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

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

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U.S. VETERINARY DRUG SHORTAGES:
INDUSTRY VIEWS ON POTENTIAL CHANGES TO REGULATORY POLICY

by

Jeanne Greenwald

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

May, 2022

Copyright, 2022 Jeanne Greenwald

ii
Dedication

This work is dedicated to my husband, Ron, for his love and support, without
which this would not have been possible. But, also, to my mom, children, family, and
friends, who encouraged me every step of the way. Finally, this work is dedicated to my
dearly, missed dad who still inspires me every day.

iii
Acknowledgments

I would like to thank Dr. Frances Richmond, my advisor, for all of her expert
guidance and support. She was a pleasure to work with, and I feel very fortunate to have
had her as my advisor. She is truly amazing.
I would like to thank my committee members, including Dr. Daryl Davies, Dr.
Susan Bain, Dr. David Dzanis, and Dr. Mary Ellen Cosenza, for their time, thoughtful
comments, and encouragement.
I would also like to thank my focus group members, including Dr. Nancy Pire-
Smerkanich, Dr. Susan Bain, Mr. Michael Mlodzik, Mrs. Parul Upadhya, Mr. Ron
Phillips, and Dr. Brian Johnson, for their support and expert guidance, which helped to
improve the survey instrument.
I would like to thank my boss, Dr. Gareth Harris, for his support of my efforts.

iv
Table of Contents
Acknowledgments....................................................................................................... iii
List of Tables ............................................................................................................. vii
List of Figures ............................................................................................................. ix
Abstract ....................................................................................................................... xi
Chapter 1: Overview .................................................................................................... 1
1.1 Introduction ............................................................................................ 1
1.2 Statement of the Problem ....................................................................... 6
1.3 Purpose of the Study .............................................................................. 8
1.4 Importance of the Study ......................................................................... 9
1.5 Delimitations, Limitations, and Assumptions ...................................... 10
1.6 Organization of Thesis ......................................................................... 11
1.7 Definitions ............................................................................................ 11
Chapter 2: Literature Review ..................................................................................... 14
2.1 Introduction .......................................................................................... 14
2.2 A Historical Overview of Human Drug Shortages in the U.S. ............ 15
2.2.1 Early History of U.S. Drug Shortages .................................... 16
2.2.2 FDA Establishes a Drug Shortage Program ........................... 18
2.2.3 U.S. Government Evaluation of the U.S. Human Drug
Shortage Issue ......................................................................... 20
2.2.4 New U.S. Legislation to Reduce Drug Shortages: The Last
Decade .................................................................................... 25
2.2.5 International Society for Pharmaceutical Engineering (ISPE)
Drug Shortage Survey ............................................................ 28
2.2.6 Quality and Economic Incentives ........................................... 29
2.2.7 FDA’s Strategic Plan for Preventing and Mitigating Drug
Shortages ................................................................................ 35
2.2.8 ISPE Drug Shortage Prevention Plan ..................................... 38
2.2.9 Risk Assessment Tools ........................................................... 39
2.2.10 FDA Annual Drug Shortage Reports ...................................... 41
2.2.11 FDA Root Causes and Potential Solutions 2019 Report ........ 46
2.2.12 Mitigating Emergency Drug Shortages (MEDS) Bill and the
Coronavirus Aid, Relief, and Economic Security (CARES) Act
................................................................................................ 48
2.3 An Overview of U.S. Animal Drug Shortages ..................................... 52
2.4 Regulatory Framework for U.S. Animal Drug Shortages .................... 54
2.5 U.S. Veterinary Drug Shortages: Industry Views on Potential Changes
to the Regulatory Policy ....................................................................... 57

v
2.5.1 Literature Search..................................................................... 57
2.5.2 Concern about Veterinary Drug Shortages ............................. 60
2.5.3 Perceived Causes and Solutions for Veterinary Drug Shortages
................................................................................................ 63
2.5.4 Approaches to the Current Research ...................................... 68
Chapter 3: Methodology ............................................................................................ 72
3.1 Introduction .......................................................................................... 72
3.2 Survey Development ............................................................................ 72
3.3 Survey Delivery ................................................................................... 73
3.4 Survey Analysis ................................................................................... 74
Chapter 4: Results ...................................................................................................... 76
4.1 Survey Participation ............................................................................. 76
4.2 Demographic Profile of the Respondents ............................................ 77
4.3 Familiarity with U.S. Drug Shortage Regulations, Policy, and Guidance
Documents ........................................................................................... 83
4.4 Views on Key Definitions .................................................................... 88
4.5 Experience with U.S. Veterinary Drug Shortages ............................... 91
4.6 Advanced Notice of U.S. Veterinary Drug Shortages and Failure to
Report ................................................................................................... 97
4.7 Publicly Available List of Veterinary Drug Shortages ...................... 102
4.8 Expedited Inspections and Submission Reviews ............................... 106
4.9 Risk Management Plans and Tools .................................................... 110
4.10 Quality Metrics .................................................................................. 117
4.11 Compounding ..................................................................................... 120
4.12 Regulatory Policy Implications of New Regulations for Veterinary
Drug Shortages ................................................................................... 123
4.13 Other Views from the Survey Participants......................................... 127
Chapter 5: Discussion .............................................................................................. 129
5.1 Overview ............................................................................................ 129
5.2 Methodological Considerations ......................................................... 129
5.2.1 Limitations ............................................................................ 129
5.2.2 Delimitations ........................................................................ 132
5.3 Consideration of Results .................................................................... 135
5.3.1 Expediting Submission Reviews and Inspections ................ 135
5.3.1.1 Reporting and Enforcement of Reporting ................ 140
5.3.1.2 Risk Management Plans .......................................... 144
5.4 Future Directions and Concluding Thoughts ..................................... 146
References ................................................................................................................ 149
Appendix A. Comments about Reporting .................................................. 159

vi
Appendix B. Comments about Enforcement ............................................. 162
Appendix C. Comments about Expediting FDA Actions .......................... 164
Appendix D. Comments about Quality Metrics ......................................... 165
Appendix E. Comments about Risk Management plans ........................... 167
Appendix F. Job Role versus Key Policy Questions ................................. 169

vii
List of Tables
Table 1: Acronyms ........................................................................................................11
Table 2: ISPE Drug Shortages Prevention Plan Recommendations .............................39
Table 3: Overview of FDA Drug Shortage Annual Report Data ..................................44
Table 4: Comparison of Human and Veterinary Drug Shortage Regulatory
Frameworks................................................................................................57
Table 5: Summary of Search Results from Several Databases .....................................59
Table 6: Summary of Additional Search Results ..........................................................59
Table 7: Other Roles of Survey Respondents ...............................................................78
Table 8: Other Organizational Levels of Participants ...................................................79
Table 9: Cross Tabulation of Company Size versus Types of Marketed Drugs ...........82
Table 10: Cross Tabulation of Familiarity with Documents versus Job Function .........86
Table 11: Cross Tabulation of Familiarity with Documents versus Job Position ...........88
Table 12: Other Root Causes for Veterinary Drug Shortages Experienced by
Respondents ...............................................................................................92
Table 13: Actions Taken by FDA-CVM to Address Veterinary Drug Shortages ..........93
Table 14: Other Actions taken by FDA-CVM to Address Veterinary Drug
Shortages ....................................................................................................93
Table 15: Trends Contributing to Increases U.S. Veterinary Drug Shortages ................94
Table 16: Other Comments from Participants about Trends Contributing to
Shortages ....................................................................................................95
Table 17: Problems with the Way U.S. Veterinary Drug Shortages are
Currently Managed ....................................................................................96
Table 18: Other Comments about the Way Veterinary Drug Shortages are
Handled ......................................................................................................96
Table 19: Participant Comments on Reporting Veterinary Drug Shortages ...................99
Table 20: Examples of Comments from Participants about Enforcement of
Reporting..................................................................................................102
Table 21: Survey Participants Ranking of Veterinary Stakeholders in Need of a
Public List ................................................................................................103
Table 22: Other Veterinary Stakeholders in Need of a Public List ..............................104
Table 23: Top Reasons for Having a Public List of Veterinary Drug Shortages .........105
Table 24: Top Reasons for Not Having a Public List of Veterinary Drug
Shortages ..................................................................................................106
Table 25: Other Reasons for Having or Not Having a Public List ...............................106
Table 26: Comments about Prioritizing and Expediting Submission and
Inspections ...............................................................................................109
Table 27: Top Reasons for Having Risk Management Plans .......................................111
Table 28: Top Reasons for Not Having Risk Management Plans ................................112

viii
Table 29: Other Reasons to Have or Not Have Risk Management Plans .....................113
Table 30: Other Comments about Extending the Risk Management Plan
Requirement .............................................................................................114
Table 31: Views on the Most Important Components of the PDA Risk Tool ..............116
Table 32: Participants Views of the Most Important Aspects of the ISPE Tool ..........117
Table 33: Participant Comments About Other Tools or Programs ...............................117
Table 34: Comments from Participants about Introducing a Quality Metrics
Initiative ...................................................................................................120
Table 35: Other Comments about Using Compounding to Solve Veterinary
Drug Shortages.........................................................................................123
Table 36: Comments about the Potential for Unfairness in the Marketplace ...............125
Table 37: Cross Tabulation of New Regulations Causing Unfairness vs.
Company Size ..........................................................................................125
Table 38: Other Comments on Funding of Government Costs ....................................127
Table 39: Other Views about U.S. Veterinary Drug Shortages from the Survey
Participants ...............................................................................................128

ix
List of Figures
Figure 1: New and Prevented Human Drug Shortages (2005 – 2012) .............................5
Figure 2: Human Drug Shortages by Primary Reason in 2012 ........................................6
Figure 3: U.S. Drug Shortages (2005-2010) ..................................................................20
Figure 4: Injectable Molecules by Market Concentration, 2010 ....................................23
Figure 5: Proposed FDA Actions to Mitigate and Prevent Drug Shortages ..................24
Figure 6: FDA's Strategic Plan to Mitigate and Prevent Drug Shortages ......................37
Figure 7: PDA Risk Register and Prevention - Response Plan ......................................40
Figure 8: Number of New Drug Shortages per Year (2010 – 2018) ..............................41
Figure 9: Number of Prevented Drug Shortages per Year (2010 – 2018) .....................42
Figure 10: Number of Ongoing Drug Shortages per Year (2013 – 2018) .......................43
Figure 11: Overview of FDA Efforts Reported in the Annual Reports
(2014 - 2018)..............................................................................................45
Figure 12: Evolution of the U.S. Regulatory Framework for Human Drug
Shortages ....................................................................................................51
Figure 13: Proposed Animal Drug Compounding Conditions to Avoid FDA
Enforcement Action ...................................................................................68
Figure 14: Five Major Areas of Human Health Drug Shortage Regulation ....................69
Figure 15: Description of the Human Health Drug Shortage Regulations ......................70
Figure 16: Consideration of the Proposed Regulations and Regulatory Agency
Objectives ..................................................................................................71
Figure 17: Functional Roles of Survey Respondents .......................................................77
Figure 18: Organizational Level of Survey Respondents ...............................................78
Figure 19: Years of Experience of Survey Respondents ..................................................79
Figure 20: Size of Companies in which Survey Respondents Work ...............................80
Figure 21: Types of Veterinary Drugs Marketed by the Respondent’s
Companies..................................................................................................80
Figure 22: Number of FDA Approved Applications held by Companies........................83
Figure 23: Familiarity with Regulations, Policy, and Guidance Documents ...................84
Figure 24: Views on Definition of a Drug Shortage ........................................................89
Figure 25: Views on the Definition of Medically Necessary ...........................................90
Figure 26: Number of Veterinary Drug Shortages Experienced by Respondents ...........91
Figure 27: Root Causes of Veterinary Drug Shortages Experienced by
Respondents ...............................................................................................92
Figure 28: Effects of a Requirement to Report U.S. Veterinary Drug Shortages ............98
Figure 29: Participant Views on Enforcement of a Reporting Requirement .................101
Figure 30: Consequences of a Requirement to Expedite Inspections and
Reviews ....................................................................................................108
Figure 31: Requirement for Risk Management Plans ....................................................110

x
Figure 32: Use of Available Tools by Respondents to Avoid Veterinary Drug
Shortages ..................................................................................................115
Figure 33: Respondents Views on the Effects of a Quality Metrics Initiative ...............119
Figure 34: Industry Views on Compounding to Solve Veterinary Drug
Shortages ..................................................................................................122
Figure 35: Views on Impact of Veterinary Drug Shortage Regulations ........................124
Figure 36: Participant Views on the Cost of New Veterinary Drug Shortage
Regulations ..............................................................................................126
Figure 37: Survey Participant Views on Funding of Government Costs .......................126

xi
Abstract

Animal drugs experience drug shortages just as human drugs do. However,
certain types of reporting and follow-up required during human drug shortages are not
required when shortages occur for animal drugs. Would a more rigorous system of
regulations like that in place for human drugs in the U.S. be seen as useful and welcome
in the animal health industry? This exploratory study used a survey approach to examine
the potential impact of such changes by examining the views and experience of
professionals in pharmaceutical organizations supplying animal drugs to the U.S. market
and who have experience with U.S. veterinary drug shortages. A triad of principles
relating to the goals of regulation was used to structure the survey and help interpret and
frame the research results. Respondents believed that veterinary drug shortages have
increased over the last 5-10 years. Most respondents commonly thought that the FD&C
Act should be extended to require that manufacturers report shortages of medically
necessary veterinary drugs to the U.S. FDA.
Further, most supported the adoption of requirements that the U.S. FDA prioritize
and expedite submissions and inspections associated with shortages of medically
necessary veterinary drugs. However, most respondents did not favor requirements for
risk management plans due to concerns with costs in excess of the value they might
create. These findings suggest that a reevaluation of animal drug regulations might be
supported by the animal health industry in order to increase the safety and availability of
needed animal medications.

1
Chapter 1: Overview
1.1 Introduction
Veterinary drug shortages are a significant challenge for stakeholders that use,
manufacture, distribute, and regulate veterinary drug products. Without needed drugs,
veterinarians find it difficult to provide safe and effective care for animals. Companies
that produce veterinary drugs in short supply can lose revenue, market share, and
reputation. Thus, regulators face difficult choices about how to foster a secure but safe
supply of needed medicines to protect animals and public health. When an animal drug is
in short supply, it may be necessary to adopt less-desirable solutions, including
substituting inferior medications, such as compounded veterinary drugs, or delaying
treatment or procedures until the needed medicine becomes available. Dr. Lynne White-
Shim, Assistant Director of the American Veterinary Medical Association (AVMA)
Scientific Activities Division, said, "Veterinarians have relatively few drugs they can use
to treat the wide range of species and conditions they see. So, drug availability and
shortages being part of that remains a critical issue in veterinary medicine.” (Burns,
2010)
Many believe that the incidence of veterinary drug shortages is increasing,
becoming an important issue for veterinary medicine (Burns, 2010; Khuly, 2015).
Nevertheless, the Food, Drug, and Cosmetic Act (FD&C Act) does not include any
provisions pertaining to the prevention or mitigation of veterinary drug shortages. The
Food and Drug Administration’s Center for Veterinary Medicine (FDA CVM) has had a
supplemental policy guide in place for managing veterinary product shortages since 2000
(FDA, 2000). CVM limits their involvement to shortages of medically necessary

2
veterinary products (MVNPs), which are "used to treat or prevent a serious disease or
condition or needed to assure the availability of safe food products of animal origin, and
there is no other available source of that product or alternative drug that is judged by
CVM’s veterinary staff to be an adequate substitute.” (FDA, 2000)
Although CVM encourages manufacturers to report veterinary drug shortages
voluntarily, CVM often learns about veterinary drug shortages from other sources such as
veterinarians, animal producer associations, the press, consumer groups, or through
routine regulatory submission review, surveillance, and enforcement activities (FDA,
2000). Since 2011, CVM has only listed approximately twenty-five shortages of MNVPs
on their website (FDA, 2020a). As of May 2020, the FDA website for animal drug
shortages includes fourteen ongoing MVNP shortages. Eleven were related to
manufacturing delays, which include both facility remediation and product manufacturing
issues, three were attributed to increased demand, and half of the shortages were related
to injectables (FDA, 2020a). Because CVM becomes involved late, it has typically been
unable to prevent shortages of MVNPs but instead uses its limited powers and resources
to minimize ongoing shortages, where possible. CVM’s policy guide states that they will
consider special actions, such as discussions with industry, accelerations of reviews, or
enforcement discretion, but only after a “bona fide shortage situation is confirmed.”
(FDA, 2000) However, such a process to confirm a bona fide shortage is lengthy. FDA
must demonstrate that a potential for shortage exists, that the product is medically
necessary, and that risks and benefits to public health have been considered carefully
(FDA, 2000).

3
CVM indicated in the 2011 report, A Review of FDA’s approach to Medical
Product Shortages, that “many manufacturers who experience shortages are becoming
less likely to return to production because products compounded from bulk drug
substances have addressed the need and manufacturers are likely to have difficulty
regaining market share.” (FDA, 2011) The fact that veterinarians may decide to use less
expensive compounded drugs when an FDA-approved veterinary drug is not available
may suggest that some veterinarians may not fully appreciate the risks (Lau, 2015). Thus,
CVM is rightfully concerned about the risks of compounded drugs. Its recently issued
draft Guidance for Industry #256, Compounding Animal Drugs from Bulk Drug
Substances, outlines requirements for compounding, pharmacovigilance reporting, and
labeling necessary to avoid enforcement consequences. This increased set of
requirements and additional scrutiny may reduce the future use of compounding as a
solution to veterinary drug shortages (FDA, 2019a). In addition, CVM has taken more
interest in veterinary drug shortages recently by directly engaging manufacturers about
the potential for veterinary drug shortages, such as those that were related to Hurricane
Maria and the COVID-19 pandemic. It has issued an interim Guidance for Industry,
Reporting and Mitigating Animal Drug Shortages during the COVID-19 Public Health
Emergency; and participated in a well-publicized workshop, Animal Pharmaceutical
Supply Chain Disruptions, at Kansas State University in September 2019 (Campbell
Thornton, 2017; FDA, 2020b; Peralta and Bailey, 2019).
By contrast to the relatively modest FDA oversight described above for managing
veterinary drug shortages, stronger policies have been put into place for human drug
shortages. The increasing numbers of human drug shortages, particularly for life-saving

4
human drugs, have been recognized as posing a significant public health issue and have
prompted amendments that have strengthened the FD&C Act with respect to human drug
shortages. It now requires all manufacturers of life-saving medicines to notify FDA of
potential disruptions and discontinuations six months in advance or as soon as possible
and provide the reason for the disruption. It further gives the FDA authority to enforce
the reporting of impending drug shortages and to consider expediting application reviews
and inspections as well as the risks and impact of drug shortages before issuing warning
letters or taking enforcement action (S 3187, 2012). These measures resulted in an
immediate doubling of reported drug shortages. At the same time, the number of drug
shortages that were prevented increased more than four-fold (Figure 1) (FDA, 2013a), as
FDA expedited regulatory reviews and exercised flexibility and discretion with respect to
its quality requirements and responses to inspections (FDA, 2019c). Over the next four
years, the numbers of new and prevented drug shortages decreased, suggesting that the
newly implemented regulations were effective. However, a more recent upward trend,
albeit modest, in the number of new, ongoing, and prevented drug shortages between
2016 – 2018 may indicate that the problem was not completely solved (FDA, 2019c). The
drug shortage legislation was strengthened further, as this dissertation was being
developed as part of the Phase 3 Coronavirus Aid, Relief, and Economic Security
(CARES) Act. This legislation extends manufacturer reporting requirements to drug
substances, requires application holders to prepare risk-mitigation plans, and requires
FDA to prioritize and expedite reviews and inspections related to critical drug shortages
(HR 748, 2020).

5
Figure 1: New and Prevented Human Drug Shortages (2005 – 2012)

Source: Strategic Plan for Preventing and Mitigating Drug Shortages (FDA, 2013a)

The policies that FDA developed for human drugs may be helpful to consider in
the context of potential changes in the regulatory policy for veterinary drug shortages.
Also helpful to consider are the detailed analyses that FDA has conducted to understand
the reasons for human drug shortages that undoubtedly are shared by veterinary products.
FDA summarized the main reasons for human medicine shortages in their Strategic Plan
for Preventing and Mitigating Drug Shortages (FDA, 2013a). They observed that quality
and manufacturing issues caused approximately 66% of the shortages (Figure 2) (FDA,
2013a). The International Society of Pharmaceutical Engineering (ISPE) drilled more
deeply into the nature of those quality and manufacturing issues in its Drug Shortages
Survey (ISPE, 2013), finding that most were related to problems with aseptic processing
equipment and production system challenges during technology transfers or product
development (ISPE, 2013).

6
Figure 2: Human Drug Shortages by Primary Reason in 2012

Source: Strategic Plan for Preventing and Mitigating Drug Shortages (FDA, 2013a)

1.2 Statement of the Problem
Veterinary drug shortages affect animals, veterinarians, pet owners, and animal
producers in similar ways as human drug shortages affect people and their healthcare
providers. FDA acknowledges this in the Drug Shortages: Root Causes and Potential
Solutions report issued in October 2019 when they stated, "many of the same concerns
apply to veterinary medicines used to treat service, companion, and food-producing
animals." (FDA, 2019b) However, the policies of CVM with regard to the management
and oversight of MNVP shortages have not evolved in the same way as they did for
human drug shortages (FDA, 2000; FDA, 2011) Over the past several years, expanded
legislation aimed at preventing and mitigating human drug shortages has been
implemented as part of the effort to assure the availability of critical medicines to patients
(S 3187, 2012, HR 748, 2020). Further, increased scrutiny of the causes of human drug
shortages has painted an insightful picture of the areas of greatest concern.

7
Given the importance of veterinary drugs both for the food supply and the pet
animal sectors, it seems timely to ask whether it is time to revise current approaches and
policies related to veterinary drug shortages. However, systematic information about root
causes and solutions in the veterinary industry are missing, and without such information,
it is difficult to know whether the patterns and solutions attempted for human drugs are
completely relevant. We do not know, for example, whether the root causes of such
issues related to quality and manufacturing that were so apparent in the analyses of
human drug shortages are also most responsible for veterinary drug shortages and
whether the measures taken for human drug shortages would be the right solutions for
veterinary shortages. For example, FDA has instituted a program of voluntary quality
metrics and incentives for human drug manufacturers (FDA, 2016a), but it is not clear
whether veterinary drug manufacturers would regard a similar program as useful and
acceptable. Further, certain risk-based tools were introduced to help industry identify and
plan for potential shortages; manufacturers were required to develop risk-management
plans for life-saving human medicines and make them available upon FDA inspection. If
veterinary drug manufacturers developed similar risk-management plans for MVNPs,
would this prevent veterinary drug shortages?
Understanding the answers to these and other related questions are important as a
basis for policy development because such policy has far-reaching business implications.
Care must always be taken to avoid overregulation, which itself might cause shortages,
for example, if companies abandon development or marketing plans for certain veterinary
drugs because the costs of managing the added requirements become too high. Based on
the information available to date, little evidence exists to understand whether industry

8
would see the different regulatory policies and industry tools recently introduced for
human drugs as helpful or unpalatable.
To be effective, the policies to prevent and mitigate veterinary drug shortages
should address certain basic requirements for effective regulation: to protect the supply of
drug to veterinarians and animal owners; to assist the regulators in protecting public
health by assuring safety, effectiveness, quality; to assure that manufacturers have a level
playing field and the best possible opportunity to assure revenue, market share, and
reputation. Up to now, there has been little discussion about policy changes in connection
with veterinary drug shortages. Thus, we have little systematically collected evidence to
understand if the industry would, in fact, be persuaded to favor policy changes in order to
reduce numbers and durations of veterinary drug shortages.
1.3 Purpose of the Study
The goal of this research was to explore industry views on changing the
regulatory policies, metrics, and incentives to align the rules to manage U.S. veterinary
drug shortages with those of human drugs. The study was performed using a novel survey
tool directed toward industry stakeholders in regulatory affairs, supply chain
management, quality, manufacturing, and technical operations. The survey was based on
a conceptual framework that helped me to explore the effects of regulatory change on
safety, quality, costs, and fairness for manufacturers of different types and sizes. To this
end, I posed questions about the experiences of these industry stakeholders with previous
and current veterinary drug disruptions. I explored whether the industry stakeholders
agree or disagree with potential changes in regulatory policy for veterinary drugs
shortages. A focus group helped to fine-tune the survey.

9
1.4 Importance of the Study
To my knowledge, this was the first academic research study aimed at gaining a
better understanding of veterinary drug shortages in the U.S. It has many potential
applications.
This research may benefit the CVM, whose goal is to protect public health by
assuring a consistent supply of safe and effective veterinary medicines in the U.S.
marketplace. Its observations should be useful for CVM to consider when developing
future regulatory policies and procedures related to U.S. veterinary drug shortages.
It may also benefit veterinarians, pet owners, and animal producers who are
frustrated and concerned when the medicines that they need are not available.
Veterinarians may need to prescribe inferior medications or delay treatments until
medicines become available. Veterinary drug shortages put an increased burden on the
veterinarian, pet owner, and animal producer to explore other options, which take time
and effort and may increase the overall cost of care. In addition, they can even cause
economic losses if the shortages affect animal producers (Khuly, 2015). These
stakeholders may appreciate regulatory reform that improves veterinary drug availability.
The proposed research may also prove valuable to the animal health industry in
their efforts to meet market demands with a stable supply of animal drugs. Business
performance is affected when a drug cannot be provided. Efforts to remediate drug
shortages may divert research and development resources, which can then delay the
introduction of new medicines. Drug shortages may affect the pharmaceutical
manufacturer's reputation and can result in a loss of trust in the company. Appropriate
regulatory reform without regulatory overreach may help the animal health industry to

10
prevent or mitigate drug shortages of veterinary medicines, a goal critical to the growth
and development of the animal health industry.
1.5 Delimitations, Limitations, and Assumptions
This study explored industry views related only to the regulatory framework
governing U.S. veterinary drug shortages. Although it references the regulatory
framework for U.S. human drugs, it does not look in any detail at the views and
experiences in the human drug industry. Further, it does not extend its reach to the
regulatory frameworks for veterinary drug shortages in other countries. It does not
explore experiences or views related to other types of veterinary product shortages, such
as vaccines or medical devices.
A survey tool was used for this study which included only a limited number of
questions in order to avoid overwhelming the participants, who might then become
unwilling to participate. This may have limited the amount of information that could have
been collected. The study was also limited by the number and experience of industry
participants with appropriate experience because the animal health industry and the
number of reported veterinary drug shortages are relatively modest. Thus, it was difficult
to engage as many potential participants as might be possible in a survey with a broader
area of focus. As a result, the survey provides only a sampling of appropriate individuals
who are sufficiently interested in the research topic to complete a survey, and this has the
potential to bias the results. Further, the responses provided by the study participants
may have been influenced by their relationship with their organizations; they may have
found it difficult to answer based on their specific knowledge and experience, or they
may not have answered truthfully. Finally, the survey may have been limited by my

11
skills in preparing an unbiased survey because of my concurrent experience and
employment in the animal health industry.
1.6 Organization of Thesis
Chapter 1 introduces the field, provides a statement of the problem, and describes
the importance and constraints on the study performed. Chapter 2 outlines the literature
relevant to the field and establishes the research framework used to examine this area.
Chapter 3 defines the methods. Chapter 4 reviews the results of the study. Chapter 5
discusses the significance and validity of the findings.
1.7 Definitions
Table 1: Acronyms
Acronym Meaning
ADUFA Animal Drug User Fee Act
AGDUFA Animal Generic Drug User Fee Act
AHA American Hospital Association
APhA American Pharmacist’s Association
ASCO American Society of Clinical Oncology
AVMA American Veterinary Medical Association
API Active Pharmaceutical Ingredient
ASHP American Society of Health Pharmacists
ASPE Office of the Assistant Secretary for Planning and Evaluation
AVMA American Veterinary Medical Association
BLA Biologics License Application
CAPA Corrective and Preventive Action

12
Acronym Meaning
CARES
Act
Phase 3 Coronavirus, Aid, Relief, and Economic Security Act
CBER Center for Biologics Evaluation and Research
CDC Centers for Disease Control and Prevention
CDER Center for Drug Evaluation and Research
CMO Contract Manufacturing Organization
CMS Centers for Medicare and Medicaid Services
CVM Center of Veterinary Medicine
EMA European Medicines Agency
EHS Environmental, Health, and Safety
FDA Food and Drug Administration
FD&C Act Food, Drug, and Cosmetic Act
FDASIA Food and Drug Administration Safety and Innovation Act
FAQ Frequently Asked Question
GAO U.S. Government Accountability Office
GMP Good Manufacturing Practices
ICH
The International Council for Harmonization of Technical Requirements
for Pharmaceuticals for Human Use
ISPE International Society for Pharmaceutical Engineering
JAVMA Journal of the American Veterinary Medical Association
MEDS Mitigating Emergency Drug Shortages Bill
MNVP Medically Necessary Veterinary Product
NDA New Drug Application
NF National Formulary
PDA Parenteral Drug Association

13
Acronym Meaning
SME Subject Matter Expert
USP United States Pharmacopeia
VA Department of Veterans Affairs
VIN Veterinary Information Network
Y2K The Year 2000

14
Chapter 2:Literature Review
2.1 Introduction
The U.S. has a drug shortage problem (Pflanzer, 2017).
What is a drug shortage? A shortage is a state or situation in which something-
such as a drug- cannot be obtained in sufficient amounts (Merriam-Webster, 2021). The
American Society of Health-System Pharmacists (ASHP) defines a drug shortage as a
situation that causes pharmacists or providers to make changes to medications or choose
alternative drugs due to a problem with the supply of a preferred product (ASHP, 2018).
Alternatively, the FD&C Act defines a drug shortage as a period when the demand or
projected demand for a drug within the United States exceeds the supply of the
medication (S 3187, 2012). FDA defines a drug shortage as “a situation in which the total
supply of all clinically interchangeable versions of an FDA‐regulated drug is inadequate
to meet the current or projected demand at the patient level.” (FDA, 2011) The PDA
offers yet another definition:
…the occurrence of internal or external situations (single or in
combination of both), which could result in an interruption of supplies of a
medicinal product if not adequately addressed and controlled. Such
potential drug shortages very often arise from special cause problems
(PDA, 2014).

Over the last ten years, these definitions have been consulted more frequently as
the number of drug shortages has increased dramatically. In May 2018, FDA
Commissioner Scott Gottlieb released a statement on FDA’s Work to Mitigate Shortages
of Intravenous Drugs, Shorten Supply Chain Disruptions and Predict Better
Vulnerabilities (Gottlieb, 2018) that captures the essence of the drug shortage issue:

15
Without question, one of the most frustrating challenges that health care
providers and patients must contend with is when a drug that is medically
necessary and critical to patient care is unavailable due to a shortage. We
know that the uncertainty over how long a drug will be in shortage, how to
ration the supplies in the meantime, or worse, how to prepare for a sudden
event that might place unforeseen demands on a product that is in short
supply, adds burden and stress on providers and patients. Shortages are
an inevitable consequence of an imperfect system (Gottlieb, 2018).

A growing body of information has examined the importance and priority given to
the shortages of drugs affecting people. However, drug shortages impact animals as well.
Their effects are most visible on the frontlines, where veterinarians and animal owners
face the direct consequences of such shortages. Dr. Patty Khuly highlights these
concerns in her website post on August 8, 2015, titled Drug Shortages in Veterinary
Medicine: Why Pets get the Short End of the Stick. She expresses her frustration with the
continued short supply of the FDA-approved veterinary drug, Apoquel
®
, a canine once-
daily non-steroidal medication for canine atopic dermatitis, as one example at the time.
She makes the point that pets “…suffer disproportionately concerning drug shortages.
Percentage-wise, pets use more generic drugs than people do; pets comprise a smaller
market than people or even agricultural animals do, and people have moral and political
capital.” (Khuly, 2015)
Shortages impact the ability of veterinarians to provide appropriate animal
therapy; they lead to suboptimal substitutions, delays in treatment or procedures,
medication errors, and increased time and money spent on treatment.
2.2 A Historical Overview of Human Drug Shortages in the U.S.
Much can be learned about the dynamics of drug shortages in general by first
examining the extensive literature associated with shortages of human drugs that have

16
been seen over the last century. Thus, this chapter begins by discussing the early history
of drug shortages, the establishment of the FDA drug shortage program, the initial U.S.
government evaluation of the drug shortage issue, and changes in the U.S. legislation
related to drug shortages. The overview then considers the perspectives of the
pharmaceutical industry and FDA from both a quality and economic point of view.
Finally, the overview discusses plans and tools developed by FDA and the industry to
mitigate and prevent drug shortages. As drug shortages continue to persist, further FDA
plans and legislative proposals are described.
2.2.1 Early History of U.S. Drug Shortages
Drug shortages have been a subject of concern for more than a century. Before
the United States entered into World War I in 1917, the National Research Council’s
Committee on Chemistry worried about the potential for wartime drug shortages because
some important drugs were imported from Germany, which was an enemy in that war.
The committee made it their mission to facilitate the manufacture of medically important
synthetic drugs in the U.S. and to reduce the extraordinary prices being charged by some
profiteers along the supply chain during the war. Several U.S. manufacturers were
granted special licenses to produce the drugs covered by confiscated German drug
patents, for example, to manufacture and distribute the anti-syphilitic drug Salvarsan, and
the local anesthetic, Novocain (Cooper, 2012; Stieglitz, 1917; Unknown, 1922).
In the 1970s, another significant drug shortage occurred when intravenous
penicillin G, one of the most widely used antibiotics in U.S. hospitals, became hard to
secure. An article by B.J. Culliton titled Penicillin G: Suddenly a Shortage (Culliton,
1976) noted that the manufacturer, Squibb and Sons, was evasive when questioned about

17
that shortage. In response to inquiries from the Johns Hopkins Hospital, Squibb
identified that the company had run out of penicillin but did not offer a clear explanation
regarding its cause. However, according to Culliton, the shortage occurred when Squibb
encountered difficulties in production transfer when it moved part of its manufacturing
operations to another facility. That move was driven by the need to comply with new
FDA Good Manufacturing Practice (GMP) regulations, designed to assure that penicillin
would not cross-contaminate other drugs in a shared facility. Johns Hopkins Hospital was
able to secure a sufficient supply to last a few weeks by stockpiling the drug from another
vendor for patients for whom the drug would be essential and by switching all other
patients to alternative antibiotics.
This penicillin shortage did not cause a serious public health issue for Johns
Hopkins but did trigger some panic. It also raised the concern that no one was monitoring
the drug supply to anticipate shortages (Culliton, 1976). M. H. Stolar, a representative of
the American Society of Hospital Pharmacists (AHSP), wrote a letter in response to the
article by Culliton. He identified that ASHP was aware that several other drugs, including
injectable anesthetics, vasopressor agents, and electrolyte additives, were also in short
supply. Concerned about the increasing frequency of such shortages, AHSP and the FDA
created a drug-shortage monitoring program that would help physicians and pharmacists
anticipate shortages, understand the scope and duration of those events and prevent the
spread of inaccurate information (Stolar, 1976).
Further shortages of penicillin G occurred in 1994 and 1999. In the 1994 incident,
the sole manufacturer of penicillin G sodium reported that the company supplying the
active pharmaceutical ingredient (API) had stopped production in the prior year and

18
predicted an imminent shortage of injectable drug products. FDA recommended
penicillin G potassium as an alternative, and at the same time, identified a promising new
API supplier whose product was being tested. Until the situation resolved, the
manufacturer of the penicillin sodium retained an emergency stock of the product, and
physicians with patients who could not use a substitute were told to call the manufacturer
(JAMA, 1994). In the 1999 incident, a different manufacturer recalled all of its penicillin
products and stopped production to address FDA deficiencies at its manufacturing site.
In this case, FDA assisted health care professionals in finding alternative manufacturers,
provided information about alternative treatments, and recommended the use of existing
supplies only for patients who could not be treated with an alternative drug (CDC, 1999).
FDA and Centers for Disease Control (CDC) published an update in March 2000,
indicating that they had identified an FDA-approved, temporary supplier of penicillin G
sodium in Austria that was capable of supplying the U.S. under a drug shortage
emergency-allocation program (CDC, 2000; JAMA, 2000).
2.2.2 FDA Establishes a Drug Shortage Program
At the start of the 21
st
century, the FDA began to change its approach to drug
shortage management. Worries that supply chains could be affected by the “Y2K”
computing challenges, FDA’s Center for Drug Evaluation & Research (CDER) put into
place a small drug shortage program (DSP) in 1999 to support manufacturers and
pharmacies facing critical drug supply issues (Kweder and Dill, 2013). Although no Y2K
events occurred, the need for ongoing drug shortage coordination became more apparent
as the FDA continued to receive requests for information about drugs in short supply
from diverse stakeholders. Many of those initial requests were regionally rather than

19
nationally based, so they were approached by facilitating communication amongst
distributors, pharmacies, and hospitals in a particular region. However, more significant
shortages became apparent over time; these incidents appeared to be related to
manufacturing issues that would have a broader set of consequences and were not as
simple to resolve.
Before 2011, the requirements for dealing with drug shortages were modest at
best. Under section 356c of the Food, Drug, and Cosmetic Act, a sole-source
manufacturer of a medically necessary drug that was “life-supporting, life-sustaining, or
intended for use in the prevention of a debilitating disease or condition”, was required to
inform FDA six months in advance if that product was to be discontinued (21USC§356c,
2020b). However, the FDA had no enforcement authority if the manufacturers failed to
notify it (FDA, 2011). To understand the problem of shortages further, CDER staff began
to collect additional information about products, manufacturers, submission reviews, and
compliance activities related to shortages or potential shortages. Through these activities,
CDER identified an increase in the number of drug shortages between 2005 and 2010
(Figure 3) (FDA, 2011). This trend attracted the attention of physicians, patients,
Congress, and the press (FDA, 2011).

20
Figure 3: U.S. Drug Shortages (2005-2010)

Source: A Review of FDA’s Approach to Medical Product Shortages (FDA, 2011)

2.2.3 U.S. Government Evaluation of the U.S. Human Drug Shortage Issue
In 2011, a report titled Economic Analysis of the Causes of Drug Shortages
(Hanninger, Jessup, and Koehler, 2011) was issued by the Office of the Assistant
Secretary for Planning and Evaluation (ASPE), located in the Office of Science and Data
Policy in the U.S. Department of Health and Human Services. ASPE stated that the
prescription drug and vaccine markets are “characterized by sporadic shortages of
individual drugs and occasional periods during which several in class are in shortage,"
which appears to be an “unusual feature of this market.” (Hanninger, Jessup, and
Koehler, 2011) Sterile injectable oncology products were most commonly the products in
shortage. ASPE suggested that shortages of these drugs occur because "neither the
quantity of these products needed by consumers nor the quantity of these products

21
produced by manufacturers is very responsive to short term changes in price.”
(Hanninger, Jessup, and Koehler, 2011) ASPE attributed the class-wide shortages of
sterile injectables to a "substantial expansion in the scope and volume of products
produced by the industry without a corresponding expansion in manufacturing capacity."
(Hanninger, Jessup, and Koehler, 2011) This expansion coincided with a high rate of
recent patent expirations but slower-than-usual availability of generic alternatives, as the
companies promising generic options still needed to build manufacturing capacity.
Further, some companies that could provide generic alternatives were still making
competitive decisions about which products to pursue. Thus, ASPE predicted that the
increased incidence of drugs in short supply would “likely resolve” as new suppliers
entered and competed more effectively in ways that increased the overall capacity of the
industry (Hanninger, Jessup, and Koehler, 2011).
FDA then pursued a more detailed analysis of drug shortages by reviewing the
available literature, talking with external stakeholders, and analyzing their internal data
related to drug shortages. In their report of October 31, 2011, titled A Review of FDA’s
Approach to Medical Product Shortages (FDA, 2011), FDA identified that the number of
drug shortages had tripled between 2005 and 2010, primarily due to problems with sterile
injectable products (80%); nearly half (43%) of those shortages were attributed to quality
issues at the manufacturing facilities. FDA helped to prevent 38 drug shortages in 2010
and 99 drug shortages in the first nine months of 2011 by expediting the reviews of
supplements to the NDAs that requested approval of new manufacturing sites, suppliers,
and specifications (71%); by exercising regulatory flexibility and discretion in GMP
expectations (20%); and by asking other firms to increase production (7%). When

22
shortages did occur, the FDA typically had four remedies that they attempted to use.
FDA asked other firms to increase output (31%), assisted manufacturers to mitigate
safety issues related to quality problems (28%), or expedited the review of regulatory
submissions (26%). In a few instances, the FDA even allowed the controlled importation
of similar products approved abroad (5%) (FDA, 2011).
Not only were shortages of sterile injectables most common, but they were also
more challenging to prevent or mitigate because their manufacturing processes were
typically more complex and more likely to impact safety (FDA, 2011). The impact of a
shortage in these products can be particularly problematic because acceptable substitutes
can be hard to find. In 2010, 60% of the sterile injectable molecules in the U.S. market
were sole-sourced (Figure 4) (FDA, 2011). If a sole-sourced injectable goes into
shortage, it is not simple to set up production elsewhere. Manufacturing flexibility is
hampered because manufacturing processes are typically complex, personnel must have
specialized expertise, and, in some cases, products may have to be isolated from other
production lines (FDA, 2011). Also, many manufacturers were moving to "just in time”
manufacturing practices that minimized the volume of stocked products that could be
accessed in the face of a manufacturing issue. FDA concluded that the drug shortage
problem arose from a complex interplay of factors related to connected economic, legal,
regulatory, policy, and clinical decisions (FDA, 2011). Parties contributing to the issues
included raw ingredient suppliers, active pharmaceutical ingredient (API) manufacturers,
final drug manufacturers, wholesalers, group purchasing organizations, clinicians, and
patients. FDA proposed several short- and long-term actions to address the issue of drug
shortages and these are listed in Figure 5.

23
Figure 4: Injectable Molecules by Market Concentration, 2010

Source: A Review of FDA’s Approach to Medical Product Shortages (FDA, 2011)

24
Figure 5: Proposed FDA Actions to Mitigate and Prevent Drug Shortages

Source: A Review of FDA’s Approach to Medical Product Shortages (FDA, 2011)

 Remind manufacturers to notify FDA in advance of a
shortage of a sole sourced medically necessary drug
and urge them to voluntarily notify FDA of other
potential disruptions
 Develop guidance to help industry report information
about potential drug shortages
 Increase FDA drug shortage staffing
 Maintain a database which captures the characteristics
of drug shortages
• Support legislation requiring industry to notify FDA of
drug shortages and give FDA the power to enforce early
notification
Short-
Term
 Assess useful mitigation and prevention strategies and
consider new approaches
 Determine what is causing the quality issues and
develop approaches to address them
 Encourage manufacturers to create back up plans to
assure continued supply
 Assess if a “sentinel reporting network” would improve
early warning of drug shortages
 Communicate drug shortages to the public and improve
the FDA drug shortage website
 Improve communication between the FDA offices
involved in drug shortages
 Urge transparency of distributor practices
• Develop a model that can predict drug shortages
Long-
Term

25
2.2.4 New U.S. Legislation to Reduce Drug Shortages: The Last Decade
Both the increases in numbers of drug shortages and better information on the
origins and impact of drug shortages drove efforts at higher governmental levels to
intervene in what was becoming a crisis. In 2011, former President Obama signed
Executive Order 13588 that directed the FDA to "help to prevent and reduce current and
future disruptions in the supply of life-saving medicines." (Obama, 2011) This order
expanded the requirement for all manufacturers to notify FDA of potential disruptions
and discontinuations of critical medicines in advance and allowed FDA to conduct an
expedited review of regulatory submissions in cases where this action would prevent or
mitigate drug shortages. The order further instructed FDA to report any unacceptable
behaviors such as stockpiling or profiteering to the Department of Justice (Obama, 2011).
The U.S. Government Accountability Office (GAO) issued a report, Drug
Shortages FDA's Ability to Respond Should Be Strengthened (GAO, 2011), soon
thereafter, in December 2011. It provided this report as testimony before the U.S. Senate
Committee on Health, Education, Labor, and Pensions. The report showed that the
number of drug shortages grew year over year between 2006 and 2011; generic injectable
drugs accounted for over half of the shortages (GAO, 2011). The GAO evaluated 15
significant drug shortages that occurred between 2009 and 2011 and found that they were
caused primarily by difficulties in upgrading sterile facilities or securing an adequate
supply of active ingredients (GAO, 2011). It also observed that an initial problem often
gave rise to additional manufacturing problems after the shortage began. Only a few
manufacturers manufactured some of the drugs involved in shortages. When one of the
manufacturers was unable to supply their usual volume of product, other manufacturers

26
were not always able to increase their production to meet the demand (GAO, 2011). The
report recognized the efforts made by the FDA to respond when informed of a shortage
and recognized that the nature of the efforts varied depending on the level of public
health risk and cause of the shortage. (GAO, 2011) They noted that FDA typically
communicates information about drug shortages on the FDA website and offers
assistance to manufacturers or encourages other manufacturers to increase production.
However, they also recognized that FDA has minimal power to protect public health
against drug shortages because reporting is required only when life-supporting and life-
sustaining drugs manufactured by sole manufacturers were discontinued. Because most
drug shortages are not related to discontinuations, the FDA typically becomes aware of a
drug shortage from health care providers or consumers who have begun to be affected by
the shortage when options to mitigate the shortage become limited (GAO, 2011). The
report noted that FDA does not maintain data on drug shortages. Thus, it cannot monitor
trends or determine if the actions that it has taken have been effective (GAO, 2011). The
report concludes that the FDA needs more authority to actively prevent and mitigate drug
shortages. It specifically recommends that FDA should: 1) allocate more of their
resources to the drug shortages program, 2) establish an FDA drug shortages system to
track and share information, 3) set priorities for assuring supply of medically necessary
drugs, and 4) establish metrics to evaluate the effectiveness of the agency's response to
drug shortages. (GAO, 2011)
Subsequently, on July 9, 2012, the Food and Drug Administration Safety and
Innovation Act (FDASIA) amended the FD&C Act to require manufacturers of "life-
supporting or sustaining drugs, or drugs intended for use in the prevention or treatment of

27
a debilitating disease or condition" (S 3187, 2012) to notify the FDA if the supply of
these medically necessary drugs would be discontinued or disrupted. This notification
was required at least six months in advance or as soon as possible for a rapidly
developing problem. The Act now required manufacturers to provide the reason for the
disruption, and FDA was given the responsibility to distribute the information to the
appropriate stakeholders, such as physicians, health providers, and patient organizations.
Importantly, the FDA was also authorized to enforce the compliance of manufacturers
that were required to notify the FDA of impending drug shortages. The FDA would now
issue a letter to manufacturers who failed to report, insisting on an explanation for
noncompliance and giving the recipient 30 days to provide the required information.
After 45 days, the FDA would make that letter public on the FDA website unless the
manufacturer could provide a legitimate reason for failing to provide the required
response. The Act included provisions for FDA to expedite the review of submitted
NDA/BLA supplements related to manufacturing and quality-related changes and to
schedule inspections that might accelerate approvals for needed manufacturing in a new
or deficient site. The Act also directed FDA to provide annual drug-shortage reports to
Congress; maintain a drug-shortage list to include drug name, manufacturer, reason for
shortage, and duration; and form a task force to develop and execute a strategic plan.
Finally, the Act required FDA to consider the risk and impact of drug shortages before
issuing warning letters or taking any enforcement actions against companies that might
cause the company to discontinue the production of needed drugs (S. 3187, 2012). Many
more drug shortages were reported in 2011 and 2012 after all of these actions, but it is

28
likely that numbers would have been even higher without the intervention of the FDA to
help prevent many drug shortages (FDA, 2013a).
2.2.5 International Society for Pharmaceutical Engineering (ISPE) Drug Shortage
Survey
Drug shortages affect U.S. supplies but also supplies globally. To address the
issue at an international level, in 2012, the International Society for Pharmaceutical
Engineering (ISPE) also formed a Drug Shortage Taskforce. This task force conducted a
survey, the ISPE Drug Shortages Survey (ISPE, 2013), to explore the quality and
technical reasons for drug shortages and to gain better insight into possible solutions.
The report, issued in June 2013, agreed with the findings of FDA that causes were
multifactorial but often centered on manufacturing deficiencies. It noted that a
significant proportion (>40%) of incidents could be linked to problems with aseptic
production equipment and that production system issues during technology transfer or
product development were implicated in about a fifth of incidents. They further discussed
what they believed to be success factors in manufacturing programs implemented to
prevent drug shortages. These included having strong quality systems as demonstrated
by a track record of positive GMP inspections; corporate goals related to
avoiding/preventing drug shortage; strong relationships with the regulatory authorities;
and the presence of resources, incentives, and metrics related to preventing drug
shortages. More than a third of respondents in that survey identified a need to improve
the level and quality of interactions with health authorities to prevent or recover from a
drug shortage. In particular, those survey respondents working with sterile products
indicated that problems might be mitigated through the more rapid approval of new

29
production lines (58%) and more timely responses to the findings of investigations (37%)
(ISPE, 2013).
2.2.6 Quality and Economic Incentives
Woodcock and Wosinska of FDA CDER published an article in February 2013
titled Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages
(Woodcock and Wosinska, 2013). This article, like the ISPE survey, suggested that the
large number of shortages could be attributed in large part to manufacturing and quality
issues, particularly for generic sterile injectable drugs, where such issues contributed to
56% of injectable-product shortages. The issues ranged from quality-related shutdowns,
decisions to discontinue a product because of quality-related issues to failures of an aging
or insufficient infrastructure or capacity constraints. These shortages were linked to what
they saw as disincentives to improve quality.
One major disincentive discussed by Woodcock and Wosinska was seen to stem
from the current economic structure of the generic marketplace. It is expensive to
maintain a superior quality system or to replace or add new equipment to improve
consistency and capability. However, the generic marketplace is price-driven, with the
underlying assumption that all generic drug products are equivalent in terms of quality.
As a result, the primary purchasing consideration for a generic drug is its price rather than
its quality. Further, even if the end-user were to be concerned about quality, no system
exists for an end-user to know if the quality of one drug is better than another. Purchasers
can check available FDA information such as MedWatch reports, recall notices, warning
letters, or 483 inspection forms to gain better insight. However, this time-consuming
research is unlikely to provide a complete picture because, generally, multiple

30
manufacturers are involved in the manufacture of the raw materials, active ingredients,
and drug products, and their state of quality is not always transparent to the end-user. In
addition, given that there are only a few manufacturers of generic injectables for the U.S.,
an end-user may find that they have few options to compare. These considerations must
be added to other identified challenges restricting manufacturing improvements, such as
workforce reductions and just-in-time inventory approaches (Woodcock and Wosinska,
2013; Fox and Tyler, 2013).
Finding the root causes of drug shortages is complicated by the fact that
disruption on a single manufacturing line can lead to shortages of multiple drugs at the
same time. For example, a manufacturer recalled ten different sterile drugs in 2011
related to problems with sterility assurance, the presence of metal particles in vials, and
low fill volumes on one line. FDA then inspected the facility and cited GMP violations,
which led the manufacturer to shut down its facility while remediation efforts took place.
This shutdown affected the availability of over 100 drugs, 85 considered medically
necessary. In another example, shortages of several oncology drugs in 2010 were found
to be associated with three specialized production lines operated by two manufacturers;
once these lines were up and running, the shortages resolved. (Kweder and Dill, 2013)
Quality issues with generic injectable products are not always obvious. Some
types of defects related to sterile products are neither homogeneous nor readily apparent
even across a single batch. They can be challenging to detect by the sampling and test
methods in place before the release of the product and can increase over time. Also,
patients using generic injectable drugs often have compromised immune systems or
complicated disease states, so adverse events are commonly attributed to their medical

31
conditions rather than their defective drug product. These kinds of adverse events then
would fail to be captured through typical pharmacovigilance reporting systems. Once
defects are found, they can require extensive investigations and remediation, which often
result in drug shortages and even discontinuations depending on the profit margins
(Woodcock and Wosinska, 2013).
Woodcock and Wosinska suggest that the failure to incentivize quality fosters a
reactive approach where the manufacturer waits for problems to occur before taking
action. They also expressed concern that the FDA’s use of “regulatory flexibility” and
“enforcement discretion” when there is a problem further enables that reactive approach.
It sets up an expectation that special provisions will be made for sub-quality products in
the event of a shortage. Instead, they advanced the well-accepted view that quality must
be built into the facility, process, equipment, people, and procedures, and this requires
consistent investment to ensure a reliable drug supply. To this end, Woodcock and
Wosinska encouraged the market to reconsider its primary driver of price over quality
(Woodcock and Wosinska, 2013).
Another approach to encourage quality improvements, proposed by Schweitzer,
was for FDA to issue letter grades for manufacturing site inspections based on quality.
He suggested that some purchasers might be willing to pay more for a product from a
manufacturer with the highest "A" rating; others might be satisfied with "B" or "C" level
quality for a more reasonable price. Lower grades provide a warning to manufacturers
that they need to improve as well as a warning to purchasers that quality issues may
introduce a higher risk of problems. Schweizer suggested that this rating system could be
worth trying because experience with rankings in other sectors- hospitals, restaurants, and

32
consumer products- have influenced consumer choice (Schweitzer, 2013). Others have
suggested that FDA establish a published dean’s list of companies that demonstrate
quality excellence (Villax, 2014) or offer shortened regulatory reviews or other attractive
types of regulatory advantages (Chabner, 2011; Van Trieste, 2013).
To increase the focus on quality, the FDA issued a draft guideline, Submission of
Quality Metrics Data (FDA, 2016a), in 2015 and a subsequent revision in 2016. This
guideline describes an initiative that is voluntary to the manufacturers to collect and
monitor certain quality information such as lot acceptance rate, product quality complaint
rate, and invalidated out-of-specification data. These data are then used to detect early
signals of risks to consumers as well as potential drug shortages and to focus FDA
inspection resources efficiently. Participating firms are rewarded by being included on
publicly posted lists that acknowledge their level of participation in the program. FDA
expressed the hope that the reporter list would give participating firms some advantage
with their business partners and customers and thus serve as a reward for their efforts
toward proactive quality (FDA, 2016a).
Medina and Richmond (2015) provided insight on the acceptability of quality
metrics and ratings by surveying industry views. They found that the FDA metrics most
likely to be shared by industry with the FDA were “lagging” metrics, such as warning
letters, Form 483 inspection observations, and complaint rates. Industry respondents
were more reluctant to share “leading metrics”, such as manufacturing error rates and lot
rejection/return rates related to process performance, which could potentially identify
issues much earlier. Respondents to that survey believed that ratings might incentivize
higher quality but worried about game-playing to achieve the higher ratings. Some

33
suggested that investments might be directed at “quality audit programs and employee
training rather than capital expenditures such as buying new equipment or opening new
manufacturing sites”, which may not help to resolve the root causes of the drug shortage
crisis (Medina and Richmond, 2015).
Some skepticism also exists about the ways in which consumer behavior might be
modified. Unlike consumer products, drug prescriptions are typically filled by
pharmacists without consultation regarding options for the choice of one generic brand
over another. For example, Susan Joseph, Director of Good Manufacturing Practices
Compliance and Quality Assurance Systems at Astra Zeneca has stated that her company
is not willing to share their 10-12 internal quality metrics publicly because they do not
have evidence that customers would use this type of information to make purchasing
decisions. She maintains that these metrics are internal tools to improve quality and
performance, would be "impractical” to manage, confuse the end-users and not be value-
added in reducing drug shortages (Barlas, 2013).
The GAO issued a report in July 2016 titled Drug Shortages: Certain Factors are
Strongly Associated with this Persistent Public Health Challenge (GAO, 2016). It
concluded that shortages of sterile anti-infective and cardiovascular drugs between 2012
and 2014 were strongly associated with a decline in the number of suppliers and the
failure of at least one supplier to meet manufacturing standards resulting in a warning
letter. It further recognized that shortages were more common for generic drugs with
lower profit margins. Agreeing with previously stated opinions, the GAO suggested that
generic sterile manufacturers may be electing to discontinue production when profit
margins decrease or when faced with the need to shut down operations to correct

34
deficiencies. The report reiterated the findings that only seven sterile manufacturers
supplied drugs in the U.S., and many had received warning letters between 2010 and
2013. FDA had expedited many regulatory submissions related to generic drugs during
that timeframe. This action may have accounted for the observed decrease in new drug
shortages between 2010 and 2016, but the number of ongoing shortages remained high.
The GAO also reinforced the message that a newly interested manufacturer would need
to implement a complex set of manufacturing operations and gain FDA approvals, and
these requirements would pose a substantial disincentive for entry, given the low-profit
margins of generics. The report suggests that some mechanism to maintain a reasonable
generic product price may be important to incentivize new investments in their
production facilities (GAO, 2016).
Duffy (2012) also confronted the issue of economic incentives. She points out
that the Medicare Prescription Drug, Improvement and Modernization Act of 2003 places
a cap of 6% on increasing reimbursement rates per six months, which stunts the pricing
potential for prescription drugs. She argues that throttling drug prices in this way
interferes with the economic principle of supply and demand. Because generic drugs
have such low-profit margins, manufacturers can simply become disinterested in the
unfavorable business proposition that they present. She suggests that some type of
incentive is needed, particularly for important but low-margin drugs, and proposes that
Medicare allow for adjustable reimbursement rates that take into consideration the supply
and demand for the drug (Duffy, 2012). Similarly, Barlas suggests that critical generic
medicines be subsidized by government, in a way like that used to incentivize American

35
farmers, and that the subsidy payments be directed toward responsible manufacturers
with strong quality metrics (Barlas, 2013).
2.2.7 FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages
As required by FDASIA, FDA issued its Strategic Plan for Preventing and
Mitigating Drug Shortages in October 2013 (FDA, 2013a). The plan describes the FDA's
ongoing efforts to address drug shortages, identifies the next steps that the agency plans
to take, and provides recommendations for other involved stakeholders.
FDA contends that the most critical step in preventing or minimizing a drug
shortage is early FDA notification. Since FDASIA, the FDA receives approximately
60 notifications per month from a variety of stakeholders, including manufacturers,
professional organizations, and patients (FDA, 2013a). The FDA then attempts to verify
that the shortage either exists or threatens through market research and communication
with stakeholders, including manufacturers. Once confirmed, its drug shortage staff
coordinates a mitigation response based on the medical necessity of the drug. It forms an
internal cross-functional team that may have representatives from multiple centers. For
example, a drug shortage may require input from CDER Drug Shortage Staff, Office of
Regulatory Affairs District Drug Shortage Coordinators, CDER Office of Compliance,
Office of New Drugs, Office of Pharmaceutical Science, and Office of Communications.
Together the members of the team decide on a response appropriate to the situation.
They can expedite inspections and submission reviews, use temporary enforcement
discretion, provide investigation assistance, take risk mitigation actions, or intervene in
specific ways for batches that do not meet requirements. FDA also communicates with
external stakeholders, including patients, physicians, and other interested parties,

36
primarily through the FDA website, but also through public meetings at which it can also
discuss drug shortage policy.
FDA's strategic plan has two primary goals. The first is to strengthen the
mitigation response, to prevent supply disruptions from turning into drug shortages. The
second is to develop long-term prevention strategies to address the root causes of drug
shortages, which will reduce the likelihood of drug shortage occurrence (Figure 6) (FDA,
2013a).

37
Figure 6: FDA's Strategic Plan to Mitigate and Prevent Drug Shortages

Source: Strategic Plan for Preventing and Mitigating Drug Shortages (FDA, 2013a)

FDA encouraged manufacturers to predict and act proactively to reduce the risks
of critical drug shortages. Because shortages were often associated with manufacturing
deficiencies, it asked all stakeholders to propose incentives to promote the manufacture
of high-quality drugs. FDA also suggested that customers use publicly available
information to purchase medicines from manufacturers with track records indicating good
 Establish a procedure to perform a risk-benefit
assessment prior to taking a compliance action which
may cause a drug shortage
 Improve interactions with the Drug Enforcement
Agency with respect to shortages of controlled
substances
 Develop a procedure for issuing noncompliance
letters for failure to notify FDA about drug shortages
 Consider expiry extension as mitigation for shortages
 Collect drug shortage information in a new database
and assess progress on drug shortage prevention and
mitigation
 Help manufacturers resolve manufacturing and supply
issues and encourage the use of best practices
 Develop smart phone application and enhance the
website to improve public communication
Mitigate
 Create positive incentives for improving manufacturing
quality
 Consider new ways to address shortages
• Expedite reviews of submissions aimed to mitigate
drug shortages and improve quality
• Collaborate with stakeholders researching drug
shortages and prevention strategies
Prevent

38
quality to support and incentivize companies with good practices. It encouraged all
stakeholders to refrain from hoarding products before and during drug shortages, from
buying products from a dubious supplier, or from participating in the "gray market" to
profit from drugs in short supply (FDA, 2013a).
2.2.8 ISPE Drug Shortage Prevention Plan
Drug shortage responses were also being formulated outside of the U.S. In 2014,
ISPE published the ISPE Drug Shortages Prevention Plan, A Holistic View from Root
Cause to Prevention (ISPE, 2014), in response to the European Medicines Agency’s
(EMA) request for proposals that might prevent drug shortages caused by manufacturing
and quality issues. ISPE used their 2013 survey results as a starting point, then
conducted interviews with industry and regulatory leaders to identify potential strategies
to address the root causes of drug shortages. The plan then attempted to provide a
comprehensive toolkit that drug manufacturers could use to prevent drug shortages. It
outlined a framework with six dimensions: Corporate Quality Culture, Robust Quality
System, Metrics, Business Continuity Planning, Communications with Authorities, and
Building Capabilities. Within each, it provided detailed discussion, case studies, and
examples of metrics related to drug shortage mitigations. Table 2 includes specific
recommendations and points to consider for each dimension resulting from the analysis.
The plan was formulated for a global audience but cautioned that differences in
regulatory requirements between different countries would have to be considered.

39
Table 2: ISPE Drug Shortages Prevention Plan Recommendations
Corporate Quality Culture
Evaluate quality culture
Set up decision-making procedures
Proactively manage trends and signals.
Establish a problem escalation process
Evaluate resilience of supply chain
Develop management ability to handle crises
Set up cross-functional response teams
Have routine quality review meetings with cross-
functional attendance
Robust Quality System
Establish a life-cycle management business process
Continuously validate manufacturing processes
Management-level review of deviations and trends
Ensure investigations get to the root causes
Follow through with CAPAs and perform effectiveness
checks
Establish a knowledge management system and subject
matter experts
Employ sound scientific, risk-based approaches.
Perform a drug shortage centered risk assessment of
facilities and equipment
Ensure risk mitigation strategies for critical materials
used in manufacturing
Metrics
Establish drug shortage metrics as a basis for continuous improvement
Business Continuity Planning
Strive for a reliable supply chain through integration of
supply chain, quality systems, and effective
management
Build redundancy based on risks
Prepare crisis management and disaster recovery plans
Communication with Authorities
Have a supply risk escalation process
Communicate potential supply risks to the regulatory
authorities
Relay plans to resolve the issue
Discuss regulatory submission content and timing
Building Capability
Foster training and interaction across functions
Create an environment of continuous learning and
sharing
Use mentorship to build capability
Source: ISPE Drug Shortages Prevention Plan, A Holistic View from Root Cause to
Prevention (ISPE, 2014)
2.2.9 Risk Assessment Tools
Tools have also been introduced by the Parenteral Drug Association (PDA) and
ISPE to help industry to avoid drug shortages caused by manufacturing and quality
issues. In 2014, the Parenteral Drug Association issued Technical Report No. 68, Risk-
Based Approach for Prevention and Management of Drug Shortages (PDA, 2014). It
proposes the use of a risk register and a prevention - response plan, two approaches that
seem practical and user-friendly for manufacturers. The risk register is designed to

40
capture risks that could lead to shortages and is intended to be reviewed and revised
routinely. The prevention - response plans contain activities based on the level of risk.
Information included in the risk register and prevention and response plan are provided in
Figure 7.
Figure 7: PDA Risk Register and Prevention - Response Plan

Source: Technical Report No. 68, Risk-Based Approach for Prevention and Management
of Drug Shortages (PDA, 2014)

The report suggests that risk registers and prevention and response plans could be
discussed proactively with health authorities (PDA, 2014).
In 2015, ISPE published the Drug Shortage Assessment and Prevention Tool
(ISPE, 2015). This tool uses the same six-dimensional framework-Corporate Quality
Culture, Robust Quality System, Metrics, Business Continuity Planning,
Communications with Authorities, and Building Capabilities- described previously in
their 2014 Drug Shortage Prevention Plan (ISPE, 2014). The tool provides an overview
of each dimension and paints a picture of the ideal situation. Questions are posed for
•description of risks
•affected markets
•level of risk (based on therapeutic use, availability of alternatives, and likelihood of
shortage)
•risk control actions and risk indicators
Risk Register
•building safety stock
•global supply strategy planning
•capacity planning
•understanding availability of alternative therapies in the marketplace
•regulatory strategies to gain expedited reviews from the relevant health authorities
for any changes necessary to the marketing applications
Prevention - Response Plan

41
each dimension; by answering the questions, manufacturers can identify any gaps or
weaknesses in their operations related to that particular dimension. Interestingly, the tool
suggests measuring maturity levels for each dimension to help manufacturers benchmark
their progress. The ISPE tool is so comprehensive that it could probably not be
completed in a short timeframe. Manufacturers can either pick and choose from the
dimensions presented in the tool according to what they think is most relevant for their
organization or work systematically to develop maturity in all the dimensions over time
(ISPE, 2015).
2.2.10 FDA Annual Drug Shortage Reports
FDA issued the 2018 annual drug shortage report in October 2019. It documented
the number of new drug shortages between 2010 and the end of 2018, as shown in
Figure 8.
Figure 8: Number of New Drug Shortages per Year (2010 – 2018)

Source: FDA Report on Drug Shortages for Calendar Year 2018 (FDA, 2019c)

42
It was striking that new drug shortages were particularly prevalent at the start of
the reporting period, in 2010 and 2011, after which the rate of new shortages decreased
significantly (FDA, 2019c). However, additional data, shown in Table 3, identifies a slow
but consistent increase in the number of manufacturers submitting notifications and the
number of shortages that were mitigated or prevented since 2013 (see also Figure 9).
Data in Table 3 shows that the most common FDA action is to expedite review of
applications, but FDA also accelerated facility inspections and re-inspections and used
regulatory flexibility/discretion to improve the outcomes (FDA, 2014; FDA, 2015; FDA,
2016b; FDA, 2017; FDA, 2018; FDA, 2019c).
Figure 9: Number of Prevented Drug Shortages per Year (2010 – 2018)

Source: FDA Report on Drug Shortages for Calendar Year 2018 (FDA, 2019c)

The number of ongoing drug shortages steadily dropped between 2013 and 2017
and rose in 2018 (Figure 10) (FDA, 2019c). This increase was attributed to the closure of
one particular facility for remediation. Nonetheless, the increased number of ongoing
shortages in 2018 remains of concern in the face of FDA efforts to mitigate and prevent

43
drug shortages over the past five years. An overview of the Annual Report Data and
FDA’s efforts between 2014 and 2018 is shown in Table 3.
Figure 10: Number of Ongoing Drug Shortages per Year (2013 – 2018)

Source: FDA Report on Drug Shortages for Calendar Year 2018 (FDA, 2019c)

Additional events and activities of note occurred in 2018. Funding allocations by
Congress increased the resources available for FDA activities related to drug shortages.
A new method to mitigate shortages was introduced as well. FDA has been reviewing
stability data provided by manufacturers to allow extensions on expiry dates for product
batches that are already on the market. These expiry extensions are published on the FDA
drug shortage website. Also, FDA has engaged other stakeholders, such as the Centers
for Medicare and Medicaid Services (CMS) and the Department of Veterans Affairs
(VA), as well as the public, from whom it can collect input on the economic drivers of
drug shortages and potential mitigation/prevention strategies. Finally, the FDA is also
considering ways to help the industry and other stakeholders identify critical facilities and

44
products and create contingency plans ahead of drug shortages (FDA, 2019c). An
overview of FDA’s efforts to address Drug Shortages is provided in Figure 11.
Table 3: Overview of FDA Drug Shortage Annual Report Data
2018 2017 2016** 2015** 2014** 2013**
Number of Manufacturers that
submitted a Notification
 # of Notifications/# of
Manufacturers

575/96

520/86

186/67

131/47

125/52

202/39
Expedited Review 167 132 102 116 100 177
Expedited Establishment Inspections/
Re-Inspections
12 30 10 11 10 63
Exercised Regulatory Flexibility and
Discretion
 # of instances/# of products

79 / 52

57 / 33

25 / 15

19 / 37

30 / 31

76 / 68
Names of manufacturers issued letters
for not reporting drug shortages
Teva
Accord*
Fresenius.
Kabi*
None Par
Teva
None Bristol-
Myers
Squibb
Corden
Pharma
Latina
None
Number of Drug Shortages occurring
in 2018
 Identified
 Prevented
 Ongoing

54
160
67

39
135
41

26
63
48

26
128
64

44
78
74

44
140
97
*not posted to FDA website, letters issued in error
**data covers the first three quarters of the year

Sources: FDA Report on Drug Shortages for Calendar Years between 2013 and 2018;
(FDA, 2014; FDA, 2015; FDA, 2016b; FDA, 2017; FDA, 2018; FDA, 2019c)

45
Figure 11: Overview of FDA Efforts Reported in the Annual Reports
(2014 - 2018)

Sources: FDA Report on Drug Shortages for Calendar Years between 2013 and 2018
(FDA, 2014; FDA, 2015; FDA, 2016b; FDA, 2017; FDA, 2018; FDA, 2019c)

Drug Shortage Data System implemented to record and evaluate drug shortage information
Created a Drug Shortage Assistance Award to recognize manufacturers demonstrating commitment to
the prevention or mitigation of drug shortages.
Improved clarity of the Manual of Policies and Procedures which defines the responsibilities of the
drug shortage staff and the interactions between FDA groups related to drug shortages
Launched an improved drug shortage website to provide more information to the public
Started having quarterly calls with international counterparts to share information about drug
shortages
2014
Launched a mobile app which provides up to date information on drug shortages to the public
Integrated FDA data systems and user interfaces
Published two blogs and one article
Provided eight presentations to professional, patient advocacy, and industry trade associations
2015
Introduced the CDER Shortage Tracker, an enhanced system for drug shortage data
Provided six presentations to professional, patient advocacy, and industry trade associations
Announced first Drug Shortage Assistance Award
2016
Performed a risk assessment of the impact of Hurricane Maria on the U.S. drug supply and
workedwith partners to avert drug shortages associated with facilities in Puerto Rico
10 presentations were given to professional, patient advocacy, and industry trade associations
Announced two additional Drug Shortage Assistance Awards
2017
FDA drug shortage task force worked with Centers for Medicare and Medicaid Services (CMS) and
the Department of Veterans Affairs (VA) to evaluate the drivers of drug shortages and potential
solutions
Held sessions with the Centers for Medicare and Medicaid Services (CMS) and the Department of
Veterans Affairs (VA) and a public meeting to collect input
Helped industry create contingency plans for critical facilities and products
Reviewed stability data to see if expiry extensions were possible so that patients and providers can
elect to continue to use those batches
Announced two additional Drug Shortage Assistance Awards
Started discussions with the United States Pharmacoepiea (U.S.P.) about compendial changes which
may cause drug shortages
2018

46
2.2.11 FDA Root Causes and Potential Solutions 2019 Report
In 2018, FDA created a Drug Shortages Task Force consisting of senior officials
from the FDA, Centers for Medicare and Medicaid Services, the Department of Defense,
the Department of Veterans Affairs, the Federal Trade Commission, and the Office of the
Assistant Secretary for Preparedness and Response within the Department of Health and
Human Services. The task force specifically considered the root causes and driving
forces associated with the drug shortages between 2013-2017. The Task Force also
consulted with others, including the Defense Advanced Research Projects Agency, the
U.S. Department of the Treasury, the Drug Enforcement Administration, and the U.S.
Department of Justice. Public comments were collected by docket during a public
meeting held in November 2018. It then issued a report titled Drug Shortages: Root
Causes and Potential Solutions in October 2019 (FDA, 2019b). Like the earlier report of
Woodcock and Wosinska (2013), the 2019 report concludes that economic forces are the
primary root cause of drug shortages. Economic theory predicts that price tends to rise if
demand exceeds supply until the higher prices cause reductions in demand (Henderson,
1922). However, in the case of drug shortages, increases in price do not necessarily
decrease the demand, presumably because sick patients need to be treated regardless. The
task force concluded that drug shortages were instead related to three factors:
 No incentives to produce drugs that will have low-profit margins
 No market recognition or reward for manufacturers that invest in mature quality
management systems
 Limits on the expansion of manufacturing output because of supply chain and
regulatory hurdles (FDA, 2019b)

47
According to the 2019 report, the struggle of drug companies to maintain their
market presence often was marked by a “race to the bottom”, in which products were
chosen based on price rather than quality (FDA, 2019b).
The task force made three recommendations for “enduring solutions” in the 2019
report:
1. Private and public stakeholders should collect and share more information about
the impact of drug shortages on health outcomes and costs, as well as the
contracting practices which may be contributing to drug shortages.
2. A rating system available to purchasers, government purchasing organizations,
and consumers should be considered to incentivize manufacturers to improve their
quality management systems.
3. Financial incentives that encourage investments in the reliable manufacture of
lower profit drugs should be developed as part of private sector contracts. (FDA,
2019b)
The FDA reinstated its commitment to better manage the drug shortage issue.
Steps in this direction are reflected in three legislative proposals to the administration’s
2020 fiscal year budget. The first would expand Section 506C(a) of the FD&C Act to
allow the FDA to impose penalties for failing to notify the Agency about drug shortages.
The second would give the FDA the power to require that companies conduct routine risk
assessments of their supply chains and prepare related risk-mitigation plans. The third
would authorize the FDA to require that a drug sponsors evaluate and label a product
with the longest possible expiration date that is scientifically justified (FDA, 2019b).

48
In addition, FDA indicated their intention to issue two new guidance documents
for industry. The first one, Guidance for Industry, Notifying FDA of a Permanent
Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act
(FDA, 2020c), provides manufacturers with more instructions about reporting drug
shortages, and the other, not yet published, will discuss recommendations for preparing
risk management plans. Finally, FDA mentions ICH Guideline Q12: Technical and
Regulatory Considerations for Pharmaceutical Product Lifecycle Management as a
pathway to reduce regulatory oversight post-approval. This would reward companies that
can demonstrate a strong technical understanding of the product and process and have
established a mature quality system (FDA, 2020c).
2.2.12 Mitigating Emergency Drug Shortages (MEDS) Bill and the Coronavirus Aid,
Relief, and Economic Security (CARES) Act
In addition to the legislation proposed by FDA, Senator Susan Collins and
Senator Tina Smith introduced the Mitigating Emergency Drug Shortages (MEDS) Bill
to Congress on October 29, 2019. This bill proposes changing the language from an
optional "may" when FDA considers expediting reviews and inspections of products in
short supply to the more mandatory "shall." The bill also proposed manufacturers
disclose more information about causes, expected impact, and the estimated duration of
shortages; to prepare contingency and redundancy plans for medically necessary
medicines; and extend the reporting requirements to active ingredients (S 2723, 2020).
The bill also engages players outside of the confines of FDA to consider the drug
shortage problem. It requires the Department of Health and Human Services to create a
report with recommendations for market-based incentives or other appropriate
mechanisms to incentivize manufacturing of products in, or at risk for, a shortage. It also

49
requires that the Department of Health and Human Services (DHHS) and Department of
Homeland Security (DHS) conduct a risk assessment associated with shortages of critical
drugs that could affect national security. The MEDS bill has support from several major
healthcare organizations, including the American Pharmacist’s Association (APhA),
American Society of Health-System Pharmacists (ASHP), American Society of Clinical
Oncology (ASCO), and the American Hospital Association (AHA) (S 2723, 2020).
Before the MEDS bill made its way through Congress, the COVID-19 pandemic
put a spotlight on the criticality of drug availability as well as its dependence on a global
supply chain. Senator Susan Collins asserted that doctors and healthcare workers should
not have to worry about whether drugs would be available to treat the patients when the
healthcare system is acutely overburdened, as is the case with the pandemic. According
to her website, even without the pandemic, drug shortages translate into $230 million per
year in U.S. drug costs and $216 million per year in increased resource costs as health
providers search for alternatives (Susan Collins, 2020). In addition, 13 percent of the
active pharmaceutical ingredients, including important antibiotics, anesthetics and pain
relievers used in U.S. products, are manufactured in China, the first country affected by
the COVID-19 pandemic. If China, or other countries, became unable to supply the
materials because of production challenges, national stockpiling, or increased demand,
then drug shortages will occur. For this reason, she emphasized her view that FDA should
have a high level of visibility into the supply chain (Susan Collins, 2020; Cerullo, 2020).
These concerns were taken seriously. Certain parts of the MEDS bill were incorporated
into the Phase 3 Coronavirus, Aid, Relief, and Economic Security (CARES) Act which
was signed into law on March 27, 2020.

50
 The drug shortage reporting requirements are now extended to include active
pharmaceutical ingredients.
 FDA must expedite the review of drug applications and inspections. This
includes marketing applications, abbreviated new drug applications, supplements,
and associated inspections.
 Manufacturers must report more information to FDA, including information about
the issue causing the shortage, the extent and duration of the shortage, and the
impact on distribution and availability.
 FDA must provide inspection reports associated with manufacturing
establishments that have reported drug shortages to the FDA drug shortages staff.
 FDA must provide a quarterly drug shortage report to CMS.
 Manufacturers must develop risk management plans, including redundancy plans
for essential medicines that would be provided to FDA.
 Manufacturers must report the amount of each drug manufactured and distributed
to FDA annually or upon request during a public health emergency (HR 748,
2020 USC. 2020c).
Both Senators Collins and Smith strongly believe that the legislation will prevent
drug shortages, increase the affordability and accessibility of prescription drugs, and help
health workers and patients (Susan Collins, 2020).
In summary, the regulatory framework to manage human drugs shortages in the
U.S. has evolved considerably over the past 20 years. Figure 12 summarizes the major
changes in the regulatory framework related to human drug shortages over time. Progress
has been made to understand and address some aspects of this complex and multi-faceted
issue, but concerns continue to persist. As a result, the regulatory framework may
potentially change even further in the future.

51
Figure 12: Evolution of the U.S. Regulatory Framework for Human Drug
Shortages

Sources: (21USC§356c, 2020b; Obama, 2011; S 3187, 2012; HR 748, 2020)

52
2.3 An Overview of U.S. Animal Drug Shortages
Human health has understandably been the area in which priority has been given
to drug shortage policy. However, drug shortages also affect animals. Ideally, animals
are treated with veterinary drugs approved by the FDA’s Center for Veterinary Medicine
(CVM). Like human drugs reviewed by CDER and CBER, animal drugs are reviewed by
CVM to make sure that they are safe and effective for their intended uses and are
manufactured, labeled, and packaged properly. However, veterinarians are not limited to
the use of FDA-approved veterinary drugs. Because a relatively limited number of FDA-
approved veterinary drugs are available in comparison to the diversity of animals and
disease conditions, the Animal Medicinal Drug Use Clarification Act of 1994 allows
veterinarians to treat animals “extra label” with FDA-approved human drugs. Extra label
use refers to the use of an approved drug in a manner that is not in accordance with the
approved label directions. They can also use veterinary drugs meant for other species or
conditions or compounded drugs made in compliance with 21CFR530 (21CFR§530,
2020).
Because animals are often treated with human drugs, human drug shortages can
also affect animals, their owners, and clinical caregivers. The 2019 Drug Shortages: Root
Causes and Potential Solutions report (FDA, 2019b), described above, explicitly
acknowledges that "although the focus of the report is on human drugs, many of the same
concerns apply to veterinary medicines used to treat service, companion, and food-
producing animals” (FDA, 2019b). The report includes a clarifying footnote which states,

53
Under certain conditions, the Animal Medicinal Drug Use Clarification
Act of 1994 allows for the use of approved human drugs in animals.
Because veterinarians, especially those in the companion animal field,
often use human drugs in their patients, shortages of human drugs can
affect veterinary medicine (FDA, 2019b).

However, animal drug shortages can also occur, with consequences similar to
those associated with human drug shortages. A few examples of U.S. animal drug
shortages illustrate these similarities.
Immiticide
®

Immiticide (melarsomine dihydrochloride) is a sterile powder for injection used to
treat heartworm infections in adult dogs. In December 2009, the sole U.S. finished
product manufacturer of the drug announced a temporary shortage due to "unforeseen
technical difficulties” (Fiala, 2009b). The problem was initially ascribed to issues
securing the active ingredient, but the company also had been experiencing
manufacturing and quality issues since 2009. The company shut down operations in
November 2011 after an FDA inspection identified significant deviations from good
manufacturing practices at its manufacturing site (Zeltner, 2013). Subsequently, the site
and much of its business were sold. The manufacturer indicated that they had spent over
$350 million rehabilitating the aging facility but estimated that another $700 million
would have been necessary to remediate the problems (Perkins, 2015). In September
2011, FDA temporarily allowed limited quantities of the drug product to be sourced from
a European manufacturer (Zeltner, 2013) and the American Heartworm Society issued
recommendations to help veterinarians manage their patients in the meantime (Fiala,
2015). Finally, eight years after the initial notification of the shortage, the FDA approved
Diroban (melarsomine dihydrochloride), a generic of Immiticide (DVM360-Staff, 2017).

54
Vetsulin
®

Vetsulin
®
(porcine insulin zinc suspension) is a sterile injectable suspension used
to manage diabetes in dogs and cats. In November 2009, the product failed to meet a
specification during stability testing. The manufacturer stopped U.S. distribution, and
FDA- CVM recommended that animals be switched to other insulin products (Fiala,
2009a). In May 2010, FDA allowed the drug sponsor to offer a limited supply of the
product through a "Critical Needs" program to address medical concerns that presented
when certain animals were switched to other insulin products. (Peterson, 2011) The
“Critical Needs” program was discontinued the following year because of sterility issues,
and the product was unavailable while manufacturing remediation was carried out
(DVM360-Staff, 2011). All of the manufacturing issues were eventually resolved, and the
product was relaunched in April 2013, four years after the initial problems had been
reported (Lau, 2013).
Multiple Sterile Products
Several U.S. veterinary drugs manufactured by one manufacturing site became
unavailable in August 2019 due to sterility issues. As a result, the manufacturer decided
to recall 34 products in May 2019. In December 2019, the manufacturer indicated that
they had made significant capital investments to resolve the issues and announced a plan
to resume normal production by the second half of 2020 (McDonald, 2019).
2.4 Regulatory Framework for U.S. Animal Drug Shortages
The regulatory framework for U.S. veterinary drug shortages has not changed
significantly since its inception in 2000. The FDA-CVM issued Supplemental Policy
Guide 1240.4170, CVM Medically Necessary Veterinary Drug Product Shortage

55
Management Guide (FDA, 2000), setting out the procedure for “evaluation of essential
drug shortage situations so that appropriate actions can be taken promptly” (FDA, 2000).
CVM’s policy is to try to prevent or alleviate shortages of MNVPs. Their response to a
shortage is prioritized based on protection of public health, animal health, and the
environment. CVM requests in the guide that drug shortages be reported to them.
However, no regulation or requirement is in place for veterinary products. CVM
generally learns about drug shortages from various stakeholders, including
manufacturers, veterinarians, animal producer associations, industry, the press, and
consumer groups, or through their own surveillance and compliance activities. When
such a report is received, CVM assesses the situation. Any shortages are directed to the
Drug Shortage Coordinator, who proceeds to determine as quickly as possible whether
the drug is medically necessary and whether special actions are needed to address the
shortage. According to the guideline, special actions may include talking to industry
about their manufacturing plans, expediting reviews of regulatory submissions, or, in
extraordinary circumstances, using enforcement discretion to give time for remediation to
take place. CVM also evaluates the possibility to substitute other products and examines
whether such a substitution would have negative effects on human food safety. CVM
cannot always prevent a shortage of MNVP but is in a unique position to coordinate
activities that might minimize the extent and impact of the shortage (FDA, 2000).
Since 2011, the FDA Center of Veterinary Medicine (CVM) has described about
twenty-five shortages of MNVPs on their website. The website uses a question-and-
answer format to explain how their drug shortage program works and includes tables that
briefly summarize current and resolved drug shortages. The tables identify the date,

56
product, company, and reason for the drug shortage. Reasons often identify issues such
as manufacturing delays or increased demand. For some drug shortages, the website
provides links to CVM updates, which include more information about a specific
shortage (FDA, 2020a).
CVM has taken more interest in veterinary drug shortages recently by directly
engaging manufacturers about the potential for veterinary drug shortages related to
Hurricane Maria and the COVID-19 pandemic (Campbell Thornton, 2017). It has issued
an interim Guidance for Industry, Reporting, and Mitigating Animal Drug Shortages
during the COVID-19 Public Health Emergency. This guidance encourages voluntary
reporting of all veterinary drug shortages regardless of whether the drug is designated as
medically necessary. However, the guidance is clear that CVM will only prioritize and
expedite their review of regulatory applications associated with medically necessary
veterinary drugs (FDA, 2020b). Also, CVM participated in a well-publicized workshop,
Animal Pharmaceutical Supply Chain Disruptions, at Kansas State University in
September 2019 (Peralta and Bailey, 2019). A comparison of the regulatory frameworks
for human and animal drugs shortages is provided in Table 4. It demonstrates that the
human drug shortage framework currently includes much stricter regulatory requirements
than the animal drug shortage framework.

57
Table 4: Comparison of Human and Veterinary Drug Shortage Regulatory
Frameworks
Regulatory Framework Component Human Drug Shortages Veterinary Drug Shortages
Manufacturers of critical medicines, to notify
FDA of potential disruptions and
discontinuations six months in advance, or as
soon as possible. Reporting extends to active
ingredients.

Required Not required, but encouraged by FDA-
CVM
Manufacturers must provide the reason,
impact, and expected duration of the
disruption
Required Not required, but encouraged by FDA-
CVM
FDA distributes the information to
stakeholders

Required Not required, but FDA-CVM does
provide available information on their
website
FDA enforces the notifications of impending
drug shortages.

Required Not required
FDA expedites reviews of supplements and
inspections related to critical drug shortages

Required Not required, but FDA-CVM does
expedite if drug is deemed medically
necessary
FDA provides annual drug-shortage reports
to Congress

Required Not required
FDA maintains a drug shortage list Required Not required, but FDA-CVM
maintains a list on their website
FDA to develop and execute a strategic plan Required Not required
FDA to consider the risk and impact of drug
shortages before issuing warning letters or
taking any enforcement actions
Required Not required, unclear if FDA-CVM
does this in some cases
Manufacturers of critical medicines are
required to develop, maintain, and implement
a redundancy risk management plan which is
subject to FDA inspection
Required Not required
Manufacturers must report the amount of
each drug manufactured, prepared,
compounded, or processed for commercial
distribution annually or upon request by
FDA during a public health emergency
Required Manufacturers are required to report
the amount of product sold annually in
the Drug Experience Report.
2.5 U.S. Veterinary Drug Shortages: Industry Views on Potential Changes to the
Regulatory Policy
2.5.1 Literature Search
To begin explorations into views on veterinary drug shortages, advantage was
taken of the “search everything” function that aggregates search results from several

58
libraries at the University of Southern California. Two searches were performed, one
using the search term “animal drug shortage” and the other using the search term
“veterinary drug shortage.” Based on a research article by Grindlay, Brennan, and Dean
(2012), the Scopus and CAB Abstracts databases cover the basic veterinary journals best
with 98.3% and 97.5%, respectively; CAB Abstracts were also identified to have the best
coverage, 90.2%, for the full list of veterinary journals. Thus, searches were also
performed in the CAB Abstracts and Scopus databases. Additionally, the Nexus, Uni,
PubMed, Google Scholar, and Web of Science databases were searched. Duplicates of
the same article and articles with no seeming relevance or written in languages that were
not clear to me were excluded from the results. A summary of these search results is
provided in Table 5. Only one FDA press statement and one television newscast were
identified as relevant in this search.

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Table 5: Summary of Search Results from Several Databases
Total # of
Results
Excluded Included Results
U.S.C. Library 3 2 1 1
Nexus Uni 7 6 1 1
CAB Abstracts 0 0 0 0
Scopus 0 0 0 0
PubMed 0 0 0 0
Google Scholar 1 1 0 0
Web of Science 0 0 0 0

In addition, the search term “drug shortage” was used to search the Journal of the
American Veterinary Medical Association (JAVMA), the website of the American
Veterinary Medical Association (AVMA), DVM360 magazine, and Veterinary
Information Network (VIN) News Services. Duplicate results, articles related to specific
human drug shortages affecting animals, and articles related to a specific animal drug
shortage or manufacturer were excluded. The results of these searches are summarized in
Table 6.
Table 6: Summary of Additional Search Results
Total # of
Results
Excluded Included Results
JAVMA 255 254 1 1
AVMA website 33 27 6 6
DVM 360
magazine
6 6 0 0
VIN News
Service
45 41 4 4

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The literature search on veterinary drug shortages produced a paucity of grey
literature and news articles. No systematic research related to industry views was found
to deal specifically with potential changes to the regulatory policy associated with
veterinary drug shortages in the U.S. However, some anecdotal information within this
body of data was considered to facilitate my research. The information was assessed to
understand whether veterinary drug shortages appeared to be of concern to stakeholders
and, if so, what were the perceived causes and solutions to such shortages.
2.5.2 Concern about Veterinary Drug Shortages
Most industry stakeholders, including veterinarians, FDA-CVM, animal owners,
and manufacturing firms, appear to be concerned about veterinary drug shortages.
Veterinarians are particularly vocal about their concerns because only a small number of
FDA-approved veterinary drugs are available for the wide range of species and diseases
veterinarians treat. Any loss of such veterinary drugs can have a significant effect on
their ability to treat their animal patients (Burns, 2010). Many have expressed their belief
that drug shortages are trending upward in numbers, and this trend is an important issue
for veterinary medicine (Burns, 2010; Khuly, 2015). In the event of shortages, veterinary
staff spend considerable time and effort to contact manufacturers and distributors as they
try to secure supplies, identify alternatives, and prioritize patients (Burns, 2010). The
American Veterinary Medical Association (AVMA) summarized their views about
veterinary drug shortages in their comments on FDA’s report, A Review of FDA’s
Approach to Medical Product Shortages (FDA, 2011). AVMA emphasized the
importance of drug availability for animals and the value of FDA-approved drugs, which
are proven safe and effective (AVMA, 2011).

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FDA-CVM has also been concerned about veterinary drug shortages for two
decades or more. Its concern has been reflected in its stated policies to “prevent or
alleviate undue animal suffering and animal production hardships caused by shortages of
medically necessary veterinary products.” (AVMA, 2003) Dr. Julie Bailey, FDA-CVM
Deputy Director of the Division of Manufacturing Technologies, reemphasized that
concern at a seminar on Animal Pharmaceutical Supply Chain Disruptions (Peralta and
Bailey, 2019) at Kansas State University in September 2019. She identified that the
protection of public health was at the root of FDA-CVM’s main concern related to animal
drug shortages. However, she also explained that FDA has limited power to manage such
shortages. For example, FDA cannot require manufacturers to make a drug or to
distribute it in a certain way. Thus, FDA tries to intercede by working with firms
involved in the shortage, including the primary firm that is having difficulty to supply the
drug and additional firms that could manufacture the drug for use in the U.S. market
(Peralta and Bailey, 2019). In the article On Back Order, Drug Shortages seem to be
Increasing in Veterinary Medicine posted by Katie Burns (2010), Dr. Martine
Hartogensis, Deputy Director of the FDA-CVM Office of Surveillance and Compliance,
described how FDA-CVM had worked closely with manufacturers to mitigate the
shortages of Immiticide
®
and Vetsulin
®
described in Section 2.3. More recently, at the
FDA-CVM Animal Health Institute Quarterly meeting held on November 13, 2019, Dr.
Steve Solomon, Director of the FDA-CVM, again expressed FDA-CVM’s concern about
veterinary drug shortages. He drew attention to a passage in the FDA report: Drug
Shortages: Root Causes and Potential Solutions (FDA, 2019b), which states, “Although
the focus of the report is on human drugs, many of the same concerns apply to veterinary

62
medicines used to treat service, companion, and food-producing animals” and indicated
that FDA-CVM is interested to work with industry on the prevention and mitigation of
veterinary drug shortages (Solomon, 2019). Other examples of FDA-CVM’s attention to
drug shortages are reflected in their proactive approach in engaging manufacturers about
potential drug shortages and offering assistance following Hurricane Maria and during
the COVID-19 Pandemic (Campbell Thornton, 2017; Lau, 2020; Cima and Larkin,
2020).
Animal owners only see veterinary drug shortages occasionally when their
animals need to be treated for illness or disability, but these occasions are particularly
upsetting for them. In a Minneapolis TV news report, pet owners were surprised to learn
about shortages of animal drugs, including those used to treat heartworm, diabetes, and
dry eye in dogs that might prevent their animals from receiving the most effective
medicine. One woman summarized the concern by saying, “it’s hard because, of course,
you love your dog and want what’s best for them.” (Unknown, 2011) Another woman
said that she exercises her dog regularly in order to avoid having to go to a veterinarian as
a result of health problems. The emotional element of these concerns is illustrated also
by her quote, “such a good dog, so lucky to have him.” (Unknown, 2011)
According to Ron Phillips, Vice President of Public Affairs for the Animal Health
Institute, manufacturers are concerned about veterinary drug shortages and “work
diligently to quickly resolve these issues when they arise. Each is unique and must be
addressed on a case-by-case basis.” (Burns, 2010). Mike Mlodzik, Associate Director of
Regulatory Affairs for Boehringer Ingelheim, confirmed this when he spoke at the
Kansas State University Seminar on Animal Pharmaceutical Supply Disruptions in

63
September 2019. He stated that manufacturers are concerned about veterinary drug
shortages because disruptions have a financial effect but can also affect relationships and
reputation with customers and suppliers. He made the point that companies spend
considerable time and resources trying to mitigate disruptions (Mlodzik, 2019).
However, not all potential stakeholders appeared to share the concerns of health
care professionals and pet owners. For example, one financial analyst was more sanguine
about animal drug shortages. His comments, made after a merger between two animal
health companies had failed, suggested that more animal medications might be needed in
the future, and these heightened demands could lead to occasional shortages. However,
he held the opinion that “As long as there is a demand for a drug, someone will produce
it” (DeKok, 2011).
2.5.3 Perceived Causes and Solutions for Veterinary Drug Shortages
A review of even the anecdotal literature gave few insights into the perceived
causes and solutions to veterinary drug shortages beyond those already identified for
human drug shortages. Gigi Davidson, Director of Clinical Pharmacy Services at North
Carolina State University, suggested that mergers, discontinuations, and manufacturing
issues caused veterinary drug shortages, as they often do for human drug shortages,
whereas Dr. Scott Handler, Director of Marketing, Communications, and Education for
Webster Veterinary Supply asserts that increased surveillance by FDA is to blame
(Burns, 2010).
Perhaps the most useful overviews to detail the causes of drug shortages have
come from presentations at the Kansas State University Seminar, Animal Pharmaceutical
Supply Disruptions, in September 2019. Dr. Julie Bailey, FDA-CVM Deputy Director of

64
the Division of Manufacturing Technologies, repeated the frequently cited causes of low
generic drug pricing, immature or substandard quality systems, and regulatory challenges
(Peralta and Bailey, 2019). Mike Mlodzik, Associate Director Regulatory Affairs at
Boehringer Ingelheim Animal Health, characterized the disruptors as either internal (e.g.,
equipment breakdown, fire or explosion, transport or shipping issues) or external (e.g.,
natural disasters, price increases, mergers/acquisitions, geopolitical instability, or legal
restrictions) (Mlodzik, 2019). Dr. Brian Johnson, Executive Director API Technology at
Merck Animal Health, while presenting at Kansas State University in Olathe, Kansas,
characterized related disruptions in the supply of needed active ingredients that resulted
from several subordinate factors, including more rigorous health authority inspections;
significant changes in environmental, health, and safety (EHS) requirements leading to
factory closures, relocations, and price increases; increasing global regulatory registration
requirements; attrition in the overall active ingredient supply base; and a lack of
commitment by suppliers to make the active ingredients for small animal drug products
(slides in possession of J. Greenwald).
Most of the solutions suggested for shortages at the same meeting reflect solutions
for human drug shortages. From the FDA perspective, Dr. Bailey proposed that FDA-
CVM might consider quality metrics, shift their inspection approaches from GMP to
quality maturity, and use of science-based quality assessments, which may allow for
increased use of risk-based approaches for regulatory inspection, real-time release
mechanisms, and post-approval change processes (Peralta and Bailey, 2019). She
encouraged animal health firms to embrace the concepts in ICH Q8 Pharmaceutical

65
Development, ICH Q9 Quality Risk Management, ICH Q10 Pharmaceutical Quality
System, and soon ICH Q12 Lifecycle Management.
From an industry perspective, Mlodzik and Johnson suggested that additional
solutions might lie in the management of relationships with contract manufacturing
organizations (CMOs) and suppliers. Mlodzik noted that distance, language barriers, and
resource requirements make it more difficult to oversee offshore CMOs and suppliers. He
suggested that supply disruptions might be avoided through closer partnerships between
the firms and their CMOs and suppliers. For example, firms could spend more time
auditing the facilities and working with the CMOs and suppliers to address critical issues.
Also, firms and CMOs could collaborate more openly on regulatory assessments of
changes, regulatory submissions, and communications with FDA-CVM. Finally, Mlodzik
proposed that shortages might be mitigated by establishing CMO/supplier quality metrics
as well as developing business continuity plans (Mlodzik, 2019). Johnson reemphasized
the critical nature of collaboration between the firm and the supplier to assure the high
quality of the suppliers’ service and reliability. In his view, the firm-supplier relationships
tended to be stronger when the firm transfers its intellectual property for the active
ingredient to the supplier or works with the supplier directly to develop the technology
for an existing active ingredient. In these cases, the pharmaceutical firm has a higher
level of control and influence over the quality of the active ingredient as well as the
approvability of the associated regulatory submissions. He asserted that relationships are
weaker when a firm purchases an existing or new generic from a supplier without any
technical involvement. Therefore, Johnson advocates that firms work as closely as
possible with its suppliers on the technology as well as quality, environmental health, and

66
safety (EHS), and regulatory aspects initially and over time (slides in possession of J.
Greenwald).
Although quality improvements might go a long way toward reducing the number
of veterinary drug shortages, they are not able to address all of the identified causes. One
obvious solution might be a change in regulations to give FDA additional oversight, as
was done to improve human drug shortages. Surprisingly, veterinary advocates for this
type of solution are noticeably less vocal in the available literature. The AVMA Council
on Biologic and Therapeutic Agents concluded in September 2010 that “drug shortages
are a fact of life in veterinary practice.” (Burns, 2010) Their seeming resignation in part
may stem from the availability of drug compounding as a “safety valve” for the
production of drugs for non-food animals. According to Fred Gingrich, a member of the
AVMA task force developing proposed legislation on veterinary compounding,
veterinary compounding “has increased dramatically over the past five years due to more
and more drug shortages and the return of drugs that are many times the original price.”
(Lau, 2015) Gingrich noted that many veterinarians “cavalierly” use compounded drugs
instead of FDA-approved drugs because they are much less expensive, and they may not
fully appreciate the risks of using compounded drugs.
Nonetheless, such risks can be devastating. For example, in 2009, Franck’s
Pharmacy incorrectly compounded a vitamin and mineral supplement and caused a fatal
overdose of 21 Venezuelan polo team ponies at the International Polo Club of Palm
Beach (Lau, 2015). In another example, a formulation of clenbuterol, a bronchial dilator,
appears to have been compounded to contain 70 times the concentration of the FDA-
approved drug and likely led to deaths of two horses and adverse reactions in 11 others

67
(Thompson et al., 2011). Such issues have led some in the industry to believe that
veterinary compounding regulations are “poised for change” (Lau, 2015). Consistent with
that belief, FDA-CVM issued draft Guidance for Industry #256, Compounding Animal
Drugs from Bulk Drug Substances (FDA, 2019a) in November 2019, which attempts to
balance FDA-CVM’s “concerns about the safety, effectiveness, and quality of animal
drugs, which have not gone through agency premarket review, with the need for such
drugs when no FDA-approved drug can be used to treat the animal.” (FDA, 2019a) The
guideline focuses on specific risk areas, which include human and animal safety, food
safety, copying FDA-approved drugs, which is a disincentive to use the legal framework,
and selling compounded drugs as office stock which exposes larger numbers of patients.
The conditions under which FDA-CVM proposes not to take enforcement action if
addressed according to the guideline are described in Figure 13. If enforced, such
tightened compounding rules could affect drug shortages by increasing the costs of
compounding and decreasing the numbers of drug suppliers, thus reducing the viability of
using compounded drugs as an easy solution for many animal drug shortages (Lau,
2015).

68
Figure 13: Proposed Animal Drug Compounding Conditions to Avoid FDA
Enforcement Action

Source: FDA-CVM Draft Guidance for Industry #256, Compounding Animal Drugs from
Bulk Drug Substances, November 2019 (FDA, 2019a)

2.5.4 Approaches to the Current Research
As the literature review shows, stakeholders have suggested a number of potential
solutions for U.S. veterinary drug shortages, some reflecting areas of concern shared with
human drugs and others that seem somewhat different. In this research, I am interested in
whether some of the interventions that have already been introduced for human drug
shortages should also be implemented for animal drugs. From the literature, it is unclear
whether the animal drug industry would view the legal and regulatory changes imposed
General
Drugs are compounded under the supervision of a veterinarian or a pharmacist in a state-licensed or Federal
facility.
Drugs are compounded in accordance with USP and comply with applicable USP-NF monographs
Adverse events and product defects are reported to FDA by the veterinarian or pharmacy that compounded the
drug within 15 days of awareness.
Compounded drugs are labeled with drug information, the contact information for the compounding pharmacy
or veterinarian and the prescribing veterinarian, statement to report adverse events to FDA, statement that the
drug is a compounded drug, and the statement Caution: Federal law restricts this drug to used by or on the
order of a licensed veterinarian.
With Patient Specific Prescriptions for Nonfood-Producing Animal
The drug is dispensed by the pharmacy directly to the prescribing veterinarian or the patient’s owner or by the
veterinarian to the patient’s owner.
The compounded drug is not a copy of a marketed FDA approved drug and if the compounded drug contains
the same active moiety as a marketed FDA approved drug then there must be documentation that it will
produce a clinical difference in the identified patient and the reason the available FDA approved drug cannot
be used.
Without Patient-Specific Prescriptions (Office Stock) for Nonfood-Producing Animals
The drug is compounded from a bulk drug substance listed on FDA’s List of Bulk Drug Substances for
Compounding Office Stock Drugs. This list will not include bulk substances when there is an FDA-approved
drug available to treat the condition or the ability to compound from an FDA-approved drug.
The drug is only dispensed to the owner of the animal or to another veterinarian in the same practice and
location.
Compounding Drugs for Use as Antidotes for Food-Producing Animals
The drug is compounded from a bulk drug substance listed on FDA’s List of Bulk Drug Substances for
Compounding Office Stock Drugs.
The veterinarian establishes and documents a scientifically based withdrawal time that ensures the residues of
the antidote and toxin are not present in the animal at the time of slaughter or that the animal does not enter the
food supply.

69
on human drugs as an effective and acceptable strategy to mitigate animal drug shortages.
Those changes to the regulations came from the FDASIA and CARES Acts and were a
result of serious concerns about the increasing trend of human drug shortages observed
by the FDA, shown above in Figure 3. They require more rigorous management and
oversight in five areas, shown in Figure 14 and briefly described in Figure 15.
Figure 14: Five Major Areas of Human Health Drug Shortage Regulation

Source: 21USC 356c, Discontinuance or interruption in the production of life-savings
drugs, 2020 (21USC§356c, 2020b).

70
Figure 15: Description of the Human Health Drug Shortage Regulations

Source: 21USC 356c, Discontinuance or interruption in the production of life-savings
drugs, 2020 (21USC§356c, 2020b).

The requirements identified above are all actions that involve the intervention of
regulatory agencies. Thus, before the requirements are put into place for veterinary
products, it is useful to ask whether those regulations can accomplish the broader
objectives of those agencies. Typically, regulations are put into place to achieve one or
more of three objectives captured in the mission statements of two of the regulatory
agencies most involved in the sale of animal drugs, the FDA and the Federal Trade
Commission. These include not only 1) protecting public health by ensuring the safety,
effectiveness, and quality of the regulated product, but also 2) assuring that regulations
do not unduly favor one industry subgroup over another, and 3) assuring that the costs
associated with satisfying the requirements are not out of proportion with the benefits that
they produce or the availability of the products to consumers. These areas have been

71
used in the past to frame surveys that investigate industry views on the appropriateness of
certain legislative or regulatory changes (Ramsey, 2013; Turnbull, 2016; Wiley, 2019).
The regulatory changes are considered in the context of the triadic framework in
Figure 16.
Figure 16: Consideration of the Proposed Regulations and Regulatory Agency
Objectives
Regulatory Agency Objectives Considerations and Questions
Safety, Effectiveness, and
Quality
The aim of the proposed regulations is to ensure safe and effective life-saving
animal drugs are available when needed.
 Will the proposed regulations be effective in the mitigation or
prevention of animal drug shortages?
 Will the proposed regulations introduce any new risks in terms of the
safety, effectiveness, or quality of animal drugs?
Level Playing Field
The proposed regulations are equally applicable to all companies
manufacturing life-saving animal drugs.
 Will it be possible for different size companies to meet the proposed
regulations?
 Will it be possible for companies manufacturing higher percentages
of life-saving medicines versus non-life-saving medicines to meet
the proposed regulations?
Cost Implications
There are cost implications for industry and the government.
For example, the government will need resources to immediately work on
reported drug shortages and to expedite reviews and inspections. Industry will
need resources to prepare risk mitigation plans.
 What are the cost implications for government and for industry?
 Should the government costs be covered by ADUFA/AGDUFA fees
or federal funding, or both?

In this study, I examined the five areas in which previous legislation has been
strengthened for human drugs to explore how the animal drug industry sees the benefits
and drawbacks of adopting similar regulations to prevent and mitigate veterinary drug
shortages. In addition, the potential changes were assessed in the context of the key
objectives of regulation.

72
Chapter 3: Methodology
3.1 Introduction
The purpose of this study was to evaluate the views of professionals working at
firms manufacturing and distributing veterinary drugs in the U.S. regarding veterinary
drug shortages. Specifically, the survey explored whether these professionals believe that
the legal and regulatory changes imposed on human drugs would be useful in preventing
and mitigating animal drug shortages. The survey was organized using the triadic
framework previously used by Ramsey (2013), Turnbull (2016), and Wiley (2019), which
consisted of important policy objectives previously discussed in Section 2.5.4 to be
considered prior to introducing new FDA regulations. This study included four steps:
literature review (see Chapter 2), development of an industry survey, dissemination of the
survey, and analysis of the results and written conclusions.
3.2 Survey Development
The survey was developed using a web-based survey application tool, Qualtrics
(www.Qualtrics.com). The survey included questions about:
 the respondent’s background
 views about introducing veterinary drug shortage regulations similar to those for
human drug shortage regulations in terms of safety, effectiveness, and quality;
maintaining a level playing field, and cost implications
 the use of quality metrics and risk-based approaches to prevent or mitigate
veterinary drug shortages
The question types included a combination of suggested-choice questions such as
multiple choice and preference questions, as well as open-ended questions where
respondents provided free text answers.

73
A focus group was convened prior to finalizing and deploying the survey. The
purpose of the focus group was to provide critical feedback on the survey content based
on the purpose of the research. The focus group participants were asked to comment on
the organizational flow of the survey and the overall content, clarity, and format of its
questions. Focus group members were also asked to identify gaps in areas relevant to the
survey topic. The focus group included participants from industry and academia.
Participants were selected based on their knowledge of drug shortages, experience with
veterinary drug shortages, and experience with survey development.
All participants were provided with an electronic copy of the draft survey prior to
the focus group meeting. The draft survey was reviewed and discussed at an online web
conference for the convenience and collaboration of the participants. The meeting lasted
approximately 90 minutes and began with a short overview of the intended research and
purpose of the study. Each survey question was discussed in detail for possible
improvements to the content and clarity. Afterward, the survey was updated to
incorporate the feedback from the focus group.
To ensure the final survey tool in the Qualtrics system works properly, the survey
was sent to three individuals to verify that the emails were received, responses could be
entered, and the resulting data could be analyzed.
3.3 Survey Delivery
The survey was deployed to professionals employed by firms involved with the
manufacture and distribution of veterinary drugs in the U.S. and have direct experience
with veterinary drug shortages. Specifically, the following methods were used:

74
1. A direct survey link was sent by the Qualtrics tool to all 37 of the industry
participants of the Kansas State University Seminar, Animal Pharmaceutical
Supply Disruptions, held September 26, 2019. Periodic reminders were sent to
non-responders, and government participants were excluded.
2. An excel list of the sponsors of NADAs and ANADAs from the FDA Green Book
was downloaded from the FDA website. Of the 130 sponsors, 48 associated with
applications for medical gases were excluded. Contact information for 63
sponsors was found and used to contact relevant individuals either by email,
online on the company website or in two cases, by mail, for two companies that
only had a physical address.
3. People working in regulatory affairs, supply chain, quality, marketing, operations,
and technical operations roles at the NADA and ANADA sponsor companies in
the FDA Green Book were identified on LinkedIn and through professional
contacts. Using this approach, 116 people were contacted using LinkedIn, and 67
were contacted using email.
4. Five animal health industry organizations were identified and asked to distribute
the survey to their membership. These organizations included the Animal Health
Institute, Kansas State University, United Veterinary Services Association;
Generic Animal Drug Alliance, and the LinkedIn Community of the Animal
Health Corridor. The survey was shared by the Animal Health Institute, Kansas
State University, and the Generic Animal Drug Alliance with their memberships,
and an invitation to participate in the survey was posted on the Animal Health
Corridor LinkedIn Community page.
No financial compensation or incentive was offered to encourage participation.
3.4 Survey Analysis
The results of the survey were collected and stored in Qualtrics. The Qualtrics
survey data were cross tabulated, graphed, and analyzed to measure the results. The
results were used to provide information about industry’s views on introducing new
regulations related to preventing and mitigating veterinary drug shortages in terms of the
regulatory goals associated with the triadic framework used for this study.
Questions which requested choices to be ranked in order of importance were
analyzed using weighted averages. In such cases, each rank was assigned a weight. For
example, rank #1 was assigned a weight of 5, rank #2 was assigned a weight of 3, and

75
rank # three was assigned a weight of one. The weighted averages were then calculated
as follows:
Weighted average = ((number of responses ranked #1 x 5) + (number of responses
ranked #2 x 3) + (number of responses ranked #3 x 1)) / (# of respondents)
In this example, the choice with the highest weighted average was considered as
the most important to the respondents.

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Chapter 4: Results
4.1 Survey Participation
The survey was active from January 23, 2021, through May 7, 2021. Links to the
survey were sent directly to 37 potential participants who attended the seminar at Kansas
State University on Animal Pharmaceutical Supply Disruptions in September 2019, and
for whom I had personal contact information. Of the 37 potential participants, eight
started the survey, and eight completed at least one question providing a response rate of
22% (8/37). A larger group of 79 participants, which included professional contacts and
industry members of the Animal Health Institute (AHI) and the Generic Animal Drug
Association (GADA), accessed the survey using the anonymous link, and 77 of these
participants completed at least one question giving a drop-out rate of 3% (2/77).
Combining both methods of participation, 85 respondents completed at least one
question. Three respondents responded “No” to the first question in the survey, which
asked if they work or had worked in the animal health industry. This negative response
automatically took these three respondents to the end of the survey. Excluding these three
respondents, 65/82 respondents answered all questions. The 17 dropouts occurred
throughout the survey, but the majority dropped out after answering “yes” to the first
question, at the end of the demographics section, or just prior to the last question of the
survey, which asked if they had any other views, they would like to share.
According to the Checklist for Reporting of Results of Internet E-Surveys
(CHERRIES), duplicate entries from the same user within, for example, 24 hours, should
be checked (Eysenbach, 2004). The dataset was checked, and one potential instance of a
duplicate entry was found. However, the participant only filled in the survey responses

77
after the demographics section once. Therefore, multiple entries by the same participant
were not considered to be a problem for this dataset.
4.2 Demographic Profile of the Respondents
The majority of respondents to the survey worked or consulted for a company that
manufactures or distributes veterinary drugs for the United States (96%, 82/85). Many
respondents worked in regulatory affairs (42%, 33/79), marketing (15%, 12/79), or
manufacturing (10%, 8/79) (Figure 17). Functions such as technical operations (8%,
6/79), quality (6%, 5/79), and supply chain (6%, 5/79) were also represented. Ten
respondents indicated that their functions differed from those listed, and their responses
are summarized in Table 7. Each of these other functions was represented by one
respondent (1%, 1/79).
Figure 17: Functional Roles of Survey Respondents
In what discipline is your primary job function? (N=79)

78
Table 7: Other Roles of Survey Respondents
“bioequivalence studies, portfolio development, marketing and regulatory”
“business development, management”
“development”
“external MFG”
“management”
“part regulatory part R&D”,
“procurement”
“R&D Program Management”
“Technical Services”
“Veterinary Services”

The largest groups of respondents were Directors/ Associate Directors (34%,
30/79) or Vice Presidents/ Executive Directors (27%, 21/79). Fourteen percent (11/79)
were Senior Managers or Managers, 9% (7/79) were Consultants, and 5% (4/79) were
Senior Specialists or Specialists (Figure 18). Eleven percent of respondents were at other
levels, which are summarized in Table 8.
Figure 18: Organizational Level of Survey Respondents
What is your current position? (N=79)

79
Table 8: Other Organizational Levels of Participants
“Technical Services Veterinarian”
“Sr. Vice President”
“Regulatory Specialist”
Reg Affairs / Prod Dev”
“Chief Regulatory Officer”
“Practicing Veterinarian”
“President”
“President and CEO”

Respondents selected the number of years that they had worked in the animal
health industry (Figure 19). About half (42%, 33/79) had worked in the industry for over
20 years, 19% (15/79) for 11-20 years, 27% (21/79) for 6-10 years, and 13% (10/79) for
five years or less.
Figure 19: Years of Experience of Survey Respondents
How many years of experience do you have working in the animal health industry?
(N=79)

Respondents were employed by companies of different sizes (Figure 20).
Approximately half (43%, 33/77) worked at companies with > 5,000 employees, 23%
(23/77) with 501 – 5000 employees, and 34% (26/77) with 1-500 employees.

80
Figure 20: Size of Companies in which Survey Respondents Work
What is the approximate size of the company for which you work? (If you work for an
animal health company that is part of a human health company, then indicate the number
of employees for the animal health part of the company.) (N=77)

Respondents were employed by companies marketing various veterinary drugs in
the U.S. (Figure 21). Almost all worked for companies that marketed veterinary drugs for
companion animals (93%, 73/75) and/or food-producing animals (88%, 59/75). A few
respondents worked for companies that did not market veterinary drugs for companion
animals (7%, 5/75) or food-producing animals (13%, 9/75). Most also worked for
companies marketing pioneer veterinary drugs (89%, 60/75) and generic veterinary drugs
(91%, 63/75). A few worked for companies that are not marketing pioneer veterinary
drugs (11%, 7/75) or generic veterinary drugs (9%, 7/75).
Figure 21: Types of Veterinary Drugs Marketed by the Respondent’s Companies
What types of veterinary drugs are marketed by your company in the U.S.? (N=75)

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The number of responses greatly exceeded the number of respondents suggesting
that many respondents worked with products in two or more categories. The question,
“What is the approximate size of the company for which you work?” was cross tabulated
with the question, “What types of veterinary drugs are marketed by your company in the
U.S.?” in Table 9. The majority of medium (M) and large (L) companies marketed
companion animal (M:100%, 18/18; L: 100%, 33/33), food animal (M: 94%, 15/16; L:
97%, 30/31), pioneer (M: 94%, 16/17; (L: 94%, 30/32), and generic veterinary drugs (M:
94%, 15/16; L: 88%, 28/32) in the U.S., whereas small companies (1-500 employees) had
lower representations in each category; 80% (20/25) in companion animal drugs, 63%
(12/19) in food animal drugs, 65% (10/20) in pioneer veterinary drugs, and 83% (19/23)
in generic veterinary drugs.

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Table 9: Cross Tabulation of Company Size versus Types of Marketed Drugs

What is the approximate size of the current company for which
you work?

Total
1-500
employees
501-5,000
employees
> 5,000
employees
I am not
sure
What types of veterinary drugs are marketed by your current company
in the United States?
Yes (Companion Animal) 72 20 18 33 1
94% 80% 100% 100% 100%
No (Companion Animal) 5 5 0 0 0
6% 20% 0% 0% 0%
I do not know 0 0 0 0 0
(Companion Animal) 0% 0% 0% 0% 0%
Yes (Food Animal) 58 12 15 30 1
87% 63% 94% 97% 100%
No (Food Animal) 9 7 1 1 0
13% 37% 6% 3% 0%
I do not know 0 0 0 0 0
(Food Animal) 0% 0% 0% 0% 0%
Yes (Pioneer) 60 13 16 30 1
86% 65% 94% 94% 100%
No (Pioneer) 7 5 1 1 0
10% 25% 6% 3% 0%
I do not know (Pioneer) 3 2 0 1 0
4% 10% 0% 3% 0%
Yes (Generic) 63 19 15 28 1
88% 83% 94% 88% 100%
No (Generic) 7 3 1 3 0
10% 13% 6% 9% 0%
I do not know (Generic) 2 1 0 1 0

3% 4% 0% 3% 0%

About a third of the respondents (38%, 27/72) worked for companies that had
over 100 approved NADA or ANADA applications, whereas 17% (12/72) had 21-100
applications, 32% (23/72) had 1-20 applications, and 14% (10/72) had no applications
(Figure 22).

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Figure 22: Number of FDA Approved Applications held by Companies
Approximately how many FDA Approved New Animal Drug Applications (NADA) or
Abbreviated New Animal Drug Applications (ANADA) does your company have? (N=72)

4.3 Familiarity with U.S. Drug Shortage Regulations, Policy, and Guidance
Documents
All participants were asked to describe their level of familiarity with three
documents related to drug shortages (Figure 23). Only a small minority (19%, 14/75) had
read the U.S. human drug regulations. Nearly half (48%, 36/75) had heard of the U.S.
human drug regulations but had not read them, and the rest (33%, 25/75) were unfamiliar
with the human regulations. Over a third of respondents (40%, 30/75) had read the FDA-
CVM policy guide on veterinary drug shortages, whereas nearly half (47%, 35/75) had
heard of the FDA-CVM policy guide on veterinary shortages but had not read it, and only
13% (10/75) were unfamiliar with them. The FDA-CVM Guidance for Industry #271
was read by about 40% of the respondents but was familiar to but not read by 37%
(28/75). About a quarter of the respondents were not familiar with the Guidance.

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Figure 23: Familiarity with Regulations, Policy, and Guidance Documents
Are you familiar with the following documents? (N=75)

A cross tabulation was performed to compare the level of familiarity with the
FDA-CVM documents versus job role to understand which roles were most and least
familiar with these documents (Table 10). Of the 32 respondents working in Regulatory
Affairs, 66% (21/32) had read FDA-CVM Policy 1240.4170, 28% (9/32) had heard of it
but not read it, and 6% (2/32) were not familiar. Of the five respondents working in
Quality, 40% (2/5) had read FDA-CVM Policy 1240.4170, 40% (2/5) had heard of it but
not read it, and 20% (1/5) were not familiar. Of the five respondents working in Supply
Chain, none had read FDA-CVM Policy 1240.4170, 60% (3/5) had heard of it but not
read it, and 40% (2/5) were not familiar. Of the eight respondents working in
Manufacturing, none had read FDA-CVM Policy 1240.4170, 88% (7/8) had heard of it
but not read it, and 12% (1/8) were not familiar. Of the five respondents working in
Technical Operations, none had read FDA-CVM Policy 1240.4170, 80% (4/5) had heard
of it but not read it, and 20% (1/5) were not familiar. Of the 10 respondents working in
Marketing, 40% (4/10) had read FDA-CVM Policy 1240.4170, 50% (5/10) had heard of

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it but not read it, and 10% (1/10) were not familiar. Of the 10 respondents working in
other roles, 30% (3/10) had read FDA-CVM Policy 1240.4170, 50% (5/10) had heard of
it but not read it, and 20% (2/10) were not familiar.
Of the 32 respondents working in Regulatory Affairs, 66% (21/32) had read FDA-
CVM Guidance for Industry 271, 25% (8/32) had heard of it but not read it, and 9%
(3/32) were not familiar. Of the five respondents working in Quality, 20% (1/5) had read
FDA-CVM Guidance for Industry 271, 40% (2/5) had heard of it but not read it, and 40%
(2/5) were not familiar. Of the five respondents working in Supply Chain, none had read
FDA-CVM Guidance for Industry 271, 60% (3/5) had heard of it but not read it, and 40%
(2/5) were not familiar. Of the eight respondents working in Manufacturing, none had
read FDA-CVM Guidance for Industry 271, 63% (5/8) had heard of it but not read it, and
37% (3/8) were not familiar. Of the five respondents working in Technical Operations,
20% (1/5) had read FDA-CVM Guidance for Industry 271, 60% (3/5) had heard of it but
not read it, and 20% (1/5) were not familiar. Of the 10 respondents working in
Marketing, 40% (4/10) had read FDA-CVM Guidance for Industry 271, 30% (3/10) had
heard of it but not read it, and 30% (3/10) were not familiar. Of the 10 respondents
working in other roles, 30% (3/10) had read FDA-CVM Guidance for Industry 271, 40%
(4/10) had heard of it but not read it, and 30% (3/10) were not familiar.

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Table 10: Cross Tabulation of Familiarity with Documents versus Job Function

In what discipline is your primary job function?

(N=75)

Total
Reg
Affairs Quality
Supply
Chain Mfg
Tech
Ops Mktg Other
Are you familiar with the following
documents?
FDA-CVM Policy Guide 1240.4170
Yes, I have read it. 30 21 2 0 0 0 4 3
Yes, I have heard of
it but not read it.
35 9 2 3 7 4 5 5
No, I am not
familiar.
10 2 1 2 1 1 1 2
FDA-CVM Guidance for Industry #271
Yes, I have read it. 30 21 1 0 0 1 4 3
Yes, I have heard of
it but not read it.
28 8 2 3 5 3 3 4
No, I am not
familiar.
17 3 2 2 3 1 3 3

A cross tabulation comparing familiarity with the FDA-CVM documents versus
job position was performed to understand which positions were most and least familiar
with the documents (Table 11). Of the 19 Vice Presidents or Executive Directors, 37%
(7/19) had read FDA-CVM Policy 1240.4170, 58% (11/19) had not read it but were
familiar with it, and 5% (1/19) were not familiar with it. Of the 27 Directors or Associate
Directors, 37% (10/27) had read FDA-CVM Policy 1240.4170, 48% (13/27) had not read
it but were familiar with it, and 15% (4/27) were not familiar with it. Of the four Senior
Specialists or Specialists, 25% (1/4) had read FDA-CVM Policy 1240.4170, 50% (2/4)
had not read it but were familiar with it, and 25% (1/4) were not familiar with it. Of the
nine Senior Managers or Managers, 33% (3/9) had read FDA-CVM Policy 1240.4170,
44% (4/9) had not read it but were familiar with it, and 22% (2/9) were not familiar with
it. Of the seven Consultants, 57% (4/7) had read FDA-CVM Policy 1240.4170, and 43%
(3/7) had not read it but were familiar with it. Of the nine respondents at other job levels,

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56% (5/9) had read FDA-CVM Policy 1240.4170, 22% (2/9) had not read it but were
familiar with it, and 22% (2/9) were not familiar with it.
Of the 19 Vice Presidents or Executive Directors, 42% (8/19) had read FDA-
CVM Guidance for Industry # 271, 32% (6/19) had not read it but were familiar with it,
and 26% (5/19) were not familiar with it. Of the 27 Directors or Associate Directors,
33% (9/27) had read FDA-CVM Guidance for Industry # 271, 48% (13/27) had not read
it but were familiar with it, and 19% (5/27) were not familiar with it. Of the four Senior
Specialists or Specialists, 25% (1/4) had read FDA-CVM Guidance for Industry # 271,
50% (2/4) had not read it but were familiar with it, and 25% (1/4) were not familiar with
it. Of the nine Senior Managers or Managers, 44% (4/9) had read FDA-CVM Guidance
for Industry # 271, 33% (3/9) had not read it but were familiar with it, and 22% (2/9)
were not familiar with it. Of the seven Consultants, 57% (4/7) had read FDA-CVM
Guidance for Industry # 271, and 29% (2/7) had not read it but were familiar with it, and
11% (1/9) were not familiar with it. Of the nine respondents at other job levels, 44%
(4/9) had read FDA-CVM Guidance for Industry # 271, 22% (2/9) had not read it but
were familiar with it, and 33% (3/9) were not familiar with it.

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Table 11: Cross Tabulation of Familiarity with Documents versus Job Position

What is your current position?

(N=75)

Total
VP/
E Dir
Dir/Assoc
Dir
Sr Spec/
Spec
Sr Mgr/
Mgr
Consult-
ant Other
Are you familiar with the following documents?
FDA-CVM Policy Guide 1240.4170

Yes, I have read it. 30 7 10 1 3 4 5
Yes, I have heard
of it but not read it.
35 11 13 2 4 3 2
No, I am not
familiar.
10 1 4 1 2 0 2
Total 19 27 4 9 7 9
FDA-CVM GFI #271

Yes, I have read it. 30 8 9 1 4 4 4
Yes, I have heard
of it but not read it.
28 6 13 2 3 2 2
No, I am not
familiar.
17 5 5 1 2 1 3
Total 19 27 4 9 7 9

4.4 Views on Key Definitions
Respondents were asked for their views on certain aspects of FDA’s definitions of
drug shortages for humans and animals. First, they were asked whether the two
definitions that currently differ should be the same (Figure 24). Respondents appeared
almost equally split in their opinions; 40% (29/73) did not think that the definition of a
veterinary drug shortage should be the same, whereas 37% (27/73) thought that it should.
About a quarter, 23% (17/73), were not sure.

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Figure 24: Views on Definition of a Drug Shortage
The FD&C Act defines a human drug shortage as a permanent discontinuance in the
manufacture of a drug or an interruption of the manufacture of a drug that is likely to
lead to a meaningful disruption in the supply of that drug in the United States.

FDA-CVM guidance states a veterinary drug shortage includes an actual or potential
shortage, including a disruption or anticipated disruption in the supply chain for a drug
product or any component of the drug product for the U.S. market.

Do you think FDA-CVM should consider adopting the drug shortage definition from the
FD&C Act? (N=73)

Additional questions explored three aspects relating to the use of the term
“medically necessary”, as defined by FDA-CVM (Figure 25). First, respondents were
asked whether they felt that the definition of medically necessary should be changed from
"treat or prevent a serious animal disease or condition" to "one that is life-supporting,
life-sustaining, or intended for use in the prevention or treatment of a debilitating disease
or condition...” Most commonly, respondents (44%, 33/75) thought that the definition
should be changed, but a significant minority (36%, 27/75) did not agree. The remainder
nether agreed or disagreed (16%, 12/75) or were not sure (4%, 3/75).
Second, respondents were asked whether the phrase, "and no other available
source of that product or adequate alternative drug substitute exists", should be removed.
About half (52%, 39/75) felt that it should be removed, whereas about a third (36%;
27/75) felt that it should be kept, 7% (5/75) were not sure, and 5% (4/75) neither agreed
nor disagreed. Third, they were asked whether the phrase, "Owner inconvenience and
non-therapeutic uses are inappropriate reasons for classifying a product as medically

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necessary", should be removed. Half of respondents (51%, 38/75) thought that it should
be removed, whereas a third (33%; 25/75) thought that it should be kept, 5% (4/75)
neither agreed nor disagreed, and 11% (8/75) were not sure.
Figure 25: Views on the Definition of Medically Necessary
The FD&C Act defines a medically necessary human drug as one that is life-supporting,
life-sustaining; or intended for use in the prevention or treatment of a debilitating disease
or condition, including any such drug used in emergency medical care or during surgery
or critical to public health.

FDA-CVM guidance defines a medically necessary veterinary product as one used to
treat or prevent a serious animal disease or condition or is needed to ensure the
availability of safe food products of animal origin, and no other available source of that
product or adequate alternative exists. Owner inconvenience and non-therapeutic uses
are inappropriate reasons for classifying a product as medically necessary.

Do you think the FDA-CVM's definition of medically necessary should be modified with
respect to the following to be more similar to the FD&C Act? (N=75)

Change "treat or prevent a serious animal disease or condition" with "one that is life-
supporting, life-sustaining, or intended for use in the prevention or treatment of a
debilitating disease or condition..."

Remove "and no other available source of that product or adequate alternative drug
substitute exists."

Remove
"Owner inconvenience and non-therapeutic uses are inappropriate reasons for
classifying a product as medically necessary."

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4.5 Experience with U.S. Veterinary Drug Shortages
Respondents were asked to identify the number of veterinary drug shortages that
they had experienced (Figure 26). Just under one third (30%, 22/73) had experienced
more than three veterinary drug shortages, 26% (19/73) had experienced 2-3 veterinary
drug shortages, 19% (14/73) experienced one shortage, and 25% (18/73) had not
experienced a veterinary drug shortage.
Figure 26: Number of Veterinary Drug Shortages Experienced by Respondents
During your career, have you been involved with a shortage of a U.S. veterinary
drug? If so, how many times? (N=73)

Respondents were asked about the primary root causes of the veterinary shortages
that they had experienced (Figure 27). Many pointed to a shortage of active ingredient
(27%, 40/153), GMP compliance issues (19%, 31/153), and/or regulatory delays (17%,
26/153). Fewer respondents attributed the shortages to increased demand (9%, 15/153),
shortage of inactive ingredients or packaging components (9%, 13/153), discontinuance
of manufacture (8%, 10/153), delay in shipping (4%, 6/153), and/or natural disaster (3%,
5/153). Five respondents listed other root causes (3%, 5/153), provided in Table 12. Two
respondents did not know the root cause of the veterinary drug shortage.

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Figure 27: Root Causes of Veterinary Drug Shortages Experienced by
Respondents
When you were involved with a U.S. veterinary drug shortage, what was the primary root
cause? (Select more than one if necessary) (N=153 responses from 53 respondents)

Table 12: Other Root Causes for Veterinary Drug Shortages Experienced by
Respondents
“COVID”
“Regulatory discontinuation of product, consent decree”
“competitor had problems – creating opportunity for our company”
“mfg difficulties; competitor out of market to demand increases”
“production problems”.

The survey participants were asked if their company had voluntarily informed
FDA-CVM of the veterinary drug shortages. The majority (81%, 43/53) responded “yes”,
4% (2/53) responded “no”, and 15% (8/53) did not know (not illustrated). They were then
asked if FDA-CVM took any actions to prevent or mitigate the veterinary drug shortage
(Table 13). Over a quarter (26%, 18/72) responded that FDA-CVM prioritized and/or
expedited a regulatory review, 17% (12/72) that it used enforcement discretion, 11%
(8/72) that it prioritized or expedited a regulatory inspection, and 8% (6/72) that it

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contacted other manufacturers to see if they could ramp up. Under a quarter of
participants (22%, 17/72) responded that FDA-CVM did not take any of the listed
responses. A further 11% (8/72) responded that they did not know if FDA-CVM took any
action. Three respondents listed other actions that FDA-CVM took and are summarized
in Table 14.
Table 13: Actions Taken by FDA-CVM to Address Veterinary Drug Shortages
Did FDA-CVM take any of the following actions to prevent or mitigate the shortage of
the veterinary drug? (Select any that apply) (N=72 responses from 53 respondents)

Prioritize/Expedite a Submission/Application Review 25%
No, FDA did not take any of the listed actions 24%
Use enforcement discretion
(i.e., allow temporary import of unapproved product)
17%
Prioritize/Expedite a regulatory inspection 11%
Contact other manufacturers to see if they can ramp up production 11%
I do not know 8%
Other 4%

Table 14: Other Actions taken by FDA-CVM to Address Veterinary Drug
Shortages
“compassionate use of clinical goods”
“FDA-CVM only took actions if the product was medically necessary”
“CVM offered to assist by writing a correspondence to another agency”
“Arnel Peralta (CVM) took six months to properly respond and dismissed the issue since
customers were not complaining”
The survey participants were asked if they felt that the number of veterinary drug
shortages in the U.S. had increased over the past 5-10 years. About half (52%, 27/52)
responded “yes”, 12% (6/52) responded “no”, and 37% (19/52) responded “I do not
know” (not illustrated). The participants who responded “yes” were asked about the

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contribution of certain factors previously identified as potentially important in creating
shortages (Table 15). About a quarter (27%, 21/77) pointed to an increase in global
regulatory submission and inspection requirements associated with changes, and 26%
(20/77) identified difficulties in gaining rapid regulatory approval of changes. Less
frequently, 14% (11/77) identified a lack of commitment by suppliers to manufacture
small quantities needed for animal products; 14% (11/77) identified aging manufacturing
facilities; and 10% (8/77) identified changes in environmental, health, and safety
requirements leading to factory closures, relocation, or price increases. Respondents
provided other comments on contributing factors (8%, 6/77) (Table 16).
Table 15: Trends Contributing to Increases U.S. Veterinary Drug Shortages
What trends do you think are contributing to an increase in the number of U.S. veterinary
drug shortages over the past 5-10 years? (Select more than one if necessary) (N=77
responses from 28 respondents)
Increase in global regulatory submission and inspection
requirements associated with changes
27%
Difficulty gaining rapid regulatory approval of changes (i.e.,
changes in manufacturing sites, active ingredient suppliers, or
components)
26%
Lack of commitment by suppliers to manufacture quantities
needed for small animal products
14%
Aging manufacturing facilities 14%
Changes in environmental, health, and safety requirements
leading to factory closures, relocation, or price increases
10%
Other (see Table 16) 8%

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Table 16: Other Comments from Participants about Trends Contributing to
Shortages
“increased demand”
“Old products that are not well formulated or hardy to changes”,
“I think there are more veterinary drugs and veterinary generics than in the past. 20 years ago
we had like three veterinary approved systemic drugs and a few topical drugs. We have
MANY more now.”
“High cost of controlled substance production and management”
“Failure in Stability”,
“Availability of API”.

When respondents were asked if they were concerned about the way in which
U.S. veterinary drug shortages are handled currently, 47% (25/53) responded “yes”, 42%
(22/53) responded “no”, and 11% (6/53) responded “I do not know” (not illustrated).
Participants who responded “yes” were asked to identify what they viewed as the top
three problems in order of importance with the way that U.S. veterinary drug shortages
were managed (Table 17). Responses in the first, second, and third positions were
weighted with a 5, 3, and 1, respectively. The weighted averages were calculated using
the number of respondents (N=25) as the denominator and show the top three results
selected by the 25 survey respondents are: “FDA acts only after confirming a veterinary
drug shortage exists, the drug is medically necessary, and no other suitable alternative
exists” (weighted average, 2.4), “Reporting veterinary drug shortages to FDA is
voluntary” (weighted average, 2.1), and “FDA-CVM accepts compounded drugs as
suitable to FDA-approved drugs experiencing shortages” (weighted average, 2.0). Other
problems mentioned by the survey participants are summarized in Table 18.

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Table 17: Problems with the Way U.S. Veterinary Drug Shortages are
Currently Managed
Please indicate what you think are the top three problems with the way U.S. veterinary
drug shortages are managed currently. (Please drag and drop up to three in order of
importance) (N=73 responses from 25 participants)
Rank Position
#1 #2 #3
Weight 5 3 1
Weighted
Average
Top Three Problems
Based on Weighted
Average
FDA-CVM acts only after confirming a
shortage exists, the drug is medically necessary,
and no other suitable alternative exists
7 5 2 2.4 1
Reporting veterinary drug shortages to FDA-
CVM is voluntary
6 8 5 2.1 2
FDA-CVM accepts compounded drugs as
suitable alternatives to FDA-approved drugs
experiencing shortages
3 4 8 2.0 3
Companies do not have adequate redundancy
risk management plans to prevent veterinary
drug shortages
1 1 3 1.4
Other (see Table 18) 7 4 2 0.7
Companies have inadequate quality systems to
prevent veterinary drug shortages
1 3 3 0.4
Table 18: Other Comments about the Way Veterinary Drug Shortages are
Handled
“Processes and timelines are too long”
“Lack of communication and sharing of forecasted shortages between industry and FDA-CVM, and
taking counter actions to avoid imminent shortages”
“FDA CVM is not open and transparent when reaching out to other potential manufacturers to alleviate a
drug shortage”
“Currently there seems to no defined process at CVM to support 21CFR514.8(b)(2)(iv) (which is also
mentioned in GFI 83).”
“CVM/FDA has allowed illegal pharmacy compounders to devalue the animal drug markets and usurp the
business from cGMP compliant manufacturers of FDA approved API and FDF products, which has
effectively removed and/or eliminated redundancy amongst FDA approved product manufacturers.”
“CVM wants to see customer complaints of shortages then CVM complains when we inform our
customers where to voice their concerns.”
“Based on CVM's approach to suitable alternatives, a company is forced to register alternate sites for key
APIs/excipients which can be costly and not necessarily guarantee same quality of product.”

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4.6 Advanced Notice of U.S. Veterinary Drug Shortages and Failure to Report
Manufacturers of human drugs are required by the FD&C Act to report shortages
of medically necessary medicines six months in advance or as soon as possible. The
survey participants were asked if they thought that the FD&C Act should be amended to
require manufacturers of veterinary drugs to report to FDA shortages of medically
necessary veterinary drugs in the same way. The majority (63%, 45/71) responded “yes”,
30% (21/71) responded “no”, and 7% (5/71) responded “I do not know.” (not illustrated).
A cross tabulation to evaluate the views of the respondents in different job roles about
having a requirement to report shortages of medically necessary veterinary drugs in
advance was performed, and the results are summarized in Appendix F. The results show
the response from all job roles were generally in favor of this requirement.
The survey participants were then asked what they thought would be the effects of
such a law (Figure 28). When asked if the effect would be minimal because medically
necessary veterinary drugs are infrequently in short supply, about a quarter of participants
(27%, 19/71) agreed, 19% (13/71) neither agreed nor disagreed, under half of participants
(44%, 31/71) disagreed, and 10% (7/71) did not know. When asked if reporting would be
a significant burden on industry, 30% (21/71) agreed, 24% (17/71) neither agreed nor
disagreed, 41% (29/71) disagreed, and 6% (4/71) did not know. When asked if reporting
would allow FDA-CVM to mitigate/prevent veterinary drug shortages more effectively,
more than half (65%, 46/71) agreed, 11% (8/71) neither agreed nor disagreed, 20%
(14/71) disagreed, and 4% (3/71) did not know. When asked if reporting would cause
FDA-CVM resources to be diverted from other important activities such as approving
new applications, 18% (13/71) agreed, a third (32%, 23/71) neither agreed nor disagreed,

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about a third disagreed (34%, 24/71), and 15% (11/71) did not know. When asked if
reporting would allow FDA-CVM to track and trend veterinary drug shortages more
effectively, over three quarters (77%, 54/71) agreed, 10% (7/71) neither agreed nor
disagreed, 10% (7/71) disagreed, and 3% (2/71) did not know. Examples of other
comments provided by the survey respondents about reporting veterinary drug shortage
reporting are provided in Table 19, and the complete list of comments is in Appendix A.
Figure 28: Effects of a Requirement to Report U.S. Veterinary Drug Shortages
Some have suggested the need for a new law that requires companies to report shortages
of medically necessary veterinary drugs. If such a law were to be passed, what do you
think would be its effects? (N=71 responses)

There would be minimal effect because few veterinary drugs are medically necessary.

Reporting would be a significant burden on industry.

FDA-CVM could more effectively prevent/mitigate veterinary drug shortages.

FDA-CVM resources would be diverted from other important work (e.g., approving new
applications).

FDA-CVM could track and trend veterinary drug shortages more effectively.

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Table 19: Participant Comments on Reporting Veterinary Drug Shortages
Please provide any comments you have about extending the reporting requirements for
drug shortages to veterinary drugs. See Appendix A for the full list of comments.
Examples of Comments for Extending the Reporting Requirements
“Better ensures the obligation a company and the FDA--CVM has to the welfare and health care of
animals, and in turn to pet parents and veterinarians for medically important drugs.”
“It would give generic companies more information to target needed generic products. Some companies
may not consider shortages important if the sales $$ are not high enough.”
“The idea is sound provided the FDA / CVM will do something with the data and not just make it an
exercise in bookkeeping. IF CVM has the headcount and resources to expedite the approval of api, and
to rapidly respond when inspections / approvals are needed, this will be an effective strategy”
Examples of Comments against Extending the Reporting Requirements
“Since Veterinarians have the broadest prescription authority of any health professional in the US, this is
a non-issue as they can substitute very easily.”
“Unless the sponsor is the only provider of a given medically necessary drug, it would not benefit the
industry or the customers to require shortage reporting. It is generally advantageous to report shortages
or potential shortages to the CVM as soon as possible to develop mitigation strategies. If a company
chooses not to act on a shortage, then that is a business decision. Again, unless the sponsor is the sole
provider then the impact to animals and to the public is not significant.”
“Vet drug manufacturing will have greater burden unless FDA agree with EU and other regulatory
bodies around the Globe to Unify. Is imp to ensure that smaller companies can follow requirements as
well......Lower cost of goods are critical”
Examples of Comments neither for nor against Extending the Reporting Requirements
“Reporting is only useful if FDA then actually acts on the information. There is potential for the
assessment of potential future drug shortages to be a subjective assessment. It's not always black and
white. Also, very few animal drugs are granted medically necessary veterinary product status.”
“There should be clear definitions around MNVP and how to assess the potential impact on the food
chain. It would be helpful to have criteria, decision tree/risk assessment to help sponsors to evaluate the
need to report and a reasonable time for reporting from identifying the potential risk until reporting is
needed. Otherwise, it will be a lot of noise and difficult to select what is a real issue or not. The French
authority requires reporting such shortages and they have provided guidelines for the Marketing
authorization holders to perform a risk assessment to help them decide if a notification is required or not
so the authority is not overwhelmed and the sponsors do not have the burden to report any minor issue,
but only the critical ones.”
“The issue arises if we are looking for Potential Shortages or ACTUAL confirmed shortages. Would
need to be "confirmed" shortages as potential happens often and is difficult to judge. Ie confirmed it will
happen in the future. not wait until happens. even then it is a difficult topic to predict in a global
company.”

The FD&C Act requires FDA to issue letters to manufacturers that fail to report
shortages of medically necessary human drugs in advance. FDA is required to redact the
letter to remove confidential information and make it public on the FDA website unless
the manufacturer can prove there is an error or reasonable basis for not reporting. The

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survey participants were asked if they thought that this type of enforcement requirement
would be important if there were to be a requirement to report shortages of veterinary
drugs. About half (54%, 38/71) responded “yes”, 34% (24/71) responded “no”, and 13%
(9/71) responded “I am not sure” (not illustrated). A cross tabulation to evaluate the
views of the respondents in different job roles about having a requirement to enforce
reporting of shortages of medically necessary veterinary drugs in advance was performed,
and the results are summarized in Appendix F. The results show all job roles were in
favor or neutral with respect to this requirement.
The survey participants were asked how strongly they agreed or disagreed with
four statements related to that type of enforcement (Figure 29). Just under a half (44%,
32/72) agreed with the statement, “Industry is unlikely to report without some type of
enforcement”, 22% (16/72) neither agreed nor disagreed, 28% (20/72) disagreed, and 6%
(4/72) were not sure. Over a third of participants (38%, 27/72) agreed with the statement,
“FDA-CVM should not enforce reporting of veterinary drug shortages”, 24% (17/72)
neither agreed nor disagreed, 35% (25/72) disagreed, and 4% (3/72) were not sure. More
than half (54%, 39/72) agreed with the statement, “Publicizing failure to report is too
extreme as an enforcement mechanism”, 26% (19/72) neither agreed nor disagreed, 13%
(9/72) disagreed, and 7% (5/72) were not sure. A majority (64%, 46/72) agreed with the
statement, “Other enforcement approaches should be considered.”, 22% (16/72) neither
agreed nor disagreed, 7% (5/72) disagreed, and 7% (5/72) were not sure. Examples of
other comments by the survey respondents about the enforcement of veterinary drug
shortages were sorted by whether or not they supported enforcement actions in Table 20.
The complete list of comments is provided in Appendix B.

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Figure 29: Participant Views on Enforcement of a Reporting Requirement
Please indicate your level of agreement with the following statements related to FDA
enforcement of industry reporting of shortages of medically necessary veterinary drugs:
(N=72)
Industry is unlikely to report without some type of enforcement.

FDA-CVM should not enforce reporting of veterinary drug shortages.

Publicizing failure to report is too extreme as an enforcement mechanism.

Other enforcement approaches should be considered.

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Table 20: Examples of Comments from Participants about Enforcement of
Reporting
Please provide any comments you have about extending the requirement for FDA to
enforce drug shortage reporting requirements to veterinary drugs. See Appendix B for
the complete list of comments. (N=18)

Comments For Enforcement of Reporting
“In line with previous comment, FDA could use some sort of incentive to report shortages.”
“It could be a staggered approach, with enforcement slowly becoming stricter to give stakeholders time
to address conflicts which will arise from these exercises.”
“Requirement cannot be Optional as companies will not report - Easy Direct reporting helps”
“I don't think public release of failure to comply should be the first enforcement step. Compliance
enforcement should be tiered with public notification being reserved for the most egregious, repeat
offenders.”
“I am a fan of positive reinforcement and not punishment. If FDA can show that reporting benefits the
health of animals by providing a short track to alternative options, every company is going to report.”
Comments Against Enforcement of Reporting
“Enforcement without facilitating minimizing the conditions that lead to the shortage is not responsible
or helpful”
“It is important to manage the public opinion - FDA does not have a very good track record to not blame
the manufacturer, on the contrary. If such reporting becomes mandatory and public, this will create a
blaming environment that would not help the manufacturer to focus on fixing the problem, but will
waste their time and energy to manage public opinion and law enforcers. Especially that it is first made
public and only afterwards the sponsor or the manufacturer have the opportunity to correct - so it means
that there is a risk that something damaging and untrue is first published on the FDA website and by the
time the statement is corrected, the company’s reputation is already damaged.”
“FDA issued letters are of little consequence and have little meaning to practitioners and consumers.”
“Companies should be obligated to inform the veterinary community about shortages, and actions being
taken to fairly distribute available product. Likewise, the FDA-CVM should be informed to create a
collaboration with the company on how to jointly manage the shortage, and determine how, if at all, the
regulatory body can assist in the solution. Companies do not need to be shamed on a website. Customers
will hold them very accountable.”
“CVM ineffectively manages voluntarily reported shortages. I would worry about their ability to address
a greater number of reported shortages.”
“At some point this would require more work for FDA, which means more FTEs which at some time
would likely be pushed to the industry as ADUFA fees.”
4.7 Publicly Available List of Veterinary Drug Shortages
To assess the importance of a publicly available list of veterinary drug shortages,
survey participants were asked to rank the various veterinary stakeholders from one to
seven according to their level of need for such a public list (Table 21). The responses
were weighted according to rank position from one to seven, and the weighted averages

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were determined using the number of respondents as the denominator (N=66).
Participants most commonly ranked veterinarians and their staff (weighted average, 1.5)
as having the greatest need for a public list of veterinary drug shortages. Animal
producers were more frequently ranked as second and distributors as third. The majority
of respondents (weighted average, 6.8) ranked the category “other” as least likely to need
a public list. However, three survey respondents did identify three other stakeholders,
which are listed in Table 22.
Table 21: Survey Participants Ranking of Veterinary Stakeholders in Need of a
Public List
The FD&C Act requires FDA to distribute information about medically
necessary human drug shortages to physicians, health providers, and patient
organizations. To fulfill this requirement, FDA posts the name of the drug, name of each
manufacturer involved with the drug, the reason for the shortage, and the estimated
duration of the shortage publicly on its website and mobile device app.

Please rank the following veterinary stakeholders in the order of which may need a
public list of veterinary drug shortages. The stakeholder that needs it most should be at
the top. (Drag and drop) (N=66)

# of Responses in Each Position

#1 #2 #3 #4 #5 #6 #7
Weighted
Average
Rank based on
Weighted
Average
Weight 1 2 3 4 5 6 7

Veterinarians and their staff
45 10 10 1 0 0 0
1.5
1
Animal Producers
1 27 16 17 4 1 0
3.0
2
Distributors
7 14 18 12 9 6 0
3.3
3
Drug Manufacturers
11 11 13 11 6 14 0
3.5
4
Pet Owners
1 3 8 14 27 10 3
4.6
5
Animal Shelters
0 1 1 10 20 34 0
5.3
6
Other (Table 22)
1 0 0 1 0 1 63
6.8
7

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Table 22: Other Veterinary Stakeholders in Need of a Public List
“drug substance manufacturer”
“pharmacy”
“USDA and Extension Agents”

The survey participants were asked if having a public list of medically necessary
veterinary drug shortages is important. A majority (80%, 55/69) indicated “yes”, 14%
(10/69) indicated “no”, and 6% (4/69) indicated “I do not know” (not illustrated). A
cross tabulation to evaluate the views of the respondents in different job roles about
having a requirement for a public list of shortages of medically necessary veterinary
drugs was performed, and the results are summarized in Appendix E. The results show
all job roles were generally in favor of this requirement.
The participants were asked to select the top three reasons for having a public list
of veterinary drug shortages. The number of responses in positions one, two, or three
were tabulated and weighted five, three, and one, respectively. The weighted average was
determined for each reason. The most frequently selected top reason was “a central
source of information” (weighted average, 3.6). “Helps stakeholders make decisions”
(weighted average, 2.5) and “manufacturers may not communicate” (weighted average,
1.4) were the second and third most frequently selected top reasons by the participants
(Table 23).

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Table 23: Top Reasons for Having a Public List of Veterinary Drug Shortages
Please drag and drop the top three reasons you think there should be a public list of U.S.
medically necessary veterinary drug shortages. (N=189 responses from 63 participants)

# of Responses in
Each Position Weighted
Average
Top
Three
Reasons
for a List
#1 #2 #3
Weight 5 3 1
Central Source of Information 32 17 13 3.6 1
Helps Stakeholders make decisions 15 23 15 2.5 2
Manufacturers may not communicate 7 11 19 1.4 3
Stakeholders know when there are shortages 5 7 4 0.8
Manufacturers can report directly 2 2 0 0.3
Leads to hoarding/price spikes 2 1 1 0.2
Affects a manufacturer's reputation 0 0 3 0.0
Other (see Table 25) 0 1 0 0.0
List potentially interferes with market competition 0 0 0 0.0

The participants were asked to select the top three reasons for not having a public
list of veterinary drug shortages (Table 24). The number of responses in positions 1, 2, or
three were tabulated and weighted 5, 3, and 1, respectively. The weighted average was
determined for each reason. The most frequently selected top reason was “leads to
hoarding and price spikes” (weighted average, 2.9). The “list potentially interferes with
market competition” (weighted average, 2.1) was the second most frequently selected top
reason, and “manufacturers can report directly” (weighted average, 1.3), and “affects a
manufacturers reputation” (weighted average, 1.3) were tied for third. Other reasons
provided by participants are summarized in Table 25.

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Table 24: Top Reasons for Not Having a Public List of Veterinary Drug
Shortages
Please drag and drop the top three reasons you think there should NOT be a public list of
U.S. medically necessary veterinary drug shortages. (N=168 responses from 58
participants)

# of Responses in
Each Position
Weighted
Average
Top
three
Reasons
for No
List
#1 #2 #3
Weight 5 3 1
Leads to hoarding/price spikes
24 13 10 2.9
1
List potentially interferes with market competition
10 19 12 2.1
2
Manufacturers can report directly
10 5 11 1.3
3
Affects a manufacturer's reputation
7 11 10 1.3
3
Stakeholders know when there are shortages
5 4 3 0.7

Other (see Table 25)
1 1 1 0.2

Manufacturers may not communicate
1 1 0 0.1

Central Source of Information
0 0 0 0.0

Helps Stakeholders make decisions
0 0 0 0.0

Table 25: Other Reasons for Having or Not Having a Public List
(1) “Improper use if information not resulting in the best interest of the veterinarian/pet
owner/producer.”
(2) “Potential inaccuracies in reporting and keeping updated information, hence
misinforming the public/stakeholders.”
“The added bureaucracy is not outweighed by appropriate benefits”
“Difficulty to enforce fairly across manufacturers”
“Stakeholders know more in advance that there will be a shortage”
4.8 Expedited Inspections and Submission Reviews
The survey participants were asked whether FDA-CVM should be required to
prioritize and expedite the review of regulatory submissions and establishment
inspections associated with medically necessary veterinary drugs, as is done for
medically necessary human drugs. The majority, 87% (61/70), responded “yes”, and 13%
(9/70) responded “no” (not illustrated). A cross tabulation to evaluate the views of the
respondents in different job roles about having a requirement to expedite submission

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reviews and inspections associated with shortages of medically necessary veterinary
drugs was performed, and the results are summarized in Appendix F. The results show
all job roles were generally in favor of this requirement.
Participants were then asked what they thought would happen if this new
requirement were to be introduced (Figure 30). A majority (60%, 43/70) thought that the
number of veterinary drug shortages would decrease, but 17% (12/70) neither agreed nor
disagreed, 14% (10/70) disagreed, and 7% (5/70) did not know. Only 9% (6/70) thought
expediting inspections and submission reviews would damage market competition, 27%
(19/70) neither agreed nor disagreed, 54% (38/70) disagreed, and 10% (7/70) did not
know. A few respondents (10%, 7/70) thought that expediting submission reviews and
inspections would increase the number of quality or safety issues, whereas 21% (15/70)
neither agreed nor disagreed, 64% (45/70) disagreed, and 4% (3/70) did not know. Just
over half of the respondents (51%, 36/70) thought that expediting submission reviews
and inspections would impact other regulatory submissions, 23% (16/70) neither agreed
nor disagreed, 17% (12/70) disagreed, and 9% (6/70) did not know. Examples of
comments related to expediting inspections and submission reviews for veterinary drug
shortages are summarized in Table 26, and the complete list of comments is in Appendix
C.

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Figure 30: Consequences of a Requirement to Expedite Inspections and Reviews
What do you think would happen if a new requirement were introduced that required
FDA-CVM to prioritize and expedite submissions and associated establishment
inspections for medically necessary veterinary drugs in a shortage situation? (N=70)

The number or duration of veterinary drug shortages would decrease.

The change would damage market competition.

Quality, safety, and/or effectiveness issues would increase.

This would impact the review and approval of other types of important regulatory
submissions.

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Table 26: Comments about Prioritizing and Expediting Submission and
Inspections
Please provide any comments you have about extending the requirement for FDA to
prioritize and expedite regulatory submissions and associated inspections related to
medically necessary veterinary drug shortages. Representative comments are provided.
The complete list of comments is provided in Appendix C.
Comments For
“It worked for Covid vaccines.”
“This makes perfect sense if in fact these drugs are medically necessary. FDA
should be solution-oriented based on providing the best care and welfare of
animals, and in turn, their owners.”
“This may be an incentive for manufacturers to report shortages.”
“If a compound is truly medically necessary. it is for the good of the nation that
we prioritize the said drugs and we do not want those to be in shortage.”
Comments Neither for nor against
“FDA reviews should in general be faster. 30 days for simple, 90 for more
complex changes for the full process should be plenty of time.”
“In regards to "Quality, safety, and/or effectiveness issues would increase.", I
believe it all depends on what would be the minimum requirements by the
agency for the "expedited approval" of such drugs. E.g.: full safety profile, but
sufficient basis for effectiveness, etc. In regards to "This would impact the
review and approval of other types of important regulatory submissions.", I
believe it depends on the resources of the agency plus how many shortages the
industry faces in average each year. It may consume resources and impact
regular processes, or it may not.”
“Shortage list is useful. CVM needs to have flexibility in prioritizing their own
processes.”
Comments Against
“This will divert resources from approving new animal drugs and supplements.
CVM does not have the resources like CDER/CBER do.”
“CVM is already understaffed and far behind schedule with current
responsibilities. IF this is enacted, it would necessitate larger staffs and shorter
turn-around times”
“While it is necessary to implement prioritization, the limited FDA resources
would inevitably impact review of other submissions. The anticipated impact
would be an increased number of incomplete letters for the non-prioritized
submissions as FDA would not have enough time to review them. I would rather
the FDA extend the review period of a submission impacted in the queue by a
prioritized submission by a couple months intending to achieve a full review and
submission approval.”

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4.9 Risk Management Plans and Tools
The participants were asked if they thought that manufacturers of medically
necessary veterinary drugs should be required to have redundancy risk management plans
that identify and assess risks to the supply of the drug for each establishment in which it
is manufactured, and which are subject to FDA-CVM review (Figure 31). Less than a
quarter (23%, 16/69) responded “yes”, over half (59%, 41/69) responded “no”, and 17%,
(12/69) did not know.
Figure 31: Requirement for Risk Management Plans
The FD&C Act requires manufacturers of medically necessary human drugs to maintain
and implement, as appropriate, a redundancy risk management plan that identifies and
assesses risks to the supply of the drug for each establishment in which it is
manufactured. These risk management plans are subject to FDA review. Do you think
that manufacturers of medically necessary veterinary drugs should be required to have
redundancy risk management plans that are subject to FDA-CVM review? (N=69)

A cross tabulation was performed to evaluate the views of the respondents in
different job roles about having a requirement to have redundancy risk management plans
for medically necessary veterinary drugs, and the results are summarized in Appendix F.
Over half, 60% (3/5), of respondents whose job roles were in Technical Operations
thought that redundancy risk management plans should be required, 20% (1/5) did not
think risk management plans should be required, and 20% (1/5) were unsure. In contrast,
respondents in other job roles were either neutral or not in favor having a requirement for
risk management plans.

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The participants were asked to select the top three reasons for having risk
management plans for medically necessary veterinary drugs (Table 27). The number of
responses in positions one, two, or three were tabulated and weighted five, three, and one,
respectively and the weighted average was determined for each reason. The most
frequently selected top reason was “the number or duration of veterinary drug shortages
would decrease” (weighted average, 3.3). The “impact of veterinary drug shortages on
the reputation of manufacturers would decrease” (weighted average, 1.5) was the second
most frequently selected top reason, and “the financial impact of veterinary drug
shortages on manufacturers would decrease” (weighted average, 1.3) was third. Other
reasons provided by participants are summarized in Table 29, and additional comments
about risk management plans are provided in Table 30.
Table 27: Top Reasons for Having Risk Management Plans
Please drag and drop the top three reasons you think a requirement for manufacturers of
medically necessary veterinary drugs to have redundancy risk management plans would
be important. (N=123 responses from 46 participants)

# of Responses in
Each Position Weighted
Average
Top
Three
Reasons
for a List
#1 #2 #3
Weight 5 3 1
The number or duration of veterinary drug shortages would
decrease
26 5 7 3.3 1
The impact of veterinary drug shortages on the reputation of
manufacturers would decrease
4 12 15 1.5 2
The financial impact of veterinary drug shortages on
manufacturers would decrease
4 13 2 1.3 3
Quality, safety, and/or effectiveness of veterinary drugs would
increase
5 4 8 1.0
Time and resources spent by industry would increase 2 3 2 0.5
Manufacturers may choose to discontinue medically necessary
veterinary products
2 2 1 0.4
The cost of veterinary drugs would increase 3 0 1 0.3
Other (Table 29) 0 2 0 0.1
Survey participants were asked to select the top three reasons for not having risk
management plans (Table 28). The number of responses in positions one, two, or three

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were tabulated and weighted 5, 3, and 1, respectively, and the weighted average was
determined for each reason. The most frequently selected top reason was “Manufacturers
may choose to discontinue medically necessary veterinary products” (weighted average,
2.8). The “cost of veterinary drugs would increase” (weighted average, 2.6) was the
second most frequently selected top reason, and “time and resources spent by industry
would increase” (weighted average, 2.4) was third. Other reasons provided by
participants are summarized in Table 29, and additional comments about risk
management plans are provided in Table 30.
Table 28: Top Reasons for Not Having Risk Management Plans
Please drag and drop the top three reasons you think a requirement for manufacturers of
medically necessary veterinary drugs to have redundancy risk management plans is NOT
important. (N=146 responses from 57 participants)

# of Responses in
Each Position
Weighted
Average
Top
Three
Reasons
for No
List
#1 #2 #3
Weight 5 3 1
Manufacturers may choose to discontinue medically
necessary veterinary products
18 21 6 2.8 1
The cost of veterinary drugs would increase 21 11 12 2.6 2
Time and resources spent by industry would increase 16 14 17 2.4 3
Quality, safety, and/or effectiveness of veterinary drugs
would increase
0 2 2 0.1
The impact of veterinary drug shortages on the reputation
of manufacturers would decrease
1 0 1 0.1
The number or duration of veterinary drug shortages
would decrease
1 0 0 0.1
Other (see Table 29) 0 0 2 0.0
The financial impact of veterinary drug shortages on
manufacturers would decrease
0 0 1 0.0

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Table 29: Other Reasons to Have or Not Have Risk Management Plans
For Risk Mitigation Plans
“If a plan was preapproved by the CVM, it could be quickly implemented in the event of a shortage.
This would diminish time to resolve the issue and decrease the initial drain on CVM resources.”
“It would also be in the best interest of the company to have contingency plans for such products in the
event of a shortage. i.e., the time and resources spent in finding solutions once the shortage is already
established would be reduced.”
Against Risk Management Plans
“Redundancy plans without a commitment for sales is risky. It is an open market today and redundancy
is a company choice.”
“The plans may not be able to manage all the issues outside the control of the company or predict
unforeseen occurrences.”

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Table 30: Other Comments about Extending the Risk Management Plan
Requirement
Please provide any comments you have about extending the requirement to have
redundancy risk management plans to medically necessary veterinary drug
manufacturers. (N=14) Representative comments are provided in this table. The
complete list of comments is provided in Appendix D.
For Voluntary Risk Management Plans
“I believe this should be part of the manufacturers responsibility to maintain their supply chain; it’s just
smart business. It should be driven by increased regulatory burden.”
“I consider that having redundancy risk management plans can be in the best interest of a company,
however, I am not entirely sure if being enforced under mandatory requirement by the agency is the best
route or not.”
“I see both positive and negative. I think that there should be risk mitigation plans/redundancy,
however, this will have a significant financial impact, especially on small manufacturers. So, if a
veterinary product is identified as MNVP, there should be some support from government for the
manufacturer – and this may create an unfair competition. In addition, it is not clear what FDA would
review in such plans – that has to be defined as such plans contain a lot of confidential and financial
information that should not be subject of this review. So, it is complex. My tendency is to increase the
collaboration between the agency and industry to work on such plans more on a voluntary basis and not
to enforce as this may have a devastating impact especially on smaller manufacturers.”
For Extending Requirements for Risk Management Plans
“Such a requirement does require sponsors to consider implications of shortages prior to occurrence and
perhaps implement more robust preventive measures.”
Against Extending the Requirements for Risk Management Plans
“Medically necessary products are often niche products. Their manufacture should not be made even
less attractive by adding more bureaucracy.”
“More regulation means less market entries and higher prices for the market leading companies.”
“The plans may be too burdensome in time and resources to be practical. All reasonable quality control
measures based on risk and return will normally be taken by companies. It’s in their best interests to set
up best practices that can keep their operations running smoothly without downtime or shortages.”
Neither For nor Against Extending the Requirements for Risk Management Plans
“Companies do not prioritize this. They often have one manufacturer for a drug substance, excipients,
tubing, etc. When problems arise, it’s too late for them to pivot.”
“The issue here is about national security. Currently there, as I understand it, are no means to support
the additional costs of redundancy plans, thus in a low-cost environment of Animal Health, having
strong redundancy plans can increase cost. Note that the key is to have a mechanism to qualify a backup
supplier, avoid regulatory hurdles, and ensure that the supplier is ready to produce. However, for API
production, it often cannot be started fast enough, even if they are approved because API production
times are long lead time. So, there is an issue here, the key is to have enough volume to justify back up
suppliers or hold lots of stock which does increase costs and often can expire, there are many factors that
need to be managed to get it right.”

The survey participants were asked if they had taken advantage of the PDA
Technical Report No. 68 Risk Based Approach to the Prevention and Management of

115
Veterinary Drug Shortages or the ISPE Drug Shortage Assessment and Prevention Tool
(Figure 32). Only 7% (5/69) of the participants had used the PDA tool, 70% (48/69) had
not used the PDA tool, and 23% (16/69) did not know. Only 3% (2/69) had used the
ISPE tool, 75% (52/69) had not used the ISPE tool, and 22% (15/69) did not know.
Figure 32: Use of Available Tools by Respondents to Avoid Veterinary Drug
Shortages
Have you taken advantage of either of the following tools over the past five years to
avoid veterinary drug shortages? (N=69)

To assess the most important aspects of the PDA Technical Report No. 68, Risk
Based Approach for the Prevention and Management of Drug Shortages, with respect to
U.S. veterinary drug shortages, survey participants were asked to rank the various
prevention-response characteristics in terms of importance for preventing veterinary drug
shortages as either “very important” (weight 5), “somewhat important” (weight 3), or
“not important” (weight 1) (Table 31). Those that responded “I do not know” were not
considered in the calculation. Participants most commonly ranked global supply chain
strategy planning (weighted average, 4.5) as most important, followed by capacity
planning (weighted average, 4.4), regulatory strategies to gain expedited reviews from

116
relevant health authorities for any changes in marketing applications (weighted average,
4.4), and building safety stock (weighted average, 4.2). Understanding the availability of
alternative medicines in the marketplace appeared less important to the participants
(weighted average, 3.5).
Table 31: Views on the Most Important Components of the PDA Risk Tool
The PDA Technical Report No. 68, A Risk Based Approach for the Prevention and
Management of Drug Shortages, includes a risk register and a prevention-response
plan. If you were to use this tool, please rank the prevention-response components of this
approach in terms of the importance of preventing and managing your veterinary drug
shortages. (N=68)

Very
Important
Somewhat
Important
Not
Important
N
Weighted
Average
Weight 5 3 1

Global Supply Chain Strategy
Planning
50 16 0 66 4.5
Capacity Planning 45 20 0 65 4.4
Regulatory Strategies to Gain
Expedited Reviews from Relevant
Health Authorities for any Changes in
Marketing Applications
44 18 1 63 4.4
Building Safety Stock 45 17 4 66 4.2
Understanding Availability of
Alternative Medicines in the
Marketplace
23 32 7 62 3.5
To understand which strategies described in the ISPE Drug Shortage Assessment
and Prevention Tool would most likely be used by participants to address their drug
shortages, the participants were asked to rank the ISPE strategies from one to six based
on their likelihood to use (Table 32). The responses were weighted according to rank
position from one to six, and the weighted averages were determined. Participants most
frequently ranked business continuity (weighted average, 2.9) as the most important
strategy to prevent veterinary drug shortages. Having a robust quality system (weighted
average, 3.2) was most frequently ranked second, and building capabilities (weighted
average, 3.3) ranked third. The majority of respondents (weighted average, 4.4) ranked

117
the metrics as the least likely strategy they would employ. Other comments from the
survey participants about tools or programs to prevent and manage veterinary drug
shortages are presented in Table 33.
Table 32: Participants Views of the Most Important Aspects of the ISPE Tool
The ISPE Drug Shortage Assessment and Prevention Tool includes strategies for six
aspects related to drug shortages. Please rank the six aspects in the order you would use
them to address your veterinary drug shortage issues (1=first, 6=last).

Rank

#1 #2 #3 #4 #5 #6

Weight 1 2 3 4 5 6 N Weighted Average
Business Continuity Planning 15 14 11 12 7 3 62 2.9
Robust Quality System 10 10 13 17 11 1 62 3.2
Building Capabilities 16 12 7 5 8 14 62 3.3
Corporate Quality Culture 10 12 6 15 9 10 62 3.5
Communications with Authorities 9 7 14 7 12 13 62 3.7
Metrics 2 7 11 6 15 21 62 4.4

Table 33: Participant Comments About Other Tools or Programs
Please provide any comments you have about tools or programs aimed at preventing and
managing veterinary drug shortages.
“API availability and review times at FDA have been the primary reasons for delays – therefore the
safety stock building seems to be the only attractive measure in the list as well as transparency to FDA
about the situation and the need for faster reviews.”
“I ranked Corporate Quality Culture last because if you do not have this as a fundamental part of any
product there will be issues impacting many aspects of product manufacturing and distribution that
would not rise to the level of a shortage. Hopefully FDA takes action on these kinds of organizations
prior to this aspect leading to a shortage scenario.”
“Monitoring changes in market conditions for the products to understand impacts on product demand.”
4.10 Quality Metrics
Quality Metrics is a voluntary program in which manufacturers of human drugs
are encouraged to report certain quality-related metrics to the FDA. FDA uses the data to
conduct risk-based inspections and to predict and mitigate drug shortages. FDA rewards
manufacturers publicly on their website if they participate. The survey participants were

118
asked if they thought FDA-CVM should have a similar initiative for veterinary drugs.
Over one-third (37%, 25/68) responded “yes”, 43% (29/68) responded “no”, and 21%
(14/68) were unsure (not illustrated). Participants were then asked what they thought
would happen if this new initiative were to be introduced for veterinary drugs
(Figure 33). Just over 10% (13%, 9/67) thought that the number of veterinary drug
shortages would decrease, 42% (28/67) neither agreed nor disagreed, 33% (22/67)
disagreed, and 12% (8/67) did not know. One third (34%, 23/67) thought that the number
of FDA inspections would increase, 27% (18/67) neither agreed nor disagreed, 25%
(17/67) disagreed, and 13% (9/67) did not know. Two thirds of respondents (66%,
44/67) thought the extra reporting would require significant effort by the industry,
whereas 18% (12/67) neither agreed nor disagreed, 12% (8/67) disagreed, and 4% (3/67)
did not know. Similarly, almost two-thirds of the respondents (64%, 43/67) thought the
extra reporting would require significant effort by FDA-CVM, 16% (11/67) neither
agreed nor disagreed, 12% (8/67) disagreed, and 7% (5/67) did not know. Just over half
of respondents (55%, 37/67) thought industry was unlikely to share this information with
FDA-CVM, 25% (12/67) neither agreed nor disagreed, 12% (8/67) disagreed, and 7%
(3/67) did not know. Almost two-thirds of respondents (64%, 37/67) thought that the
value of the reward was not apparent, 18% (12/67) neither agreed nor disagreed, 13%
(9/67) disagreed, and 4% (3/67) did not know. Examples of comments related to
introducing an initiative to report Quality Metrics to FDA-CVM for veterinary drugs are
summarized in Table 34, and the complete list of comments is in Appendix D.

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Figure 33: Respondents Views on the Effects of a Quality Metrics Initiative
What do you think would be the effect of a new initiative where manufacturers
voluntarily report quality metrics to FDA-CVM? (N=67)

The number or duration of veterinary drug shortages would decrease.

The number of FDA inspections would increase.

This extra reporting would require significant effort by industry.

The extra reporting would require significant effort by FDA-CVM.

Industry is unlikely voluntarily share this type of information with FDA-CVM.

The value of the reward is not apparent.

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Table 34: Comments from Participants about Introducing a Quality Metrics
Initiative
Please provide any comments you have about introducing an initiative to report Quality
Metrics to FDA-CVM for veterinary drugs. (N=10) Representative comments are
provided and the complete set of comments is provided in Appendix D.
For a Quality Metrics Initiative
“I think that such initiative would help in prioritizing inspections and making transparent the rational for
the next inspection. There is of course a time needed to build trust and to validate that those metrics
reflect the true quality system at the site, so it may be an initial increase in FDA inspections in the
beginning to validate those metrics, afterwards this should help building trust with the agency and also it
will help the agency to better manage the budget and prioritize the inspections, whilst ensuring that
quality does not decrease. There should be maybe some other checks and controls in place to ensure that
the metrics are not reflective of the real risk - as a Quality professional I fully understand that it is not
possible just to trust metrics, there should be an inspection plan or on spot checks to confirm that the site
is trustworthy. This can be built as this is a usual life of any Quality Assurance unit.”
Against a Quality Metrics Initiative
“If this is voluntary then the only organizations that would participate are those without issues and
sufficient resources to generate these data. Under those circumstances the initiative does not achieve the
presumed desired outcome of attempting to identify poor performing manufacturing sites. Even if a site
has good metric outcomes, there is no obvious benefit to provide these data as it does appear it places
you an increased chance of inspection.”
“It appears to be over regulation. Manufacturers already follow approved specs for quality production.
These must be followed, and are looked at in FDA inspections. Adverse event reporting is already in
place as a monitor on quality.”
“This issue is already addressed by the Annual Quality Review for each Product.”
“I would want to understand how reporting on metrics of production are in scope for the Government for
reporting? this means the CVM is getting into the supplier management business. is this what we want?
Of course, ensuring low defect rate is important just like any manufacturing metric, and companies
should be doing this anyways, but reporting manufacturing capabilities to the CVM is likely out of
scope. perhaps ONLY for medically necessary if to be installed for national security reasons.”
Neither for Nor Against a Quality Metrics Initiative
“Because of its voluntary nature, I believe those with good metrics would report, and those would not
very good metrics may not. Hence, the "good" may be more visible, whereas the "bad" may not be
reported, which could result in an unbalanced overall analysis, hence most of my answers are "I do not
know".”
“Some of the metrics may be derived differently from one company to another, for instance some quality
groups are more conservative than others. Some groups are larger and have more resources to commit to
this effort than smaller ones.”
4.11 Compounding
Shortages of FDA-approved veterinary drugs are often addressed by replacing
them with products compounded from bulk drug substances that are not approved by
FDA. FDA-CVM uses enforcement discretion with these compounded products. FDA-

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CVM Draft guidance #256, Compounding Animal Drugs from Bulk Drug Substances,
outlines FDA's current thinking on this topic. Participants were asked what they thought
about compounding as a solution to veterinary drug shortages (Figure 34). Just over one-
fifth (22%, 15/68) thought that compounding products is a good way to solve the
veterinary drug shortage problem, 22% (15/68) neither agreed nor disagreed, 51%
(35/68) disagreed, and 4% (3/68) did not know. Almost half (49%, 33/67) agreed with the
use of products compounded from bulk drug substances as long as those products accord
with FDA-CVM guidance #256, 12% (8/67) neither agreed not disagreed, 37% (25/67)
disagreed, and 1% (1/67) did not know. A majority of respondents (88%, 59/67) thought
FDA-CVM should consider the risks versus benefits of the compounded drug when
expediting the options to restore an FDA-approved drug to the marketplace, whereas 3%
(2/67) neither agreed nor disagreed, and 9% (6/67) disagreed. Over three-quarters of the
respondents (76%, 51/67) thought compounded drugs expose the patient to potentially
serious health risks because compounded drugs do not have proven safety or
effectiveness and are not manufactured under cGMP, 16% (11/67) neither agreed nor
disagreed, 4% (3/67) disagreed, and 3% (2/67) did not know. Over half of respondents
(60%, 40/67) thought temporary use of compounded drugs, although risky, is necessary
at times when no alternatives exist, 18% (12/67) neither agreed nor disagreed, 18%
(12/67) disagreed, and 4% (3/67) did not know. Almost two-thirds of respondents (93%,
62/67) thought that compounding of a product should not be permitted once the FDA-
approved drug shortage is resolved because this undermines the FDA approval process,
3% (2/67) neither agreed nor disagreed, and 4% (3/67) disagreed. Other comments from

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the survey participants about the use of compounding to solve veterinary drug shortages
are provided in Table 35.
Figure 34: Industry Views on Compounding to Solve Veterinary Drug Shortages
Shortages of FDA-approved veterinary drugs are often addressed by products
compounded from bulk drug substances which are not approved by FDA. FDA-CVM
uses enforcement discretion with these compounded products. FDA-CVM Draft
guidance #256, Compounding Animal Drugs from Bulk Drug Substances, outlines FDA's
current thinking on this topic. What do you think about compounding as a solution to
shortages of U.S. veterinary drugs? (Select all that apply)

I think compounding products when there is a shortage is a good solution to the veterinary drug shortage
problem. (N=68)

I agree with the use of products compounded from bulk drug substances as long as those products accord
with FDA-CVM guidance #256 which requires, for example: use of only listed bulk substances, labeling,
adverse event reporting, and following USP standards. (N=67)

FDA-CVM should consider the risks versus benefits of the compounded drug when expediting the options
to restore an FDA-approved drug to the marketplace. (N=67)

Compounded drugs expose the patient to potentially serious health risks because compounded drugs do not
have proven safety or effectiveness and are not manufactured under cGMP. (N=67)

Temporary use of compounded drugs, although risky, is necessary at times when no alternatives exist.
(N=67)

Once the FDA-approved drug shortage is resolved, compounding of that product should not be permitted
because this undermines the FDA approval process. (N=67)

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Table 35: Other Comments about Using Compounding to Solve Veterinary
Drug Shortages
For Compounding to Solve Veterinary Drug Shortages:
“While I do not like compounding, sometimes it is the only option to treat gravely ill pets. I'd
like to see more regulation to make compounding safer”
Against Compounding to Solve Veterinary Drug Shortages:
“ALLOWING GMP PRODUCING COMPANIES TO QUICKLY USE ANOTHER GMP
PROVIDER IS A VERY QUICK WAY VERSUS TAKING RISKS ON UNKNOWN
QUALITYOF FORMULATIONS WITHOUT TESING.”
“CVM should work with the approved facility to "compound" their own unapproved version of
their drug until the shortage can be resolved.”
“Compounders need to assume the liability of their drug compounding products.”
“I feel very strongly that Regulatory Authorities don’t do nearly enough in this arena. Quality
pharmaceutical products will be discontinued in the future because of illegal competition from
compounders.”
“Illegal compounding of products similar, or identical to FDA approved products should be
eliminated because they are Illegal!”
4.12 Regulatory Policy Implications of New Regulations for Veterinary Drug
Shortages
Participants were asked if they thought that introducing new veterinary
regulations and initiatives similar to those for U.S. human drug shortages
would introduce new risks in terms of safety, effectiveness, or quality of veterinary drugs
(Figure 35). Less than one-tenth (7%, 5/68) thought that introducing new veterinary
regulations and initiatives to address veterinary drug shortages would introduce new risks
in terms of safety, 71% (48/68) disagreed, 3% (2/68) did not know, and 19% (13/68)
indicated maybe. Only 6% (4/68) thought that introducing new veterinary regulations and
initiatives would introduce new risks in terms of effectiveness, 72% (49/68) disagreed,
4% (3/68) did not know, and 18% (12/68) indicated maybe. Only 10% (7/68) thought
that introducing new veterinary regulations and initiatives would introduce new risks in
terms of quality, 65% (44/68) disagreed, 3% (2/67) did not know, and 22% (15/68)
indicated maybe.

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Figure 35: Views on Impact of Veterinary Drug Shortage Regulations
Do you think that introducing new veterinary regulations and initiatives similar to those
for U.S. human drug shortages, as discussed in this survey, would introduce new risks in
terms of safety, effectiveness, or quality of veterinary drugs? (N=68)

Safety

Effectiveness

Quality

The survey participants were asked if they thought that introducing new
veterinary regulations and initiatives like those for U.S. human drug shortages would
create unfairness in the marketplace. Over one-third (38%, 26/68) responded “yes”, 37%
(25/68) responded “no”, 16% (11/68) responded “I do not know”, and 9% (6/68) had
other comments which are presented in Table 36.

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Table 36: Comments about the Potential for Unfairness in the Marketplace
“Initially-yes; in the long run – no”
“It will be harder for small companies to comply.”
“Possibly”
“There needs to be a control by FDA to ensure some manufacturers/sponsors are not habitually
taking advantage of the proposed shortage guidance versus establish robust supply chain”
“UNFAIRNESS IN THE MARKET PLACE IS A POTENTIAL BUT THE FOCUS ON
MEDICALLY NECESSARY IS APPROPRIATE”
“Yes, greater burden for manufacturers, and especially for smaller companies.”
A cross tabulation was performed which compared the responses to the question, “Do you
think that introducing new veterinary drug shortage regulations would create unfairness in the
marketplace size?” with the size of the company at which they worked (Table 37). The
respondents who thought that new regulations would cause unfairness consisted of 10% (7/67)
from small businesses, 10% (7/67) from medium size businesses, and 16% (11/67) from large
size businesses. The respondents who thought that new regulations would not cause unfairness
were present in 12% (8/67) of small businesses, 9% (6/67) of medium size businesses, and
15% (10/67) of large size businesses.
Table 37: Cross Tabulation of New Regulations Causing Unfairness vs.
Company Size
N=67

What is the approximate size of the current company
for which you work?
# of Employees

1-500 501-5,000 > 5,000 I am not sure

Do you think
introducing new
veterinary regulations
and initiatives like
those for US human
drug shortages would
create any unfairness
in the marketplace?
Yes

7 7 11 1
No

8 6 10 0
I do not know

3 2 6 0
Comment

3 2 1 0

The survey participants were asked if they thought that introducing new
veterinary regulations and initiatives like those for U.S. human drug shortages would be
too costly for industry or government (Figure 36). Half of the respondents (50%, 34/68)
thought that this would be too costly for the industry, 19% (13/68) disagreed, and 31%
(21/68) did not know. Over a third of the respondents (38%, 26/68) thought that this

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would be too costly for the government, 28% (19/68) disagreed, and 34% (23/68) did not
know.
Figure 36: Participant Views on the Cost of New Veterinary Drug Shortage
Regulations
Do you think that introducing new veterinary regulations and initiatives like those for
U.S. human drug shortages would be... (N=68)?

too costly for industry?

too costly for the government?

The survey participants were asked how government costs associated with new
regulations and initiatives to address veterinary drug shortages should be funded
(Figure 37). A majority (65%, 53/68) thought federal funding should be used, 17%
(14/68) that industry user fees should be used, and 9% (7/68) did not know. Nine percent
(7/68) had other ideas that are summarized in Table 38.
Figure 37: Survey Participant Views on Funding of Government Costs
How do you think that government costs associated with any new regulations and
initiatives for veterinary drug shortages should be funded? (Select all that apply) (N=68)

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Table 38: Other Comments on Funding of Government Costs
“Combination of Federal and Industry sources”
“Decrease the burden of other, less meaningful regulations and structure it so that it is cost-neutral at
worst and cost-savings at best.”
“I agree with “user fees” as well, but not necessarily increasing those, but re-distributing accordingly and
as needed.”
“Industry fees have grown exponentially yet CVM is still only ~30% funded by user fees (FDA is
~70%)”
“Should be funded by the organizations required to comply with the guidance”
“Maybe some combination”
“none”
4.13 Other Views from the Survey Participants
The survey participants were asked if they would like to share other views about
U.S. veterinary drug shortages that were not covered by the survey questions. The other
views are presented in Table 39.

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Table 39: Other Views about U.S. Veterinary Drug Shortages from the Survey
Participants
“A large gap with this overall topic is human-labeled Rx used extra-label by veterinarians. Some of these
molecules would not 'hit the radar' as being supply issues in the human market, but they would be if
crossover use to the animal health market were considered. The animal health market is often the first
customer segment to be cut-off from human-labeled Rx supply or to experience supply reductions due to
priority needs of the human market. Many vet practices needed to turn to compounding or alternative
molecules when this happens.”
“Adding bureaucracy rarely helps.”
“I believe the allowance of mass production of animal drugs by "compounders" adds to the problem of
drug shortages. It removes the price incentive necessary for manufacturers to introduce generic versions
and to maintain the cost of manufacturing proprietary animal drugs under much more strict regulation
than compounders face.”
“Improve the readiness and responsiveness of current veterinary drug shortages and MNVP program and
process is a good start”
“Is important and critical to ensure that requirement changes are needed in Vet industry and not to be
made only because they are applicable for Human drugs.”
“Open and honest communication between industry and CVM is critical in resolving drug shortages.
CVM needs consistency within their divisions to expedite resolution to shortages. Additionally,
cooperation Between CVM and the District Office (responsible for inspection) is another critical link in
the chain. Three-way conversations between industry, CVM and the District could help expedite the
process. However, this only happens and the request of industry. Cost is another driver in the veterinary
industry. Without the additional financial support of third-party payers (insurance), the financial viability
of some veterinary drugs does not exist.”
“There are so many reasons for shortages to occur but it is rarely a company’s inability to plan supply, top
reasons are API supply, animal health business not attractive for supply companies, changes at a supplier
leading to approvals taking a while, quality inspections, 'VMF issues' and lists of questions for technical
certitude of the filing, new regulation changes in quality expectations and EHS issues to name a few. the
sources of drug shortages are often, API supply chain, quality inspection or plant shutdowns, sometimes
packaging components. and rarely DP OOS or lack of ability to make a compound with good technical
quality. it is 'procedural quality' and the inspections failures and these rarely are truly impacting drug
technical quality - i.e., testing passes. Thus, if we have ways to accept compounds when the quality can be
confirmed by testing while issues and shortages are fixed, this is a good way to reduce shortages. Again,
many cases are where the inspections for items take out a supplier because standards have become so
much higher and the DP quality is rarely truly off spec. It is a focus on prevention of issues and raising
standards. The idea of compounding without the controls and GMP requirements imposed on drug
approval process including stability testing or other traditional requirements placed on GMP producers seems
quite surprising. The drug shortages are created by the CVM based on inspections and reviews of GMP
and importantly dissolution results and efficacy etc. If we have a solution to rapid approvals of new API
sources or other remedies, you should not need to take the risk for compounding. It would be good to see
the statistics and educate on compounding more widely if this is considered acceptable and why.”
“The question on source of funding is interesting because I had not considered this throughout the
survey. It's difficult because 1) Industry does not want to pay for it 2) We don't need bigger FDA, i.e.,
more Federal Spending”
“There should be less formal regulations, and greater cooperation and collaboration between companies
and FDA-CVM in forecasting and communicating shortages, and then coming up with a joint plan to
resolve the shortage. Ideally, a "go to" commission or person in the agency set up for action that
advocates for the welfare of animal patients, owners and veterinarians.”

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Chapter 5: Discussion
5.1 Overview
Veterinary drug shortages affect veterinary drug availability, a critical issue in
veterinary medicine (Burns, 2010). Although several U.S. regulations exist to mitigate
and prevent shortages of life-saving human drugs, no comparable regulations and only
limited FDA-CVM policies and guidelines are in place for life-saving veterinary
medicines (21USC§356c, 2020b; FDA, 2000; FDA, 2020b). The research results
presented here consider how one important stakeholder, the professionals in the animal
health industry, view current regulations and whether a revision of the current approaches
and policies toward veterinary drug shortages would be useful.
5.2 Methodological Considerations
5.2.1 Limitations
The choice of research tool is well-known to impose limitations on the depth and
breadth of a research study (Sue and Ritter, 2007). For this research, an online survey tool
was used. Online survey tools have many advantages, including efficiency, wide
geographic reach, ease of use, low cost, and flexibility (Ball, 2019; Sue and Ritter, 2007).
However, as identified previously, “if sample selection and question validation are
overlooked, the data generated by an online survey can be extremely biased, and the
results may not be replicable or robust.” (Ball, 2019) Thus, the limitations of this
approach with respect to sample selection and question development must be considered
when assessing the validity of the results.
In the ideal research study, every professional associated with the U.S. animal
health industry would have been invited to participate. However, this was not possible

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because no available list of animal health industry professionals could be found. As a
result, a sample of this population was selected by using multiple approaches to identify
individuals most likely to have relevant experience with animal drugs and their shortages.
Potential respondents in one group that participated in the Animal Pharmaceutical Supply
Chain Disruptions Workshop at Kansas State University were personally invited via
email, but several other solicitations were directed at sponsors and technical/regulatory
professionals responsible for NADAs and ANADAs and members of relevant
professional societies. As a result, the sample is enriched with senior-level regulatory
affairs professionals. One could argue that this may actually be of value for this
specialized research topic, which requires significant knowledge of the animal health
industry. It was clear from the results that regulatory professionals were more likely to
have read the relevant human and animal regulations. The demographic results confirm
further that most held senior-level positions, had over six years of experience, and had
experienced U.S. veterinary drug shortages.
One factor that is important for gauging the representativeness of the sample is
response rate. However, this can only be done when the individual surveys are all
directed using a unique link to each recipient. In this study, only the Kansas State
seminar group was provided with unique links, and the response rate, in this case, was
22%. This response rate is consistent with other electronic surveys reported previously
(Saleh and Bista, 2017; Hart et al., 2009; Sue and Ritter, 2007). It might not be surprising
if some of the attendees of a seminar program considered themselves as inappropriate
participants; some amount of self-selection might be useful, given the diversity of
backgrounds often represented in such an audience. Further, there is no guarantee that the

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attendees represent a random cross-section of the population in general. For example,
senior individuals in challenging job functions may not have attended because of other
commitments.
Most survey respondents, however, participated using an anonymous link. It was
not possible to assign a response rate to this group, so the representativeness of the
sample could only be gauged from the demographic profiles of the respondents. In
addition, the use of anonymous links has the disadvantage that such a method cannot
prevent single participants from submitting multiple survey responses if they were
motivated to influence the survey results in a particular way (Ball, 2019; Eysenbach,
2004). However, the Qualtrics software allowed us to check for multiple entries by the
same participant, and no such evidence could be found.
Another aspect which has the possibility to limit the validity of survey results
relates to the survey questions themselves. Do they appear reasonable for acquiring the
necessary data? Are they relevant to the topic? Are they asked in a way that could bias
the response? Do they elicit answers that are generalizable? (Ball, 2019) One way to
check that the survey questions are worded with sufficient clarity and specificity is to use
a focus group to critique the survey questions (Oimet et al., 2004). This approach had
been found to improve the quality of similar online surveys in the past (Turnbull, 2016;
Ramsey, 2013). For this study, the survey questions were modified usefully from the
feedback of a focus group of university faculty experienced with developing research
surveys as well as subject matter experts in the animal health industry with interest in this
topic.

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An additional concern related to survey content is the possibility that participants
will find the survey too onerous and fail to start or complete it. Much research has shown
that longer surveys recruit fewer participants and have lower completion rates (Galesic
and Bosnjak, 2009). Feedback from the focus group about the length of this survey was
mixed. It reflected the tension between having more questions to deepen the content and
having a realistic limit on length to assure participation. The design of the survey to be
completed in about 15 minutes was, therefore, a compromise. I incorporated certain
measures that were previously recommended to increase completion rate, such as
informing participants about the length of the survey at the beginning and incorporating
skip logic to assure that participants were not faced with too many questions that they
could not answer (Galensic and Bosnjak, 2009). Nonetheless, it is possible that the 21%
drop-out rate that still was seen could be due to the length of the survey. It is also
possible, however, that the deeper content of later questions was beyond the experience
of some participants and caused them to abort the survey. That survey fatigue was not a
major factor was suggested by the finding that the responses of the other 79% of
participants who did complete the survey showed no trend toward “straight line”
responses (i.e., “I am not sure” or “neither agree nor disagree”) that might indicate survey
fatigue (Herzog and Bachman, 1981).
5.2.2 Delimitations
Although veterinary drug shortages can occur in all countries in which such
products are marketed, this study is limited to veterinary drug shortages in the U.S.
Challenges in other countries remain of interest, but the few policies and systems in place
to deal with veterinary drug shortages are nationally or regionally based and differ from

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the systems in the U.S (e.g., EMA, 2021; Canada, 2021). One goal of this research was to
identify potential opportunities for change in the U.S. system that might help to alleviate
the problems associated with drug shortages, so the delimitation to this jurisdiction
seemed appropriate. Further research to identify whether similar problems or solutions
exist in other countries would be a valuable subject of future research.
Another delimiting feature of the study was the use of the current U.S. human
drug shortage regulations and FDA/FTC policy objectives as a framework to explore
potential changes to U.S. veterinary drug shortage policy. This framework excluded
consideration of drug shortage policies in other U.S. agencies, such as the Environmental
Protection Agency (EPA) or United States Department of Agriculture (USDA), that
regulate animal pesticides and animal vaccines, respectively. Examining these additional
policies would, however, have lengthened the survey substantially and perhaps distract
from the specific challenges and solutions that are primarily in the purview of the FDA.
The study was delimited to professionals working in the animal health industry
whose work is likely to be affected by U.S. veterinary drug shortages. The views of other
stakeholders such as veterinarians, animal owners, and government are not explored.
When the study was being designed, some thought was given to include other
stakeholders. However, the views of these groups have already been examined in some
detail. Further, their views can differ because of their diverse perspectives and interests
(Burns, 2010; AVMA, 2011; FDA, 2011; Untitled, 2011; Khuly, 2015; Peralta and
Bailey, 2019; FDA, 2019b). Thus, their inclusion would diffuse the results.
Additionally, many of the questions would not be appropriate for these groups, so
different questions might be needed to probe their views and experiences.

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The animal health professionals invited to participate in the survey were not
limited to a particular job function; effort was taken to invite professionals working in
different roles such as regulatory affairs, quality, supply chain, operations, and marketing
to capture a range of industry experiences and perspectives. Nonetheless, 42% of the
respondents were regulatory affairs professionals, as noted above. This was most likely
because the survey was distributed by the AHI and GADA trade associations to relatively
large groups of members who typically work in regulatory affairs. The
overrepresentation may then reflect the relatively larger number of regulatory
professionals who received the survey through the trade associations versus those in other
job functions who did not. As a result, this enrichment must be borne in mind when
interpreting the results to be sure that opinions expressed primarily by regulatory affairs
professionals are not overgeneralized to other groups whose views and experiences may
differ (Ball, 2019; Andrade, 2020). For example, the results of this survey showed that
participants in most job roles were not in favor of a requirement for risk management
plans, yet participants from technical operations were slightly in favor.
Finally, this study is delimited by the unique timeframe during which it was
conducted, six months after FDA-CVM issued Guidance for Industry #271, Reporting
and Mitigating Animal Drug Shortages during the COVID-19 Public Health Emergency.
This document encourages industry to report veterinary drug shortages and discusses
expediting submission reviews and inspections for medically necessary veterinary
products. Thus, the study provides a snapshot of industry views held during a particular
point in time and may not reflect future views, especially if the policy changes.

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5.3 Consideration of Results
This research into industry views on regulatory policy was conducted using two
frameworks. The first framework was based on the elements of U.S. human drug-
shortage regulations that go beyond veterinary regulations, including 1) expediting
reviews and inspections, 2) reporting and enforcement of reporting, 3) and development
of risk management plans. Thus, the survey addresses the views of industry related
specifically to the usefulness of adding some or all of these elements to veterinary drug
requirements. The second divides that evaluation by examining the likelihood that new
regulations would help achieve three objectives considered important for regulations
more generally. These include its ability to 1) protect public health by ensuring the
safety, effectiveness, and quality of the regulated product, 2) assure that regulations do
not unduly favor one industry subgroup over another, and 3) foster timely access to
products by assuring that the costs and hurdles associated with satisfying the
requirements do not reduce the availability of products or unduly countermand the
benefits that the regulations would produce (Ramsey, 2013; Turnbull, 2016; Wiley,
2019). The results of this investigation were analyzed and interpreted in the context of
these two frameworks.
5.3.1 Expediting Submission Reviews and Inspections
Not surprisingly, respondents strongly favored adopting approaches that expedite
submission reviews and inspections. These can be a final hurdle that prevents an FDA-
approved product in shortage from returning to the market. Respondents in favor of
expediting reviews and inspections commented that such an action would be “solution-
oriented”, “ensures the best care and welfare of animals”, and is “for the good of the

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nation.” Their views align with the stated position of the professional association,
AVMA, which “emphasizes the importance of drug availability for animals and the value
of FDA-approved drugs which are proven safe and effective”. They also appear to reflect
the sentiments of veterinarians who have few alternative options (AVMA, 2011). Thus,
the results here are consistent with a wider consensus that shortages of animal drugs
constitute “a critical issue in veterinary medicine” (Burns, 2010) that could be usefully
addressed by accelerating approvals and inspections. They thus would help to achieve the
third stated objective of good regulatory policy, stated above, to support timely access to
the medical products.
However, accelerating reviews and inspections may have a potential downside.
Some have questioned whether such actions would degrade the safety and quality of the
released products and thus conflict with another of the above-stated objectives of good
regulations (Woodcock and Wosinska, 2013). If FDA expedites a review or inspection, is
it still able to assure safety, effectiveness, and quality in the same way that it could for a
conventional review or inspection? Many shortages occur in the first place because of
quality issues. FDA’s Strategic Plan for Preventing and Mitigating Drug Shortages
reported in 2013 that more than 80% of human drug shortages resulted because of quality
issues associated with facility remediations or manufacturing issues (FDA, 2013a).
The results of this survey suggest that quality issues, including cGMP issues,
might also be at the root of many veterinary drug shortages. Thus, the frequent
intervention to “save” drugs in short supply by expediting regulatory actions may have
negative consequences. Woodcock and Wosinska expressed concern that the FDA’s
reactive use of “regulatory flexibility” and “enforcement discretion” might cultivate the

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expectation that special provisions would be offered routinely, and these might prop up
sub-quality products (Woodcock and Wosinska, 2013). A better solution, in their view,
would be to prevent production problems proactively by embracing stronger measures to
address quality such as those laid out in ICH Q8 Pharmaceutical Development, ICH Q9
Quality Risk Management, and ICH Q10 Pharmaceutical Quality System, as well as ICH
Q12 Lifecycle Management. These standards are all planned to be adopted as VICH
guidelines.
Similarly, at the Kansas State Workshop in 2019, FDA-CVM speakers suggested
that companies move away from simply focusing on passing GMP inspections and
instead adopt more proactive methods to ensure systemic quality by using quality metrics
or introducing more science-based quality assessments. Such modifications could assist
FDA to move toward risk-based approaches for regulatory inspections and submissions
(Peralta and Bailey, 2019). These proposed changes have the potential to reduce
shortages in the longer term, but they are not quick fixes.
Further, even if such solutions were implemented, they might not correct other
root causes for veterinary drug shortages that do not derive from quality problems.
Regulatory delays and shortages of active ingredients could also cause some veterinary
drug shortages; these challenges may not be linked to deficiencies in quality
management. Numerous comments pointed to the challenges of supply chain issues. It is
unclear whether those were more relevant at the time of this survey when pandemic-
related supply chain disruptions were severe or whether such supply chain issues have
been an ongoing concern worthy of further analysis and intervention.

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The reservations expressed by the FDA about product quality do not seem to have
influenced the opinions of those in industry. Instead, most respondents believed that
accelerating reviews and inspections could reduce the number and duration of shortages
without degrading product quality or safety. The few respondents who were unsure or
unsupportive instead seemed more concerned that FDA might have insufficient resources
to support the added workload that this new obligation might present. This would
potentially slow approvals for all companies trying to obtain timely market registrations
for their veterinary products.
Nevertheless, improving quality systems to stabilize drug supply is a goal worth
setting. The primary reason for human drug shortages have been quality issues
associated with facilities and product manufacturing (FDA, 2013a). The results of this
survey suggest at least 20% of animal drug shortages are associated with quality-related
issues. Additional measures have been proposed that might indirectly help to signal
potential supply disruptions. For example, Woodcock and Wosinska proposed voluntary
reporting of quality metrics as a proactive way to incentivize quality as a solution to
human drug shortages, and this was further suggested by Dr. Julie Bailey of FDA-CVM
as a possible solution for veterinary drug shortages (Woodcock and Wosinska, 2013;
Peralta and Bailey, 2019). The respondents here had varying views about whether a
quality metrics program would be helpful to reduce the number of veterinary drug
shortages. One participant thought that such an initiative could help FDA build trust with
sites in the long term; this might encourage FDA to conduct fewer inspections without
sacrificing quality. The view is consistent with one of Bailey’s proposed solutions to
veterinary drug shortages presented at the Animal Pharmaceuticals Supply Chain

139
Interruptions Workshop at Kansas State University in 2019, that FDA should “develop a
system for measuring quality management maturity (e.g., quality metrics), then FDA can
exercise a more flexible regulatory approach, ensuring that high quality drug products are
on the market.” (Peralta and Bailey, 2019)
However, others expressed concern that such a program might require significant
effort for both industry and FDA and may not prove useful. For example, one survey
respondent commented that the only organizations that would report this information
voluntarily would be “those without issues and with sufficient resources to generate these
data”, so such measures “would not achieve the presumed desired outcome of attempting
to identify poor performing manufacturing sites.” Other survey respondents were
concerned about “overregulation”-that requirements for specifications, product annual
quality reviews, and adverse event reporting already exist to assure quality. Most
believed that their companies would be hesitant to share this type of information. Their
responses are consistent with sentiments previously expressed by some in the human drug
industry. For example, Susan B. Joseph, Director of Good Manufacturing Practice
Compliance and Quality Assurance Systems at AstraZeneca does not want to share the
10-12 key performance indicators that her company uses internally because these are
“internal tools to drive continuous improvement.” (Barlas, 2013) Similarly, the research,
Incentivizing Quality in the Manufacture of Pharmaceuticals: Industry Views on Quality
Metrics and Ratings, by Medina and Richmond, found that most respondents would be
reluctant to share “leading metrics” related to process performance which would be more
relevant than “lagging metrics” in predicting drug shortages (Medina and Richmond,

140
2015). Based on the available information, there does not yet appear to be agreement on
the usefulness of quality metrics as a tool to prevent drug shortages.
5.3.1.1 Reporting and Enforcement of Reporting
FDA has also attempted to mitigate shortages for human drugs by introducing
requirements for mandatory reporting so that shortages could be tracked more easily
(Obama, 2011; S 3187, 2020). Most respondents in this study also appeared to favor
such requirements for veterinary shortages. However, individuals in Regulatory Affairs
appeared to be more cautious than those in other job functions, at least from the small
numbers captured here. Some of that caution might relate to logistical considerations
because reporting requirements would increase the workload of regulatory personnel.
This might be a particular concern for smaller companies with limited resources and thus
violate the objective of good regulation to assure a level playing field for all players.
Concerns were expressed by some that the extra effort would only be worthwhile if
“FDA actually then acts on the information” and does “not just make it an exercise in
bookkeeping.”
Nonetheless, the level of positivity was surprising given that industry does not
often favor an increase in regulatory requirements. The positive opinions seem to be
driven by the belief that reporting would allow FDA-CVM to react more quickly to
mitigate or prevent drug shortages. AVMA seems to think similarly. In their comments
on the FDA report, A Review of FDA’s Approach to Medical Product Shortages, it has
encouraged “more frequent FDA-industry cross-communication” to mitigate and prevent
drug shortages (AVMA, 2011). In addition, many suggested that such reporting could
increase the stability of drug supply only if it were enforced through effective oversight

141
and penalties for noncompliance. Certainly, having a system that requires and enforces
such reporting has effectively driven better information-sharing for human drugs. After
U.S. requirements to report human drugs were introduced in 2011 and 2012 (Obama,
2011; S 3187, 2020), FDA observed a 6-fold increase in notifications that it credited, at
least in part, to preventing approximately 200 drug shortages in 2011 and 280 drug
shortages in 2012 (FDA, 2013b; FDA, 2019c).
However, new regulatory requirements do not come free. Some respondents
expressed concern that FDA-CVM would need more resources and stronger internal
procedures to respond and enforce effectively. When such regulations were introduced
for human drugs, additional resources had been allocated so that FDA could strengthen
its infrastructure and clarify how its staff would be organized to respond immediately
following notification of a supply disruption or shortage (FDA, 2013a). Further, many
survey respondents were concerned that resource limitations might erode FDA-CVM’s
ability to perform other key functions such as reviewing and approving animal drug
applications. Similar concerns had been expressed prior to the implementation of the
human drug regulations. The 2011 Government Accountability Office Report to
Congressional Requesters, Drug Shortages FDA’s Ability Respond Should be
Strengthened, stated:
Agency officials estimated, in addition to those staff working in the Drug
Shortage Program, 25 full-time equivalent employees provided some level
of assistance in preventing, alleviating, and resolving shortages – for
example, by conducting determination of medical necessity and reviewing
application supplements. However, these additional staff also have other
primary responsibilities (GAO, 2011).

Nevertheless, the 2013 PDUFA report indicated that the new resource allocations
appeared to be sufficient in the case of the imposition of new regulations for human

142
drugs. Standard applications approved during the first review cycle increased to the
highest levels ever recorded in FY 2012, and agency met or exceeded 11 of 12
performance goals. These metrics would seem to support the view that the activities
associated with drug shortages, also high in this period, did not interfere with the
traditional reviewing functions of the Center and thus did not interfere with the timely
access to drugs (FDA, 2013b). These findings may not, however, guarantee that similar
outcomes will be seen for FDA-CVM, which is a much smaller Center with many
different oversight and reviewing responsibilities and a relatively small cadre of
reviewers.
Survey respondents were also concerned about confusion in the implementation
of the reporting requirements that might lead to unnecessary drug-shortage reporting.
Comments suggested that more guidance should be provided so sponsors could better
assess which shortages should be reported and that “easy direct reporting” would help
with compliance. One respondent suggested that unnecessary reporting might be
decreased by introducing a guideline like that of the French Authority, which allows
sponsors to assess the need to report by using a risk assessment tool. Some stakeholders
in human health have even proposed that FDA develop a list of essential medicines to
facilitate reporting (FDA, 2019b). However, FDA has maintained that such a list would
not account for variables such as “new drug approvals, changing quality conditions in
manufacturing facilities, changes in medical practice, and other variables that could
change over time” (FDA, 2019b). This is consistent with the comment of one respondent
that shortages are a “a very difficult topic to predict in a global economy.” As a result, it

143
may be difficult to avoid unnecessary reporting if a reporting requirement is
implemented.
Any requirement to report must be associated with oversight and enforcement, but
how to enforce can be contentious. Most survey respondents did not favor the reporting
of noncompliance to the public. One respondent, for example, suggested that it might
lead to a “blaming environment that would not help the manufacturer focus on fixing the
problem, but will waste their time and energy to manage public opinion”. Concern was
also expressed that FDA-CVM might publish false information that could damage the
firm’s reputation and that the misperception could not be erased even after the
misinformation was corrected. To avoid this situation, the human health regulation gives
the firm an opportunity to correct inaccurate information by providing a 30-day window
in which to respond to an enforcement letter before the letter is made public, a grace
period that FDA has already been shown to respect (FDA, 2019c). Some respondents felt
that the public release of failure should be reserved for “the most egregious, repeat
offenders.” The effectiveness of this kind of enforcement action was also queried by one
respondent, who believed that practitioners and consumers do not pay attention to FDA
letters. Some respondents appeared instead to prefer positive reinforcement over punitive
measures, suggesting a “short track to alternative options” or an equivalent to the “Drug
Shortage Assistance Award” created by FDA in 2014 to publicly recognize firms
demonstrating commitment to preventing drug shortages (FDA, 2019c).
The issue of reporting has achieved greater significance during the Covid-19
pandemic in the last two years. During this time, the unfortunate use of the animal drug,
ivermectin, as an unapproved human treatment, and the shortage of active ingredients and

144
other supplies for manufacturers of other animal products, have made it difficult to meet
needs for some animal drugs (Cima and Larkin, 2020; Hahn, 2020; Ross, 2021). In
response, FDA encouraged drug shortage reporting in the animal sector by issuing an
interim Guidance for Industry, Reporting and Mitigating Drug Shortages during the
COVID-19 Public Health Emergency (FDA, 2020b). At the Animal Health Institute
Triannual Meeting held October 19, 2021, FDA-CVM shared data showing that
93 potential or confirmed product shortages were reported between February 2020 and
October 14, 2021, and 51 of these shortages were averted during that period (Burnsteel,
2021). Whether the experience that they gained with regard to veterinary reporting will
result in a more enduring policy change remains to be seen.
5.3.1.2 Risk Management Plans
However, not all measures to reduce drug shortages were viewed to be as useful
as the other two types of interventions described above. For example, most respondents
did not favor requirements for risk management plans, which they felt would add costs
and burden without adding much value. Risk management planning can be expensive, but
according to one respondent, it often also adds new activities such as qualifying backup
manufacturers or holding extra stock which can expire unsold. One survey respondent
commented that this requirement might be too expensive in a low-cost environment like
animal health with “no means to support the additional costs of redundancy plans.”
Concerns were expressed that requiring such plans might even affect business decisions
to discontinue the production of drugs with narrow profit margins and thus compromise
the availability of medically necessary “niche” products or products made by small

145
companies already struggling financially. Some commented that such plans might be
unable to predict unforeseen circumstances beyond the control of the firm.
Not all respondents, however, had such negative opinions. Some pointed out that
risk management plans would be in the best interest of the company; they might reduce
the resources spent in finding solutions for an imminent shortage and lead firms to
consider robust preventive measures. In line with these observations, best practices for
handling drug shortages, discussed at the Animal Pharmaceuticals Supply Chain
Interruptions Workshop at Kansas State University in 2019 (Mlodzik, 2019), included the
development of business continuity plans that would include risk management plans.
Additionally, most respondents ranked “business continuity planning” and “global supply
chain strategy planning” as the most important components of the ISPE Drug Shortage
Assessment and Prevention Tool and PDA Technical Report No. 68, Risk Based
Approach for the Prevention and Management of Drug Shortages (ISPE, 2015; PDA,
2014). However, the majority of survey respondents had not utilized the PDA or ISPE
tools to try to avoid veterinary drug shortages. This is likely due to a lack of awareness
by the respondents in the animal health industry of these tools, which were developed
specifically for human drug shortage prevention. Nevertheless, several aspects of these
tools may be useful for the animal health industry to consider to minimize the risk of
veterinary drug shortages.
In the absence of risk management plans and other actions by FDA-CVM to
expedite availability of FDA-approved veterinary drugs, compounding will persist as the
common “risk management” solution for veterinary drugs in short supply. This solution
is clearly not optimal. Compounded drugs are not proven to be safe or effective in the

146
same way as manufactured drugs (FDA, 2019a). Further, compounded animal drugs are
not required to meet FDA cGMP standards of quality (FDA, 2019a). This lower bar for
use can have safety consequences, well-illustrated, for example, by the tragic deaths of 21
polo ponies overdosed by an incorrectly compounded supplement from Franck’s
Pharmacy (Lau, 2015). Unsurprisingly, most respondents in this study strongly
disapproved of compounding as a way to address veterinary drug shortages. They ranked
the current policy- in which FDA accepts the use of compounded drugs as a valid
alternative to FDA-approved drugs experiencing shortage- as one of the top three
problems with the way that U.S. veterinary drug shortages are currently handled. Many
survey respondents believed that compounding exposes animals to potentially serious
risks. Thus, they believed that FDA-CVM should recognize that a compounded drug
may be a riskier option than working with other industry providers or prioritizing
submissions to speed the availability of FDA-approved veterinary drugs. FDA-CVM
appears to recognize this concern. To improve the safety of compounded drugs, FDA-
CVM has drafted Guidance for Industry #256, Compounding Animal Drugs from Bulk
Drug Substances, which narrows the conditions for compounding under which FDA-
CVM will use enforcement discretion (FDA, 2019a). Whether this guideline improves
the safety of compounded animal drugs remains to be seen and could be an interesting
topic for future consideration.
5.4 Future Directions and Concluding Thoughts
A principal goal of regulation is to ensure safety, quality, and effectiveness of
drug products. The results from this study suggest that most participating animal health
professionals see additional regulatory oversight as useful to help to achieve this goal.

147
Thus, the time may be right for regulators to reconsider the approaches that they take
when managing veterinary drug shortages. A beginning step in this direction might be
seen in the recent publication by the FDA of interim Guidance for Industry # 271,
Reporting and Mitigating Animal Drug Shortages during the COVID-19 Public Health
Emergency, that provides greater clarity about the process of reporting veterinary drug
shortages (FDA, 2020b). It remains to be seen whether this first foray into possible
approaches will produce longer-lasting guidance or stricter regulations. However, a
systematic reevaluation of current regulations and additional options might align
veterinary regulations more closely with those already in place for human drugs.
The responses to this survey are instructive in defining the views of one principal
stakeholder. Most of the views identified here come from individuals in regulatory
affairs, a division that typically understands best the regulatory landscape. However, drug
shortage regulations have a broad reach to affect many departments such as supply chain,
procurement, commercial affairs and marketing, legal affairs, and quality assurance, for
example. It would be interesting to explore the usefulness of different regulatory
solutions through the eyes of a larger sample of animal health professionals with other
functional roles. Further, hurdles may exist because of challenges with other types of
regulations, such as import-export or controlled substance rules, managed by other
agencies. A thorough knowledge of this broader landscape would be key to assuring that
the regulatory solutions to impending shortages take into account the broader experiences
and pressures on the animal drug industry. In addition, any new regulations will have
implications for other stakeholders, including the drug compounding pharmacies, which
may have different views. Compounding as a solution to drug shortages is of some

148
concern, so regulations might also be directed at making the compounding industry safer.
A holistic approach to the problem may extend beyond the requirements for accelerated
approval, enhanced reporting, and the implementation of risk management plans.
However, these areas would seem to be a good place to start.

149
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159
Appendix A. Comments about Reporting
Complete List of Comments on Extending Drug Shortage Reporting for Veterinary Drugs
Comments Against Extending the Reporting Requirements
“Happy with the status quo.”
“I tend to discourage additional regulations unless absolutely necessary.”
“Reporting drug shortages publicly could lead to more hoarding or lead to competitive
advantages.”
“Reporting itself does not help. Faster review of changes might help.”
“Since Veterinarians have the broadest prescription authority of any health professional
in the US, this is a non-issue as they can substitute very easily.”
“Unless the sponsor is the only provider of a given medically necessary drug, it would
not benefit the industry or the customers to require shortage reporting. It is generally
advantageous to report shortages or potential shortages to the CVM as soon as possible
to develop mitigation strategies. If a company chooses not to act on a shortage, then
that is a business decision. Again, unless the sponsor is the sole provider then the
impact to animals and to the public is not significant.”
“Vet drug manufacturing will have greater burden unless FDA agree with EU and
other regulatory bodies around the Globe to Unify. Is imp to ensure that smaller
companies can follow requirements as well......Lower cost of goods are critical”
“Extending the reporting requirements for drug shortages to veterinary drugs could be
a burden to the animal health industry.”
“While I don't think there should be a law governing it, I believe that sponsors should
spend more effort to manage their supply chains effectively and be aware of when they
will/may be a shortage.”
Comments For Extending the Reporting Requirements
“Better ensures the obligation a company and the FDA--CVM has to the welfare and
health care of animals, and in turn to pet parents and veterinarians for medically
important drugs.”
“I would support reporting, if it would trigger an acceleration of the permission to use
alternative drugs including those which are in a late-stage licensing process, so animals
could be cared for better and faster. If the reporting would be just for statistical
purpose, I don't see any sense in it.”
“In addition to above, the CVM should also introduce provision of priority review
(similar to humans) where less than three generics are available in the market so that
the shortages shall be mitigated.”
“It would give generic companies more information to target needed generic products.
Some companies may not consider shortages important if the sales $$ are not high
enough.”

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“The idea is sound provided the FDA / CVM will do something with the data and not
just make it an exercise in bookkeeping. IF CVM has the headcount and resources to
expedite the approval of api, and to rapidly respond when inspections / approvals are
needed, this will be an effective strategy”
“There are currently so few products that have approved NADA that would fall into
this category - of course this could change at some point in the future as new
therapeutics are approved, but I know I see a huge need for this at this time. Most
companies, if they have one of these, are already complying with the voluntary
guidance.”
Comments Neither for or Against Extending the Reporting Requirements
“Reporting is only useful if FDA then actually acts on the information. There is
potential for the assessment of potential future drug shortages to be a subjective
assessment. It's not always black and white. Also, very few animal drugs are granted
medically necessary veterinary product status.”
“CVM needs close cooperation between the internal Divisions i.e., Office of
surveillance and Compliance and Division of Manufacturing Technologies”
“Text about when to report shortages would need to be very clear. It seems that many
would not report until they knew with 100% certainty that they couldn't resolve the
problem. This would often not meet the "6 months in advance" preference.”
“NA”
“The one who report shortages should hold the accountability to ensure the report is
accurate.”
“The whole process and subsequent results responsiveness from the current FDA-CVM
Office on Drug Shortages is exceedingly slow and arduous!”
“There should be clear definitions around MNVP and how to assess the potential
impact on the food chain. It would be helpful to have criteria, decision tree/risk
assessment to help sponsors to evaluate the need to report and a reasonable time for
reporting from identifying the potential risk until reporting is needed. Otherwise, it will
be a lot of noise and difficult to select what is a real issue or not. The French authority
requires reporting such shortages and they have provided guidelines for the Marketing
authorization holders to perform a risk assessment to help them decide if a notification
is required or not so the authority is not overwhelmed and the sponsors do not have the
burden to report any minor issue, but only the critical ones.”
“It would need to be combined with also a scope reduction in what medically
significant means in Animal Health. This way the additional effort would be better
balanced with the reduced frequency of reporting needs.”
“My experience is that we have allot of old drug products that last a long time and
work. The challenge is the cost needs to decline and suppliers drop the products over
time as the products have low margin. We start seeing shortages on these products to
get people to MFG these types of products.”

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“The issue arises if we are looking for Potential Shortages or ACTUAL confirmed
shortages. Would need to be "confirmed" shortages as potential happens often and is
difficult to judge. I.e., confirmed it will happen in the future. not wait until happens.
even then it is a difficult topic to predict in a global company.”

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Appendix B. Comments about Enforcement
Complete List of Other Comments from Participants about Enforcement of Reporting
Comments For Enforcement of Reporting
“I believe the industry should be encourage to report these and incentive to do it.”
“In line with previous comment, FDA could use some sort of incentive to report
shortages.”
“It could be a staggered approach, with enforcement slowly becoming stricter to give
stakeholders time to address conflicts which will arise from these exercises.”
“Requirement cannot be Optional as companies will not report - Easy Direct reporting
helps”
“I don't think public release of failure to comply should be the first enforcement step.
Compliance enforcement should be tiered with public notification being reserved for
the most egregious, repeat offenders.”
“I am a fan of positive reinforcement and not punishment. If FDA can show that
reporting benefits the health of animals by providing a short track to alternative
options, every company is going to report.”
Comments Against Enforcement of Reporting
“Extending the requirements to veterinary drugs would increase the workload from AH
industry.”
“Enforcement without facilitating minimizing the conditions that lead to the shortage is
not responsible or helpful”
“Requiring shortage reporting, as noted, is quite difficult. there needs to be a very clear
delineation of what is considered a shortage and should be medically necessary only if
to be applied. the issue is that in many companies the shortages come as surprises due
to FDA inspections or Raw material shortages or sudden safety and IH shut downs in
China or other. Due to competitive cost pressure in animal health, it is common only
one supplier exists for a company. this is fact. so, these issues come up and the ability
to switch suppliers is very low. you simply cannot start up a new supplier in the time
frame to recover from the problems. now regarding shortages, it is common to try to
get a backup in place quickly and try to mitigate the shortage. it is always a race and
this is where the issues come. tough to really know if you will stock out or not in many
cases.”
“Status quo should remain. Keep reporting voluntary.”
“I tend to discourage additional regulations unless absolutely necessary”
“It is important to manage the public opinion - FDA does not have a very good track
record to not blame the manufacturer, on the contrary. If such reporting becomes
mandatory and public, this will create a blaming environment that would not help the
manufacturer to focus on fixing the problem, but will waste their time and energy to
manage public opinion and law enforcers. Especially that it is first made public and

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only afterwards the sponsor or the manufacturer have the opportunity to correct - so it
means that there is a risk that something damaging and untrue is first published on the
FDA website and by the time the statement is corrected, the company’s reputation is
already damaged.”
“FDA/CVM does not have the personnel to enforce. They can't monitor compounding
pharmacies so they certainly can't do this either.”
“FDA issued letters are of little consequence and have little meaning to practitioners
and consumers.”
“Companies should be obligated to inform the veterinary community about shortages,
and actions being taken to fairly distribute available product. Likewise, the FDA-CVM
should be informed to create a collaboration with the company on how to jointly
manage the shortage, and determine how, if at all, the regulatory body can assist in the
solution. Companies do not need to be shamed on a website. Customers will hold them
very accountable.”
“CVM ineffectively manages voluntarily reported shortages. I would worry about their
ability to address a greater number of reported shortages.”
“Awareness of medically necessary drugs is driven by either the end user (the
Veterinarian) or the drug manufacturer. In both cases the drug manufacturer takes the
brunt of the negative consequences. Mergers and acquisitions cause a portfolio review
and out of the combined company, small volume or lower profit margin products are
the first to be cut from the new combined portfolio. Additionally anti-trust laws force
the new larger corporation to divest some of its duplicate products to prevent a
monopoly. Divesting and site transfers of drug products can easily take 18 to 24
months. This time lag is caused by regulatory oversight and process. CVM would need
to step in to accelerate the transfer process to help prevent a shortage.”
“At some point this would require more work for FDA, which means more FTEs
which at some time would likely be pushed to the industry as ADUFA fees.”

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Appendix C. Comments about Expediting FDA Actions
Complete List of Comments by Respondents about Extending the Requirement to Expedite
Submission Reviews and Inspections for Veterinary Drug Shortages
Comments in Favor
“It will help in getting approval in a shorter period of time.”
“It worked for Covid vaccines.”
“This makes perfect sense if in fact these drugs are medically necessary. FDA should
be solution-oriented based on providing the best care and welfare of animals, and in
turn, their owners.”
“If a compound is truly medically necessary. it is for the good of the nation that we
prioritize the said drugs and we do not want those to be in shortage.”
Comments Neither in Favor nor Against
“FDA reviews should in general be faster. 30 days for simple, 90 for more complex
changes for the full process should be plenty of time.”
“FDA would have to adjust to the new condition and hire more people”
“In regards to "Quality, safety, and/or effectiveness issues would increase.", I believe
it all depends on what would be the minimum requirements by the agency for the
"expedited approval" of such drugs. E.g.: full safety profile, but sufficient basis for
effectiveness, etc. In regards to "This would impact the review and approval of other
types of important regulatory submissions.", I believe it depends on the resources of
the agency plus how many shortages the industry faces in average each year. It may
consume resources and impact regular processes, or it may not.”
“It depends on which Office or Division is conducting the review as to the impact it
would have on current reviews of INAD's by the industry.”
“Some publicized shortages can lead to better market competition as companies seize
opportunities to prioritize filing or launching a product.”
“CVM is already understaffed and far behind schedule with current responsibilities.
IF this is enacted, it would necessitate larger staffs and shorter turn-around times”
“Shortage list is useful. CVM needs to have flexibility in prioritizing their own
processes.”
“This may be an incentive for manufacturers to report shortages.”
Comments Against
“This could potentially help alleviate veterinary drug shortages. However, as was
mentioned above, I tend to discourage additional regulations unless absolutely
necessary.”
“This will divert resources from approving new animal drugs and supplements. CVM
does not have the resources like CDER/CBER do.”
“While it is necessary to implement prioritization, the limited FDA resources would
inevitably impact review of other submissions. The anticipated impact would be an
increased number of incomplete letters for the non-prioritized submissions as FDA
would not have enough time to review them. I would rather the FDA extend the
review period of a submission impacted in the queue by a prioritized submission by a
couple months intending to achieve a full review and submission approval.”

165
Appendix D. Comments about Quality Metrics
Complete List of Comments by Respondents about Introducing an Initiative for
Quality Metrics for Veterinary Drug Shortages
For a Quality Metrics Initiative
I think that such initiative would help in prioritizing inspections and making transparent the
rational for the next inspection. There is of course a time needed to build trust and to validate
that those metrics reflect the true quality system at the site, so it may be an initial increase in
FDA inspections in the beginning to validate those metrics, afterwards this should help
building trust with the agency and also it will help the agency to better manage the budget and
prioritize the inspections, whilst ensuring that quality does not decrease. There should be
maybe some other checks and controls in place to ensure that the metrics are not reflective of
the real risk – as a Quality professional I fully understand that it is not possible just to trust
metrics, there should be an inspection plan or on spot checks to confirm that the site is
trustworthy. This can be built as this is a usual life of any Quality Assurance unit.
Against a Quality Metrics Initiative
I agree that this will require more effort for all parties involved.
If this is voluntary then the only organizations that would participate are those without issues
and sufficient resources to generate these data. Under those circumstances the initiative does
not achieve the presumed desired outcome of attempting to identify poor performing
manufacturing sites. Even if a site has good metric outcomes, there is no obvious benefit to
provide these data as it does appear it places you an increased chance of inspection.
It appears to be over regulation. Manufacturers already follow approved specs for quality
production. These must be followed, and are looked at in FDA inspections. Adverse event
reporting is already in place as a monitor on quality.
This issue is already addressed by the Annual Quality Review for each Product.
I would want to understand how reporting on metrics of production are in scope for the
Government for reporting? This means the CVM is getting into the supplier management
business. Is this what we want? Of course, ensuring low defect rate is important just like any
manufacturing metric, and companies should be doing this anyways, but reporting
manufacturing capabilities to the CVM is likely out of scope. Perhaps ONLY for medically
necessary if to be installed for national security reasons.
Neither for Nor Against a Quality Metrics Initiative
Because of its voluntary nature, I believe those with good metrics would report, and those
would not very good metrics may not. Hence, the “good” may be more visible, whereas the
“bad” may not be reported, which could result in an unbalanced overall analysis, hence most of
my answers are “I do not know”.

166
Very difficult process as KPI metrics varies
Very hard to have a commonly understood definition for those metrics. Probably ends up in a
long debate about metrics definitions in inspections. Different products have different process
stability profiles, sometimes difficult to make drugs are medically necessary.
Some of the metrics may be derived differently from one company to another, for instance
some quality groups are more conservative than others. Some groups are larger and have more
resources to commit to this effort than smaller ones.

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Appendix E. Comments about Risk Management plans
Complete List of Comments by Respondents about Extending the Requirement for
Risk Management Plans to Medically Necessary Veterinary Drug Manufacturers

For Voluntary Risk Management Plans
I believe this should be part of the manufacturers responsibility to maintain their
supply chain; it’s just smart business. It should be driven by increased regulatory
burden.
I consider that having redundancy risk management plans can be in the best interest of
a company, however, I am not entirely sure if being enforced under mandatory
requirement by the agency is the best route or not.
I see both positive and negative. I think that there should be risk mitigation
plans/redundancy, however, this will have a significant financial impact, especially on
small manufacturers. So, if a veterinary product is identified as MNVP, there should
be some support from government for the manufacturer – and this may create an unfair
competition. In addition, it is not clear what FDA would review in such plans – that
has to be defined as such plans contain a lot of confidential and financial information
that should not be subject of this review. So, it is complex. My tendency is to increase
the collaboration between the agency and industry to work on such plans more on a
voluntary basis and not to enforce as this may have a devastating impact especially on
smaller manufacturers.
I think that manufacturers should have a back-up plan, but don’t think that FDA should
have to approve the plan.
For Extending Requirements for Risk Management Plans
Such a requirement does require sponsors to consider implications of shortages prior to
occurrence and perhaps implement more robust preventive measures.
Against Extending the Requirements for Risk Management Plans
As was mentioned above, I tend to discourage additional regulations unless absolutely
necessary.
Medically necessary products are often niche products. There manufacture should not
be made even less attractive by adding more bureaucracy.
More regulation means less market entries and higher prices for the market leading
companies.
The plans may be too burdensome in time and resources to be practical. All reasonable
quality control measures based on risk and return will normally be taken by companies.
It’s in their best interests to set up best practices that can keep their operations running
smoothly without downtime or shortages.
We do not want increased burden of increased regulation and FDA oversight.

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Neither For nor Against Extending the Requirements for Risk Management Plans
Companies do not prioritize this. They often have one manufacturer for a drug
substance, excipients, tubing, etc. When problems arise, it’s too late for them to pivot.
The issue here is about national security. Currently there, as I understand it, are no
means to support the additional costs of redundancy plans, thus in a low-cost
environment of Animal Health, having strong redundancy plans can increase cost.
Note that the key is to have a mechanism to quality a backup supplier and avoid
regulatory hurdles. And ensure that the supplier is ready to produce. However, for
API production, it often cannot be started fast enough, even if they are approved
because API production times are long lead time. So, there is an issue here, the key is
to have enough volume to justify back up suppliers or hold lots of stock which does
increase costs and often can expire, there are many factors that need to be managed to
get it right.
There seems to be a real lack of understanding of the veterinary drug industry by the
folks who wrote and asked these questions. Both on a regulatory side and a market
side. I would urge USC to work with Kansas State University, the only graduate
program in Animal Health Regulatory Affairs, to help them better understand the
needs, approval process and issues!

169
Appendix F. Job Role versus Key Policy Questions

Reg
Affairs
Quality
Supply
Chain
Mfg Tech Ops Mktg Other
Do you think that the FD&C Act should be extended to require manufacturers of veterinary
drugs to report to FDA any shortages of medically necessary veterinary drugs?
Yes 50.0% 80.0% 100.0% 71.4% 60.0% 77.8% 60.0%
No 43.3% 20.0% 0.0% 28.6% 20.0% 11.1% 30.0%
I do not know 6.7% 0.0% 0.0% 0.0% 20.0% 11.1% 10.0%
If an advanced reporting requirement were to be put in place for shortages of medically
necessary veterinary drugs, do you think this type of enforcement (posting letters to
manufacturers on public website) requirement would be important?
Yes 46.7% 60.0% 80.0% 57.1% 40.0% 55.6% 60.0%
No 40.0% 20.0% 0.0% 42.9% 40.0% 22.2% 40.0%
I am not sure 13.3% 20.0% 20.0% 0.0% 20.0% 22.2% 0.0%
Do you think having a public list of medically necessary veterinary drug shortages is
important?
Yes 80.0% 80.0% 100.0% 66.7% 100.0% 66.7% 80.0%
No 13.3% 0.0% 0.0% 33.3% 0.0% 22.2% 20.0%
I do not know 6.7% 20.0% 0.0% 0.0% 0.0% 11.1% 0.0%
Should similar regulations for expediting/prioritizing reviews and inspections be applied for
medically necessary veterinary drug shortages?
Yes 83.3% 80.0% 100.0% 100.0% 100.0% 88.9% 80.0%
No 16.7% 20.0% 0.0% 0.0% 0.0% 11.1% 20.0%
I do not know 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%
Do you think that manufacturers of medically necessary veterinary drugs should be required to
have redundancy risk management plans that are subject to FDA-CVM review?
Yes 13.8% 40.0% 20.0% 33.3% 60.0% 22.2% 20.0%
No 79.3% 40.0% 40.0% 50.0% 20.0% 33.3% 70.0%
I do not know 6.9% 20.0% 40.0% 16.7% 20.0% 44.4% 10.0%

Abstract (if available)

Abstract Animal drugs experience drug shortages just as human drugs do. However, certain types of reporting and follow-up required during human drug shortages are not required when shortages occur for animal drugs. Would a more rigorous system of regulations like that in place for human drugs in the U.S. be seen as useful and welcome in the animal health industry? This exploratory study used a survey approach to examine the potential impact of such changes by examining the views and experience of professionals in pharmaceutical organizations supplying animal drugs to the U.S. market and who have experience with U.S. veterinary drug shortages. A triad of principles relating to the goals of regulation was used to structure the survey and help interpret and frame the research results. Respondents believed that veterinary drug shortages have increased over the last 5–10 years. Most respondents commonly thought that the FD&C Act should be extended to require that manufacturers report shortages of medically necessary veterinary drugs to the U.S. FDA. Further, most supported the adoption of requirements that the U.S. FDA prioritize and expedite submissions and inspections associated with shortages of medically necessary veterinary drugs. However, most respondents did not favor requirements for risk management plans due to concerns with costs in excess of the value they might create. These findings suggest that a reevaluation of animal drug regulations might be supported by the animal health industry in order to increase the safety and availability of needed animal medications.

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Asset Metadata

Creator Greenwald, Jeanne (author)

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

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2022-05

Publication Date 12/30/2021

Defense Date 12/15/2021

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

Tag animal,disruptions,drug,OAI-PMH Harvest,pharmaceutical,shortages,supply chain,U.S.,veterinary

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Cosenza, Mary Ellen (committee member), Davies, Daryl (committee member)

Creator Email jegreenw@usc.edu,jgreenwald18@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC110454550

Unique identifier UC110454550

Legacy Identifier etd-GreenwaldJ-10322

Document Type Dissertation

Format application/pdf (imt)

Rights Greenwald, Jeanne

Type texts

Source 20220112-usctheses-batch-907 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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Repository Name University of Southern California Digital Library

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