster Food and Drug
Administration always a better Food and Drug Administration’. Food Drug Law Journal
60(2), pp. 261-338.
205
APPENDIX A. FINAL VERSION OF QUALTRICS SURVEY
This 15-minute survey seeks to understand stakeholder views on the regulatory
environment for generic drug products. It is part of research associated with the Doctor
of Regulatory Science degree at the University of Southern California. Your answers are
important to the success of the study and will be kept completely anonymous. At the end
of the survey, there will be an option to voluntarily participate in a follow-up phone
interview. You can also receive the survey results upon request once the study is
completed. Thank you in advance for your participation.
Q1 Which of the following best describes your position?
o Associate/Specialist (1)
o Scientist (2)
o Manager/Senior Manager (3)
o Director/Senior Director (4)
o VP (5)
o CEO/COO (6)
o Consultant (7)
o Other (please specify) (8)
________________________________________________
206

Q2 Which of the following best describes your company/organization? Check all that
apply.
▢ Drug substance/API manufacturer/supplier (1)
▢ Manufacturer of generic drug products (2)
▢ Manufacturer of innovative drug products (3)
▢ Manufacturer of medical devices (4)
▢ Consulting service for drug manufacturers (5)
▢ Trade Association/Organization (6)
▢ Contract Development and Manufacturing Organization (CDMO) (7)
▢ Other (please specify) (8)
________________________________________________

Q3 Please indicate your level of experience within the generic drugs industry
o ˂2 years (1)
o 2 - 5 years (2)
o 6 - 10 years (3)
o 11 - 20 years (4)
o ˃20 years (5)

207
Q4 What is your primary job function?
o Regulatory Affairs (1)
o Product Development (2)
o Manufacturing / Operations (3)
o Marketing (4)
o Legal (5)
o Government Affairs (6)
o Management / Business Development (7)
o Other (please specify) (8)
________________________________________________

Q5 How would you characterize the size of your most recent company/organization?
o Small ( (1)
o Mid-sized (500 - 5,000 employees) (2)
o Large (>5,000 employees) (3)
o Do not know (4)

Q6 Please indicate how many original Abbreviated New Drug Applications (ANDA) the
company for which you work or consult generally submits to the U.S. FDA annually.
o 1 – 5 (1)
o 6 – 10 (2)
o Over 10 (3)
o Do not know (4)

208
This section explores your views specific to GDUFA’s core goal of enhancing access
to generic drugs by expediting the availability of these products.

Q7 How important would you rate the following factors in impeding access to generic
drugs in the US?

Very important
(1)
Important (2)
Somewhat
important (3)
Not important
(4)
Cannot
answer (5)
Delays in FDA review and
approval of ANDAs (1) o o o o o
Anticompetitive misuse of
restricted distribution
REMS by brandholders (2)
o o o o o
Brandholders extending
the period of brand
protection by repeatedly
filing new patent
applications - Evergreening
(3)
o o o o o
Pay-for-delay settlement
agreements between
brandholders and generic
companies (4)
o o o o o
Increasing scientific,
clinical, and regulatory
complexities in drug
development (5)
o o o o o
Insufficient regulatory FDA
guidance on the
development of generics
(6)
o o o o o
Lack of incentives for
generics due to drug price
errosion over the last few
years (7)
o o o o o
Lack of incentives due to
small market size (8) o o o o o
New generic drugs
approved but not being
launched (9)
o o o o o
New innovative drugs
approved but not being
launched (10)
o o o o o
Inconsistencies in FDA
review (11)
o o o o o
209

Q8 According to the FDA, more than half of approved generics have never been
launched or have a discontinued marketing status. Please rank the following potential
reasons from most (1) to least (5) probable for the lower numbers of generic drug
launches.

To reposition the list, right click on the line you wish to move and then drag it up or
down
______ Technical / Manufacturing challenges (1)
______ Thin profit margins – Can’t compete against multiple or larger competitors (2)
______ Low forecasted volumes (3)
______ Settlement deals with branded companies for generics company to delay launch
of its product (4)
______ Strategic corporate decision on product launch timing (5)

210
Q9 In regard to the use of restricted distribution REMS to impede or limit generic
competition, please indicate your level of agreement with the following statements:

Agree (1)
Neither agree nor
disagree (2)
Disagree (3) Cannot answer (4)
In some cases there may
be legitimate safety
justifications for a
temporary refusal by
branded drug
companies to provide
drug samples. (1)
o o o o
Access to product
samples has been
facilitated when FDA
issues letters to
brandholders stating
ANDA sponsor's BE
study protocols contain
safety protections
comparable to
applicable REMS for the
RLD (2)
o o o o
In some cases,
intervention from FDA
can instead create
additional bureaucratic
hurdles to generic
companies' efforts to
acquire RLD samples (3)
o o o o
The only way to solve
this problem is statutory
solution (4)
o o o o

Q10 A consequence of GDUFA has been an increase in the number of deficiency letters
that FDA issues to generic drug sponsors during ANDA review. Please give your
211
opinion on the importance of the following leading causes for the increase in
deficiencies?

Very important
(1)
Important (2)
Somewhat
important (3)
Not important
(4)
Cannot answer
(5)
Increased
scrutiny in the
FDA review
process (1)
o o o o o
Declining quality
of ANDA
submissions by
sponsors rushing
to submit to
secure first to file
or first to market
opportunities (2)
o o o o o
Lack of clarity in
FDA regulatory
requirements (3)
o o o o o
Lack of pre-
submission
interaction and
communication
with FDA (4)
o o o o o
Strategic issuance
of RTRs and CRLs
by OGD to assure
they meet the
GDUFA goal date
(5)
o o o o o
Lack of adequate
expertise and / or
training on the
part of new FDA
reviewers (6)
o o o o o
Inconsistencies in
FDA reviews (7) o o o o o
Challenges
related to
increasing
complexity in
drug
development (8)
o o o o o
Others (9)
o o o o o
212

Q11 In the past five years, what percentage of complete response letters did the company
for which you work or consult receive because it could not meet the shorter FDA
timelines imposed since GDUFA for responding to information requests or discipline
review letters?
o 0% (1)
o Less than 10% (2)
o 10 – 50% (3)
o More than 50% (4)
o Don’t know /not applicable (5)

Q12 To what extent do limited resources affect the ability of the company for which you
work or consult to meet the deadlines for responses to information requests and discipline
review letters set by FDA?
o Major (1)
o Moderate (2)
o Minor (3)
o Not a problem (4)

If you can, please provide any additional comments from your experience regarding the
ability of companies to meet the deadlines set by FDA to respond to information requests
and discipline review letters.
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q13 How often has the company for which you work or consult requested from OGD
extensions in the response deadlines because it cannot address the large number of
213
information requests or discipline review letters within the short timelines for response
under GDUFA?
o 100% (1)
o 50 - 99% (2)
o 10 - 50% (3)
o (4)
o 0 (5)

Q14 Which one of the following statements is the most appropriate regarding the
readiness of the company for which you work or consult to address the increasing number
of deficiency letters during ANDA review?
Regulatory Affairs function (1) Other functional groups (2)
My company is adequately staffed
to respond to the increasing
number of deficiency letters. (1)
o o
My company needs additional
resources to respond to the
increased number of deficiency
letters. (2)
o o
My company has outsourced the
work needed to respond to the
increased number of requests to an
entity or a consultant outside of the
organization. (3)
o o
My company has outsourced other
important regulatory activities to an
entity or a consultant outside of the
organization in order to free
internal staff to respond to the
increased number of information
requests and discipline review
letters (4)
o o
Cannot answer (5)
o o

214
Q15 What level of impact do you believe the following challenges will have on the
efforts of a company to submit a substantially complete ANDA of high quality?

Strong
impact (1)
Some impact
(2)
Little impact
(3)
No impact (4)
Cannot
answer (5)
Disagreements between
the R&D, manufacturing
and regulatory functions
on submission
requirements (1)
o o o o o
Inadequate quality of
submission information or
documentation from
external parties (raw
material/component
supplies, contract testing
or manufacturing sites) (2)
o o o o o
Pressures from
management to secure a
first-in-line position by
rushing submission (3)
o o o o o
High turnover of key R&D
staff members (4)
o o o o o
Insufficient qualified
staffing of the regulatory
team (5)
o o o o o
Challenges related to
quality of bioequivalence
studies (6)
o o o o o
Challenges related to
quality of manufactured
product runs (7)
o o o o o
Lack of understanding of
new or evolving regulatory
submission requirements
(8)
o o o o o
Failure to apply Quality by
Design (QbD) principles to
the development of the
drug products (9)
o o o o o
Interaction with FDA prioir
to submission (10)
o o o o o
Other (11)
o o o o o

215

Q16 Complex generics are drugs for which it is particularly difficult to establish
therapeutic equivalence to the reference listed drug. The designation is reserved for
drug products identified by the FDA as requiring extensive physicochemical
characterization or non-conventional bioequivalence studies to demonstrate
sameness to the reference listed drug.

Which of the following choices identifies the current state of expertise in the
development of complex generics at the company for which you work or consult?
o Our current staff has complex drug development expertise and we have
successfully filed multiple complex generic ANDAs. (1)
o We have not filed any complex generic ANDA, but have successfully hired new
staff with complex drug product development expertise and are currently working on
complex generics projects. (2)
o We are interested in developing complex generics, but are having difficulties
hiring qualified staff with complex drug product development expertise. (3)
o We are evaluating available options with regard to outside consultants with
complex drug development expertise. (4)
o Our current staffing lacks complex drug product development expertise and we
are currently not planning to develop complex generics. (5)
o Cannot answer (6)

216
Q17 The successful development of a complex generic may be impeded by certain
barriers. From the list below, please indicate the level of importance these barriers
represent to the company for which you work or consult when considering the
development of complex generic drugs

Extremely
important (1)
Somewhat
important (2)
Not at all
important (3)
Cannot answer
(4)
Lack of financial resources
(1) o o o o
Lack of FDA guidance (2)
o o o o
Technical/Clinical/Regulatory
challenges (3)
o o o o
Finding/hiring
knowledgeable staff with
complex drug development
experience (4)
o o o o
Development more
expensive than warranted by
potential market return (5)
o o o o
Long development timeline
(6)
o o o o
Other (7)
o o o o

217
This section explores your views specific to GDUFA’s core goal of improving
transparency between the FDA and industry.

Q18 Please indicate your position on the following questions regarding the impact of
GDUFA on transparency.

Improved
(1)
Stayed the same
(2)
Worsened (3)
Cannot answer
(4)
How would you characterize
the level of transparency
exhibited by FDA compared
to the pre-enactment of
GDUFA? (1)
o o o o
Has the implementation of
GDUFA changed the
effectiveness of your
communications with the
Office of Generic Drugs
(OGD)? (2)
o o o o

If you can, please provide any additional comments from your experience on the impact
of GDUFA on transparency.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

218
Q19 How would you evaluate the level of company initiated interaction between the
company for which you work or consult and the Office of Generic Drugs (OGD) in
the past two years?
During development (1) During review (2)
Extensive formal interactions
(including scheduled meetings,
many controlled correspondences)
(1)
▢ ▢
Extensive informal interactions
(frequent telephone or email
interactions) (2)
▢ ▢
Some formal interactions (possibility
of meetings, some controlled
correspondences) (3)
▢ ▢
Some informal interactions
(possibility of telephone or email
interactions) (4)
▢ ▢
Minimal interactions (rare
occurrences of interactions) (5)
▢ ▢
No interactions (6)
▢ ▢

Q20 How would you evaluate the quality of information received from the company
initiated interactions between the company for which you work or consult and the
Office of Generic Drugs?
o Excellent (1)
o Good (2)
o Satisfactory (3)
o Poor (4)

If you can, please provide any additional comments regarding the quality of information
received from company initiated interactions between the company you're associated
with and the Office of Generic Drug.
________________________________________________________________
________________________________________________________________
________________________________________________________________

219
Q21 Under GDUFA, FDA committed to enhance scientific and regulatory clarity for
generic drug developers by issuing relevant guidance documents. Please indicate
your views on the following statements regarding FDA guidance development.
Always (1) Frequently (2) Sometimes (3) Rarely (4)
Cannot answer
(5)
FDA takes
feedback from
stakeholders into
consideration in
the development
of guidance
documents. (1)
o o o o o
FDA sets
priorities on its
new guidance
development in
alignment with
specific drug
development
activities sought
by industry. (2)
o o o o o
In situations
where ANDA
sponsors have
proposed
alternative
approaches to
those specified in
guidance
documents, FDA
has accepted
such approaches,
provided they
can be
scientifically
justified. (3)
o o o o o
FDA guidance
documents are
written based on
sound scientific
principles and /
or reliable
scientific
evidence. (4)
o o o o o

220
Q22 Please indicate your level of agreement with the following statements regarding the
Office of Generic Drugs controlled correspondence process for requesting
information on a specific element of generic drug product development.

Strongly
agree (1)
Agree (2)
Neither
agree nor
disagree (3)
Disagree (4)
Strongly
disagree (5)
Cannot
answer (6)
In my company’s
experience, OGD is
responding to
controlled
correspondences from
sponsors within the
GDUFA committed
timelines. (1)
o o o o o o
OGD responses to
controlled
correspondences
provide sufficient
information and clarity
regarding FDA’s
expectations and
requirements. (2)
o o o o o o
My company is satisfied
with the relevance of
information provided
by FDA in responses to
controlled
correspondences. (3)
o o o o o o
In my company’s
experience, when there
is no guidance for a
particular situation, FDA
has accepted
approaches developed
by sponsors, provided
the proposed
approaches represent
sound scientific
judgment. (4)
o o o o o o
221
Q23 Please indicate to what extent you agree or disagree with each of the following
statements in relation to formal meetings (pre-ANDA and between the Office of
Generic Drugs and sponsors of generic drugs.

Strongly
agree (1)
Agree (2)
Neither agree
nor disagree
(3)
Disagree
(4)
Strongly
disagree (5)
Cannot
answer
(6)
FDA will generally schedule
meetings with sponsors
within a timeframe
favorable to incorporate
recommendations and / or
guidance to the product
development program. (1)
o o o o o o
Meeting with FDA prior to
initiating clinical
development significantly
improves ANDA review
efficiency. (2)
o o o o o o
Meeting with FDA after
clinical development but
prior to ANDA submission
significantly improves
ANDA review efficiency. (3)
o o o o o o
Meetings with FDA have
been helpful in navigating
scientific and technological
challenges in the
development of generic
versions of complex drug
products. (4)
o o o o o o
The relevance of an FDA
meeting to discuss the
development of a non-
complex generic drug is
diminished, due to
availability of relevant
guidance documents and /
or the controlled
correspondence process is
sufficient to address
challenges for these types
of programs. (5)
o o o o o o
In case of divergence of
view, generic companies
are fearful of disagreeing
or pushing back on the
Agency’s feedback. (6)
o o o o o o

222
Q24 In your opinion does the current ANDA review process provide consistent
evaluations when reviewed by different reviewers?
o Always (1)
o Frequently (2)
o Sometimes (3)
o Cannot answer (4)
Can you please provide any additional comments regarding the consistency of the ANDA
review process.
________________________________________________________________
________________________________________________________________
________________________________________________________________

This section explores your views specific to GDUFA’s core goal of improving drug
quality and safety.

Q25 How do you rate the quality of compliance inspections in terms of depth and
rigor since the implementation of GDUFA?
o Excellent (1)
o Good (2)
o Satisfactory (3)
o Poor (4)

IF you can, please provide any additional comments from your experience regarding the
quality of FDA compliance inspections.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
223
________________________________________________________________

Q26 Do you have any concerns regarding FDA compliance inspections?
o Yes (1)
o No (2)

Display This Question:
If Do you have any concerns regarding FDA compliance inspections? = Yes is selected

Q27 What is your specific concern regarding FDA compliance inspections? Select all that
applies.
▢ Timing of inspections (1)
▢ Expertise of inspectors (2)
▢ Scope of inspections (3)
▢ Consistency of inspections (4)
▢ Quality of inspection reports (5)
▢ Other (please specify) (6)
________________________________________________

Q28 In the last two years has a delay occurred in approval of any ANDAs with which
you have been associated, because FDA site inspections were slow to occur?
o Yes (1)
o No (2)

Please provide any additional comments regarding delays in approval of any ANDAs
with which you have been associated, because FDA site inspections were slow to occur.
____________________________________________________________________
________________________________________________________________
________________________________________________________________
224

Q29 Has the company for which you work or consult experienced an increase in
frequency of FDA compliance inspections of the facilities used in manufacturing,
packaging and testing of its drug substances or products?
o Yes (1)
o No (2)
o Not sure (3)

Display This Question:
If Has the company for which you work or consult experienced an increase in frequency of FDA
compliance = Yes is selected

Q30 Please identify how increased frequency in compliance inspections has altered the
company for which you work or consult’s perspective to quality improvement.
▢ Heightened sense of awareness regarding quality improvement (1)
▢ Increase in activities related to quality improvement (2)
▢ Decrease in activities related to quality improvement (3)
▢ No change (4)
▢ Other (please specify) (5)
________________________________________________

225
This section explores your views specific to the general performance of GDUFA.

Q31 Please indicate your level of agreement with the following statements
Agree (1)
Neither agree
nor disagree
(2)
Disagree (3)
I don’t know
(4)
Under GDUFA, the
ANDA approval rate has
improved to our
company’s satisfaction.
(1)
o o o o
Many generic drug
programs associated
with the user fees
program are above and
beyond the GDUFA
commitments. (2)
o o o o
GDUFA is executed
within the scope it was
intended. (3)
o o o o
GDUFA is executed with
an appreciation for the
hypercompetitive
dynamics of the generic
drugs industry. (4)
o o o o
The measured progress
of GDUFA is an incentive
to bring companies to
the GDUFA III
negotiation table to
discuss further program
expansion. (5)
o o o o

226
Q32 With the current FDA decision making model, is the overall quality of generic drugs
better under the GDUFA system?
o Yes (1)
o No (2)
o Cannot answer (3)

Please provide any additional comments regarding your assessment of the overall quality
of generic drugs under the GDUFA system.
________________________________________________________________
____________________________________________________
________________________________________________________________
________________________________________________________________

Q33 As part of future GDUFA III negotiations, please rank the following initiatives in
order of preference from most (1) to least (5) important intiative to prioritize user
fees funding for.

To reposition the list, right click on the line you wish to move and then drag it up or
down.

______ Initiatives targeted at improving review consistency - e.g. increasing reviewer
training (1)
______ Initiatives targeted at enhancing guidance development for complex generics (2)
______ Initiatives targeted at achieving parity in effectivness and frequency of domestic
and foreign facility inspections (3)
______ Initiatives aimed at streamlining post-marketing lifecycle and pharmacovigilance
surveillance programs (4)
______ Initiatives targeted at improving the drug review timing - e.g. recruiting
additional review staff (5)

Please provide any additional comments regarding intiatives to prioritize user fees
funding as part of any future GDUFA III negotiations.
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

227

Q34 What in your opinion has been the greatest success of the GDUFA program?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Q35 What have been the greatest challenges of the GDUFA program?
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

228
APPENDIX B. CROSS-TABULATION OF RESPONDENTS’ LEVEL OF
EXPERIENCE AND VIEWS ON CHALLENGES TO SUBMITTING A
HIGH QUALITY ANDA

Please indicate your level of experience
within the generic drugs industry

˂2 years 2 - 5 years 6 - 10 years 11 - 20 years ˃20 years Total
What level of impact do you believe the
following challenges will have on the
efforts of a company... - Disagreements
between the R&D, manufacturing and
regulatory functions on submission

Strong impact 1 5 12 12 5 35
Some impact 0 5 4 12 4 25
Little impact 1 1 6 4 2 14
Cannot answer 0 1 0 0 0 1
Total 2 12 22 28 11 75
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Inadequate
quality of submission information or
documentation from external parties
( t il/ t li

Strong impact 1 6 12 9 7 35
Some impact 0 6 8 16 4 34
Little impact 1 0 2 3 1 7
Cannot answer 0 0 0 2 0 2

Total 2 12 22 30 12 78
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Pressures from
management to secure a first-in-line
position by rushing submission
Strong impact 0 8 11 14 11 44
Some impact 2 3 10 11 1 27
Little impact 0 1 1 2 1 5
Cannot answer 0 0 0 1 0 1

Total 2 12 22 28 13 77
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - High turnover of
key R&D staff members
Strong impact 1 3 6 8 4 22
Some impact 0 10 10 14 3 37
Little impact 1 0 4 4 4 13
Cannot answer 0 0 0 2 1 3

Total 2 13 20 28 12 75
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Insufficient
qualified staffing of the regulatory team
Strong impact 0 8 7 12 6 33
Some impact 0 4 11 9 4 28
Little impact 2 0 3 3

2 10
Cannot answer 0 0 0 2 0 2
Total 2 12 21 26 12 73
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Challenges
related to quality of bioequivalence
studies
Strong impact 1 9 9 11 7 37
Some impact 0 1 7 14 1 23
Little impact 1 1 4 3 5 14
Cannot answer 0 0 0 1 0 1

Total 2 11 20 29 13 75
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Challenges
related to quality of manufactured
product runs
Strong impact 1 5 8 11 5 30
Some impact 0 5 8 12 6 31
Little impact 1 2 5 4 1 13
Cannot answer 0 0 0 1 0 1

Total 2 12 21 28 12 75
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Lack of
understanding of new or evolving
Strong impact 0 3 9 14 7 33
Some impact 0 9 8 5 4 26
Little impact 2 1 3 8 1 15
229
regulatory submission requirements
Cannot answer 0 0 1 1 0 2

Total 2 13 21 28 12 76
What level of impact do you believe the
following challenges will have on the
efforts of a company... - Failure to
apply Quality by Design (QbD)
i i l h d l f h

Strong impact 0 4 8 8 8 28
Some impact
0 5 6 11 1 23
Little impact 2 3 5 8 2 20
Cannot answer
0 0 0 2 1 3
Total 2 12 19 29 12 74
What level of impact do you believe the
following challenges will have on the
efforts of a company... - Interaction
with FDA prioir to submission
Strong impact 0 5 7 10 5 27
Some impact 1 4 9 16 5 35
Little impact
1 4 5 3 1 14
Cannot answer
0 0 0 1 1 2

Total 2 13 21 30 12 78

230
APPENDIX C. CROSS-TABULATION OF RESPONDENTS’ COMPANY SIZE
AND VIEWS ON CHALLENGES TO SUBMITTING A HIGH QUALITY
ANDA

How would you characterize the size of your most
recent company/organization?

Small (<500
employees)
Mid-sized (500 -
5,000
employees)
Large (>5,000)
employees)
Do not
know
Total
What level of impact do you believe
the following challenges will have on
the efforts of a compan... -
Disagreements between the R&D,
manufacturing and regulatory
f i bi i i
Strong impact 11 10 14 0 35
Some impact 7 7 10 0 24
Little impact 2 5 7 0 14
Cannot answer 0 0 1 0 1
Total 20 22 32 0 74
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Inadequate quality
of submission information or
documentation from external parties (raw

Strong impact 13 7 15 0 35
Some impact 6 15 12 0 33
Little impact 2 2 3 0 7
Cannot answer 0 0 2 0 2

Total 21 24 32 0 77
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Pressures from
management to secure a first-in-line
position by rushing submission
Strong impact 14 9 20 0 43
Some impact 6 13 8 0 27
Little impact 0 2 3 0 5
Cannot answer 1 0 0 0 1

Total 21 24 31 0 76
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - High turnover of
key R&D staff members.
Strong impact 7 7 8 0 22
Some impact 7 13 17 0 37
Little impact 3 3 6 0 12
Cannot answer 2 1 0 0 3

Total 19 24 31 0 74
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Insufficient
qualified staffing of the regulatory team.
Strong impact 12 8 12 0 32
Some impact 7 11 10 0 28
Little impact 1 2 7 0 10
Cannot answer 1 0 1 0 2

Total 21 21 30 0 72
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Challenges related
to quality of bioequivalence studies.
Strong impact 9 12 16 0 37
Some impact 7 7 8 0 22
Little impact 4 3 7 0 14
Cannot answer 1 0 0 0 1

Total 21 22 31 0 74
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Challenges related
to quality of manufactured product runs.
Strong impact 10 9 11 0 30
Some impact 9 8 14 0 31
Little impact 1 5 6 0 12
Cannot answer 1 0 0 0 1

Total 21 22 31 0 74
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Lack of
understanding of new or evolving
regulatory submission requirements.
Strong impact 10 10 12 0 32
Some impact 10 8 8 0 26
Little impact 0 6 9 0 15
Cannot answer 1 0 1 0 2
231

How would you characterize the size of your most
recent company/organization?

Small (<500
employees)
Mid-sized (500 -
5,000
employees)
Large (>5,000)
employees)
Do not
know
Total

Total 21 24 30 0 75
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Failure to apply
Quality by Design (QbD) principles to the
development of the drug products.
Strong impact 9 5 14 0 28
Some impact
5 10 7 0 22
Little impact 5 6 9 0 20
Cannot answer
2 1 0 0 3

Total 21 22 30 0 73
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Interaction with
FDA prioir to submission.
Strong impact 9 8 10 0 27
Some impact 8 13 14 0 35
Little impact
2 3 8 0 13
Cannot answer
2 0 0 0 2

Total 21 24 32 0 77
What level of impact do you believe the
following challenges will have on the
efforts of a compan... – Other.
Strong impact 0 0 2 0 2
Some impact 0 0 0 0 0
Little impact 0 0 0 0 0
Cannot answer 4 3 3 0 10

Total 4 3 5 0 12

232
APPENDIX D. CROSS-TABULATION OF NUMBER OF ANDAS
RESPONDENT’S COMPANY SUBMITTED AND VIEWS ON
CHALLENGES TO SUBMITTING A HIGH QUALITY ANDA

1 - 5 6 - 10 Over 10 Do not know Total
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Disagreements between the
R&D, manufacturing and regulatory
functions on submission requirements
Strong impact 10 5 14 6 35
Some impact 11 2 9 2 24
Little impact 6 1 4 3 14
Cannot answer 0 0 1 0 1
Total 27 8 28 11 74
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Inadequate quality of
submission information or documentation
from external parties (raw
material/component supplies, contract
testing or manufacturing sites)
Strong impact 11 5 13 6 35
Some impact 14 3 12 4 33
Little impact 3 1 2 1 7
Cannot answer 0 0 2 0 2

Total 28 9 29 11 77
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Pressures from management
to secure a first-in-line position by rushing
submission
Strong impact 13 2 20 8 43
Some impact 12 6 6 3 27
Little impact 2 1 2 0 5
Cannot answer 1 0 0 0 1

Total 28 9 28 11 76
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - High turnover of key R&D
staff members
Strong impact 8 3 7 4 22
Some impact 13 3 15 5 36
Little impact 4 2 5 2 13
Cannot answer 2 0 1 0 3

Total 27 8 28 11 74
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Insufficient qualified
staffing of the regulatory team
Strong impact 11 5 11 6 33
Some impact 12 3 9 3 27
Little impact 3 0 5 2 10
Cannot answer 1 0 1 0 2
Total 27 8 26 11 72
What level of impact do you believe the
following challenges will have on the
efforts of a compan... - Challenges related
to quality of bioequivalence studies
Strong impact 11 6 13 7 37
Some impact 9 2 8 3 22
Little impact 6 0 7 1 14
Cannot answer 1 0 0 0 1
Total 27 8 28 11 74
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Challenges related to
quality of manufactured product runs
Strong impact 11 3 9 7 30
Some impact 9 5 14 2 30
Little impact 6 0 5 2 13
Cannot answer 1 0 0 0 1

Total 27 8 28 11 74
What level of impact do you believe the
following challenges will have on the efforts
of a compan... - Lack of understanding of
Strong impact 8 7 12 6 33
Some impact 16 0 7 2 25
Little impact 4 1 7 3 15
Cannot answer 1 0 1 0 2
233

1 - 5 6 - 10 Over 10 Do not know Total
new or evolving regulatory submission
requirements
Total 29 8 27 11 75
What level of impact do you believe the
following challenges will have on the efforts
of a company... - Failure to apply Quality by
Design (QbD) principles to the development
of the drug products
Strong impact 6 4 14 4 28
Some impact 11 2 7 2 22
Little impact 7 2 7 4 20
Cannot answer 3 0 0 0 3

Total 27 8 28 10 73
What level of impact do you believe the
following challenges will have on the
efforts of a company... - Interaction with
FDA prior to submission
Strong impact 10 4 8 4 26
Some impact 12 3 17 3 35
Little impact 6 1 4 3 14
Cannot answer 1 0 0 1 2
Total 29 8 29 11 77
What level of impact do you believe the
following challenges will have on the efforts
of a company... - Other
Strong impact 1 0 1 0 2
Some impact 0 0 0 0 0
Little impact 0 0 0 0 0
Cannot answer 2 1 5 3 11

Total 3 1 6 3 13

234
APPENDIX E. CROSS-TABULATION OF RESPONDENTS’ COMPANY SIZE
AND VIEWS RELATING TO THE CHALLENGES IN DEVELOPING
COMPLEX GENERIC DRUGS

How would you characterize the size of
your most recent company/organization?

Small (<500
employees)
Mid-sized
(500 - 5,000
employees)
Large
(>5,000)
employees)
Do not
know
Total
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Lack of financial resources
Extremely
important
11 14 18 0 43
Somewhat
important
5 9 8 0 22
Not at all important 4 1 5 0 10
Cannot answer 0 1 2 0 3

Total
20 25 33 0 78
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Lack of FDA guidance
Extremely
important
11 14 14 0 39
Somewhat
important
8 11 12 0 31
Not at all important
1 0 6 0 7
Cannot answer
0 0 1 0 1

Total 20 25 33 0 78
The successful development of a complex
generic may be impeded by certain barriers.
From the list... -
Technical/Clinical/Regulatory challenges
Extremely
important
12 18 18 0 48
Somewhat
important
7 7 12 0 26
Not at all important
0 0 2 0 2
Cannot answer
1 0 1 0 2

Total 20 25 33 0 78
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Finding/hiring
knowledgeable staff with complex drug
development experience
Extremely
important
9 9 19 0 37
Somewhat
important
10 14 9 0 33
Not at all important
1 1 3 0 5
Cannot answer
0 1 2 0 3

Total 20 25 33 0 78
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Development more
expensive than warranted by potential
market return
Extremely
important
11 12 12 0 36
Somewhat
important
6 9 10 0 25
Not at all important
2 3 9 0 14
Cannot answer
1 0 2 0 3

Total 20 25 33 0 78
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Long development timeline
Extremely
important
11 10 17 0 38
Somewhat
important
7 13 11 0 31
Not at all important
0 1 2 0 3
Cannot answer
1 1 3 0 5

Total 19 25 33 0 77
The successful development of a complex
generic may be impeded by certain barriers.
From the list... - Other
Extremely
important
1 0 0 0 1
Somewhat
important
0 0 2 0 2
Not at all important
0 0 0 0 0
Cannot answer
2 2 4 0 8

Total 3 2 6 0 11
235
APPENDIX F. CROSS-TABULATION OF RESPONDENTS’ COMPANY SIZE
AND VIEWS ON THE OVERALL PERFORMANCE ASSESSMENT OF
GDUFA

How would you characterize the size of your
most recent company/organization?

Small (<500
employees)
Mid-sized
(500 - 5,000
employees)
Large (>5,000)
employees)
Do not
know
Total
Please indicate your level of agreement
with the following statements - Under
GDUFA, the ANDA approval rate has
improved to our company’s satisfaction.
Agree 10 7 10 0 27
Neither agree nor
disagree
6 10 11 0 27
Disagree 0 2 5 0 7
I don’t know 2 4 6 0 12
Total 18 23 32 0 73
Please indicate your level of agreement
with the following statements - Many
generic drug programs associated with the
user fees program are above and beyond
the GDUFA commitments.
Agree 6 4 5 0 15
Neither agree nor
disagree
9 9 12 0 30
Disagree 0 2 4 0 6
I don’t know 3 8 11 0 22

Total 18 23 32 0 73
Please indicate your level of agreement
with the following statements - GDUFA is
executed within the scope it was intended.
Agree 11 9 10 0 30
Neither agree nor
disagree
6 7 15 0 28
Disagree 0 3 2 0 5
I don’t know 1 4 5 0 10

Total 18 23 32 0 73
Please indicate your level of agreement
with the following statements - GDUFA is
executed with an appreciation for the
hypercompetitive dynamics of the generic
drugs industry.
Agree 3 3 9 0 15
Neither agree nor
disagree
10 8 11 0 29
Disagree 4 9 5 0 18
I don’t know 1 2 6 0 9

Total 18 22 31 0 71
Please indicate your level of agreement
with the following statements - The
measured progress of GDUFA is an
incentive to bring companies to the
GDUFA III negotiation table to discuss
further program expansion.
Agree 11 6 13 0 30
Neither agree nor
disagree
5 11 7 0 23
Disagree 0 2 2 0 4
I don’t know 2 4 10 0 16
Total 18 23 32 0 73

Abstract (if available)

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

Regulatory programs to foster medical product development: user experience in the United States and Japan

PDF

Experience with breakthrough therapy designation: an industry survey

PDF

Challenges in the implementation of Risk Evaluation Mitigation Strategies (REMS): a survey of industry views

PDF

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

PDF

Incentivizing quality in the manufacture of pharmaceuticals: manufacturers' views on quality ratings

PDF

Examining the cord blood industry views on the biologic license application regulatory framework

PDF

Examining the regulatory framework for drug compounding: industry views and experiences

PDF

Implementation of good manufacturing practice regulations for positron emission tomography radiopharmaceuticals: challenges and opportunities perceived by imaging thought leaders

PDF

Regulatory CMC strategies for gene and cell therapies during mergers and acquisitions: a survey of industry views

PDF

An integrated framework to evaluate customer service delivery: a study of electronic systems at FDA's Los Angeles Import Operations Branch

PDF

Implementation of unique device identification in the medical device industry: a survey of the change management experience

PDF

The impact of incomplete monographs on the OTC drug industry: a survey investigation of industry views

PDF

Views on global harmonization of pharmacopeial standards: a survey of key stakeholders

PDF

U.S. veterinary drug shortages: industry views on potential changes to regulatory policy

PDF

Regulation of pediatric cancer drug development: an industry perspective

PDF

Risk management and recalls: a survey of medical device manufacturers

PDF

Design control for software medical devices: an industry survey of views and experiences

PDF

Regulatory dissonance in the global development of drug therapies: a case study of drug development in postmenopausal osteoporosis

PDF

Current practices in biocompatibility assessment of medical devices

PDF

Benefits-risk frameworks: implementation by industry

Asset Metadata

Creator Ako-Arrey, Donatus Ayuk (author)

Core Title Effect of GDUFA legislation on the development and approval of generic drugs: a survey of industry views and experiences

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 02/07/2020

Defense Date 10/03/2019

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

Tag ANDA,FDA user fees,GDUFA,generic drugs,OAI-PMH Harvest

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Davies, Daryl (committee chair), Richmond, Frances (committee chair), Hamrell, Michael (committee member), Kuo, Benson (committee member)

Creator Email akoarrey@usc.edu,akoarreyd@yahoo.ca

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-266956

Unique identifier UC11674998

Identifier etd-AkoArreyDo-8156.pdf (filename),usctheses-c89-266956 (legacy record id)

Legacy Identifier etd-AkoArreyDo-8156.pdf

Dmrecord 266956

Document Type Dissertation

Rights Ako-Arrey, Donatus Ayuk

Type texts

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

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

Repository Name University of Southern California Digital Library

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