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

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

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THE IMPACT OF INCOMPLETE MONOGRAPHS ON THE OTC DRUG INDUSTRY: A
SURVEY INVESTIGATION OF INDUSTRY VIEWS
By
S. Valerie Ramsey

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

May 2013

Copyright 2013 S. Valerie Ramsey
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DEDICATION
I would like to dedicate this dissertation to my husband, Kyle, who encouraged me throughout
my Master’s and Doctoral programs and who was always immensely understanding and
supportive of my aspiration to complete this work.

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ACKNOWLEDGEMENTS
I would like to thank everyone who supported and encouraged me throughout my doctoral
studies and everyone who helped make this dissertation a reality. I would like to specifically
thank my thesis advisor, Dr. Frances Richmond, for her selfless and unending encouragement,
patience, expert guidance and advice. Her vast knowledge and expertise in the field of global
regulatory sciences is an inspiration. I would also like to thank my committee members
including Dr. Gerald Loeb, Dr. Hilton Kaplan, and Dr. Daryl Davies for their many insightful
comments and recommendations that improved the contents of this dissertation. I would also
like to thank my focus group members including Dr. Bill Cooley, Dr. Mike Caswell, Dr. Barbara
Kochanowski, David Spangler, Esq., and Dr. Michael Jamieson for their gracious support and
expert professional guidance. And finally, I would like to thank my fellow students in the 2010
doctoral class for their support and encouragement over the last three years.

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TABLE OF CONTENTS
DEDICATION 2
ACKNOWLEDGEMENTS 3
LIST OF TABLES 8
LIST OF FIGURES 9
ABSTRACT 11
CHAPTER 1: OVERVIEW OF THE STUDY 12
1.1 Introduction 12
1.2 Statement of the Problem 16
1.3 Purpose of the Study 18
1.4 Importance of the Study 19
1.5 Limitations, Delimitations, Assumptions 21
1.6 Definitions 22
1.7 Organization of the Study 24
CHAPTER 2: LITERATURE REVIEW 25
2.1 Introduction 25

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2.2 History of the OTC Review Process 27
2.2.1 OTC Regulatory Foundations 27
2.2.2 Regulating OTC Drugs More Systematically 28
2.2.3 Phases of the OTC Review Process 31
2.3 Significant Developments Since 1972 36
2.3.1 Ingredient Accomplishments 36
2.3.2 Procedural Inefficiency 37
2.3.3 Changes in OTC Support and Regulation 38
2.3.4 Recently Identified Quality Concerns: Drug Impurities 41
2.4 Problems with Incomplete Monographs 42
2.4.1 The Sunscreen Monograph 46
2.4.2 The Laxative Monograph 47
2.4.3 The Antimicrobial Monograph 48
2.4.4 The Skin-Bleaching Monograph 49
2.4.5 The Vaginal Drug Products Monograph 50
2.4.6 Internal and External Analgesics Monographs 50
2.5 FDA Perspectives and Positions 52
2.5.1 The Need for Pharmaceutical Regulation 52
2.5.2 Possible Reasons for the Delay in Finalizing OTC Monographs 53
2.5.3 FDA Compliance Actions 55
2.6 OTC Industry Perspectives and Positions 56

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2.6.1 Manufacturers and the Role of FDA Guidance Documents 56
2.6.2 Possible Types of OTC Monograph Excursions 57
2.6.3 Implications of Monograph Excursions by Manufacturers 58
2.7 Framing the Study of OTC Regulatory Policy 60
2.8 Summary and Research Direction 64
CHAPTER 3: METHODOLOGY 66
3.1 Introduction 66
3.2 Survey Development and Delivery 66
3.3 Data Analysis 71
CHAPTER 4: RESEARCH RESULTS 72
4.1 Results of Focus Group 72
4.2 Analysis of Survey Respondents 73
4.3 Survey Responses Regarding Standards for the Industry 78
4.4 Safety and Effectiveness Responses 92
4.5 Responses on Efficiencies in Research, Commercialization, and Costs 95
4.6 Cross-Tabulations 100
4.7 Interview Results 101

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CHAPTER 5: SUMMARY AND CONCLUSIONS 106
5.1 Considerations of the Methodology 106
5.1.1 Appropriateness of the Survey Questions 107
5.1.2 Sampling of Respondents 109
5.1.3 Interviews 112
5.2 Consideration of Results 113
5.2.1 Safety and effectiveness of products 114
5.2.2 Efficiencies in Product Management 116
5.2.3 Equalize Standards 117
5.3 Future Directions 122
5.4 Conclusions and Recommendations 124
REFERENCES 126
APPENDIX A 134
APPENDIX B 150
APPENDIX C 152
APPENDIX D 153

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LIST OF TABLES
Table 1: Original Categories Designated to be Covered by a Monograph 30
Table 2: Monograph Status by Active Ingredient 43
Table 3: OTC Sales by Category 51
Table 4: Areas of Survey Inquiry According to the Framework 67
Table 5: Participants in Focus Group 69

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LIST OF FIGURES
Figure 1: Phases of the OTC Drug Review ................................................................................. 32
Figure 2: The Three Objectives of Regulation ............................................................................ 61
Figure 3: What is your current position/title? .............................................................................. 75
Figure 4: If you currently work for a company that manufactures/markets OTC drugs, what is
the size of the company in terms of numbers of employees? ....................................... 76
Figure 5: Under which of the following OTC monographs are you aware that your company
manufactures/markets OTC drugs in the US? Please check all that apply. ................ 77
Figure 6: In your current or past experience, what is the OTC drug industry’s opinion regarding
adherence to non-final monographs? ........................................................................... 79
Figure 7: In your current or past experience, given that a non-final monograph is not final and is
not legally enforceable, how often do you believe excursions (differences) are made
from a non-final monograph in the OTC industry? ...................................................... 80
Figure 8: In your current or past experience, how compliant are OTC drug companies to non-
final monographs? ........................................................................................................ 81
Figure 9: In your current or past experience, how often are the following types of monograph
excursions made from a non-final monograph in the OTC industry? .......................... 83
Figure 10: In your current or past experience, which of the following non-final monographs are
the most “contentious” and may have a higher potential for excursions from the
monograph? Please check all that apply. ................................................................... 84
Figure 11: How do companies address competitors who may be making excursions from a non-
final monograph? ........................................................................................................ 87
Figure 12: Please explain why you think there are regulatory and/or business advantages when a
monograph is non-final?” (Selected responses shown by response type.) ................. 89
Figure 13: Please explain why you think there are regulatory and/or business disadvantages
when a monograph is non-final. (Selected responses.) .............................................. 91
Figure 14: In your current or past experience, when a company makes an excursion from a non-
final monograph which may affect the safety of a product, how often is clinical or
other safety-related testing conducted? ...................................................................... 93
Figure 15: How often do companies evaluate risks in each of the following areas in relation to
an excursion from a non-final OTC monograph? ....................................................... 94

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Figure 16: In your current or past experience, what is the overall impact of non-final OTC drug
monographs on OTC drug industry operations?......................................................... 95
Figure 17: In your current or past experience, how important is the impact of non-final
monographs on OTC drug industry operations?......................................................... 96
Figure 18: When an excursion is made from a non-final monograph on a commercialized OTC
drug product, are mitigation plans developed in advance for the monograph
excursions to be “corrected” once the monograph becomes final? ............................ 97
Figure 19: What is your opinion of how a non-final monograph, as opposed to a finalized
monograph, may affect product innovation? .............................................................. 98
Figure 20: What, if anything, would you change about the monograph system to improve it?
(Selected responses by type.)...................................................................................... 99

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ABSTRACT
This exploratory study examined the impact of incomplete OTC drug monographs on the OTC
drug industry by employing a survey approach. The study focused on opinions and perceptions
of survey participants who have experience in an OTC drug industry setting and who have
experience with OTC monograph products for which a monograph is not final. A triad of
principles relating to the goals of regulation was used as a framework for this research to
interpret the literature, to structure the survey, and to help interpret and frame the research
results. The three identified goals of regulation are 1) to ensure the safety and effectiveness of
drug products, 2) to facilitate efficiencies in the management of research, commercialization, and
costs, and 3) to equalize requirements and standards for the industry. The study results suggest
that non-final monographs are falling short when considering two of the three framework
elements. Although there is some evidence that non-final monographs help to ensure the safety
and effectiveness of OTC drug products, the present research suggests that efficiencies in
research and commercialization may be reduced in an environment in which monographs are not
finalized. Further, this environment contributes to the perception that an uneven playing field
exists for OTC manufacturers.

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CHAPTER 1: OVERVIEW OF THE STUDY
1.1 Introduction
Self-medication is an important way in which American consumers treat many types of illnesses.
Over-the-counter (OTC) drugs often provide effective relief in a cost-effective and accessible
manner and thus represent the first choice of treatment for many ailments. According to the
United States Food and Drug Administration (FDA), six out of every ten medications bought by
consumers are OTC drugs (FDA, 2010a). More than 80 therapeutic categories of OTC drugs
exist and represent an estimated 500,000 products, including examples such as acne products,
sunscreens, laxatives, toothpastes, and medications for eye care, first aid, and colds. The
particular advantages of OTC drug products include their relatively low cost and wide safety
margins. Thus, regulatory agencies typically recognize that access to such products, which have
proven to be largely safe in the hands of the consumer, require less regulatory oversight than
products with more risks or shorter histories on the market. This view is reflected in the reduced
regulatory requirements for OTC products.
The United States (US) regulatory system for OTC products has a 40-year history of
development. The process started with a seminal decision on May 11, 1972 to officially
differentiate OTC drugs from prescription drugs, using a set of reviews to evaluate the safety and
efficacy of OTC drug products then marketed in the US. The review process was designed to
evaluate the safety and efficacy of drugs by therapeutic group, rather than on a product-by-
product basis. Drugs with safety problems were required to be removed from the market.

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Drugs that were judged to be safe and efficacious would be managed through a process in which
acceptable methods for production and labeling were specified in what came to be called a “drug
monograph.” A monograph, in this case, is a standard that defines what is allowed and how to
label an OTC drug product. Specific elements of a monograph include allowable active
ingredients, combinations of ingredients, dosages, indications, warnings, precautions, adequate
directions for use, and any other conditions or requirements necessary for safe and appropriate
use of the drug product. Under such a system, any OTC drug product that could be produced in
conformity to a monograph would be allowed to be manufactured and sold in the US without an
individual product license.
The OTC review process used to discriminate safe and effective products was originally
constructed to follow a straightforward regulatory process of notice and comment rulemaking.
The reviews relied on expert panel recommendations and information submitted from industry,
all centered on active ingredients in specific therapeutic categories. From this review was to
emerge a set of regulations that specified the content of the final monograph for each product
group. The final monograph would therefore document FDA’s intent regarding a medical
product, although interpretation and application for a specific product or situation might be
necessary on a case-by-case basis. The finalized OTC monographs would describe a given
product by therapeutic category and active ingredients, and would be more detailed and
comprehensive than many other types of FDA regulations. Thus, the collection of monographs
is often referred to as a “recipe book” for OTC drug production (CHPA, 2010a). Although
manufacturers have some discretion under a monograph in regard, for example, to inactive

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ingredients and product claims, many characteristics and requirements of a drug product are
typically well defined in a final monograph. Once a monograph has been published,
manufacturers are obligated to satisfy its requirements. However, when a monograph is
incomplete, the picture is not so clear. Manufacturers are often placed in a situation in which
they are unsure of the exact requirements to satisfy the FDA with regard to the OTC drug that
will eventually be subject to the requirements of the final monograph when it is published.
Concerns about incomplete monographs can be identified in the current literature since several
such product monographs remain in an incomplete form. Many of these monographs have been
in this incomplete state for decades. This incomplete status affects the OTC drug industry
because it provides potential advantages and disadvantages for commercial practice and makes
some parts of product planning difficult. The information contained in an incomplete
monograph is generally considered to represent the most current thinking of the FDA and
therefore is the mechanism by which products should be marketed until FDA issues a final
monograph. Nevertheless, by its very nature, an incomplete monograph is evidence that FDA
review and examination of the category may not be finished. Until a final monograph has been
published, no substantiated and conclusive determination by the Agency can be identified to
which a company can point when trying to assure a drug’s safety and effectiveness.
The protracted process for monograph development results in a range of documents that mark
different stages of monograph formation. The most obvious examples are tentative or proposed
monographs and rules. However, there are a number of other examples. Withdrawn

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monographs are a case in point; FDA may announce that it intends to issue more information in
the future but that products already on the market may continue to be sold. Examples can also
be recognized in which the monograph is final but is expected to be revised because a significant
amendment to the contents of the monograph is pending. Yet another example is that in which a
company submits a citizen petition or perhaps even a Time and Extent Application (TEA) to
alter the tentative monograph and subsequently markets the product accordingly in the interim
and during the FDA evaluation period, which may be ongoing for years. All of these situations
may affect the approaches taken by manufacturers to develop, label, and market their products.
Financial and competitive implications for manufacturers may also influence the approaches that
are taken. Since OTC drugs are typically sold at a lower price point and profit margin than
prescription drugs, seemingly small regulatory issues or changes, particularly during the
incomplete monograph state, may significantly affect the manufacturers of those drugs.
Incomplete monographs can also affect the confidence that the OTC drug industry may have in
its commercial strategy. The final manner in which the therapeutic area will be regulated by
FDA is not known or understood completely until the monograph is finalized. Nevertheless, a
product may continue to be marketed legally, often for many years, while the monograph is
under review by FDA. Interestingly, FDA has said that it will not enforce monographs until they
are final unless there is an issue affecting safety or efficacy (FDA, 2007). This means that
companies have broad leeway to apply or not apply certain aspects of the incomplete monograph
as they see fit. This critical aspect of the monograph regulatory system gives manufacturers the
potential to deviate from an incomplete monograph. Therefore, a multitude of issues and

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ambiguous situations related to legal, ethical, competitive, financial, and compliance status may
derive from the absence of final monographs for OTC manufacturers.
Although the US pharmaceutical regulatory system is considered a mature system and a system
that many other countries strive to replicate, the system is not without areas for improvement.
The OTC monograph program was intended to provide a practical notice and comment rule-
making process to simplify the large OTC regulatory burden at the time of OTC review and
classification. It was also intended to provide a flexible system going forward. Assumed at that
time to take only a few years, the process eventually proved to be the single largest task ever
undertaken by FDA (Pray & Pray, 2003). The OTC monograph system has affected thousands
of products and has yet to be completed as of the time of this writing. What has resulted is a
complicated process that has created an opaque regulatory structure, to be interpreted by
manufacturers in various ways over long periods of time. In fact, the existence of incomplete
OTC monographs seems to defy the definition of the word regulation itself, meaning laws
prescribed by authority in order to clarify and standardize requirements.
1.2 Statement of the Problem
The OTC drug industry is a critical part of our healthcare system; it makes hundreds of
thousands of drug products many of which are in common daily use. The availability of a
monograph greatly facilitates the production and labeling of a particular OTC drug, compared to
the process needed for a prescription or OTC drug that has no monograph and that must be
approved by a very lengthy and expensive New Drug Application (NDA). However, the OTC

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manufacturer must take full responsibility to ensure that the product meets the guidelines or
requirements described in an OTC monograph. When a monograph is in a draft or tentative
state, an OTC drug is not generally subject to regulatory jeopardy based on its failure to adhere
to that monograph unless safety or efficacy issues arise. This freedom offers considerable room
for manufacturers to determine how they wish to interpret non-final monographs and to market
the affected OTC drugs. Currently, about twenty-five percent of the OTC drug monographs are
in a tentative state, affecting thousands of marketed drug products. To date, a modest literature
exists suggesting that both advantages and disadvantages may be identified by manufacturers as
a result of this situation. However, no systematic examination has been published to date about
the views of OTC manufacturers with regard to the impact of the incomplete monographs on
their business.
Because the consequences to manufacturers have received little study, a number of questions
remain difficult to answer. Does industry see the period after the publication of a tentative
monograph as a protected phase prior to promulgation of the final monograph, in which drug
products are not necessarily required to be in compliance with the specifics of the monograph?
Does this then become a unique playground for creative regulatory possibilities, as long as no
safety or efficacy concerns are posed? Does the inability to predict the date at which the
monograph will be finalized drive manufacturers to develop pre-emptive “fixes” for issues to
have in reserve in the event that the monograph becomes finalized in the near future? Or, does
industry view this phase as a legal quagmire that necessarily implies increased corporate risk that
they would try to avoid?

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1.3 Purpose of the Study
The purpose of this study is to determine the impact on industry of incomplete OTC
monographs. In this work, I wish to study whether industry regards the delay, and therefore the
opportunity to work under a tentative monograph, as a positive, negative, or perhaps even a
neutral situation. More specifically, I will study the elements that contribute to industry views
by surveying a population of industry professionals experienced in working with products
affected by incomplete OTC monographs. The survey will consist of questions relative to the
framework chosen to structure and analyze this work. The framework I will use is based on a
triad of objectives that pharmaceutical regulations are designed to accomplish: 1) to help ensure
the safety and effectiveness of drug products, 2) to facilitate efficiencies in the management of
research, commercialization, and costs, and 3) to equalize requirements and standards for the
different industry competitors and players. Thus, the survey questions will be grouped around
these three areas and will include the following topics:
 Are excursions from the tentative monograph with respect to the selection of
ingredients, dosages, forms, and indications, for example, typical when a monograph
is not final? If so, how much risk is perceived by the manufacturer in the areas of
safety and compliance?
 Does the amount of time that a monograph remains incomplete weigh into the
decision making process on how industry proceeds with its marketing strategy? Is
consideration given to the estimated date of final monograph publication and are
associated mitigation plans developed for any risks? Does industry attempt to

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persuade FDA to finalize incomplete monographs in an accelerated manner, and, if
so, upon what basis?
 How do companies deal with competitors who may be deviating from the
monograph? In such a case, is there increased pressure on other manufacturers to act
in a similar manner in order to remain competitive? Some manufacturers may see an
incomplete monograph as risky whereas other manufacturers may view it as an
opportunity to broaden OTC drug development and marketing possibilities with less
concern or fear of legal implications. What are the advantages and disadvantages in
the eyes of industry stakeholders and why?
1.4 Importance of the Study
In 2006, the FDA celebrated the 100th anniversary of its role to foster the safety of health
products in the United States. The approaches employed by FDA are commonly considered to
be the gold standard to which other countries look for model regulatory processes and programs.
When the OTC review process began in 1972, it was considered to be an innovative regulatory
approach to deal with an almost overwhelming task. The process, however, has taken much
longer to complete than originally intended and has left many products and manufacturers facing
a regulatory gray area that is not fully understood. The current published literature on OTC
monographs largely deals with the history of the program and events specific to individual
monographs but does not address how industry is affected. This study will contribute to an
understanding of the impact of the incomplete monographs on industry. It should also provide

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critical insights for policy makers and regulators in order to understand the effects of their
actions on OTC drug manufacturers. The study should also contribute to an understanding of
how affected OTC drug products are developed and marketed, from an industry point of view,
therefore providing important insights on existing marketed OTC products.
From the point of view of industry, this thesis will provide specific information on how
companies are affected by incomplete OTC drug regulation. It will help to identify problem
areas likely to occur as a result of non-final regulation as well as areas that are beneficial to
industry in such cases. The study may also provide industry with a better understanding of how
other companies are approaching risk and how they perceive and potentially mitigate such risk
for affected OTC drug products. Information from this study may also assist industry in
understanding how to approach FDA for regulatory changes.
From the point of view of the regulator, this study will provide data that may help to refine the
processes associated with future OTC regulation. Janet Woodcock, director of FDA’s Center for
Drug Evaluation and Research (CDER), has acknowledged the Agency’s slow pace of finalizing
regulations, and in particular its delays in finalizing its nonprescription drug monographs (Shiff,
2011). FDA even became the target of litigation over the pace and procedures for OTC drug
review in 1981, only 9 years after the OTC review began ("Mimi Cutler, Stephen D. Annand and
National Council of Senior Citizens, Appellants, v. Dr. Arthur Hull Hayes, Jr. et al.," 1987).
Clearly, FDA is aware of the challenges inherent in the OTC monograph system but may not be
aware of the specific ways in which it impacts the OTC industry. The results of this study
should help to illuminate issues related to OTC drugs that are currently not well understood by

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both regulators and policy makers. Ideally, the findings of the study will contribute to a better
understanding of this multi-faceted area and bring more attention to possible next steps that may
be taken by FDA to improve the regulatory environment. This study may also help to enhance
communication between industry and regulators by providing data upon which dialogue can be
based to take next steps.
1.5 Limitations, Delimitations, Assumptions
This study is delimited to the evaluation of OTC monograph drugs in the United States for which
regulation is not final or complete. For the purposes of this study, final monographs are defined
as those for which a final monograph has been established and for which no pending rules or
other pending actions exist. It is important to note that for some final monographs, a proposed
rule may exist for an ingredient, for example, which would therefore render the monograph
incomplete for our study purposes and which may, therefore, be included as part of this research.
Over-the-counter drugs that have been approved by a New Drug Application (NDA) are not
included in this study because they are not regulated by the monograph system. Similarly,
prescription drugs that have switched from Rx status to OTC status and are not part of the
monograph system are also not included for the same reason. It should also be noted that the
United States Pharmacopeia (USP) monograph system is not part of this study because the USP
monographs have a different purpose to provide testing methods for ingredients and finished
products.

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A potential limitation of this research will be the ability to sample a representative group of
appropriate individuals who work with OTC drug companies that manufacture and market
products for which there is an incomplete monograph. Identifying appropriate personnel in such
companies who will respond to a survey will be a primary challenge and will produce a sample
size that is relatively small. The level of experience of the sampled individuals may also impact
the quality of their responses, particularly in the case of evaluating risk and impact to the
company. Ideally, the surveyed individual will have regulatory experience. The willingness of
such individuals to participate in the study may be affected by the nature of the questions.
Individuals and companies may be reluctant to answer any survey questions that could be
perceived to query confidential, proprietary, or even strategic corporate information and this
must be taken into account when designing the survey. An assumption is made that individuals
will answer the questions honestly but it is possible that they may not.
1.6 Definitions
Over the counter (OTC) Drug
A drug that does not require a prescription from a healthcare provider in order to purchase it.
Advance Notice of Proposed Rulemaking (ANPR)
Publication in the Federal Register of the original expert panel’s proposed monograph. This is
commonly referred to as a Proposed Monograph.

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Notice of Proposed Rulemaking (NPR)
Publication in the Federal Register of the FDA’s response to public comments received from the
Advance Notice of Proposed Rulemaking stage. The monograph is also updated accordingly.
This is commonly referred to as a Tentative Final Monograph.
Final Monograph (FM)
Publication in the Federal Register of the final rule establishing conditions under which a
category of OTC drugs or a specific OTC drug or drugs are generally recognized as safe and
effective and not misbranded. The monograph becomes effective and enforceable on the date
specified in the order.
Incomplete or Non-Final Monograph
A monograph that has not been published in the Federal Register as a final rule. If at any point a
final monograph or rule is reopened or for which other pending actions exist, it is no longer
considered final. (It is important to note that for some final monographs, a proposed rule may
exist for an ingredient, for example, which would therefore render the monograph incomplete for
our study purposes.)
Safety
A low incidence of adverse reactions or significant side effects under adequate directions for use
and warning against unsafe use as well as low potential for harm which may result from abuse
under conditions of widespread availability (FDA, 2011c).

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Effectiveness
A reasonable expectation that in a significant proportion of the target population the
pharmacological effect of the drug, when used under adequate directions for use and warnings
against unsafe use, will provide clinically significant relief of the type claimed (FDA, 2011c).
1.7 Organization of the Study
This study is organized into 5 chapters. Chapter 1 includes an overview of the problem and an
introduction to the research. Next, Chapter 2 reviews the historical development of the
monograph system, the current state of affairs, and an analysis of current literature. Chapter 3
then defines the methodology to be used in the research including sampling, populations,
instrumentation, data collection, and analysis. Chapter 4 analyzes the results of the survey
including the specific findings related to individual survey questions. Chapter 5 then provides an
overall discussion of the research results including conclusions and implications.

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CHAPTER 2: LITERATURE REVIEW
2.1 Introduction
The role and effectiveness of government regulation has been a subject of concern for almost as
long as governments have existed. In the pharmaceutical sector, most agree that regulations are
necessary to accomplish several goals. These goals include ensuring the safety and effectiveness
of drug products relative to risks, fostering efficiencies in the management of research,
commercialization, and costs, and leveling the requirements for competitors in the marketplace
(FDA, 2009, 2012; Seiguer & Smith, 2005). The resulting regulations shape the structure and
conduct of the pharmaceutical industry and impact the development and marketing of its drug
products. On one hand, the presence of clear regulations can have a beneficial effect in
clarifying the rules for industry and avoiding inconsistent expectations, but on the other, those
same clear regulations can be seen as an impediment to creative and often profitable approaches
to product development and commercialization. This problem is of particular concern for OTC
drugs. Regulations for certain therapeutic categories of drugs have not been finalized by the
FDA. The role and effectiveness of OTC monograph regulation from an industry point of view,
including its outcomes and impact, are not well understood and thus are the subject of research
to be described in this thesis.
OTC monograph drugs without a final FDA determination regarding safety and effectiveness are
routinely sold and used by consumers. The reasons for this incomplete regulation are multi-
factorial. The regulatory review system for OTC drugs was intended to be a transparent, multi-

26
step process to protect the rights of both consumers and manufacturers while encouraging input
from all concerned. The need for transparency and input was considered essential to the
legitimacy and representativeness of the regulatory process. Although the OTC review process
was designed to be simple to understand, the number of elements to be studied and the
requirements for multiple activities related to its execution have ensured that the process itself
has become lengthy and inherently complicated. Much has been written in the literature about
the monograph regulatory process including the progress and complications of developing
regulatory policy. However, there is a paucity of information in the literature specifically
addressing the impact of incomplete monographs on the industry.
In the literature analyzed in this chapter, I first examine the regulatory history of OTC drugs.
The need for systematic regulation of OTC drugs became apparent in the second half of the
twentieth century and has since resulted in a complex history of more than forty years. Next, the
current regulatory environment surrounding OTC products is examined. I describe the
monographs that are still in process and the major issues that have been identified as a result
from both FDA and industry perspectives. Finally, a framework is identified and explained in
which OTC drug regulations and pharmaceutical policy can be interpreted and examined.

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2.2 History of the OTC Review Process
2.2.1 OTC Regulatory Foundations
Federal pharmaceutical regulations have existed in the United States for over one hundred years.
The foundations for OTC drug regulation date to the Federal Food, Drug, and Cosmetic Act of
1938 (FD&C Act) which is the fundamental law controlling all drug approvals in the US.
Passage of the FD&C Act was a seminal event in response to public fears over unsafe drugs.
The Act authorized FDA to demand evidence of safety for new drugs, among other provisions.
This law, with its amendments, is still in effect today and serves as a basis for oversight of the
pharmaceutical industry by FDA.
Early iterations of the FD&C Act introduced definitions to differentiate drugs from medical
devices but were silent on subcategories of drug products. As a matter of practice, drugs were
generally segregated as “ethical” and “proprietary or over-the-counter.” The term ethical was
not clearly defined but referred to products primarily directed to be used and prescribed by
physicians and other health care professionals. It was not until 1951, however, that the Durham-
Humphrey Amendment to the FD&C Act formally differentiated prescription and OTC drugs.
The Durham-Humphrey Amendment revised the Act to add a specific section, 503(b)(1), that
defined prescription drugs as those which cannot be used safely without medical supervision and
those that must be dispensed by prescription; in all other cases, drugs must be available OTC.
Thus, any drug that could be OTC, must be OTC (Soller, 1999). This differentiation remains the
foundation and legal basis for the current two-class drug system in the United States.

28
In 1962, another significant change to the FD&C Act, the Kefauver-Harris Amendment, was
passed. This amendment strengthened the rules for drug safety and, for the first time, required
manufacturers to prove the effectiveness of the drugs that they sold. As a result of this
amendment, FDA arranged for the National Academy of Sciences and National Research
Council (NAS/NRC) to examine the effectiveness of thousands of drugs approved before the
1962 Amendment came into force. Manufacturers were ordered to submit reports containing
evidence of the efficacy claims for their drugs. This review was called the Drug Efficacy Study
Implementation (DESI) Review. The review consisted of an examination of the efficacy of all
drugs covered by NDAs, including about 3500 prescription drugs and 420 OTC drugs (FDA,
1972a). According to FDA, only about 25% of the 420 OTC drugs for which NDAs had been
submitted had an indication for which the drug could be classified as effective, leaving
approximately 75% undetermined or ineffective. As a result of this poor showing, FDA
concluded that “these evaluations (of OTC drugs) present questions that must be confronted by
industry and government” (FDA, 1972a). Consequently, FDA decided that a comprehensive
review of OTC drug products was needed to make a final determination of safety and
effectiveness. In January 1972, FDA published a proposal to begin the review.
2.2.2 Regulating OTC Drugs More Systematically
Prior to 1962, OTC drug products were not meaningfully differentiated from prescription drugs
by regulation and existed in an unclear regulatory space in which safety and efficacy were
largely unproven. OTC drugs typically did not raise serious safety questions, so that FDA
generally only acted against OTC drugs when therapeutic claims violated the misbranding

29
provisions of the FD&C Act. After 1962 and after the conclusion of the DESI review process,
FDA considered how OTC drugs could be regulated more systematically. According to FDA,
estimates in 1972 of the number of OTC drugs on the market varied from 100,000 to 500,000
(FDA, 1972a). In order to implement the efficacy requirements of the 1962 Amendment for
OTC drugs, FDA appeared to have only two options: review each marketed drug on an
individual basis or adopt new procedures that would allow OTC drugs to be grouped and then
reviewed according to therapeutic category. Because it would be impractical to review
thousands of OTC drug products individually, FDA determined that an industry-wide evaluation
by therapeutic category was the best approach. In the preamble to the 1972 proposed
rulemaking published in the Federal Register, FDA noted that resources were limited and that
case-by-case litigation to remove violative OTC products was impractical. Further, the review
process of individual products might be so lengthy given the number of products queued for
evaluation, that safety of the consumer could not be assured in the interim. Classification of
drug products into therapeutic categories was seen as feasible because only about 200 active
ingredients were estimated to be included in the thousands of marketed OTC products at the
time.
The final procedural regulations of the Review, issued in May 1972, were designed to classify
OTC drugs as “generally recognized among qualified experts as safe and effective (GRAS/E)
and not misbranded under prescribed, recommended, or suggested conditions of use” (FDA,
1972a). The OTC review was structured to include only products with the same formulation and
labeling as drugs that were already in the marketplace on or before May 11, 1972, a deadline

30
later extended to December 4, 1975 (Noah, 2006). Additionally, only drugs that had already
been marketed to a “material extent” and for a “material time” could be included in a
monograph. The original procedures established twenty-six therapeutic categories, each to be
covered by a monograph (Table 1). All the categories of products and all the active ingredients
within those categories were required to be on the US market at the time the Review began. The
26 original therapeutic categories were later further divided into 88 subcategories.
Table 1: Original Categories Designated to be Covered by a Monograph (FDA, 1972b)
Twenty-six Original Categories Designated to be Covered by a Monograph
Federal Register, May 1972
Antacids Analgesics Laxatives
Sedatives and sleep aids Antidiarrheal products Stimulants
Emetics Antitussives Antiemetics
Allergy treatments Antiperspirants Cold remedies
Sunburn treatment & prevention Antirheumatic Vitamin-minerals
Opthalmic Antimicrobial Contraceptives
Dandruff products Miscellaneous dermatologic Oral hygiene aids
Dentifrices & dental products Hemorrhoidal products Miscellaneous
Hematinics Bronchodilator & antiasthmatics

The ability of the OTC review process to proceed depended on access to data from which the
safety and efficacy of OTC drug products could be determined. In order to obtain that data,
FDA needed input from the industry and initiated what is known as a “call for data” which was a
request for previously unpublished as well as published information on OTC active ingredients

31
by therapeutic category. Although submission of data by drug companies was voluntary, the
inference was clear that failure to substantiate the general recognition of the safety and
effectiveness of a product in the OTC Review could have serious repercussions for a product that
was under OTC review. Failure to produce data either could have resulted in classification of
the product as a new drug with the consequent need for a long resubmission process, or could
have threatened removal from the market altogether (Horton, 1993). Thus, manufacturers were
generally eager to submit their information to FDA in support of the process. FDA received
over 22,000 volumes of data during the request period (Cooley, 2002). It has been suggested
that more data was developed and researched during this period of time of the review than in all
the years of FDA’s existence since 1906 ("McNamara v. C.B. Fleet," 2009).
2.2.3 Phases of the OTC Review Process
2.2.3.1 Phase 1
From a procedural standpoint, the OTC Drug Review was to consist of four distinct phases.
(Figure 1). In the first phase, which is now complete, FDA established 17 panels of outside
experts to evaluate the literature, studies, and data received for each category of OTC drugs. The
17 advisory review panels were originally created to review ingredients in nonprescription
products and determine whether the ingredients could be generally recognized as safe and
effective (GRAS/E) for self-treatment (FDA, 2010c). The term “generally recognized as safe”
was meant to signal that adverse reactions or significant side effects were infrequent, given
adequate directions for use and warnings, so that risks for harm were not unacceptable even

32
though the product would be available widely. The additional term “generally recognized as
effective” signified a reasonable expectation that the pharmacological effect of the drug would
provide clinically significant relief as claimed, in a significant portion of the target population
and when used under adequate directions for use (The Comptroller General's Report to the
Congress of the United States, 1982).
Figure 1: Phases of the OTC Drug Review
PHASE 1
Data review by expert panels Data review by expert panels
Classification of active as category I, II, or III Classification of active as category I, II, or III
Report sent to FDA Report sent to FDA
PHASE 2
FDA Review of the panel report
Development of a Proposed Monograph
PHASE 3
FDA Review comments on
the Proposed Monograph and publication of
A tentative final monograph
Publication of Proposed
Monograph in the Federal
Register
PHASE 4
FDA Review of comments on the
Tentative Final Monograph
Publication of a Final Monograph
Publication of Tentative Final
Monograph in the Federal
Register
Publication of Final
Monograph in the Federal
Register

The use of outside experts for the panels as part of the OTC Drug Review was necessary because
FDA did not have adequate personnel or the expertise to deal with the large quantity and variety
of data to be assessed. The 17 expert panels each consisted of seven voting members with

33
additional non-voting members allowed to represent industry and consumers. Most of the
panels reviewed data for more than one therapeutic category. There was no set timeline for the
panels to finish their work; they were instructed by FDA to meet “as often and for as long as
appropriate to review the data” and to prepare a report (FDA, 1972b). After completing their
reviews, each expert panel was to submit a report to FDA detailing its findings, conclusions, and
recommendations for a product monograph. The reports reflected extensive communication
between FDA, the industry, and consumer groups. The reports included labeling indications,
warnings, adequate directions for use, and any other conditions necessary for safe and
appropriate use of the drug product. The panels also placed all active ingredients into one of
three categories:
 Category I: active ingredients generally recognized as safe and effective and not
misbranded
 Category II: active ingredients determined to not be safe and/or effective
 Category III: active ingredients not clearly in either category I or category II and
needed further scientific evidence to reach a conclusion
2.2.3.2 Phase 2
In the second phase of the OTC Drug Review, FDA reviewed the expert panel’s reports. Each
was subsequently published with a proposed monograph in the Federal Register. The official
title of the publication at this stage is “Advance Notice of Proposed Rulemaking”, or more
informally, Proposed Monograph. The Federal Register publication also included a detailed

34
discussion, or preamble, that was written by FDA, where FDA commented and even explained
differences of opinion with regard to recommendations of the panel. The preamble, therefore,
became a rich resource for additional information and insights on the decisions underlying
monograph development. The Proposed Monograph typically remained open for public
comment for several months; the comment period could be extended for longer periods as
needed in the opinion of the FDA or by request through public petition. This information-
gathering process is part of “notice and comment” rulemaking that allows affected
manufacturers and other stakeholders to identify points of agreement or disagreement with the
proposed monograph. This second phase of the OTC Drug Review process is also now complete
for all products.
2.2.3.3 Phase 3
In the third stage of the Review, which is now largely complete, FDA was required to review all
comments received on the Proposed Monograph and respond to them in another published
document, Notice of Proposed Rulemaking, commonly known as a Tentative Final Monograph.
FDA has identified that the tentative final monograph is the most difficult OTC monograph
document to develop because it requires response to the voluminous comments often received
(Gardner, 1980). Commonly, a proposed monograph received between 50 and 100 comments,
but some monographs had over a thousand comments (Baumgartner, 1988). After all the
comments had been considered, a Tentative Final Monograph would be developed to share
FDA’s proposed text for a Final Monograph. Tentative Final Monographs were then opened for
public comment, leading to the last stage of the review process.

35
2.2.3.4 Phase 4
In the fourth and final stage of the OTC Drug Review, which is not complete for all categories,
FDA was to consider the comments received at the Tentative Final stage, respond to them in the
preamble, and publish a Final Monograph. This stage of the process is perhaps the most
important because its output is the final, enforceable monograph that establishes FDA’s
conclusions on the safety and effectiveness of the active ingredients and the therapeutic category
itself. This stage is also currently incomplete for approximately 25% of the monographs.
The classification of a monograph as final does not necessarily mean the process of monograph
writing has ended. At any point during monograph development and even after publication as a
final monograph, administrative procedures allow a separate rule to be published that can
classify specific ingredients as non-GRAS/E, and thereby exclude them from a monograph.
According to FDA, this process can occur in advance of a final monograph in order to expedite
completion of the OTC Drug Review. In the event that an active ingredient is identified as non-
GRAS/E in a final rule, the active ingredient may not be legally used in an OTC drug product.
In this case, the ingredient may not be used even if the main category monograph is not final.
Other conditions of the non-final monograph, however, remain non-final and are not subject to
action by FDA unless there is a safety concern.

36
2.3 Significant Developments Since 1972
2.3.1 Ingredient Accomplishments
The OTC reviews have resulted in far-reaching effects including a mixture of completed
regulatory actions on one hand, and long-standing incomplete regulations on the other. What
are examples of successful accomplishments? FDA was able to remove over 500 compounds
from the market during the original review process. FDA also eventually determined that only
270 or so active ingredients were generally recognized as safe and effective for their intended
uses. FDA also issued negative monographs and final rules for some ingredients which prohibit
the use of specific OTC drug ingredients for certain indications. Examples included boric acid
for topical acne, sulfur as a skin protectant, and mercury as a skin-bleaching agent (FDA, 1990
#87). Further, FDA completed final rules regarding specific non-monograph ingredients.
More recently in 2008, FDA attempted to finalize certain original long-standing incomplete
ingredient categories from 1973 and 1975, categories that were not reviewed by the advisory
panels because of resource limitations (FDA, 2003b). As part of the recent process, FDA
responded to a 2003 call for data regarding identified categories of ingredients that were eligible
for the original review but were not reviewed by FDA. In 2008, FDA published a proposed rule
identifying a number of active ingredients for specified indications as not meeting the GRAS/E
level of expectation because submitted data was inadequate. FDA also noted that other
ingredients for which data was submitted would be discussed in future issues of the Federal
Register. Although these actions by FDA were clearly intended to clarify the status of active

37
ingredients from decades ago, the status of such products remains “proposed” or “to be discussed
at a future time”.
2.3.2 Procedural Inefficiency
Although the OTC review system proved capable of producing regulatory actions and final
regulations in some cases, early evidence pointed to inefficiencies and slow progress. One such
example was apparent from a lawsuit, Cutler v. Hayes, initiated in 1983 and decided in 1987
after appeals. In this suit, a group of consumers alleged that regulations implementing the OTC
review program violated the FD&C Act. Specifically, the suit alleged that the non-enforcement
of the efficacy requirement for marketing OTC drugs had lasted over 20 years since the
amendment to the FD&C Act and, therefore, violated FDA’s statutory duty to act in a reasonable
timeframe. The lawsuit essentially challenged both the legality of the regulations covering the
OTC drug review and the progress of the program. The suit also alleged that FDA’s lack of
progress in completing the review program infringed on the provisions of the Administrative
Procedure Act, which disapproved unreasonable administrative delay. The claims were
eventually rejected by the courts based on the voluntary nature of many provisions in the OTC
drug system and the complexity of the review program ("Mimi Cutler, Stephen D. Annand and
National Council of Senior Citizens, Appellants, v. Dr. Arthur Hull Hayes, Jr. et al.," 1987).
Although the lawsuit did not change the FDA OTC drug review system, its organization, or its
rate of progress on monograph completion, it did bring attention to some of the program’s
shortcomings.

38
2.3.3 Changes in OTC Support and Regulation
The OTC review program and the associated supporting infrastructure at FDA existed with little
change for two decades after 1972. It became clear, however, that changes were needed to
support the OTC products and the review program in order to improve its efficiency and
effectiveness. In the early 1990s, initiatives were taken that brought new structure and culture
to parts of the FDA that were concerned with OTC drugs. Important to this process was the
creation of the Office of OTC Drug Evaluation at FDA in 1991. The purpose of the new office
was to raise awareness and expand the Division of OTC Drugs so that a higher priority could be
placed on OTC regulation (Bachrach, 1993). This office can be recognized today in its most
recent iteration as the Office of Nonprescription Products in the Office of New Drugs. Within
the Office, the Division of Nonprescription Regulation Development focuses on the
development of OTC drug monographs and other nonprescription drug activities. Also in the
early 1990s, a Nonprescription Drugs Advisory Committee was created to review OTC
ingredients and advise the FDA Commissioner on the promulgation of monographs (FDA,
2010b). This signaled an important change in FDA organization and priorities to focus more
attention on OTC drug matters.
Shortly after its reorganization, in 1993, a new final rule was issued by FDA in which 415 OTC
active ingredients were recognized as failing to meet the standards for GRAS/E. In those efforts,
111 weight control active ingredients were removed in 1991 and 102 category III ingredients in
19 monographs were banned in 1990. These ingredients were contained in seven different
tentative final monographs for which the comment period had closed and no significant data to

39
upgrade the status had been submitted to FDA. FDA noted that the new action advanced two
earlier efforts to streamline the OTC monographs.
2.3.3.1 The TEA: Time and Extent Application
A major flaw of the monograph system to emerge with time was the absence of a simple way to
admit new active ingredients into the OTC review process. Concern was expressed by industry
that this limitation impeded new product development and jeopardized the effectiveness of the
monograph system as a whole (Steinberg, 2000). The only way to amend a monograph in any
state, tentative or final, was to add a new active ingredient by means of a process called a
“Citizen Petition”. A Citizen Petition is a method available to petition the government to issue,
amend, or revoke a regulation or to take some other administrative action (FDA, 2011b). A
Citizen Petition can call for the amendment or repeal of a condition that has been included in a
proposed or final monograph. However, a Citizen Petition could only be used in the case of
OTC drugs if the product was marketed in the US before 1975; thus products introduced after
the start of the OTC review could not be included. Further, the petition process is long and
unpredictable. Although FDA states a review time of 180 days for Citizen Petitions, this
expectation is rarely satisfied. In fact, FDA can take years to respond. According to an
Inspector General Report in 1998, the Agency had a backlog of 247 citizen petitions over 180
days old, with some petitions unanswered for more than 20 years (Brown, 1998). Because of
these issues, the Citizen Petition process was viewed as an inefficient and ineffective way to
amend a monograph. A new regulatory pathway was needed.

40
In 2002, FDA initiated the Time and Extent Application (TEA) procedure in an attempt to
improve monograph processes and facilitate efficiency for new active ingredients. In this
procedure, industry or individuals could petition to add a new ingredient to a monograph if it had
been marketed either in the US after 1975 or in another country for a material time and to a
material extent, among other conditions. The newly developed TEA process had two stages.
The first stage required the submission and review of an application to determine if the request
would be eligible to proceed. If eligible, the request could then proceed to a second stage
involving the submission of safety and effectiveness data (FDA, 2011a). Development of the
TEA process did signal to industry that FDA was attempting to address concerns regarding new
monograph ingredients. However, since 2002 only one such application has been acted on by
the FDA, despite requests in six therapeutic categories regarding twelve new ingredients. The
ingredient that had been addressed, Saccharomyces boulardii for antidiarrheal use, was
found to be inappropriate for OTC classification (FDA, 2010d). The other eleven ingredients
remain unaddressed and to date, no new ingredient has been introduced via the TEA process.
2.3.3.2 The 2007 Drug Acts
Signs of ongoing concern over lengthy monograph processes have persisted into recent years. In
2007, the Nonprescription Drug Modernization Act was introduced in Congress in the wake of
questions regarding FDA’s ability to address safety concerns due to the lengthy and protracted
OTC monograph process. The Act proposed to authorize FDA to amend a monograph without
notice and public process if that OTC drug or category of drugs could be proven to pose
significant risk or to lack efficacy. The proposed Act was introduced mainly in response to

41
problems that were recognized when OTC cough and cold drugs were used in children under the
age of 6. Because the notice and comment rulemaking processes can often take years to
complete, proponents of the bill were concerned that drugs which may cause serious harm could
potentially stay on the market in the interim. The bill also proposed to have FDA, rather than the
Federal Trade Commission (FTC), regulate OTC advertising (Waxman, 2007). The bill was
referred to committee in 2007 but has not moved forward since.
Prior to 2007, it was not mandatory to report serious adverse events (SAEs) to FDA for OTC
drugs, although some companies reported this information voluntarily. In 2007, however, the
Dietary Supplement and Nonprescription Drug Consumer Protection Act came into force and
required OTC companies to report SAEs for all OTC drugs without an approved application,
including OTC monograph drugs. The requirement under the new Act signaled increased
attention to the safety and effectiveness of OTC drugs. According to the Senate Report
accompanying the bill, the reporting system would enhance FDA’s effort to identify potential
public health issues and would enable the government, manufacturers, and retailers to respond
more quickly in the event of problems (FDA, 2006a).
2.3.4 Recently Identified Quality Concerns: Drug Impurities
Although questions related to the efficiency of the monograph system have dominated
discussions of the processes that had been put in place for OTC products, a recent concern that
can also be recognized in the literature involves the quality of monograph drugs with regard to
impurities. An OTC drug monograph does not specify the type or quality of inactive ingredients

42
that may be used, nor the overall quality specifications for a drug product. Further, a drug
subject to an OTC monograph does not receive individual FDA review or approval. The
director of the Division of Non-prescription Regulation Development at FDA recently noted that
impurities in OTC monograph products are a vulnerable quality gap “because no individual
quality assessment is performed by health authorities” (Winn, 2010). In October, 2010, as a
result of growing concern and attention, a new committee including experts from FDA, the
United States Pharmacopeia (USP), and the Consumer Healthcare Products Association (CHPA)
was formed to consider how to control impurities in OTC products (IPQ, 2010). USP
monographs address the identity, quality, purity, and strength of a product or its ingredients
whereas FDA OTC drug monographs address safety and efficacy. The impact of future changes
or new regulatory requirements for monograph drugs as a result of this committee’s work is
currently unknown. How any new impurity requirements may also affect FDA monograph
drugs in a tentative or even final state is also not yet clear.
2.4 Problems with Incomplete Monographs
Monographs that have not been finalized and those with significant ongoing review processes
represent a challenge for industry. Examples include the monographs for sunscreen products,
laxatives, antimicrobial products, skin-bleaching products, vaginal drug products, and internal
and external analgesics. Additional monographs that remain in an incomplete state and for
which at least one or more significant aspects are not finalized include antiseptic first aid,
menstrual products, oral healthcare, poison treatment, and vaginal contraceptives (Table 2).

43
Table 2: Monograph Status by Active Ingredient (CHPA, 2010c)

Monograph
1
Type Active Ingredients Monograph Status
2

Acne Products Single
ingredients

resorcinol, salicylic acid, sulfur Final, August 16, 1991
benzyl peroxide Final, March 4, 2010
Combinations resorcinol/sulfur Final, August 16, 1991
External
Analgesics
Single
ingredients and
combinations
benzocaine, butamben picrate, dibucaine,
dimethisoquin, dyclonine, lidocaine,
pramoxine, tetracaine, benzyl alcohol,
camphor, camphorated metacresol, juniper tar,
menthol, phenol, phenolate sodium,
resorcinol, diphenhydramine, tripelennamine,
hydrocortisone, allyl isothiocyanate,
ammonia, methyl salicylate, turpentine oil,
histamine dihydrochloride, methyl nicotinate,
capsaicin
TFM, February 8, 1983
Internal (oral)
Analgesics
Single
ingredients and
combinations
aspirin, acetaminophen, carbaspirin, salicylate
and its salts
TFM, November 16,
1988
Anorectal Single
ingredients and
combinations
Benzocaine, benzyl alcohol, dibucaine,
dyclonine, lidocaine, pramoxine, tetracaine,
ephedrine, epinephrine, phenylephrine,
aluminum hydroxide gel, cocoa butter,
glycerin, hard fat, kaolin, lanolin, mineral oil,
petrolatum, topical starch, white petrolatum,
calamine, cod liver oil, shark liver oil, zinc
oxide, camphor, juniper, menthol, calamine,
witch hazel, alcloxa, resorcinol
Final, August 3, 1990
Antacid Single
ingredients and
combinations
Aluminum-based antacids, bicarbonate-based
antacids, bismuth-based antacids, calcium
carbonate/citrate, citrate ion, glycine,
magnesium-based antacids, milk solids dried,
phosphate based antacids, potassium-based
antacids, sodium-based antacids, silicates,
tartaric acids or its salts
Final, June 4, 1974
Anthelminitcs Single
ingredients
Pyrantel pamoate Final, August 1, 1986

44
First Aid,
antibiotic
Single and
combination
ingredients
Bacitracin, bacitracin zinc, chlortetracycline,
neomycin sulfate, tetracycline
Final, December 11, 1987
First Aid,
antiseptic
Single
ingredients and
combinations
Alcohol, benzalkonium chloride,
benzethonium chloride, camphorated
metacresol, camphorated phenol, eucalyptol,
hexylresorcinol, hydrogen peroxide, iodine
tincture, iodine topical, isopropyl alcohol,
menthol, methylbenzethonium chloride,
methyl salicylate, phenol, povidone iodine,
thymol
TFM, July 22, 1991
First Aid,
healthcare
antiseptic
Single
ingredients
alcohol, povidone iodine, tincture, isopropyl
alcohol
TFM, June 17, 1994
Anticaries Single
ingredients
Sodium fluoride/monofluorophosphate,
stannous fluoride
Final, October 6, 1995
Antidiarrheal Single
ingredients
Bismuth subsalicylate, kaolin Final, April 17, 2003
Antiemetic Single
ingredients
Cyclizine, dimenhydrinate, diphenhydramine,
meclizine
Final, August 1, 1986
Antiflatulent single
ingredient and
combinations
Simethicone, combinations with antacids Final, June 4, 1974
Antifungal Single
ingredients
Cloquinol, haloprogin, miconazole, povidone
iodine, tolnaftate, undecylenic acid
Final, September 23, 1993
Antihistamine Single
ingredients
Brompheniramine, chlorcyclizine,
chlorpheniramine, dexbrompheniramine,
dexchlorpheniramine, diphenhydramine,
phenindamine, pheniramine, pyrilamine,
thonzylamine, tripolidine
Final, December 9, 1992
Antiperspirant Single
ingredients
Aluminum chlorohydrate, aluminum
chlorhydrex, aluminum zirconium and
derivatives
Final, June 9, 2003
Antitussive Single
ingredients
Chlophedianol, codeine, dextromethorphan,
camphor, menthol
Final, August 12, 1987
Bronchodialator Single
ingredients
Ephedrine, racephedrine Final, October 2, 1986
Chole-
cystokinetic
Single
ingredients
Corn oil Final, June 10, 1983

45
Corn, Callus,
and Wart
Remover
Single
ingredients
Salicylic acid Final, August 14, 1990
Dandruff Single
ingredient and
combinations
Coal tar, pyrithione zinc, salicylic acid,
selenium sulfide, sulfur
Final, December 4, 1991
Decongestant,
Nasal
Single
ingredients
Pseudoephedrine, phenylephrine, ephedrine,
naphazoline, oxymetazoline, phenylephrine,
propylhexedrine, xylometazoline
Final, August 23, 1994
Deodorant,
Internal
Single
ingredients
Bismuth subgallate, chlorophyllin copper
complex
Final, May 11, 1990
Laxative Single
ingredients and
combinations
Polycarbophil, psyllium, bran, cellulose,
karaya, malt soup extract, glycerin, sorbitol,
mineral oil, magnesium hydroxide, sodium
phosphate/biphosphate, magnesium
citrate/sulfate, bisacodyl, sennosides, castor
oil, dehydrocholic acid, docusate, carbon
dioxide releasing agents
TFM, January 15, 1985
Menstrual
Products
Single
ingredients and
combinations
Pamabrom, ammonium chloride, caffeine TFM, November 16,
1988
Nighttime sleep
aid
Single
ingredients
Diphenhydramine Final, February 14, 1989
Opthalmics Single
ingredients and
combinations
Zinc sulfate, cellulose derivatives, dextran 70,
gelatin, polyols, polyvinyl alcohol, povidone,
lanolin preparations, oleaginous ingredients,
sodium chloride, ephedrine, naphazoline,
phenylephrine, tetrahydrozoline, water,
tonicity agents
Final, March 4, 1988
Oral
Healthcare
Single
ingredients
Benzocaine, benzyl alcohol, dyclonine,
hexylresorcinol, menthol, phenol, alum, zinc
oxide, carbamide peroxide, hydrogen
peroxide, sodium bicarbonate, sodium
perborate monohydrate, elm bark, gelatin,
glycerin, pectin, benzoin tincture
TFM, January 27, 1988
Otics Single
ingredients
Carbamide peroxide Final, August 8, 1986
Pediculicides Combinations Pyrethrum extract/piperonyl butoxide Final, December 14, 1993
Poison
Treatment
Single
ingredients
Ipecac syrup, activated charcoal TFM, January 15, 1985

46
Skin Bleaching Single
ingredients
Hydroquinone TFM, January 15, 1985
Skin Protectants Single and
combination
ingredients
Allantoin, aluminum hydroxide gel, calamine,
cocoa butter, cod liver oil, colloidal oatmeal,
dimethicone, glycerin, hard fat, kaolin,
lanolin, mineral oil, petrolatum, sodium
bicarbonate, topical starch, white petrolatum,
zinc acetate, zinc carbonate, zinc oxide,
aluminum acetate, aluminum sulfate, witch
hazel,
Final, June 4, 2003
Stimulant Single
ingredients
caffeine Final, February 29, 1988
Sunscreen Single
ingredients and
combinations
Aminobenzoic acid (PABA), avobenzone,
cinoxate, dioxybenzone, homosalate, menthyl
anthranilate, octocrylene,
octylmethoxycinnamate, octyl salicylate,
oxybenzone, padimate O,
phenylbenzimidaxole sulfonic acid,
sulisobenzone, titanium dioxide, trolamine
salicylate, zinc oxide
Final, May 21, 1999 then
an indefinite stay of
enforcement
Vaginal
Contraceptives
Single
ingredients
Nonoxynol-9 FM Pending
Vaginal Drug
Products
-- -- Withdrawn
1
Does not include categories that were reviewed and found to have no GRAS ingredients
2
Does not include proposed or final rules issued in relation to monographs
TFM=Tentative Final Monograph
2.4.1 The Sunscreen Monograph
The sunscreen monograph is an example of one of the most problematic and complex
monographs. Fifteen years after FDA first announced its proposed rulemaking on sunscreens, a
tentative monograph was published in 1993. The document was a lengthy 600 pages when the
proposed regulation and the Agency’s responses to industry were collated. However, within a
year FDA reopened the process and extended the comment period to gain more input on
questions about ultraviolet-A (UVA) protection claims and testing methods, both of which had

47
been controversial (EWG, 2010). The tentative final monograph also set an upper limit on the
level of sun protection factor (SPF) that a sunscreen could claim (Jones, 1994). In 1999, FDA
issued a final sunscreen monograph that was scheduled to be effective in 2001. However, before
it became effective, FDA delayed the effective date for another year as a response to continuing
criticism that it had not addressed UVA protection and SPF concerns. Then in December 2001,
FDA delayed the sunscreen monograph indefinitely (FDA, 2010e). Published information has
described industry’s reaction to the ongoing process and to the tentative monograph as negative
(Francis, 2010; Jones, 1994). Concerns continue to include the failure to resolve controversies
over UVA content, issues of drug versus cosmetic claims, and the continued postponement of
final regulation. Pressure was brought by the House Appropriation Committee in the form of a
report instructing the FDA to issue a final sunscreen rule by December 31, 2011. FDA did issue
a final rule in June 2011 that addressed labeling and effectiveness testing issues (Elsevier, 2011).
At the same time, FDA also issued an additional proposed rule to limit the maximum-labeled
SPF value for OTC sunscreen drug products to 50+. FDA clearly noted in the 2011 publication
that a final sunscreen monograph with GRAS/E conditions was not part of the ruling and that a
final monograph would be published at a later date. That date has yet to be determined.
2.4.2 The Laxative Monograph
The Laxative monograph has been in a tentative final state since 1985. Its progress has been
complicated by the issuance of numerous proposed and final rules on certain topics but no
overall regulatory determination has been made on drug status in this category. In part, the
difficulties in this initiative could be related to the large size of the therapeutic category, which

48
covers more than 35 active ingredients and multiple product subcategories. This monograph is
particularly noteworthy because FDA issued an alert in December 2008 regarding the safety of
sodium phosphates for bowel cleansing purposes but has not yet issued a corresponding final
rule or final monograph (FDA, 2008). In February 2011, FDA did issue an intent for proposed
rulemaking to amend the tentative final monograph; this amendment would include the
determination that sodium phosphate salts were not GRAS/E for bowel cleansing. FDA also
proposed to remove professional labeling, i.e., information directed only towards healthcare
professionals, from the final monograph when published. FDA noted that the proposed rule was
the result of a careful review of new data and safety information on the serious side effects
associated with sodium phosphate solutions for bowel cleansing purposes prior to colonoscopy.
However, no final rule has yet been issued on the topic and the monograph itself remains in a
tentative final state.
2.4.3 The Antimicrobial Monograph
The topical antimicrobial monograph has also been pending for decades although it was one of
the first to be considered for review in the 1970s. The monograph is currently in a tentative final
state and has existed in that state since 1994. Only 2 active ingredients, povidone iodine and
alcohol, are currently classified as GRAS/E for hand sanitizers (FDA, 1994a). Five other active
ingredients were reviewed and placed in Category III, meaning insufficient data was available to
determine safety and that additional scientific support was needed to make a determination.
These ingredients included triclosan, triclocarban, benzalkonium chloride, benzethonium
chloride and parachlorometaxylenol. Because the monograph is currently in a tentative final

49
state, manufacturers are able to market hand sanitizers containing these Category III ingredients.
However, manufacturers are required to submit further safety and/or efficacy data to FDA to
prevent these ingredients from being excluded in the final monograph, when published.
Meanwhile, a complaint has been filed against FDA by an environmental action group in an
effort to force the Agency to finalize the monograph in respect to two of the category III
ingredients, triclosan and triclocarban. The group alleges that the ingredients pose health risks,
and are widely marketed by manufacturers (Karst, 2010). The situation currently remains
unresolved and the controversial products remain on the market.
2.4.4 The Skin-Bleaching Monograph
In August 2006 FDA withdrew the tentative final monograph for skin-bleaching products
published in 1982 and issued a new proposed rule that would establish all skin-bleaching drug
products to be non-monograph and to require a new drug application. FDA said that the use of
hydroquinone as an active ingredient in OTC skin bleaching products cannot be justified and
proposed that no skin bleaching products should be available OTC (FDA, 2006b). Prior to 2006,
skin-bleaching products were widely used on an OTC basis (Fox, 2006). However, in the years
since 2006, no final rule has been established by FDA. This failure to act has placed
manufacturers in a regulatory gray area. In 2011, at least one manufacturer has been challenged
by state law in Texas to remove its skin-bleaching product from the market (Francis, 2011).
However, no definitive action has yet occurred and no final rule from FDA has been
promulgated.

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2.4.5 The Vaginal Drug Products Monograph
The vaginal drug products monograph was initiated in 1983 but was withdrawn in 1994. In the
withdrawal notice, FDA noted that products would be considered by later rulemaking activities
and that the withdrawal did not affect the status of currently marketed products (FDA, 1994b).
However, this means that certain vaginal products can remain on the market without a
corresponding monograph. Although a call for data on vaginal drug products was made by FDA
in 2003, the request only concerned lubricants and moisturizers that were not part of the original
category review (FDA, 2010e). Thus, certain vaginal drug products, such as medicated douches,
may continue to be marketed but without specific regulatory oversight other than that which was
in place in 1994, almost two decades ago. In this case, manufacturers are placed in a situation
with no current monograph and also in a position where innovation or significant change to
affected products is difficult, if not precarious.
2.4.6 Internal and External Analgesics Monographs
Drugs in the category of internal analgesics are responsible for the second largest volume of
sales in the OTC drug sector (Table 3). The internal analgesics monograph has been in a
tentative final state since 1988. Although a number of final rules regarding non-monograph
ingredients, professional labeling, claims and warnings have been finalized, the monograph itself
remains incomplete.

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Table 3: OTC Sales by Category (CHPA, 2010a)

The external analgesics monograph aims at regulating another large category with numerous
subcategories. It has been in an incomplete state since 1983 and has a history complicated by
proposed rules and category III ingredients. In July 2003 FDA announced that the tentative final
monograph would exclude patch, plaster, and poultice dosage forms. Although the active
ingredients commonly used in patches would still be considered GRAS/E, the use of the same
ingredients in patch, plaster, or poultice dosage forms would be Category III, and thus require
more data to make a final determination. FDA noted concerns that patches might increase

52
irritation or affect the amount of an ingredient absorbed through the skin. FDA also said that
dosages, warnings, and directions might need to be different for patches than for creams or
liquids (FDA, 2003a). Nevertheless, according to FDA policy and since the monograph is still
in a tentative final state, patch, plaster, and poultice dosage forms may continue to be sold by
manufacturers in the interim until a final monograph is published.
2.5 FDA Perspectives and Positions
2.5.1 The Need for Pharmaceutical Regulation
Federal pharmaceutical regulation by FDA is necessary, in large part, because consumers are not
generally able to evaluate the safety of medicines themselves due to the specialized knowledge
needed to do so and the significant societal impact and importance of medicines. Historically,
major shifts have occurred in the status of the consumer from a regulatory perspective.
According to Daemmrich, in the first part of the twentieth century consumers were seen as
needing state and professional protection from unethical drug manufacturers through improved
information and drug labeling. Several decades later, consumers were viewed as needing
protection from industry and from easily duped physicians by way of direct government
intervention and improved regulations (Daemmrich, 2004). In the later part of the century when
the OTC Review was initiated in 1972, then FDA Commissioner Charles Edwards stated that
FDA intended:

53
. . . to build a permanent system offering all American consumers the best possible assurance
that every over-the-counter drug . . . not only is safe and adequately labeled, but that it will do
what the manufacturer claims it will do. . .(CHPA, 2010b).

2.5.2 Possible Reasons for the Delay in Finalizing OTC Monographs
According to Wilson, the US regulatory system contains often conflicting elements—a system of
rules and, at the same time, an opportunity for openness and access (Wilson, 1989). The need
for openness and access complicates the development and implementation of those rules,
especially in the case of OTC drugs. The need for multiple stages of inputs from industry, expert
committees, regulators, and public comment all contribute to the delay in finalizing incomplete
monographs. The very essence of the design including openness and transparency of the
regulatory process may be contributing in part to its inability to finalize a contentious
monograph.
The reasons cited most often by FDA for the incomplete monographs are a lack of resources and
competing priorities. According to Peter Hutt, former Chief Counsel at FDA, the regulatory
priorities of FDA must be set and programs must be designed and developed to achieve the
greatest impact from the limited resources available (Hutt, 1995). Further, Hutt notes that
governmental regulation is often identified by the courts as a minimum requirement, and does
not necessarily satisfy the full obligation of the manufacturer to the public. In many respects,
there is an interdependence between the industry and the FDA whereby self-regulation plays a
critical role, particularly in the case of OTC monograph drugs. He goes on to state that

54
ultimately FDA relies upon the entire regulated industry for self-regulation, because resources
are never sufficient to monitor the massive drug industry.
In many instances in the literature, FDA confirms that resource limitations are, at least in part,
responsible for the delay in final regulations (Hutt, 1995). For example, FDA has noted that the
tentative final monograph is usually the most difficult step of the monograph processes to
develop. As the final step in the process, all the issues that have arisen in previous steps must be
satisfied completely. All comments must be addressed and all responses must be scrutinized by
various FDA personnel. This type of activity takes considerable time (Gardner, 1980). The
review and decision-making processes appear to be particularly long and complicated for
monographs that are complex and contain a large number of active ingredients and combinations
of ingredients. Additionally, the publication of final monographs and the promulgation of final
regulations is resource intensive for FDA. Amongst the monographs that remain incomplete, the
majority are indeed larger and more complex monographs in comparison to those that have
already been finalized.
The delay in final regulation may also depend on other technical matters. For example, safety or
efficacy information may be incomplete; additional studies may need to be undertaken or
completed for certain active ingredients or products. Monographs and subsequent regulations
are based in large part on information supplied from the industry itself. This informational
asymmetry could constitute a study of its own but is dealt with here in a general sense as a
complicating factor among many possibilities that impede monograph completion. Other

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regulatory factors or consumer-based concerns may also emerge during the time period of a
tentative final monograph, and these could require changes to the contents of a final monograph,
thereby complicating and lengthening the process.
2.5.3 FDA Compliance Actions
OTCs are sometimes referred to as a privileged class of drugs because they have significantly
different regulatory and enforcement schemes, as compared to prescription drugs. In part, this is
because FDA reviews active ingredients as part of the monograph development process, but does
not review the full formulation including excipients. In addition, the clinical evidence standard
is generally perceived to be lower for OTC drugs as compared to novel drugs (Henteleff, 1981).
All of these aspects were considered as part of the OTC Review process by FDA and addressed
as part of its description of its framework for acceptance of the active ingredients as GRAS/E
and other monograph specifications (FDA, 1972b). FDA is also responsible for assessing
compliance to the current requirements. However, a large part of the responsibility and liability
for marketing a drug, particularly an OTC monograph drug, rests with the manufacturer. Thus,
considerable attention must be paid to the way that compliance with current regulations is
enforced by the FDA in concert with industry.
According to FDA’s Janet Woodcock, “Laws and regulations establish hard boundaries and
within these lines, there is much discretion” (Woodcock, 2010). Clearly, interpretation and
application of drug regulations is necessary according to the different risk profiles of particular

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medical products and the situations in which they are used; it would be impossible to promulgate
individual regulations for every specific drug product. When regulations are not final
manufacturers have some level of discretion in these interpretations. FDA encourages
manufacturers to comply with a tentative final monograph at the earliest possible date (FDA,
1987). Nevertheless, FDA’s Compliance Policy Guidance Manual for OTC Drug Monograph
Implementation states that prior to the final publication of a monograph, it is “not in the
Agency’s interest to pursue regulatory action against a manufacturer unless failure to do so poses
a potential health hazard to the consumer” (FDA, 2007). Thus, an incomplete monograph
appears to be viewed by FDA more like a guidance document than a regulation or requirement.
Guidance documents are defined as administrative instruments not having the force of law and,
as such, allow for flexibility in approach (Lewis, 2011). Clearly, incomplete monographs do not
have the force of law and allow some flexibility in approach as long as safety is not jeopardized.
2.6 OTC Industry Perspectives and Positions
2.6.1 Manufacturers and the Role of FDA Guidance Documents
When manufacturers must determine a commercialization strategy, they can have the same
problem with incomplete monographs as they do with FDA guidance documents in that neither
has the force of law and both introduce a degree of uncertainty (Lewis, 2011). According to a
study on FDA guidance documents conducted by Seiguer and Smith, FDA perceives that
Industry desires consistency in regulatory expectations and views a level playing field amongst
competitors as centrally important. The study goes on to state that FDA officials believe

57
guidance documents to be viewed by industry as mostly final, so that the guidance documents
are treated no differently than rules (Seiguer & Smith, 2005). However, it is not clear if the OTC
industry views incomplete monographs as if they were final or whether, like guidance
documents, they are simply used to inform rather than dictate strategy. In fact, guidance
documents might be viewed as having more influence over decision making than monographs
because they often clarify an existing regulation and might be seen as a key to compliance with
the regulations. Thus, non-compliance might be more difficult to justify when defending against
a likely FDA enforcement action. The situation with OTC monographs is a little different.
FDA has already made its view clear that non-compliance with an incomplete monograph, for
non-safety reasons, bears little regulatory risk. The degree and types of approaches that may be
taken by an OTC manufacturer are not detailed in the literature and may depend, among other
factors, on the amount of risk a manufacturer is willing to undertake.
2.6.2 Possible Types of OTC Monograph Excursions
The monograph system for OTC drugs in the US gives industry a relatively simple, cost-
effective mechanism to enter the marketplace. Because active ingredients, indications, and
dosages are specified in a final monograph, constraints are placed on what a manufacturer can do
to establish market advantage. To avoid deviating from monograph specifications,
manufacturers are left with few tools, and most efforts to differentiate their products must
concentrate on the development of more convenient dosage forms, new packaging, or new drug
delivery technologies. When monographs are incomplete, however, manufacturers may
commercialize an OTC drug whose ingredients, indications, or dosages deviate from the

58
specified monograph guidelines. Thus, monograph deviations are a mechanism that can be
exploited by manufacturers to gain market advantage. Examples of approaches that a
manufacturer could take while a monograph is pending include implementing a change in
monograph formulation that has been submitted to FDA via Citizen Petition but for which FDA
has not responded. As noted earlier, Citizen Petitions can often be pending at FDA for many
years. Given this extended timeframe and FDA’s stated policy of not enforcing incomplete
monographs, a manufacturer could presume this to be a reasonable deviation for their OTC drug
product. Advantageously, such a product may have efficacy advantages, and therefore
marketing advantages, over competitive products in the same category. Such a product may
even have some form of patent protection. Other examples of a monograph deviation could
include the combination of active ingredients that are not covered by the monograph, the use of
dosage levels higher than those specified by the monograph, and the use of an ingredient that
might have pharmacological activity that is not declared on the product label.
2.6.3 Implications of Monograph Excursions by Manufacturers
A non-safety related excursion from an incomplete OTC monograph by a manufacturer may not
be obvious to consumers. Thus, regulatory inequality amongst competitors in the marketplace
may exist with little or no apparent evidence. The degree to which a largely unrecognizable
monograph deviation may affect choices made by manufacturers has not been identified in the
existing literature. As noted earlier, monographs may often remain in an incomplete state for
decades, increasing the chances that a manufacturer may need or want to make changes from it
for commercial, technical, or other reasons. In some cases, for example, when one manufacturer

59
strays from the monograph in a way that satisfies a consumer preference, other companies may
follow suit to remain competitive. Soon many products are exercising the same deviation. One
example of this state of affairs was the recommendation on labeling that saline laxatives might
be used for bowel cleansing purposes by administering two doses within 24 hours, a dosage
schedule outside of the tentative monograph guidelines. The dosage recommendation was
widely accepted and one which became commonly used by manufacturers.
When a drug company considers the wisdom of deviating from an incomplete monograph,
negligence becomes a relevant and important legal concept. The law requires that a
manufacturer exercise a standard of care that is reasonable if that level were to be judged by
others who are experts in manufacturing and selling similar products. For monograph
deviations, what would constitute negligence on the part of the manufacturer, given FDA’s
enforcement discretion in all cases except those posing safety-related concerns? Because the
consumer is able to self-diagnose and self-select OTC drug products without a learned
intermediary, more liability may reside with the manufacturer, particularly in the case of a
monograph deviation. It is unclear from the existing literature how manufacturers are
approaching and addressing liability when they decide on a strategy for an OTC drug and
whether the constraints of liability are considered to be of great concern.
Incomplete OTC monographs may lead to an unclear, and therefore a potentially unfair and
unpredictable situation for industry. However, as discussed previously, there is a certain amount
of discretion in almost every instance of applying pharmaceutical regulations to specific

60
products and situations, as regulations are inherently general by design. According to Max
Weber, the great virtue and defining characteristic of bureaucracy is its institutional method for
applying general rules to specific cases, thereby making actions of government fair and
predictable. He notes that when rules are clear, governance is better and quotes Aristotle as
saying “to seek for justice is to seek for a neutral authority; and law is a neutral authority “
(Wilson, 1989).
2.7 Framing the Study of OTC Regulatory Policy
OTC monographs are de facto regulations and, as such, have goals in common with other types
of regulations. Inspection of the literature suggests that regulations have three principal goals:
1) to ensure the safety and effectiveness of drug products, 2) to facilitate efficiencies in the
management of research, commercialization, and costs, and 3) to equalize requirements and
standards for the industry. The first two aspects of this framework are evident in FDA’s
mission and value statements where ensuring the safety and effectiveness of medical products is
a key focus and is stated as:
FDA’s vision is that all medical products are safe and effective; and the public health is
advanced and protected. FDA’s mission is to protect consumers and enhance public health by
maximizing compliance of FDA regulated products and minimizing risk associated with those
products (FDA, 2012).
The third element of equalizing requirements for industry is apparent in the regulatory mission
of another important organization, the Federal Trade Commission (FTC), which plays a role in

61
preventing unfair business and competitive practices. The regulatory objective of the FTC is
relevant not only because FTC plays a significant role in the oversight of OTC products from the
point of view of advertising, but also because it can step in when other activities affect the level
playing field. That this third role is important to industry is also suggested by Seiguer and
Smith. They found that FDA also believes that consistent regulatory expectations and a level
playing field are important to industry (Seiguer & Smith, 2005). This belief is also reflected in
FDA’s Transparency Initiatives launched in 2009 and aimed at increasing and fostering fair and
consistent enforcement of important regulatory obligations (FDA, 2009). The three objectives of
regulation are illustrated in figure 2.
Figure 2: The Three Objectives of Regulation

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A specific model for studying and framing the impact of OTC monograph regulations and
policies has not to my knowledge been identified in the literature. Nevertheless, when looking
critically at the literature, most concerns with regard to OTC monographs appear to be related to
at least one of the three main objectives of regulations. Thus an exploration of industry views of
OTC regulations and policies might be usefully framed by trying to gauge how incomplete
monographs affect these three goals of regulation.
This proposed framework has features that are common in other existing frameworks that have
been used to study medical product regulation in other sectors. For example, in a study of
orphan drug policies by Reddington, four frames were constructed to analyze congressional
testimony in relation to orphan drug regulation. The frames included: 1) economics and access,
2) patient relief, 3) rules of participation, and 4) congressional action (Reddington, 2009).
Reddington’s economics and access frame parallels the second goal of regulation in our
framework that relates to protecting efficiencies in drug research, development and
commercialization. Reddington’s patient relief frame maps to some extent onto the goal in our
framework of ensuring the safety and effectiveness of drugs; both are concerned with assisting
patients with problems by ensuring that safe and effective drugs are more readily available and,
in our case, unsafe or ineffective drugs are not. Reddington’s dual frames of rules of
participation and congressional action have congruence with the aims of the third element in our
framework of equalizing standards and requirements amongst competitors. Thus, although the
terminology used for constructing the frames are different between the two models, the elements
under consideration are similar and help to validate the choices that have been made to capture

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regulatory objectives. Further, this model would appear to relate well to the essential elements
and concerns identified in the literature reviewed earlier in chapter 2, including the safety of
Category III ingredients, the inefficiencies of unclear commercial strategies, and the inequalities
allowed by differing interpretations and application of regulations.
The research proposed here will explore whether the intended goals of the regulations regarding
OTC products envisioned when the monograph process began are being realized fully, or are
being subverted by the uncertainties in the current state of monograph production. Thus, in this
thesis, I will use the triad of objectives identified above as a means to structure a survey of
industry in order to gain insight into industry views on incomplete OTC monographs.
In considering the first aspect of our framework, that of ensuring safety for the consumer, we
might question whether the incomplete monographs will have any impact at all. FDA has said
that it will pursue action against a manufacturer if non-compliance with an incomplete
monograph results in safety-related issues. The serious adverse event reporting requirements for
OTC products, initiated in 2007, have decreased the likelihood that safety issues will go
undetected and will then have the potential to injure many people. It would seem logical to
predict that that few manufacturers will deviate from an incomplete monograph in a manner that
would affect safety because of the legal jeopardy that might result. Nevertheless, it is evident
from the literature that manufacturers are using Category III ingredients in some cases even
when published information questions the safety of those ingredients (FDA, 2006b). Thus, it
might be conceivable that a subset of manufacturers might knowingly or unknowingly deviate

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from an incomplete monograph in a way that compromises safety, especially if the guidelines
that do exist are insufficient or out of date.
More questions appear to exist with regard to the effect of incomplete monographs on the other
two main objectives of regulation. Although the literature is sparse, a few discussions have
pointed to the potential effects of incomplete monographs on the efficiency of developmental
and marketing strategies, and on producing an uneven playing field for manufacturers, as
described above. It is these elements that will be explored in particular detail in this study.
2.8 Summary and Research Direction
While the literature analyzed in this section provides a lengthy description of the monograph
system, including its history, procedures, and potential concerns, it also points to a lack of
published information on how the OTC industry perceives and handles non-final monographs.
As clearly noted in the literature, finalized regulations play an essential role in helping to ensure
safety and efficacy while standardizing requirements for commercialization. The measure of
regulatory effectiveness using our framework should be based on the extent to which the three
main objectives are achieved. According to Ratanawijitrasin and his colleagues, one way to
measure drug regulation effectiveness is to identify the effects that regulation has on relating the
final outcomes to the various regulatory functions (Ratanawijitrasin & Wondemagegnehu,
2002). However, Ratanawijitrasin further states that it is difficult to develop specific regulatory
outcome measures as the outcomes may be complicated by many factors. In our case, true final
outcomes are not possible to assess given the non-final nature of the monographs being

65
considered. Nevertheless, our focus for this research will be based on the extent to which
regulatory objectives, interim outcomes, perceptions, and approaches can be qualitatively
assessed and placed within our reference framework.
In the present study, we have elected to approach this question using both survey methodology
and selected interviews. These two methods were chosen because they fit well with the question
under investigation and allow for input from a broad audience that can be sampled purposively.
The use of the survey instrument will be tested in a pilot focus group, composed of regulatory
professionals with at least one member who has an extensive OTC drug background. The use of
a focus group will help guide the construction of the survey and should help reduce bias while
increasing both the completeness and applicability of the survey to the questions under study.
Individuals selected to participate in the survey will then be identified using inclusion criteria
that include 1) experience with incomplete OTC monograph drugs and 2) associated experience
with OTC drugs in an industry setting. The addition of interviews can add more granular input
from specific targeted individuals. Individuals for the interviews will be selected based on
experience and expertise with the OTC monograph system from policy and practitioner levels.
The selected individuals to be interviewed will complete the survey and then a follow-up
telephone interview will be conducted to expand the information base related to areas of
particular interest or sensitivity.

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CHAPTER 3: METHODOLOGY
3.1 Introduction
This study used a focus group, an on-line survey, and interview methods to explore the views of
selected members of the OTC industry regarding incomplete monographs. Survey development
was guided by information from the current literature plus informal discussions with individuals
who have experience in OTC monograph drugs. Content validity of the survey was tested by
convening a focus group to critique the survey questions and the overall instrument design to
help ensure the survey would capture the desired data. The results of the focus group were
analyzed and the survey was modified on the basis of input from the focus group. The survey
was then administered to a group of 60 pre-screened individuals, selected for their past or current
regulatory experience with monograph OTC drugs for which the monograph is incomplete.
Interviews with selected individuals who completed the survey and who agreed to participate in
an interview were conducted by telephone to gather additional information. The participants
were assured that their identities and views were protected.
3.2 Survey Development and Delivery
The survey was prepared using the web-based survey tool, Qualtrics. Questions were developed
based on information available in the literature plus informal discussions with individuals with
experience in the area of OTC monograph drugs. The survey questions were also focused
around the three objectives of regulation, according to our framework, and were divided across
the topics (Table 4).

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Table 4: Areas of Survey Inquiry According to the Framework
Area of Survey Inquiry
Safety and Effectiveness
Efficiencies in Research, Commercialization, and Costs
Requirements and Standards for Industry

Survey questions regarding safety and effectiveness included the following areas:
 What do regulatory personnel from industry think in general about incomplete
monographs with regard to their effects on product safety?
 How commonly are deviations from the tentative monograph made? Are deviations
from the tentative monograph made with respect to the selection of ingredients,
dosages, forms, and indications typical when a monograph is not final? If so, how
much risk is this perceived by the manufacturer in the areas of safety and
compliance?
Survey questions concerning efficiencies in research, commercialization and costs included the
following topics:
 How does industry view an incomplete monograph in relation to efficiency of their
business and regulatory processes?

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 What are the advantages and disadvantages that are perceived to be present when a
monograph is incomplete, and how important are these thought to be?
 Does the amount of time that a monograph remains incomplete weigh into the
decision making process on how industry proceeds with its regulatory and business
strategy? Is consideration given to the estimated date of final monograph publication
and are associated mitigation plans developed for any risks? Does industry attempt to
persuade FDA to finalize incomplete monographs in an accelerated manner, and, if
so, upon what basis?
Survey questions relating to requirements and standards for Industry included the following
areas:
 How does industry view an incomplete monograph on the ability to compete on a
level playing field with other competitors?
 How do companies deal with competitors who may be deviating from the
monograph? Do companies actively consider how competitors may be deviating
from a monograph when designing product strategies and if so, what impact does this
have? In such a case, is there increased pressure on other manufacturers to act in a
similar manner in order to remain competitive?
 Some manufacturers may see an incomplete monograph as risky whereas other
manufacturers may view it as an opportunity to broaden OTC drug development and

69
marketing possibilities with less concern or fear of legal implications. What are the
advantages and disadvantages that industry sees in each case and why?
A focus group was convened to review and provide input on the survey questions included in the
final survey instrument. In order to obtain a broad perspective, the focus group included a
mixture of individuals with academic, regulatory and business backgrounds, and included at
least one member with an extensive OTC drug background (Table 5).
Table 5: Participants in Focus Group
No. Description of Participant
1 Individual with cosmetic and OTC drug experience
2 Individual with pharmaceutical industry and clinical experience
3 Individual with OTC drug industry and consulting experience
4 Individual with pharmaceutical industry and university research experience,
medical doctor
5 Individual with OTC industry experience, OTC trade group executive
6 Individual with OTC industry experience, OTC trade group executive, lawyer
7 Individual with industry experience in the development of pharmaceuticals
8 University researcher in the pharmaceutical area, department director for
regulatory sciences

The draft survey instrument was provided electronically or in paper form to the participants at
least 10 days in advance of the focus group meeting along with high-level instructions. The
meeting was conducted via Webex and scheduled for 90 minutes. The meeting began with
introductions and a brief presentation by me, acting as the primary moderator, regarding the

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purpose of the research and the survey. General questions were discussed followed by a detailed
discussion about specific questions including proposals for improvement. Information gained
from the focus group discussions and recommendations for improvement were assessed and then
used to modify the survey accordingly.
The final survey was configured on a web-based survey platform (Qualtrics,
uscregsci.qualtrics.com) and consisted of 34 questions using a variety of single answer, Likert,
“yes/no”, “choose one”, and “open ended” questions. The length of the survey was constructed
to facilitate participation and to enable completion of the survey in a reasonable amount of time,
approximately 10-15 minutes. The operability of the survey was also assessed by sending the
survey to 10 administrative reviewers to validate that the electronic version was distributed and
received and that data could be captured correctly for analysis.
After the validation step, the survey was distributed to participants. The target populations for
this survey were regulatory professionals with current or past industry experience with OTC
monograph drugs for which the monograph is incomplete. The respondents should have at least
5 years of regulatory experience in an industry setting. Some respondents were selected using a
snowball technique, whereby those with experience with incomplete OTC monographs were
asked to recommend others they know to also be knowledgeable in this area. This technique
allowed for increased diversification in the participant population by OTC product category
experience. Most individuals were screened either by email or telephone to identify their
willingness to receive the survey and to clarify that they met inclusion criteria including 1)

71
experience with incomplete OTC monographs and 2) work with OTC products in an industry
setting. Follow-up was carried out using two staged reminders when a survey was not returned
within a 15-day period. The final question of the survey asked if the respondent would be
willing to participate in a short interview via telephone to discuss additional details of selected
OTC monograph drug topics. Of the 56 completed surveys, 24 respondents agreed to an
interview and 10 were selected based on their level of experience with incomplete OTC
monograph drugs. The interviews were conducted either in-person or by telephone.
3.3 Data Analysis
Results of the surveys were collected and stored electronically. Only the results of respondents
who answered at least 90% of the questions and completed the survey were included in the final
analysis. The Qualtrics software system automatically calculated statistical data such as
percentages, counts, minimums, maximums, standard deviations, variances and means for all of
the non open-ended questions. All applicable data was graphed and analyzed. Open-ended
responses and interview responses were analyzed for content and for any trends or commonality.

72
CHAPTER 4: RESEARCH RESULTS
4.1 Results of Focus Group
A focus group was convened to assist the investigator in designing and executing an effective
survey and to maximize the response rate by soliciting advice regarding participant recruitment
and deployment methods. The 90-minute focus group meeting, held via Webex, was divided
into three segments; the first segment was 15 minutes, the second segment was 60 minutes, and
the third segment was 15 minutes. In the first segment, the nature of the research was
summarized and the focus and structure of the survey was also discussed. In the second
segment, a detailed examination of the strengths, weaknesses, and relevance of each proposed
survey question was discussed. Emphasis was placed on ensuring that responses would yield
relevant and clear data. The focus group members recommended changes to the proposed
questions and suggested additional questions that might yield further supporting information. In
the final section, the group discussed the importance of including a listing of non-final
monographs as possible answer choices to questions regarding the experience of the respondent.
This topic was selected because the focus group members believed that the specific experience
with one or another of the incomplete monographs could affect the answers to questions.
Possible trends could then be identified by sub-stratifying the respondent’s answers with respect
to his or her monograph experience.
The members of the focus group also discussed the need to ensure anonymity for the survey
respondent. The focus group felt strongly that this would help to encourage participation and

73
establish a sense of security and confidentiality, thereby facilitating uninhibited responses. The
group also discussed methods of identifying the appropriate type of survey respondents, to
assure their backgrounds and work-related experiences were aligned with the survey topic and
purpose. Focus group members emphasized the importance of getting a good mix of
participants from companies of different sizes and from different sectors of the OTC drug
industry. These suggestions were later incorporated into the final survey, as shown in Appendix
A. Methods to deploy the survey were also discussed. Members suggested that recruitment
should rely on using a combination of direct contact and snowball techniques, and an electronic
mailing list consisting of scientific committee members from CHPA.
4.2 Analysis of Survey Respondents
Sixty links to the on-line survey were distributed between October 3, 2012 and November 19,
2012 ; 56 responses were received, yielding an overall response rate of 93%. The high response
rate can likely be attributed to pre-notification e-mails that were personally sent by the
researcher to potential respondents introducing the research and asking for their participation in
the survey. Only after agreement to participate in the research was the link to the survey
provided to the respondent. Separately, the Consumer Healthcare Products Association (CHPA)
also distributed the survey link on October 8, 2012 to a subset of their members consisting of the
legal, regulatory, and scientific affairs committees. The CHPA e-mail distribution contained 126
e-mail addressees, from which only 5 responses were received. A number of the CHPA contacts
had already been included in the original distributions of the investigator or were later included
in subsequent personal e-mail contacts by the investigator. Responding to all 34 survey

74
questions was not made mandatory and, as a result, data was not available from all 56
respondents for each of the 34 questions. Twenty-four questions did not have the full 56
responses but the majority of these questions had 55 responses. Only the results of respondents
who completed the survey were included in the final analysis; thus results from four people who
initiated the survey but did not complete it nor answer a majority of the questions were removed
from the final data set and analysis.
Of the 56 survey respondents, 27 had current job titles reflecting a principal focus in regulatory
affairs. These titles ranged from Regulatory Associate to Regulatory Vice President, and
included Regulatory Consultants. The remaining 29 respondents represented a mix of
professionals with current titles that included quality manager, lawyer, research and development
scientist/officer, medical affairs director, clinical research director, and drug safety officer
(Figure 3). All of these professionals had either current or previous experience in the drug
industry and experience with non-final OTC monographs.

75
Figure 3: What is your current position/title?

Approximately 58% (32/55) of the survey respondents were currently working for an OTC drug
manufacturing company at the time of the survey. Of those working for a company, the largest
category of respondents was employed by companies with 100-499 employees (Figure 4). The
remaining 42% (23/55) not currently working for a manufacturing company included
consultants, lawyers, and clinical research professionals with previous OTC drug industry
experience.
23
4
6
3
1
1
4
1
7
4
2
0 10 20 30
Other
Lawyer
Regualatory Consultant
Regulatory Associate
Regulatory Supervisor
Quality Manager
Regulatory Manager
Quality Director
Regulatory Director
Regulatory/Quality Vice President
Regulatory Vice President
Number of Respondents (n=56)
Current Position/title

76
Figure 4: If you currently work for a company that manufactures/markets OTC drugs, what is
the size of the company in terms of numbers of employees?

Of those working for a manufacturing company, approximately 60% were employed by
companies manufacturing and/or marketing between two and ten different OTC monograph drug
brands in the US. The survey respondents were drawn from companies in a range of product
sectors including products regulated under both final and non-final monographs (Figure 5).

23
9
1
4
14
4
0 5 10 15 20 25
Do not work for a manufacturer
10,000+
1,000-9,999
500-999
100-499
1-99
Number of Respondents (n=55)
Number of Employees

77
Figure 5: Under which of the following OTC monographs are you aware that your company
manufactures/markets OTC drugs in the US? Please check all that apply.

All but one of the respondents had experience with multiple monographs, final or non-final; the
largest category of respondents had experience with between six and ten monographs.
Additionally, all survey respondents had experience with non-final monographs; the non-final
monograph categories with which most respondents had experience included sunscreens,
external analgesics, laxatives, and oral healthcare.
14
14
11
11
6
4
4
4
2
4
4
7
4
5
1
8
8
15
6
5
1
10
3
2
1
23
2
16
11
0 5 10 15 20 25
Acne
External Analgesics
Internal Analgesics
Anorectal
Antacid
First Aid
Anticaries
Antidiarrheal
Antiemetic
Antiflatulent
Antifungal
Antihistamine
Antiperspirant
Antitussive
Bronchodialator
Dandruff
Decongestant, Nasal
Laxative
Menstrual Products
Nighttime Sleep Aids
Opthalmics
Oral Healthcare
Otics
Pediculicides
Skin Bleaching
Skin Protectants
Stimulants
Sunscreen
Vaginal Drug Products
Number of Respondents (n=33)
Monograph

78
4.3 Survey Responses Regarding Standards for the Industry
The survey included sixteen questions related to the requirements and standards for OTC drugs
and how non-final monographs are interpreted and applied. Respondents were asked how much
importance that they felt the OTC industry ascribed to adherence with non-final monographs
using a scale ranging from extreme choices, “they should be followed exactly” to “they don’t
need to be followed” (Figure 6). According to the largest category of respondents, 41% (23/56)
believed that the OTC drug industry’s opinion is that non-final monographs should be closely
followed. The second largest category, 23% (13/56), said that monographs may be generally
followed, 7% (4/56) said they can be loosely followed, and 11% (6/56) said that they don’t need
to be followed. On the other end of the spectrum, 18% (10/56) responded that they should be
followed exactly.

79
Figure 6: In your current or past experience, what is the OTC drug industry’s opinion regarding
adherence to non-final monographs?
6
4
13
23
10
0 5 10 15 20 25
They don't need to be
followed
They can be followed
loosely
They may be followed
generally
They should be followed
closely
They should be followed
exactly
Adherence to Non-final Monographs
Number of Respondents (n=56)

When probed further on the topic of monograph adherence and asked how often monograph
excursions from non-final monographs are believed to be made in the industry, 46% (26/56) of
the respondents said that excursions are commonly made and a further 29% (16/56) believed that
they are sometimes made. Only 16% (9/56) responded that they believe excursions are rarely
made and none felt that excursions are never made. Notably, 9% (5/56) of respondents reported
they believe excursions are almost always made (Figure 7).

80

Figure 7: In your current or past experience, given that a non-final monograph is not final and is
not legally enforceable, how often do you believe excursions (differences) are made from a non-
final monograph in the OTC industry?
0
9
16
26
5
0 5 10 15 20 25 30
Never
Rarely
Sometimes
Commonly
Almost Always
Frequency
Number of Respondents (n=56)

When respondents were asked “In your current or past experience, how compliant are OTC drug
companies to non-final monographs?”, 47% (26/55) felt that OTC drug companies are mostly
compliant and 33% (18/55) felt they were generally compliant. Only 4% (2/55) believed OTC
drug companies to be completely compliant (Figure 8).

81

Figure 8: In your current or past experience, how compliant are OTC drug companies to non-
final monographs?
2
7
18
26
2
0 5 10 15 20 25 30
Vaguely compliant
Loosely Compliant
Generally Compliant
Mostly Compliant
Completely Compliant
Compliance
Number of Respondents (n=55)

When questioned specifically about how often certain types of monograph excursions from non-
final monographs are made by OTC drug companies, the responses varied significantly by the
type of excursion. Respondents were presented with nine possible excursions and a 5-point scale
to rate the frequencies of the excursions, ranging from almost always to never. Of the given
possibilities, excursions reported by a majority of respondents as occurring sometimes included
the use of different active ingredient combinations (25 respondents), the use of other labeling
differences (25 respondents), the use of an active ingredient in the non-final monograph but not
identified on the label (24 respondents), the use of a different dosage regimen (21 respondents),

82
and the use of different product instructions (21 respondents). Excursions reported by a majority
of respondents as rarely occurring included use of a different indication (16 respondents), use of
a different active ingredient (22 respondents), and the use of an active ingredient identified in the
non-final monograph but not included on the label (19 respondents). Only 7 total responses
were recorded for the use of a different dosage form which may represent a comparatively low
rate of excursions employing a different dosage form that than specified in a non-final
monograph (Figure 9).

83
Figure 9: In your current or past experience, how often are the following types of monograph
excursions made from a non-final monograph in the OTC industry?

12
9
4
3
15
12
15
9
2
16
18
15
10
22
14
19
10
0
15
21
21
25
13
25
12
24
3
12
6
13
12
4
3
8
11
1
0
1
1
5
0
0
0
0
1
0 10 20 30
Use of a different
indication
Use of a different dosage
regime
Use of different product
instructions
Use of other labeling
differences
Use of different active
ingredient
Use of different active
ingredient combination
Use of active not
identified in monograph
Use of active but not
identified on label
Use of different dosage
form
Other
Number of respondents (n=55)
Frequency of Monograph Excursions
Almost Always
Commonly
Sometimes
Rarely
Never

84
Respondents were asked to identify which of the non-final monographs, based on their
experience, were the most contentious and had a higher potential for excursions from monograph
specifications. A majority of respondents (66%, 33/50) reported that the sunscreen monograph
was the most contentious. The external analgesics monograph and the skin bleaching
monographs were identified by respondents as the second and third most contentious,
respectively (Figure 10).
Figure 10: In your current or past experience, which of the following non-final monographs are
the most “contentious” and may have a higher potential for excursions from the monograph?
Please check all that apply.

3
5
1
33
14
0
9
2
9
5
10
16
0 10 20 30 40
Other
Vaginal Drug Products
Vaginal Contraceptives
Sunscreen
Skin Bleaching
Poison Treatment
Oral Healthcare
Menstrual
Laxative
First Aid
Internal Analgesics
External Analgesics
Number of Responses (n=50)
Monographs

85
Respondents were given eight possible reasons for excursions from non-final monographs and
asked to rank them from most likely to least likely. A majority of respondents (71%, 39/55)
reported that creating a marketing advantage was the most likely reason for excursions. Creating
other commercial advantages was ranked as the second most likely reason (53%, 29/55), and the
cost of meeting the non-final monograph was ranked third (42%, 23/55). Several comments in
the open text portion of the “other” category in this question also noted “ignorance of
monograph provisions” and “unfamiliarity with requirements” as reasons for excursions from
non-final monographs.
When respondents were asked about the influence played by international standards and
regulations in making an excursion from a non-final monograph, responses varied across the full
5-point scale ranging from very influential to not influential at all. Equal numbers of
respondents (31% in each category, 17/55) identified that these standards were somewhat
influential or not very influential. Equal numbers of respondents (16% in each category, 9/55)
also reported that international standards were very influential or had a neutral influence. Only
5% (3/55) said they were not influential at all.
Respondents were asked how often competitive products are evaluated when developing a new
OTC drug for which the monograph is non-final, using a 5-point scale ranging from almost
always to never. A large majority of respondents (82%) noted that competitive products already
on the market are almost always (27/55) or commonly (18/55) evaluated when developing a new
OTC monograph drug for which the monograph is non-final. Only small numbers of

86
respondents reported competitive products are sometimes evaluated (9%, 5/55), rarely evaluated
(5%, 3/55) or never evaluated (4%, 2/55).
When queried about specific activities relating to the competitive product evaluation process, all
survey respondents (100%, 55/55) reported that the competitive product labeling is always
assessed for its compliance to a non-final monograph. Similarly, 93% (51/55) of respondents
noted that competitor advertising materials and formulations were also assessed. Other activities
of note among the responses in the open-text “other” portion of the question included assessing
and analyzing any citizen petitions and analyzing social media information of the competitive
product.
Respondents had mixed responses regarding the steps that companies were seen to take with
regard to competitors who are making excursions from a non-final monograph. Respondents
were asked to use a scale, ranging from almost always to never, to answer how often specific
types of excursions are believed to be made. When asked about whether companies monitor the
competitive product to assess how well it sells, the largest group of respondents (41%, 22/55)
chose “commonly”. When asked if companies copied the competitor’s monograph excursion or
tried to find better or other monograph excursions or differences, the most common choice was
sometimes (56%, 30/54 and 44%, 24/54 respectively). When asked if companies requested that
the competitor stop excursion activities, equally common choices were “sometimes” and
“rarely” (33%, 18/54 for each answer). Initiating legal action was noted by a majority (48%,
26/54) of respondents as rarely occurring. Other actions were also noted in the open text field

87
of this question. These included sometimes having a surrogate organization inform FDA or FTC
about a competitor’s monograph excursion or referring the competitor to the National
Advertising Division (NAD) for remediation (Figure 11).
Figure 11: How do companies address competitors who may be making excursions from a non-
final monograph?

9
4
11
3
4
4
17
26
21
18
12
14
3
0
16
22
18
30
24
8
7
3
5
5
7
10
22
1
0
2
2
2
2
18
0
0 10 20 30 40
Start Legal Action
Report them to FDA
Ask them to Stop
Copy their Monograph Excursion
Try to find a Better or Other
Excursion
Monitor the Competitor Products
Other
Number of respondents (n=55)
Monograph Excursions
Almost Always
Commonly
Sometimes
Rarely
Never

88
When asked if the survey respondent or his/her company had ever been contacted by a
competitor company about their own excursion from a non-final monograph, 65% (46/55)
reported that they had not been contacted, and 35% (19/55) reported that they had been
contacted. Similarly, when asked if the FDA had ever contacted the respondent or their
company regarding an excursion from a non-final monograph, 67% (36/54) responded that they
had not been contacted by FDA, and 33% (18/54) affirmed that they had been contacted.
Respondents were asked if they believe regulatory or business advantages exist when a
monograph is non-final; 80% (44/55) responded affirmatively. When queried specifically in an
open text format to explain why advantages are believed to exist, the survey respondents’
reasons were predominately focused on two main categories: (i) the increased flexibility in
development of the OTC drug product, including its formulation and claims, and (ii) the low risk
of enforcement on excursions. One respondent also mentioned cost savings relative to reduced
testing, formulation and labeling. Selected responses from the survey question by type are
included in Figure 12.

89

Figure 12: Please explain why you think there are regulatory and/or business advantages when a
monograph is non-final?” (Selected responses shown by response type.)

Comments related to increased flexibility in development of the product including the
formulation and the claims
“If a monograph is not final, a company feels more comfortable pushing the envelope
regarding claims.”

“Absence of a final monograph may permit short cuts or “cherry picking” of compliance
requirements.” [sic]

“It allows more flexibility in manufacturing, labeling, use instructions, and most
importantly, marketing.”

“There is some room to play outside the monograph, especially with claims.” [sic]

“More freedom to try some deviations.”

“Allows time and flexibility to develop a compliant product, allows one to remain
competitive with a non-compliant competitor.” [sic]

“Since many of the non-final situations are many years’ standing, there occurs a climate of
unregulated products. Companies feel a sense of freedom to innovate without fear of
curbing regulation.”

Comments related to low risk of enforcement

“We believe we have greater flexibility, and FDA has lesser enforcement power.”

“Potential for regulatory enforcement when deviating from monograph is low.”

“There is less enforcement for deviations from non-final monographs and thus greater
flexibility for the OTC company.”

90
Conversely, when asked if the respondents believe regulatory or business disadvantages exist
when a monograph is non-final, 80% (44/55) also answered affirmatively. A majority of
responses noted that ambiguity and uncertainty in regulatory requirements exists when a
monograph is non-final, and many survey respondents suggested that the uncertainty could result
in an uneven playing field. Selected responses to the open text survey question are included in
Figure 13.

91

Figure 13: Please explain why you think there are regulatory and/or business disadvantages
when a monograph is non-final. (Selected responses.)

“It creates an unlevel playing field for those willing to take risk vs. those who aren’t
willing to take risk.”

“Both the regulators and the regulated live in an environment of uncertainty, and firm plans
are hard to set in place.”

“Unlevel playing field in terms of claims/indications.”

“There is an opportunity for more aggressive companies to take more risks, gain
competitive advantage.” [sic]

“The non-final status creates ambiguity that is subject to interpretation which may vary
from company to company. It can also create opportunities for companies to market unsafe
products. The biggest issue is that if a company takes advantage of an excursion from the
monograph, they will have to make changes should the monograph become final during the
product lifecycle. This would require additional planning during product development, or
not, depending on the amount of risk the company is willing to take.”

“Small companies exploit non-final monographs to promote non-compliant products to
competitive advantage.”

“While your company may follow the non-final monograph entirely, a competitor may
choose to deviate.”

“Other companies may feel emboldened to take positions with claims and dosage forms
that are not supported by data.” [sic]

“Allows unscrupulous individuals (i.e. garage-inventors, small companies, foreign
companies, etc.) to either sell products through ignorance or overly seek marketing
advantages in an unenforced category.”

“Significant excursions are possible.”

“Not everyone is held to the same standard.”

92
4.4 Safety and Effectiveness Responses
This section of the survey focused on questions relating to safety and effectiveness of OTC drugs
with non-final monographs and included two questions. In the first question, respondents were
asked to identify, using a scale ranging from almost always to never, how often clinical or other
safety testing is conducted on a product when an excursion from a non-final monograph is made.
The largest group of respondents (44%, 20/45) identified that clinical or other safety-related
tested is almost always conducted. Additionally, 33% (15/45) of respondents identified that
testing is conducted most of the time, while 16% (7/45) reported that testing is done sometimes,
and 7% (3/45) of respondents said that clinical or other safety testing is seldom conducted
(Figure 14).

93
Figure 14: In your current or past experience, when a company makes an excursion from a non-
final monograph which may affect the safety of a product, how often is clinical or other safety-
related testing conducted?
0
3
7
15
20
0 5 10 15 20 25
Rarely
Seldom
Sometimes
Most of the Time
Almost Always
Frequency
Number of Respondents (n=45)

In the second question, when presented with eight specific possible risk evaluation areas and
asked how often companies evaluate those risks in relation to excursions from non-final
monographs, the responses were mixed. Using a scale from almost always to never, a majority
of respondents noted that areas almost always evaluated by companies included commercial and
marketing risks (63%, 33/52), regulatory compliance risks (67%, 35/52), legal risks (69%,
36/52), financial risks (46%, 24/52), and safety risks (58%, 30/52). Product quality risks were
evenly identified (36%, 18/50) as almost always and commonly evaluated when considering
excursions from non-final monographs. Clinical risks were identified by the largest group of
respondents (33%, 17/51) as commonly evaluated. A majority of respondents (59%, 13/22) also

94
reported that other types of risks are never evaluated but the response rate for this item was
relatively low (Figure 15).
Figure 15: How often do companies evaluate risks in each of the following areas in relation to
an excursion from a non-final OTC monograph?

0
0
0
0
0
1
2
13
3
1
2
2
3
2
4
0
6
3
2
9
16
6
8
6
10
13
12
17
17
13
18
1
33
35
36
24
15
30
18
2
0 10 20 30 40
Commercial, Marketing
Risks
Regulatory
Compliance Risks
Legal Risks
Financial Risks
Clinical Risks
Safety Risks
Product Quality Risks
Other Risks
Number of respondents (n=52)
Risks
Almost
Always
Commonly
Sometimes
Rarely
Never

95
4.5 Responses on Efficiencies in Research, Commercialization, and Costs
This subcategory of the survey asked nine questions about the impact and importance of
monographs, and explored the effects of the current environment on product innovation and
development strategies. Respondents were asked about the overall impact of non-final OTC
monographs on the OTC drug industry using a 5-point scale ranging from positive to negative.
A majority of survey respondents (44%, 24/54) identified that the impact was somewhat
negative. Twenty-eight percent (15/54) noted that the impact was neutral and 19% (10/54)
identified the impact as somewhat positive. A few respondents had more extreme views
(negative impact, 7%, 4/54; positive impact, 2%, 1/54) (Figure 16).
Figure 16: In your current or past experience, what is the overall impact of non-final OTC drug
monographs on OTC drug industry operations?
4
24
15
10
1
0 5 10 15 20 25 30
Negative
Somewhat Negative
Neutral
Somewhat Positive
Positive
Impact
Number of Respondents (n=54)

96
When further asked “how important is the impact of non-final monographs on OTC drug
operations?”, 9% (5/54) responded that the impact is extremely important, 37% (20/54)
responded that the impact is very important, and 44% (24/54) that it is somewhat important
based on their current or past experience. Additionally, nine percent (5/54) responded that it is
neither important nor unimportant, and no respondents felt the impact was unimportant (Figure
17).
Figure 17: In your current or past experience, how important is the impact of non-final
monographs on OTC drug industry operations?
0
5
24
20
5
0 5 10 15 20 25 30
Unimportant
Neither Important nor
Unimportant
Somewhat Important
Very Important
Extremely Important
Importance of Impact
Number of Respondents (n=54)

Respondents were next asked how often mitigation plans are developed by OTC drug companies
for commercialized products in advance of the monograph becoming final so that excursions

97
may be “corrected” once the monograph becomes final. A majority of survey respondents felt
that mitigation plans were almost always (17%, 9/53) or commonly (42%, 22/53) developed.
One quarter (25%, 13/53) responded that mitigation plans were sometimes developed, and a
more modest number (15%, 8/53) felt mitigation plan development rarely occurred (Figure 18).
Figure 18: When an excursion is made from a non-final monograph on a commercialized OTC
drug product, are mitigation plans developed in advance for the monograph excursions to be
“corrected” once the monograph becomes final?
1
8
13
22
9
0 5 10 15 20 25
Never
Rarely
Sometimes
Commonly
Almost Always
Frequency
Number of Respondents (n=53)

Respondents were asked how much emphasis is placed on the amount of attention (i.e. news
coverage, regulatory comments, etc.) that a non-final monograph may have received in relation
to company’s regulatory and business strategy for an affected drug product. A majority of

98
respondents reported that the amount of attention is only emphasized somewhat (39%, 21/54) or
emphasized little (35%, 19/54) during the development of a company’s strategy development.
When asked their opinion of how a non-final monograph affected product innovation, views
were expressed across the whole range of choices (20%, 11/54, no effect; 31%, 17/54 somewhat
positive effect; 31%, 17/54 somewhat negative effect) (Figure 19).
Figure 19: What is your opinion of how a non-final monograph, as opposed to a finalized
monograph, may affect product innovation?
4
17
11
17
5
0 5 10 15 20
Negative Effect
Somewhat Negative Effect
No Effect
Somewhat Positive Effect
Positive Effect
Effect
Number of Respondents (n=54)

When asked if any company with which the respondent had worked had attempted to motivate
FDA to finalize a non-final monograph, 59% (32/54) responded yes and 41% (22/54) responded
no. When asked if any company had attempted to modify a non-final monograph before

99
finalization, 80% (43/54) responded yes and 20% (11/54) responded no. When further queried
about the basis for the requested modifications, most reported that the modifications were based
on new clinical data, new labeling information, and/or new ingredient data.
Survey respondents were next asked in an open text format what, if anything, they would change
about the monograph system to improve it. The responses can be separated into two main
categories, a common view (41/45 comments) in which proponents advocated finalizing and
updating the outstanding non-final monographs in a timely manner, and less common view (4/45
comments) whose advocates preferred to accept the current system (Figure 20).
Figure 20: What, if anything, would you change about the monograph system to improve it?
(Selected responses by type.)
Comments on finalizing monographs, improving timelines, and having an efficient
process for change and updates
“Give FDA the resources to finalize the monographs. It has been 50 years since the 1962
statute, and 40 years since the monographs were first proposed. Science does march on.”
[sic]
“Implement a final monograph approval system 1) that forces final approval within 2 years of
close the comment period 2) permits modification of final monographs and provides for
reasonable phase-in periods in order to not place financial burdens on companies. Only
exception to phase-in period would be where evidence clearly demonstrates public safety is at
risk by not making modification.”
“Initiate a user fee system to facilitate completion.”
“Facilitate inclusion of new active ingredients and active ingredient combinations. Above all,
finalize the monographs with a process in place to amend it when sufficient data exists to
support the change.”
“Enable “switches” after a certain period of time to be included.”

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“Would like to see an easier way of getting new materials approved into the monograph
especially if they have been used around the world for years with no safety issues.” [sic]
Comments accepting of the current system or in opposition to change
“From an industry point of view, I would do nothing to change the system. Over the course
of decades, industry has learned how to work the system.” [sic]
“Slow down the process of finalization.”
“Nothing. The problems all stem from FDA’s failure to finish it.”

4.6 Cross-Tabulations
The pool of survey respondents in this study was comprised of professionals from various
sectors of the OTC drug industry, from companies of various sizes, and from job positions such
as consultant or lawyer, operating outside of manufacturing companies. For those respondents
that were working for a manufacturing company at the time of the survey, there were concerns
prior to the research about how experience with specific non-final monographs may affect a
respondent’s answers, particularly in relation to monograph adherence, and how risk tolerant
their current company may be based on company size. In order to help address these questions
of company size and monograph adherence, cross tabulations were performed to provide further
examination of these areas (Appendix B).
For the first cross tabulation, the question “If you currently work for a company that
manufactures/markets OTC drugs, what is the size of the company in terms of numbers of
employees.” was cross tabulated with the question “In your current or past experience, what is

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the OTC industry’s opinion regarding adherence to non-final monographs?” The results
indicate a slight trend for respondents working for companies with more than 999 employees to
indicate that non-final monographs should be more closely followed. Nevertheless, the results
were not statistically significant; the approximated P value for this correlation was 0.69.
For the second cross tabulation, the question “With which of the following non-final OTC drug
monographs do you have either current or past experience working?” was cross tabulated with
the question “In your current or past experience, what is the OTC Industry’s opinion regarding
adherence to non-final monographs?” The results did not indicate any notable trends or
significance; the P value was 0.98. For other questions in the survey, the profile and experience
of the respondents did not seem to vary in any highly correlated way with the responses to
various questions.
4.7 Interview Results
The ten respondents were selected for interviews based on their level of experience with
incomplete OTC monograph drugs, according to the pre-determined research plan. The
interviews consisted of five foundational questions (see Appendix C) designed to facilitate
discussion on possible reasons why the monograph system remains incomplete, the impact on
industry, and potential methods to improve the system.

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Interviews generally commenced with open-ended questions about the reasons why non-final
monographs continue to exist. A large majority of interviewees felt that non-final monographs
still exist today because the OTC monograph system is not a priority for FDA. Many
interviewees noted that the Agency is generally occupied with other issues regarding safety and
efficacy, particularly in the prescription drug area, and that a shortage of both funds and
personnel likely contribute to the situation. The public notice and comment rulemaking system
was also recognized as contributing to the delay, particularly for large, complex monographs
with many ingredients, in that differing viewpoints and opinions must be reviewed and
addressed by FDA. One interviewee noted that FDA receives user fees for many other services
that it performs but does not have equivalent specified resources for the management of OTC
monograph drugs. This lack of financial incentive was felt to contribute to the lack of attention.
When asked if the monograph system as it stands today is meeting its intended purpose, the
responses of the interviewees were mixed. About half felt that it is mostly meeting its intended
purpose, with industry attempting to make the best of the existing situation. However, the other
half of the interviewees felt that non-final monographs are causing specific problems for the
OTC drug industry. An uneven playing field was clearly identified as a concern, whereby
various excursions from non-final monographs are being made, creating inequality among
competing products. The sunscreen monograph was mentioned several times as an example of a
lengthy and complex monograph with a large market and many products, but yet where
excursions, including the use of different, non-approved active ingredients, are known to exist.

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Regarding efforts to complete the non-final monographs, four interviewees felt that industry
should be more involved in facilitating the process, and that the process should rely less on FDA
to carry the full burden. Several referred to the fact that industry was instrumental in the early
1970s at the beginning of the monograph process, when it helped to configure the original
review panels and orchestrate calls for data, and that almost all of the monographs are based on
information voluntarily obtained from industry via the notice and comment system. One
interviewee noted that FDA is responsible to carry out the official rulemaking process but that a
working group consisting of FDA representatives, industry representatives, and CHPA
leadership members could be very useful to help complete the non-final monographs.
Conversely, four interviewees said that they do not believe that industry should be, or would
even want to be, more active in the process. They felt that industry might gain little from such
involvement, or may even be handicapped if the monograph were to be finalized. Additionally,
two interviewees mentioned that FDA may be unlikely to agree to a more active role for industry
because the industry might be viewed as having a potential conflict of interest, and that
numerous differing opinions and agendas would make the process even more lengthy and
difficult.
When asked about other ways to improve the monograph system, a variety of ideas were
described by the interviewees. The two ideas that were most common were to include clearer
guidance from FDA on submission requirements for TEAs, and to adhere to realistic timelines
for responses on citizen petitions. In the opinion of one interviewee, the absence of a way to
maintain and update the monograph system was a “serious deficit.” Interestingly, one

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interviewee introduced the idea that every drug switched from an NDA to an OTC should carry
the requirement, by regulation, for a further review to amend or expand an OTC monograph with
the new product within a specified timeframe. A mandated review to include switched drugs as
part of monographs could facilitate the entry of more OTC drugs on the market, because the
barrier to market entry is significantly lower for a monograph drug than an NDA OTC drug.
Patent and exclusivity issues would need to be addressed to ensure protection of trade secrets
and to enhance feasibility of the system, although such measures were thought by the
interviewee to be tractable. Another interviewee proposed that a third party review system,
similar to medical device clearance in the European Union, could be used as a method to review
and update the monographs periodically and systematically; such a system was also felt to be a
way to finalize the remaining monographs. In such a case, a third party system could be
designed to reduce industry influence, yet still utilize data from industry.
When asked about the possibility of user fees to maintain and update the monograph drug
system, four interviewees were not opposed to reasonable fees, provided the fees would result in
tangible action and outcomes and would not be diverted for other programs or uses. In contrast,
five of the ten interviewees said that user fees would not be supported by industry and should not
be implemented for OTC monograph drugs. Amongst the reasons that were enunciated was the
view that Congress, rather than industry, should appropriately fund and staff FDA to carry out its
assigned responsibilities without placing further financial burdens on drug companies. One
interviewee also mentioned that placing user fees on some FDA services or processes could
result in preferential treatment for those areas, at the detriment of others, and thus could amplify

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the already uneven playing field. Several interviewees expressed the view that any user fees
should be based on the size of the OTC drug company in terms of employees or sales dollars, so
that small companies would not be unduly burdened. In contrast, a single interviewee
commented that an across-the-board flat fee system would be better accepted by industry.

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CHAPTER 5: SUMMARY AND CONCLUSIONS
5.1 Considerations of the Methodology
The focus of this study was to examine the views of industry professionals with regard to the
impact non-final OTC drug monographs have on one of its key stakeholder groups, the industry
that they support. To the knowledge of the researcher, this study offers the first known
systematic investigation of such viewpoints. Thus, the opportunity was taken to look at the issue
of incomplete OTC drug monographs using several approaches including a literature analysis, a
focus group, a survey, and follow-up interviews. The use of several methods is often advocated
in methodological texts for qualitative research in order to enhance the validity of observations
by triangulation (Marshall & Rossman, 2011). Such an approach helps to address a major
concern with any singular research method in that it can capture elements of the question being
studied in a more complete and effective manner. Studies of pharmaceutical regulations and the
associated impact on industry such as that attempted here could employ a number of methods
including case studies, observational methods, interviews, surveys, or other qualitative methods.
A mixed-method approach of surveys and interviews was considered the best approach to
provide relatively large numbers of viewpoints to standardized survey questions, as well as more
in-depth input to what might be considered sensitive questions. The combination capitalizes on
the well-known advantages of each research method, and thus may strengthen the confidence in
the usefulness and generalizability of the study outcome (Marshall & Rossman, 2011).
However, it must be acknowledged that, regardless of the research methods employed,

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challenges and disadvantages exist relative to the validity of the research outcomes and these
must be assessed critically when interpreting results of the study.
Survey research methods, including interviews, have many strengths such as the ability to gain
information from a large and diverse population while maintaining anonymity, and to
standardize and quantitate the data that is derived (Trochim, 2006). However, they can also have
several potential weaknesses. Survey results can be diminished in value if the chosen questions
are not appropriate (face validity) (Bornstein, 2004), if methods to select respondents are unable
to sample from the target population adequately, if honest answers cannot be obtained, and if the
resulting data cannot be generalized to a broader population in a different time or geographical
location (external validity) (Marshall & Rossman, 2011). We were particularly concerned about
face validity in this study because several broad therapeutic categories addressed by non-final
monographs were represented amongst the respondents and interviewees. External validity was
also of concern because of the variety and size of companies that comprise the OTC drug
industry. It was at the outset unclear to what extent the views of these different sub-segments
might diverge, and whether any important areas of divergence would be captured adequately by
the sampling technique.
5.1.1 Appropriateness of the Survey Questions
Valid survey methods depend upon the ability to develop and select questions that are
appropriate to capture the intended data elements. In this research study, such concerns about
face validity were addressed, in part, by the use of a focus group of highly experienced OTC

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professionals and academic advisors to critique and suggest changes to the survey tool. The use
of a focus group prior to deployment of a survey is not the typical approach in qualitative
research. In most mixed-method approaches, the focus group follows the survey (Patton, 2002).
However, the inverted order was felt to be more helpful in this study because the questions of
interest were concerned with the survey design rather than data content.
Amongst the issues that were of concern was the length of the survey. Methodological literature
and experiences of previous researchers suggested that a long survey would discourage
participation from busy professionals targeted as the respondent population. According to
interviews conducted by Jamieson, most senior level individuals in medical product companies
expressed a reluctance to participate in a survey lasting more than 10 or 15 minutes (Jamieson,
2011). Thus, it was necessary to obtain a balance of appropriate and meaningful questions
without creating a cumbersome and lengthy tool. Additionally, the survey would ideally employ
a mix of multiple choice and/or scaled question formats which would allow some measure of
quantitation, in addition to open-ended qualitative questions that would provide an expanded and
rich text response.
Anonymity was of particular concern in this research given the potentially sensitive nature of
questions relative to OTC drug monograph excursions, company practices, and corporate
strategy. Although excursions from a non-final monograph are generally tolerated by FDA as
long as no safety or efficacy problems arise, the practice is one that many companies may be
unwilling to discuss because it could signal that the company is willing to take regulatory risks

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or even indulge in ethically or legally questionable activities. Such concerns are not limited to
this subject, but have been expressed as a potential limitation in other studies in which questions
broached ethical or legal risk-taking by companies in the course of business decisions (Bain,
2011; Chan, 2012). This concern was addressed, in part, by structuring the survey questions to
avoid asking about the specifics of individual company practices and instead asking about the
respondent’s opinions and experiences more generally. Additionally, the statement at the
beginning of the survey was felt to provide the respondents with additional confidence in the
anonymity of the responses. Nonetheless, it is not possible to be sure that the answers to some
questions are the true views of the respondents or answers that might be “politically correct.”
5.1.2 Sampling of Respondents
Gaining access to individuals with the appropriate experience and background, and then
obtaining their cooperation to complete a survey, was a challenging aspect of the research. The
survey respondents represent some of the most experienced professionals in the industry as
evidenced by the fact that over 20% had experience with between 11 and 20 monographs and
11% had experience with over 20 monographs. Additionally, the survey respondents also
included the former chief counsel at FDA, Peter Barton Hutt, who helped develop and establish
the monograph system in the early 1970s (permission granted to the researcher to identify this
respondent). When attempting to solicit the cooperation of such busy individuals, it was
considered essential to send an initial screening e-mail in order to assess interest in participation
and their time constraints. It is widely appreciated that e-mail solicitation from unknown sources
typically yields a poor response rate especially when the survey threatens to ask questions about

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sensitive information (Shannon, 2002; Sheehan, 2001). Even with all the assurances that were in
place, it was interesting that one of the respondents would only take part in the survey after the
Director of the doctoral program directly affirmed that the study was part of a doctoral research
project and that the confidentiality would be assured by the student’s supervisor.
Early in the research, it was clear that the method of sampling had to be chosen carefully
because it could not accomplish simultaneously two desirable but potentially conflicting goals,
on one hand to assure homogeneity of the group and on the other to obtain a broad input from
different subsectors of the industry. To achieve the first goal, the sampling approach could have
focused on respondents all familiar with a single specified monograph. This would have
improved the homogeneity of the pool of respondents and allowed a deeper focus on issues
related to that specific monograph. However, such an approach would have limited significantly
the breadth of data that might characterize the industry as a whole. Further, it would have
limited the pool of potential respondents substantially. This approach may have also heightened
concerns about confidentiality because only a small, potentially identifiable set of respondents
and companies would be associated with a single monograph. To achieve the second goal, a
sampling method could be adopted that looked at responses related to incomplete monographs
more generally; this was in fact the course of action that was selected. This more generalized
approach has the risk that the observations of each respondent would be specific to the
monograph(s) with which that individual had experience. Because the experiences with non-
final monographs could vary significantly between respondents, it was considered necessary to
identify the experience of each respondent with respect to the different monographs, so that

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cross-tabulations could be made to distinguish any views or trends that might be associated with
or even unique to a specific monograph. Similarly, if a respondent was currently employed by a
company, the size of the company could affect viewpoints on non-final monographs relative to
actions such as excursions and other risk-taking activities. Cross-tabulations based on company
size were helpful in evaluating the degree of heterogeneity due to this potentially confounding
variable. Confidence in the results was increased in the results when such cross-tabulations
showed little effect of company size or monograph identity on viewpoints of the respondents.
The snowball technique (Marshall & Rossman, 2011) was employed as part of the process to
identify suitable survey respondents. By more quickly finding individuals who met the inclusion
criteria and who were willing to respond to the survey, it was possible to expand the potential
pool of respondents more quickly. Although this method of recruitment might be criticized as
introducing selection bias if it provided relatively concentrated groups of respondents (Faugier,
1997) with experience in only a limited number of monograph categories, the survey results
suggested that the representation that was derived by this method provided respondents who had
experience in the full range monograph categories. This outcome was considered important for
the generalizability of the results across the OTC drug industry.
The survey results showed a wide representation of participants who had experience with a range
of non-final monograph categories and who were employed by companies of different sizes, but
it nevertheless must be acknowledged that 56 survey responses is a relatively small data set.
Further, the survey was constructed in such a way that respondents were not forced to answer all

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questions in the survey. As results showed, only a few respondents failed to answer one or more
of the questions. Nonetheless, some questions did not have a full set of 56 responses. The
dataset does capture a subset of US professionals who have at least 5 years of experience, some
part of which has included experience with non-final monographs, but we do not know the
extent to which this subset penetrated the full pool of potential respondents. There seems to be
no database that captures the names of all individuals with these characteristics. To assure that
the results are as transparent as possible, the complete survey results including absolute numbers
and verbatim responses are reported for this subset in the Appendix (Appendix D).
5.1.3 Interviews
In this study, ten survey respondents were interviewed after they had completed the survey to
explore their opinions regarding non-final monographs more deeply. The use of standardized
interview questions was felt to facilitate comparisons between interviewees and to ensure that
the survey results were consonant with the views of the participants when they were allowed
more freedom to express opinions verbally. The congruence between the responses in the
interviews and surveys suggested that the research may have reasonable external validity at least
with respect to the parts of the industry dealing with non-final monographs in the US.
Although the interviews were seen to add strength to the study results, weaknesses and
limitations of interviews must be acknowledged. An important prerequisite for a successful
interview, for example, is the need for interviewees to be forthcoming in their responses. The
interviewees must then trust the researcher. Because the interviews were solicited after

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respondents had completed the survey, it was hoped that potential interviewees would have
gained some level of confidence in the researcher and would only volunteer for an interview if
they felt comfortable to answer questions of a similar nature. Nevertheless, with only a small
number of interviewees, the quality and external validity of the responses will always be of some
concern. Further, the interview answer might be slanted depending on the introduction of bias or
leading questions (Marshall & Rossman, 2011). The researcher in this study has worked in the
OTC drug industry and with non-final monographs for more than 11 years and has also been
involved with several significant legal issues. As a result, it must be acknowledged that some
researcher bias is possible although the researcher was aware of the potential for bias and
attempted to control this bias by posing a minimal set of open-ended, general questions.
5.2 Consideration of Results
A triad of principles relating to the goals of regulation was used as a framework for this research
to interpret the literature, to structure the survey, and to help interpret and frame the research
results. These three identified policy goals of regulation are 1) to ensure the safety and
effectiveness of drug products, 2) to facilitate efficiencies in the management of research,
commercialization, and costs, and 3) to equalize requirements and standards for the industry
(FDA, 2009; Seiguer & Smith, 2005). To analyze and interpret the results of the study, we must
consider how well non-final monographs may be meeting the intended purpose of these three
identified goals of regulation.

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5.2.1 Safety and effectiveness of products
Perhaps the most critical role for pharmaceutical regulation is the protection of society from
unsafe or ineffective products (FDA, 2012). If the current system of incomplete monographs
were to result in increased risk in this regard, then strong motivation would exist to accelerate
the development of final monographs. However, the results of this survey reflect a broad general
agreement amongst respondents that non-final monographs are not a significant threat to patient
safety. Further, FDA has the legal authority and responsibility to take action if safety or
effectiveness were to come into question. Results suggest that that few manufacturers would
deviate from an incomplete monograph in a manner that would affect safety because of the
regulatory, legal, and financial jeopardy that might result from such deviations.
Safety-related concerns would most likely be important if an OTC drug manufacturer were to
consider the use of an active ingredient not already assessed by FDA and included in the relevant
monograph. The findings that products with monograph excursions are reported to be “almost
always” or “most of the time” tested for safety by the manufacturers before commercialization
may explain the relatively low incidence of safety-related issues and suggest that non-final
monographs may not be compromising the safety and effectiveness of OTC drug products.
The fact that some active ingredients not included in monographs are acceptable in other
countries might be seen as a way for companies to determine whether an excursion is worth to
make in the US. However, such international experience does not seem to have a large degree of
influence on decisions by US OTC drug manufacturers to deviate from the monograph,

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according to the survey results collated here. Nevertheless, this result does not mean such
excursions are not being considered by manufacturers in the US. Indeed, it is evident from the
survey and interviews that the OTC industry does want a more efficient and effective mechanism
to incorporate active ingredients used safely outside of the US into the monograph system.
Internationally, no system equivalent to the US monograph system exists for OTC products;
OTC products must typically be reviewed individually and given health authority approval in
order to be placed on the market (RAPS, 2010). The status of active ingredients and experience
with those ingredients also varies from country to country, even in a set of countries as
interdependent as that of the EU that are linked by a common market. It is likely that some
active ingredients marketed elsewhere legally and with a positive safety profile could be added
to the OTC monograph system if they were to be given an efficient and straightforward pathway
to do so. Harmonization of approvals in different countries is recognized as a positive way in
which to reduce unnecessary duplication of regulatory requirements, a goal for most regulatory
agencies in the world today (WHO, 2000).
When safety or efficacy questions are considered by manufacturers, much attention turns to
issues of risk and liability. The survey data suggest that most companies explicitly evaluate a
broad range of risks including legal and financial consequences when considering to deviate
from a monograph. These legal and financial considerations often reflect the very real influence
exercised by third party entities such as insurance companies and the US legal system (Congress,
1993). Gunningham and Sinclair (1998) assert that quasi-regulation by third parties (in this case
the insurance and legal institutions) may even have a more potent effect than direct government

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intervention, where quasi-regulation is defined as including a wide range of rules or
arrangements where entities influence businesses to comply, but which do not form part of
explicit government regulation.
5.2.2 Efficiencies in Product Management
Another important role of pharmaceutical regulation is to facilitate efficiencies in the
management and resource allocations for research and commercialization. The effects that non-
final monographs have on these management activities for OTC drug products appear to be
significant. The survey responses strongly suggest that non-final OTC monographs are not
facilitating efficiencies in the management of research and commercialization. Most
commonly, the impact of non-final monographs on industry operations was reported to be at
least to some degree negative, and importance was rated as somewhat to very important.
Interestingly, responses were mixed regarding the effect of a non-final monograph on product
innovation. A majority of respondents seemed to prefer that non-final monographs be completed
in order to standardize requirements and increase the transparency of expectations. This
standardization would presumably foster efficiencies in research, development, and costs both
within companies and across the OTC drug industry. However, other companies and even
companies who desire that monographs be finalized are at the same time attempting to leverage
both the perceived advantages and disadvantages of non-final monographs to their benefit in the
interim period. Some companies seem to feel a sense of independence and freedom when
working under non-final monographs, while others feel that the system is inadequate and allows

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for unproven excursions to be made. Nevertheless, uncertainty in non-final monographs appears
to be contributing to inefficiencies for at least some in the OTC industry. In a recent publication
about monograph compliance, CHPA President Scott Melville noted that “uncertainty is never
desirable when you are a regulated industry and you want to know what the rules are”
(Crawford, 2013).
Mitigation plans were almost always or commonly developed for commercialized products
before a monograph was finalized so that excursions could be “corrected” at a later time. This
result indicates that many companies are preparing a strategy for how they would change their
already-marketed product in the event of a newly finalized monograph. A majority of
respondents also reported that they had attempted to motivate FDA to finalize a non-final
monograph or had attempted to modify a monograph before finalization. It is well known that
FDA regulations can have a significant negative effect on stock prices of the pharmaceutical
industry due to anticipated costs related to new regulations or regulation changes (Dowdell,
Govindaraj, & Jain, 1992). Thus, it is advantageous for manufacturers to attempt to influence
regulations and/or prepare for those changes proactively. It is evident from the research results
that many companies are paying attention to the contents of non-final monographs and the long-
term costs and other commercial implications that could affect their products.
5.2.3 Equalize Standards
Of the three framework elements used to frame this research, the third role of pharmaceutical
regulation, to equalize requirements and standards for the industry, is perhaps most affected by

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non-final monographs. Seiguer and Smith (2005) suggested that consistent expectation and a
level playing field are important to industry, a view that they felt was shared by the FDA.
Moreover, the results of this survey strongly suggest that a majority of companies composing the
OTC drug industry also believe that requirements should be standardized.
According to FDA’s Janet Woodcock, “laws and regulations establish hard boundaries and
within these lines, there is much discretion” (Woodcock, 2010). Clearly, interpretation and
application of drug regulations is necessary based on the specific situations in which they are
used. However, minimum standards and requirements should foster a level playing field for
drug manufacturers. Prior to conducting the research phase of this study, it was postulated that a
level playing field may not exist for OTC drug products with non-final monographs. The
research validated some impressions gained from the initial review of the literature. Many
companies are reportedly making excursions from non-final monographs, to varying degrees and
frequencies, and whose prevalence and breadth were in fact greater than expected.
The fluid state of the playing field is an important force, and perhaps the most important force
driving manufacturers to make excursions from non-final monographs. The majority of survey
respondents ranked “creating a marketing advantage” as the primary reason for excursions; the
second most important reason was “creating other commercial advantages”. The impression is
gained that failure to modify product outside of monograph boundaries could have a negative
effect on sales. How companies choose to respond also seems to vary, so that the requirements
and standards for the OTC monograph industry are not interpreted, applied, and executed in an

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equal manner. This type of fluidity appears to be relatively low in risk. The survey results
indicate that competitors rarely initiate legal action against one another, or ask for a competitor
to stop monograph excursion activities. Additionally, the FDA also appears to be a relatively
minor concern from the point of view of regulatory risk. The many open-ended survey text
comments that identified a large degree of flexibility in the adherence to non-final monographs
appeared consistent with the fact that FDA has seldom been seen to take action against OTC
drug companies for excursions from non-final monographs. It is perhaps telling that 67% of
respondents reported that they had never have been contacted by the FDA about a monograph
excursion. Nevertheless, the fact that 33% of respondents were contacted by FDA also suggests
that they are not an invisible player. From this survey we do not know the nature of the
interaction. Further exploration of this question could represent an interesting future research
topic to explore.
It is relevant to note a tendency, although not statistically significant, for survey respondents
working for a larger company (more than 999 employees) to believe that non-final monographs
should be followed more closely. Larger companies appear, in general, to have a propensity to
be more compliant and have less risk tolerance than smaller companies. In a recent study by
Chan, survey respondents from larger companies more often classified their companies as formal
and self-reliant than smaller companies (Chan, 2012). Large companies are also often publicly
traded companies for whom the consequences of problems with widely distributed products can
be particularly impactful (Grunwald & Hempelmann, 2010). A greater vulnerability to legal
liability may also exist for large companies because of their ability to generate significant profit

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and cash reserves, thereby appearing as an attractive litigation target (Willing, 2001). Several
open-ended text comments from survey respondents and comments from interviewees reflect a
relatively common perception that smaller companies are more likely to deviate from non-final
monographs. Smaller companies are typically trying harder to find a foothold in the market.
Because such companies have a smaller market reach and fewer financial resources, they may
not be seen as excellent targets for large personal injury settlements and may be able to afford to
take more risk.
One of the most revealing sections of the survey involved a series of questions regarding
adherence to non-final monographs. Most survey respondents felt that non-final monographs
should be closely followed yet, at the same time, most survey respondents believed monograph
excursions occur commonly. Most respondents also felt that companies were “mostly
complaint” to non-final monographs. This seems to indicate that the OTC drug industry believes
that following a non-final monograph is the intended action desired by FDA but, at the same
time, industry also believes that excursions from non-final monographs can be made
successfully. This appears to confirm that non-final monographs may be used in some cases to
inform rather than dictate strategy, a concept similar to the role of guidance documents.
Guidance documents are defined as administrative instruments not having the force of law and,
as such, allow for flexibility in approach (Lewis, 2011).
An element that was examined further was the frequency of specific excursions from non-final
monographs. Labeling differences, the use of different active ingredient combinations, and the

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use of a different dosage form were seen to be the most common types of excursions.
Nonetheless, all types of the queried excursions were reported to occur, albeit at lower
frequencies. It is perhaps not surprising that the frequencies vary according to the product type
and to the specific details of the monograph. Nevertheless, excursions are reportedly occurring
in many ways and even include the use of a different indication, a different dosage regimen, a
different active ingredient, and different product instructions than those specified in monographs.
These responses support that the requirements for the OTC industry are not applied in a
standardized way nor is the playing field level.
Scores from a series of questions relating to competitive activities also reveal insights on the
impact of non-final monographs on the OTC industry. Respondents report that companies
“almost always” or “commonly” conduct evaluations on competitor products. Most respondents
believe that companies actively copy monograph excursions and try to find better or other
monograph excursions in order to gain market advantage. Thus, it appears that activities of
competitors are very relevant for a manufacturer when considering regulatory compliance.
Moreover, the presence of non-final monographs can create a regulatory system in which many
forces are at play in determining the actions taken by the individual manufacturer. According to
Grabosky, many regulatory systems are hybrid entities with many other participants, and thus are
influenced not only by the regulators but also by peer regulated entities and third party groups
(Grabosky, 1997). In the case of non-final monographs, it would appear that the regulated
entities (competitors) may have significant influence on each other that may trump the influence

122
played even by the regulators. Excursion decisions and activities, therefore, may be strongly
guided by the degree to which a competitor product is able to make successful excursions.
5.3 Future Directions
It is evident from this research that the monograph system needs improvements in order to assure
that its intended regulatory goals are met and maintained. Several suggestions were made by
respondents regarding ways in which the system could be improved. For example, a process to
schedule the regulatory review of ingredients that have switched from prescription to OTC status
by means of an NDA after a defined point in time might be used to identify ingredients that
could be usefully added to a monograph without the usual petition process. Some respondents
expressed the view that the implementation of user fees might be a suitable means to bring more
attention and support to the monograph system in order to facilitate finalization activities. The
prescription drug user fee program that was initiated in 1992 for prescription drugs has produced
a 50-percent increase in the speed of review at FDA (Olson, 2002). As noted in an interview of
Eugene Lambert, senior counsel at Covington and Burling LLP:
While prescription drug user fees support the agency’s costs for evaluating NDAs, including
OTC switches, and other Rx drug applications, there is no similar fee for maintaining
monographs. It’s not called the Prescription Drug User Fee Act for nothing. If you’re just
dealing with OTCs, you’re not getting the kind of financial support that you do when you’re
dealing within the agency with prescriptions. So, there is a resource issue (Gillespie, 2012).

123
The prescription user fee program, however, altered the agency’s financing arrangement by
making the FDA dependent on industry for a portion of its funding, a situation known as
“regulatory capture”. Whether this situation creates conflicts of interest or whether those
concerns are significantly diminished by the large gains in attention and review time for
prescription drugs is a debate that remains (Gillespie, 2012). Further, many industry respondents
were not in favor of a use fee system. Whether a user fee system would substantially benefit the
OTC monograph system has not been determined but warrants evaluation along with other
possible system improvements.
Systematic changes may also be necessary to address the FDA resource constraints which are
often identified as the reason for the delay in finalizing and updating monographs. Some
interviewees suggested that collaborative working groups consisting of FDA representatives,
industry representatives, and CHPA leadership members could be put into place with the specific
charge to complete non-final monographs and update existing monographs. Alternatively, a
third party review system, similar to the notified body system used for medical device clearance
in the European Union, could be used as a method to review and update the monographs
periodically and systematically. The advantage of this process would likely be a faster
completion time without such great concerns about the direct influence of industry in the
process. Such a process would not prevent the very useful ability to access product and active
ingredient data from industry. Perhaps even a combination of new regulations requiring timely
review and finalization of monographs, new regulations requiring review of OTC products
previously switched through the NDA process, and new collaborative working parties and/or

124
third party reviews could be useful to improve the monograph system and assure that its intended
regulatory goals are met and maintained.

5.4 Conclusions and Recommendations
What is evident from this research is that non-final monographs are falling short when
considering at least two of the three framework elements. Although there is some evidence that
non-final monographs help to ensure the safety and effectiveness of OTC drug products, there is
support from this research that efficiencies in research and commercialization are jeopardized by
non-final monographs and that this may tilt the playing field for different participants.
Additionally, there appears to be a schism in the views of different manufacturers. A subset of
companies appears to accept and even appreciate the benefits that derive from incomplete
monographs, but others express a preference that the monographs be finalized as soon as
possible.

OTC drugs provide an important way in which American consumers treat many types of
illnesses in a cost-effective and accessible manner. The OTC monograph system has affected
thousands of products and has yet to be completed as of the time of this writing. According to
Wilson, the US regulatory system contains often conflicting elements—a system of rules and, at
the same time, an opportunity for openness and access (Wilson, 1989). The monograph system
would appear to be a good example of such a system where rules exist but, where openness and
even excursions are possible. The concept of regulating OTC drug products with a satisfactory

125
safety profile by therapeutic class via the monograph system is a plausible mechanism of
regulation. However, this research suggests non-final monographs should not linger for long
periods of time in a non-final state if they are to fulfill the intended goals of regulation. Further,
the overall monograph system needs more efficient mechanisms by which new ingredients can
be introduced into the system and new processes to ensure that monographs are updated and
maintained. Without such changes, the OTC monograph system may be at risk of becoming
obsolete as more government focus and resources are placed on other areas. The overall impact
of incomplete monographs on the OTC industry is a mixed bag of both advantages and
disadvantages, to varying degrees and extents, for which the regulatory objectives and goals
remain incomplete.

126
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APPENDIX A
OTC Survey
The following survey is part of research associated with a doctoral dissertation in regulatory
science at the University of Southern California. Your responses are completely anonymous and
will not be associated with you or your company. There is an option at the end of the survey to
supply your contact information if you are interested in participating in a phone interview. Even
if you elect to participate in a follow-up phone interview, your responses will only be known by
the researcher and will not otherwise be tied to either you or your company. Your candid
responses are important to the validity of this research.
General and Corporate Questions
Q1 What is your current position/title?
 Regulatory Vice President
 Regulatory/Quality Vice President
 Quality Vice President
 Legal Vice President
 Regulatory Director
 Quality Director
 Regulatory Manager
 Quality Manager
 Legal Director/Manager
 Regulatory Supervisor
 Regulatory Associate
 Regulatory Consultant
 Lawyer
 Other ____________________

135
Q2 If you currently work for a company that manufactures/markets OTC drugs, what is the size
of the company in terms of numbers of employees?
 1-99
 100-499
 500-999
 1,000-9,999
 10,000+
 Do not work for a manufacturing company
If “Do not work for a manufacturing company” is selected, the survey skips to question 5.

136
Q3 Under which of the following OTC monographs are you aware that your company
manufactures/markets OTC drugs in the US? Please check all that apply.
 Acne
 External Analgesics
 Internal Analgesics
 Anorectal
 Antacid
 Anthelminitcs
 First Aid
 Anticaries
 Antidiarrheal
 Antiemetic
 Antiflatulent
 Antifungal
 Antihistamine
 Antiperspirant
 Antitussive
 Bronchodialator
 Cholecystokinetic
 Corn, Callus, and Wart Remover
 Dandruff
 Decongestant, Nasal
 Deodorant, Internal
 Laxative
 Menstrual Products
 Nighttime Sleep Aid
 Ophthalmics
 Oral Healthcare
 Otics
 Pediculicides
 Poison Treatment
 Skin Bleaching
 Skin Protectants
 Stimulant
 Sunscreen
 Vaginal Contraceptives

137
 Vaginal Drug Products
 Other ____________________

Q4 How many different OTC monograph drug brands does your company manufacture/market
in total in the US?
 1
 2-5
 6-10
 11-20
 More than 20
 Do not know

Q5 How many OTC monograph areas do you have current or previous experience with in the
US?
 1
 2-5
 6-10
 11-20
 More than 20

138
Q6 With which of the following non-final OTC drug monographs do you have either past or
current experience working? Please check all that apply.
 External Analgesics
 Internal Analgesics
 First Aid
 Laxative
 Menstrual Products
 Oral Healthcare
 Poison Treatment
 Skin Bleaching
 Sunscreen
 Vaginal Contraceptives
 Vaginal Drug Products
 Other ____________________

Requirements, Standards, and Level Playing Field Questions
Q7 In your current or past experience, what is the OTC Industry’s opinion regarding adherence
to non-final monographs?
 They should be followed exactly
 They should be followed closely
 They may be followed generally
 They can be followed loosely
 They do not need to be followed

139
Q8 In your current or past experience, given that a non-final monograph is not final and is not
legally enforceable, how often do you believe excursions (differences) are made from a non-final
monograph in the OTC Industry?
 Almost always
 Commonly
 Sometimes
 Rarely
 Never

Q9 In your current or past experience, how compliant are OTC drug companies to non-final
monographs?
 Completely compliant
 Mostly compliant
 Generally compliant
 Loosely compliant
 Vaguely compliant

140
Q10 In your current or past experience, how often are the following types of monograph
excursions made from a non-final monograph in the OTC industry?
Almost
Always
Commonly Sometimes Rarely Never Don't know
Use of a
different or
additional
indication
than in the
non-final
monograph
     
Use of a
different
dosage
regimen
than in the
non-final
monograph
(includes
dosage
amount,
schedule,
etc.)
     
Use of
different
product
instructions
from the
non-final
monograph
     
Use of other
labeling
differences
than in the
non-final
monograph
     
Use of a
different
active
ingredient
than in the
non-final
monograph
(including
     

141
category III
ingredients)
Use of a
different
active
ingredient
combination
than in the
non-final
monograph
     
Use of an
active
ingredient
identified in
the non-final
monograph
but that is
not included
on the
product
label as an
active
ingredient
     
Use of a
different
dosage form
than in the
non-final
monograph
     
Other      

142
Q11 In your current or past experience, which of the following non-final monographs are the
most "contentious" and may have a higher potential for excursions from the monograph? Please
check all that apply.
 External Analgesics
 Internal Analgesics
 First Aid
 Laxative
 Menstrual
 Oral Healthcare
 Poison Treatment
 Skin Bleaching
 Sunscreen
 Vaginal Contraceptives
 Vaginal Drug Products
 Other ____________________
 None

Q12 In your current or past experience, please rank the following reasons for excursions from
non-final monographs with 1 being the most likely reason and 8 being the least likely. Please
click on the number on the right and side and drag up or down to your desired position/rank.
______ To create a marketing advantage
______ To create other commercial advantages
______ To improve safety
______ To improve efficacy
______ Possession of company clinical or other data that supports the excursion
______ Inability to meet technical or analytical requirements of the non-final monograph
______ Cost of meeting the non-final monograph is too high
______ Other

143
Q13 In your current or past experience, how influential do you believe international standards
and regulations are when an excursion from a non-final OTC monograph is made?
 Very influential
 Somewhat influential
 Neutral
 Not very influential
 Not influential at all

Q14 In your current or past experience, when developing a new OTC monograph drug for which
the monograph is non-final, how often are competitive products evaluated for compliance to the
monograph?
 Almost always
 Commonly
 Sometimes
 Rarely
 Never

Q15 When a competitive product is evaluated for compliance to a non-final monograph, which
of the following activities are undertaken? Please check all that apply.
 Assess competitor product labeling
 Assess competitor advertising materials
 Analyze competitor product formulation
 Other ____________________

144
Q16 How do companies address competitors who may be making excursions from a non-
final monograph?
Almost Always Commonly Sometimes Rarely Never
Start legal
action
    
Report them
to FDA
    
Ask them to
stop
    
Copy their
monograph
excursion or
difference
    
Try to find
better or other
monograph
excursions or
differences
    
Monitor the
competitive
product to see
how it sells
    
Other     

145
Q17 In your current or past experience, have you or your company ever been contacted by a
competitor company about an excursion from a non-final OTC monograph?
 Yes
 No

Q18 In your current or past experience, have you or your company ever been contacted by the
FDA about an excursion from a non-final OTC monograph?
 Yes
 No

Q19 In general, do you think there are regulatory and/or business advantages when a monograph
is non-final?
 Yes
 No

Q20 If yes, please explain why you think there are advantages.

Q21 In general, do you think there are regulatory and/or business disadvantages when a
monograph is non-final?
 Yes
 No

146
Q22 If yes, please explain why you think there are disadvantages
Safety and Effectiveness Questions
Q23 In your current or past experience, when a company makes an excursion from a non-final
OTC monograph which may affect the safety of a product, how often is clinical or other safety-
related testing conducted?
 Almost always
 Most of the time
 Sometimes
 Seldom
 Rarely
 Don't know

Q24 How often do companies evaluate risks in each of the following areas in relation to an
excursion from a non-final OTC monograph?
Almost
Always
Commonly Sometimes Rarely Never
Commercial/Marketing
Risks
    
Regulatory
Compliance Risks
    
Legal Risks     
Financial Risks     
Clinical Risks     
Safety Risks     
Product Quality Risks     
Other Risks     

147
Efficiencies in Research, Commercialization, and Costs Questions
Q25 In your current or past experience, what is the overall impact of non-final OTC drug
monographs on OTC drug Industry operations?
 Negative
 Somewhat negative
 Neutral
 Somewhat positive
 Positive

Q26 In your current or past experience, how important is the impact of non-final OTC drug
monographs on OTC drug industry operations?
 Extremely important
 Very important
 Somewhat important
 Neither important nor unimportant
 Unimportant

Q27 When an excursion is made from a non-final monograph on a commercialized OTC drug
product, are mitigation plans developed in advance for the monograph excursions to be
"corrected" once the monograph becomes final?
 Almost always
 Commonly
 Sometimes
 Rarely
 Never

148
Q28 How much emphasis is placed on the amount of attention (news coverage, regulatory
comments, etc.) a non-final monograph may have received regarding a company's regulatory and
business strategy for an affected OTC drug product?
 None
 Little
 Some
 Much
 Extensive

Q29 What is your opinion of how a non-final monograph, as opposed to a finalized
monograph, may affect product innovation?
 Negative effect
 Somewhat negative effect
 No effect
 Somewhat positive effect
 Positive effect

Q30 Has any company you have worked for ever attempted to get FDA to finalize a non-
final monograph?
 Yes
 No

149
Q31 Has any company you have worked for ever attempted to modify a non-final monograph
before finalization?
 Yes
 No
If no is selected, the survey skips to question 33.
Q32 What was the basis for the requested modification to the non-final monograph? Please
check all that apply.
 New clinical data
 New ingredient data
 New analytical procedures
 New labeling information
 Other ____________________

Q33 What, if anything, would you change about the monograph system to improve it?

Q34 Would you agree to participate in a 15-20 minute phone interview to further discuss the
advantages and disadvantages of non-final OTC monographs? If so, please provide your contact
information.

150
APPENDIX B
OTC Survey Cross Tabulations
In your current or past experience, what is the OTC industry’s
opinion regarding adherence to non-final monographs?

They should
be followed
exactly
They
should be
followed
closely
They may be
followed
generally
They can
be followed
loosely
They do
not need to
be followed
Total
With which of the following non-final OTC drug monographs do you
have either past or current experience? Please check all that apply.
External
Analgesics
3 14 6 3 6 32
Internal
Analgesics
3 10 3 1 2 19
First Aid 1 10 3 1 2 17
Laxative 5 12 7 2 2 28
Menstrual
Products
0 6 1 1 2 10
Oral
Healthcare
1 11 5 3 4 24
Poison
Treatment
0 3 1 0 0 4
Skin
Bleaching
3 10 4 2 3 22
Sunscreen 5 17 10 3 6 41
Vaginal
Contra-
ceptives
1 4 1 0 1 7
Vaginal Drug
Products
3 10 4 2 2 21
Other 1 7 1 1 1 11
Total 10 23 13 4 6 56

Chi Square 26.79*
Degrees of Freedom 44
p-value 0.98
*Note: The Chi Square approximation may be inaccurate
-expected frequency less than 5.

151
If you currently work for a company that manufactures OTC drugs,
what is the size of the company in terms of numbers of employees?

1-99 100-499 500-999 1000-
9999
10000+ Do not work for a
manufacturing
company
Total
In your current or past experience, what is the
OTC industry’s opinion regarding adherence
to non-final monographs?
They should
be followed
exactly
1 2 0 1 3 3 10
They should
be followed
closely
2 5 2 0 5 9 23
They may be
followed
generally
0 4 1 0 1 7 13
They can be
followed
loosely
1 1 1 0 0 1 4
They do not
need to be
followed
0 2 0 0 0 3 5
Total 4 14 4 1 9 23 55

Chi Square 16.49*
Degrees of Freedom 20
p-value 0.69
*Note: The Chi Square approximation may be inaccurate
-expected frequency less than 5.

152
APPENDIX C
Interview Questions
# Question
1 The OTC monograph system has been in place now for more than 40 years. There have been
many monographs completed and many successes in the program, along with some monographs
that have remained in a tentative final state for decades. Why do you think there has been
relatively little attention paid to the completion of the monographs by FDA?

2 Do you think the monograph system, as it stands today, is meeting its intended purpose? The
original goal was to have a straightforward system of grouping products by therapeutic category
and classifying active ingredients according to whether they were safe and efficacious or not,
with labeling by product class. Do you think the system is working (for industry), particularly
relative to monographs that are not final?

3 Do you think industry should be more active in helping or leading the efforts to complete the
non-final monographs? Or do you see this as FDA’s responsibility and industry should not be
heavily or directly involved? Do you think some type of industry and academic board or
working group would be beneficial to help review outstanding issues, ingredients, etc. and
expedite rulemaking?

4 What do you think might be other viable ways to improve the monograph system or maybe even
other pathways for OTC drugs? A citizen petition process exists already but FDA response time
is long and the applicability for a Citizen Petition is limited to those products already on the
market before 1972. A TEA process also exists but no new ingredient has been approved via this
pathway to date.

5 Technology has changed a lot since 1972 and will likely continue in the future. What are your
thoughts on how the monograph system (or an alternative) could be kept up to date in a timely
manner with changes in regard to, for example, new ingredients and new product forms?
(Disposable cloth, spray, gummy, etc.). Should there be “user fees” in order to help make
ongoing review and timely updates possible? In your opinion, would industry be supportive of
“reasonable” user fees for OTC monograph drugs? Why or why not?

153
APPENDIX D
Survey Results
1. What is your current position/title?
# Answer

Responses %
1
Regulatory Vice
President

2 4%
2
Regulatory/Quality
Vice President

4 7%
3
Quality Vice
President

0 0%
4
Legal Vice
President

0 0%
5
Regulatory
Director

7 13%
6 Quality Director

1 2%
7
Regulatory
Manager

4 7%
8 Quality Manager

1 2%
9
Legal
Director/Manager

0 0%
10
Regulatory
Supervisor

1 2%
11
Regulatory
Associate

3 5%
12
Regulatory
Consultant

6 11%
13 Lawyer

4 7%
14 Other

23 41%
Total 56 100%

154
Other
Consultant
Principal Investigator
President
Statistical Consultant
Regulatory Coordinator
R&D scientist
Director, Global Medical Affairs and PV
scientific and regulatory consultant
consultant
Consultant
Retired Vice President
Medical Affairs
CSO
Clinical lab owner
Scientific Affairs, Dorector
VP R & D
Medical Affairs and Clinical Research
Senior Manager
Vice President Clinical Sciences
drug safety
President

Statistic Value
Min Value 1
Max Value 14
Mean 10.29
Variance 19.55
Standard Deviation 4.42
Total Responses 56

155
2. If you currently work for a company that manufactures/markets OTC drugs, what is the size
of the company in terms of numbers of employees?
# Answer

Responses %
1 1-99

4 7%
2 100-499

14 25%
3 500-999

4 7%
4 1,000-9,999

1 2%
5 10,000+

9 16%
6
Do not work for
a
manufacturing
company

23 42%
Total 55 100%

Statistic Value
Min Value 1
Max Value 6
Mean 4.20
Variance 3.61
Standard Deviation 1.90
Total Responses 55

156
3. Under which of the following OTC monographs are you aware that your company
manufactures/markets OTC drugs in the US? Please check all that apply.
# Answer

Responses %
1 Acne

14 42%
2
External
Analgesics

14 42%
3
Internal
Analgesics

11 33%
4 Anorectal

11 33%
5 Antacid

6 18%
6 Anthelminitcs

0 0%
7 First Aid

4 12%
8 Anticaries

4 12%
9 Antidiarrheal

4 12%
10 Antiemetic

2 6%
11 Antiflatulent

4 12%
12 Antifungal

4 12%
13 Antihistamine

7 21%
14 Antiperspirant

4 12%
15 Antitussive

5 15%
16 Bronchodialator

1 3%
17 Cholecystokinetic

0 0%
18
Corn, Callus, and
Wart Remover

2 6%
19 Dandruff

8 24%
20
Decongestant,
Nasal

8 24%
21
Deodorant,
Internal

0 0%
22 Laxative

15 45%
23
Menstrual
Products

6 18%
24 Nighttime Sleep

5 15%

157
Aid
25 Ophthalmics

1 3%
26 Oral Healthcare

10 30%
27 Otics

3 9%
28 Pediculicides

2 6%
29 Poison Treatment

0 0%
30 Skin Bleaching

1 3%
31 Skin Protectants

23 70%
32 Stimulant

2 6%
33 Sunscreen

16 48%
34
Vaginal
Contraceptives

0 0%
35
Vaginal Drug
Products

11 33%
36 Other

1 3%

Other
We Test many of these OTC catagories but don't manufacture

Statistic Value
Min Value 1
Max Value 36
Total Responses 33

158
4. How many different OTC monograph drug brands does your company
manufacture/market in total in the US?
# Answer

Responses %
1 1

1 3%
2 2-5

9 27%
3 6-10

10 30%
4 11-20

3 9%
5 More than 20

8 24%
6 Do not know

2 6%
Total 33 100%

Statistic Value
Min Value 1
Max Value 6
Mean 3.42
Variance 1.88
Standard Deviation 1.37
Total Responses 33

159
5. How many OTC monograph areas do you have current or previous experience with in the
US?
# Answer

Responses %
1 1

3 5%
2 2-5

18 32%
3 6-10

18 32%
4 11-20

11 20%
5 More than 20

6 11%
Total 56 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.98
Variance 1.18
Standard Deviation 1.09
Total Responses 56

160
6. With which of the following non-final OTC drug monographs do you have either past or
current experience working? Please check all that apply.
# Answer

Responses %
1
External
Analgesics

32 57%
2
Internal
Analgesics

19 34%
3 First Aid

17 30%
4 Laxative

28 50%
5
Menstrual
Products

10 18%
6 Oral Healthcare

24 43%
7
Poison
Treatment

4 7%
8 Skin Bleaching

22 39%
9 Sunscreen

41 73%
10
Vaginal
Contraceptives

7 13%
11
Vaginal Drug
Products

21 38%
12 Other

11 20%

161
Other
Diaper Rash
acne, anorectal, antacid, anticaries, antifungal, antihistamine, antiperspirant, corn/callus/wart
remover, dandruff, nasal decongestant, laxative, skin protectants,
ophthalmic:EFAE
Antacid
Cough-cold-allergy; eye
diaper rash
Healthcare antiseptic
skin protectant
We Test Many

Statistic Value
Min Value 1
Max Value 12
Total Responses 56

162
7. In your current or past experience, what is the OTC Industry’s opinion regarding
adherence to non-final monographs?
# Answer

Responses %
1
They should
be followed
exactly

10 18%
2
They should
be followed
closely

23 41%
3
They may be
followed
generally

13 23%
4
They can be
followed
loosely

4 7%
5
They do not
need to be
followed

6 11%
Total 56 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.52
Variance 1.42
Standard Deviation 1.19
Total Responses 56

163
8. In your current or past experience, given that a non-final monograph is not final and is not
legally enforceable, how often do you believe excursions (differences) are made from a non-
final monograph in the OTC Industry?
# Answer

Responses %
2
Almost
always

5 9%
3 Commonly

26 46%
4 Sometimes

16 29%
5 Rarely

9 16%
6 Never

0 0%
Total 56 100%

Statistic Value
Min Value 2
Max Value 5
Mean 3.52
Variance 0.76
Standard Deviation 0.87
Total Responses 56

164
9. In your current or past experience, how compliant are OTC drug companies to non-final
monographs?
# Answer

Responses %
1
Completely
compliant

2 4%
2
Mostly
compliant

26 47%
3
Generally
compliant

18 33%
4
Loosely
compliant

7 13%
5
Vaguely
compliant

2 4%
Total 55 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.65
Variance 0.79
Standard Deviation 0.89
Total Responses 55

165
10. In your current or past experience, how often are the following types of monograph
excursions made from a non-final monograph in the OTC industry?
# Question Almost
Always
Commonly Sometimes Rarely Never Responses Mean
1
Use of a
different or
additional
indication
than in the
non-final
monograph
0 12 15 16 12 55 3.51
2
Use of a
different
dosage
regimen
than in the
non-final
monograph
(includes
dosage
amount,
schedule,
etc.)
1 6 21 18 9 55 3.51
3
Use of
different
product
instructions
from the
non-final
monograph
1 13 21 15 4 54 3.15
4
Use of other
labeling
differences
than in the
non-final
monograph
5 12 25 10 3 55 2.89
5
Use of a
different
active
ingredient
0 4 13 22 15 54 3.89

166
than in the
non-final
monograph
(including
category III
ingredients)
6
Use of a
different
active
ingredient
combination
than in the
non-final
monograph
0 3 25 14 12 54 3.65
7
Use of an
active
ingredient
identified in
the non-
final
monograph
but that is
not included
on the
product
label as an
active
ingredient
0 8 12 19 15 54 3.76
8
Use of a
different
dosage form
than in the
non-final
monograph
0 11 24 10 9 54 3.31
9 Other 1 1 3 0 2 7 3.14

167
Other
Warnings
dont use drug facts box for labeling
NA
Combining different monographs
Claim Make non-monograph label and advertising claims

Statistic Use of a
different
or
additional
indication
than in
the non-
final
monogra
ph
Use of a
different
dosage
regimen
than in
the non-
final
monogra
ph
(includes
dosage
amount,
schedule,
etc.)
Use of
different
product
instructio
ns from
the non-
final
monograp
h
Use of
other
labeling
differenc
es than in
the non-
final
monogra
ph
Use of a
different
active
ingredient
than in
the non-
final
monograp
h
(including
category
III
ingredient
s)
Use of a
different
active
ingredient
combinati
on than in
the non-
final
monograp
h
Use of an
active
ingredien
t
identified
in the
non-final
monogra
ph but
that is not
included
on the
product
label as
an active
ingredien
t
Use of a
different
dosage
form than
in the
non-final
monogra
ph
O
t
h
e
r
Min Value 2 1 1 1 2 2 2 2 1
Max Value 5 5 5 5 5 5 5 5 5
Mean 3.51 3.51 3.15 2.89 3.89 3.65 3.76 3.31
3
.
1
4
Variance 1.14 0.92 0.88 0.99 0.82 0.80 1.05 0.97
3
.
0
7
Standard
Deviation
1.07 0.96 0.94 0.99 0.90 0.89 1.03 0.99
1
.
7
5
Total
Responses
55 55 54 55 54 54 54 54 8

168
11. In your current or past experience, which of the following non-final monographs are the
most "contentious" and may have a higher potential for excursions from the
monograph? Please check all that apply.
# Answer

Responses %
1
External
Analgesics

16 32%
2
Internal
Analgesics

10 20%
3 First Aid

5 10%
4 Laxative

9 18%
5 Menstrual

2 4%
6 Oral Healthcare

9 18%
7
Poison
Treatment

0 0%
8 Skin Bleaching

14 28%
9 Sunscreen

33 66%
10
Vaginal
Contraceptives

1 2%
11
Vaginal Drug
Products

5 10%
12 Other

3 6%

Other
skin protectant/ (cold sore)
Healthcare antiseptic
skin protectant

169
Statistic Value
Min Value 1
Max Value 12
Total Responses 50
12. In your current or past experience, please rank the following reasons for excursions from
non-final monographs with 1 being the most likely reason and 8 being the least likely. Please
click on the number on the right and side and drag up or down to your desired position/rank.
# Answer 1 2 3 4 5 6 7 8
1
To create a
marketing
advantage
39 3 2 3 3 4 1 0 55
2
To create
other
commercial
advantages
0 29 7 7 5 3 3 1 55
3
To improve
safety
7 3 5 6 11 11 11 1 55
4
To improve
efficacy
2 8 8 13 12 8 4 0 55
5
Possession
of company
clinical or
other data
that supports
the
excursion
3 8 19 7 6 4 7 1 55
6
Inability to
meet
technical or
analytical
requirements
of the non-
final
monograph
2 2 6 12 12 15 6 0 55

170
7
Cost of
meeting the
non-final
monograph
is too high
1 2 8 6 6 9 23 0 55
8 Other 1 0 0 1 0 1 0 52 55
Total 55 55 55 55 55 55 55 55 -

Other
historical
Ignorance of monograph provisions
not adequately informed on how to apply monograph
Inventors unfamiliar with regulations
Product tested in US but intended for non-US market

Statistic To create a
marketing
advantage
To create
other
commercial
advantages
To
improve
safety
To
improve
efficacy
Possession
of
company
clinical or
other data
that
supports
the
excursion
Inability to
meet
technical or
analytical
requirements
of the non-
final
monograph
Cost of
meeting the
non-final
monograph
is too high
Oth
er
Min Value 1 2 1 1 1 1 1 1
Max Value 7 8 8 7 8 7 7 8
Mean 1.98 3.25 4.69 4.18 3.91 4.80 5.42 7.76
Variance 3.13 2.82 4.14 2.52 3.31 2.27 3.03 1.22
Standard
Deviation
1.77 1.68 2.04 1.59 1.82 1.51 1.74 1.10
Total
Responses
55 55 55 55 55 55 55 55

171
13. In your current or past experience, how influential do you believe international standards
and regulations are when an excursion from a non-final OTC monograph is made?
# Answer

Responses %
1
Very
influential

9 16%
2
Somewhat
influential

17 31%
3 Neutral

9 16%
4
Not very
influential

17 31%
5
Not
influential at
all

3 5%
Total 55 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.78
Variance 1.47
Standard Deviation 1.21
Total Responses 55

172
14. In your current or past experience, when developing a new OTC monograph drug for
which the monograph is non-final, how often are competitive products evaluated for
compliance to the monograph?
# Answer

Responses %
1
Almost
always

27 49%
2 Commonly

18 33%
3 Sometimes

5 9%
4 Rarely

3 5%
5 Never

2 4%
Total 55 100%

Statistic Value
Min Value 1
Max Value 5
Mean 1.82
Variance 1.11
Standard Deviation 1.06
Total Responses 55

173
15. When a competitive product is evaluated for compliance to a non-final monograph, which
of the following activities are undertaken? Please check all that apply.
# Answer

Responses %
1
Assess
competitor
product
labeling

55 100%
2
Assess
competitor
advertising
materials

51 93%
3
Analyze
competitor
product
formulation

43 78%
4 Other

10 18%

Other
assess active drug manufacturer and final product manufacturer
Note competitor product market share
assess competitor pricing
Social media
Assess citizen petition's filed
Occasionally use as benchmark in clinical study
Quantitative analysis
efficacy

174
Statistic Value
Min Value 1
Max Value 4
Total Responses 55
16. How do companies address competitors who may be making excursions from a non-
final monograph?
# Question Almost
Always
Commonly Sometimes Rarely Never Responses Mean
1
Start legal
action
0 3 16 26 9 54 3.76
2
Report them
to FDA
2 5 22 21 4 54 3.37
3
Ask them to
stop
2 5 18 18 11 54 3.57
4
Copy their
monograph
excursion or
difference
2 7 30 12 3 54 3.13
5
Try to find
better or other
monograph
excursions or
differences
2 10 24 14 4 54 3.15
6
Monitor the
competitive
product to see
how it sells
18 22 8 3 4 55 2.15
7 Other 0 1 7 0 17 25 4.32

175
Other
Evaluate it
evaluate the competitive product in clinical trial
File NAD complaint
Have a surrogate organization inform FDA or FTC about infraction

Statistic Start legal
action
Report
them to
FDA
Ask them
to stop
Copy their
monograph
excursion
or
difference
Try to find
better or
other
monograph
excursions
or
differences
Monitor
the
competitive
product to
see how it
sells
Other
Min
Value
2 1 1 1 1 1 2
Max
Value
5 5 5 5 5 5 5
Mean 3.76 3.37 3.57 3.13 3.15 2.15 4.32
Variance 0.64 0.80 1.08 0.72 0.88 1.35 1.06
Standard
Deviation
0.80 0.90 1.04 0.85 0.94 1.16 1.03
Total
Responses
54 54 54 54 54 55 25

176
17. In your current or past experience, have you or your company ever been contacted by a
competitor company about an excursion from a non-final OTC monograph?
# Answer

Responses %
1 Yes

19 35%
2 No

36 65%
Total 55 100%

Statistic Value
Min Value 1
Max Value 2
Mean 1.65
Variance 0.23
Standard Deviation 0.48
Total Responses 55

18. In your current or past experience, have you or your company ever been contacted by the
FDA about an excursion from a non-final OTC monograph?
# Answer

Responses %
1 Yes

18 33%
2 No

36 67%
Total 54 100%

177
Statistic Value
Min Value 1
Max Value 2
Mean 1.67
Variance 0.23
Standard Deviation 0.48
Total Responses 54

19. In general, do you think there are regulatory and/or business advantages when a
monograph is non-final?
# Answer

Responses %
1 Yes

44 80%
2 No

11 20%
Total 55 100%

Statistic Value
Min Value 1
Max Value 2
Mean 1.20
Variance 0.16
Standard Deviation 0.40
Total Responses 55

178
20. If yes, please explain why you think there are advantages.
Text Responses
One example is the ability of (small) companies to sell sunscreen wipes ... in general, small
companies are able to be more competitive with non-final monographs
More leeway in molding non-final monograph information to suit the product
Allows some flexibility
Wider latitude in compliance.
No, because most follow a non-final monograph.
Allow supported claims which may outside a FM, continue to market an active ingredient
which may not have sufficient efficacy data to be supported in FM
Since many of the non-final situations are of many years' standing, there occurs a climate of
unregulated products. Companies feel a sense of freedom to innovate without fear of curbing
regulation.
Gives flexibility in formulation, labeling and advertising
flexibility in formulation, labeling and/or marketing
We believe we have greater flexibility, and FDA has lesser enforcement power.
more flexibility for formulation and labelling
Fexibility with formulation and label claims
greater flexibility
It is possible to take competitive advantage of gray areas as long as one does not stray too far.
Also it is possible that the company can better serve or protect the consumer if it has clinical
knowledge that is not covered in the monograph. The safety of the consumer should always
be the highest priority.
I think that there are advantages because it allows companies to push the envelope and make
claims that they would not necessarily be able to make if the monograph was not finalized.
Also, it allows flexibility in deciding whether to use the Drug Facts formatting, which based
on the companies I have worked for and currently am working, they prefer not to do this.
Space for flexibility and creativity when compared with final monographs
have more options in terms of formulating and labeling, primarily lowering cost of goods.
There is room for interpretation of the non-final requirements.
flexibility
Potential for regulatory enforcement when deviating from monograph is low
Because it allows marketing a safe and effective product (say a different formulation) not yet
included in a final monograph

179
Able to make product claims or use combinations that can give an advantage.
more flexibility
no comment
There is less enforcement for deviation from non-final monographs and thus greater
flexibility for the OTC company.
n/a
Existing product generates substantial income; over time, agencies change their views to
allow wider range of ingredients
The monograph is not final so there is room for "excursion".
While still tentative, there is still time to make changes and assess advantages for your best
practices to take effect.
Offers leeway
If a monograph is not final, company feels more comfortable pushing the envelope regarding
claims.
loose approach to regulation
not being required to comply with anything
Allows more flexibility in manufacturing, labeling, use instructions, and most importantly,
marketing.
Less testing on actives; less money spent.
In certain cases, such as toothache products, it will be extremely difficult to conduct
successful clinical testing. Publication of a Final Rule will force elimination of these products
from the market.
more flexibilty
Not monitored
Companies will exploit the tentative regs.
There is some room to play outside the monograph. Especially with claims.
not applicable
Absence of final monograph may permit short cuts or "cherry picking" of compiance
requirements
Allows time flexibility to develop a compliant product, allows one to remain competitive
with a non-compliant competitor
some components are not legally binding
There is more room to make non-monograph marketing claims.
Have leeway to produce better formulations, eg EYU compliant ones
more freedom to try some deviations

180
From the point of veiw that some companies don't do the required efficacy testing and other
ignore even th cGMP testing.

Statistic Value
Total Responses 48

21. In general, do you think there are regulatory and/or business disadvantages when a
monograph is non-final?
# Answer

Responses %
1 Yes

44 80%
2 No

11 20%
Total 55 100%

Statistic Value
Min Value 1
Max Value 2
Mean 1.20
Variance 0.16
Standard Deviation 0.40
Total Responses 55

181
22. If yes, please explain why you think there are disadvantages
Text Response
it creates an unlevel playing field for those willing to take risk vs those who aren't willing to
take risk
There is a glass ceiling for claims; until you bump your head, you don't know where the
limits are.
Uncertainty about when formulation and labeling changes and when required to be made.
Difficult to plan for. Usually short time to comply, ie doing new stability studies, using up
old labeling.
No precise marketplace guidance.
No, because most follow a non-final monograph.
Unlevel playing field in terms of claims/indications
indecision
Both the regulators and the regulated live in an environment of uncertainty, and firm plans
are hard to set in place.
Business plans could be adversely affected if monograph goes final but formulation/product
claims departed from proposed monograph.
competitors may take additional risks that equate with product performance
May need to "prove" properties about a new product to the Agency that are widely known,
but that are not considered legally established under the monograph.
opportunity for more aggressive companies to take more risks, gain competitive advantage
None
Image / reputation / trust is compromised
The non-final status creates ambiguity that is subject to interpretation which may vary from
company to company. It can also create opportunities for companies to market unsafe
products. The biggest issue is that if a company takes advantage of an excursion from the
monograph, they will have to make changes should the monograph become final during the
product life cycle. This would require additional planning during product development or not
depending on the amount of risk the company is willing to take.
No, I do not think there are any disadvantages because it levels the playing field in terms of
product labeling.
Greater risk when operating in these grey areas - ability to market product can come to abrupt
halt
and in some cases, product sales forecast may not extend to the final monograph date
Lack of clarity on requirements and uneven playing field

182
Less certainty in market.
Company more vulnerable to legal action about alledged adverse events
Risk of not being able to use inventory or materials when monograph becomes final
Small companies exploit non-final monographs to promote non-compliant products to
competitive advantage
It is difficult to convince managment that FDA does not accept the view outside of the
monograph that the company wants to use as support.
While your company may follow the non-final monograph entirely, a competitor may choose
to deviate from the monograph to gain a market advantage over your company.
Companies are operating under some degrees of uncertainty and Regulatory body can not
assert full enforcement.
Cost of studies to change agency positions can be prohibitive; poorer competitive products
take market share.
Risk adverse companies must evaluate the risk of being caught on the market with a product
that does not meet the final monograph.
Uncertainty in regards to assurance that the right path is being taken, when money stakes are
high.
Other companies may feel emboldened to take positions w/claims and dosage forms that are
not supported by data.
regulation levels the playing field
a company trying to comply is at a competitive disadvantage and really gets no credit for
complying
Allows unscrupulous individuals (i.e., garage-inventors, small companies, foreign
companies, etc) to either sell products through ignorance or overly seek marketing advantage
in unenforced category.
Money wasted on formulation and lobbying when monographs are being reviewed.
significant excursions possible
Affects consumers.
Companies will exploit the tentative regs at the detriment to the public.
The playing field is not even.
allows for lee way in whether it actually needs to be followed; allows for unnecesary
ambiguity given there is a rich history of safety and efficacy otherwise shouldn't be
monograph
Absence of final monograph may be treated as Final putting burden on certain companies
which is not borne by other competitors.
not everyone is held to the same standard
Uncertainty in product development and lifecycle management

183
Uncertainty stifles innovation, adds cost, increases risk.
Risk of non-compliant products once monograph finalizes, or even before it does.
more freedon to deviate
When the monograph becomes final many companies need to scramble to get their prodiuct
in compliance putting pressure on their both internal and contract labs,.

Statistic Value
Total Responses 46

23. In your current or past experience, when a company makes an excursion from a non-final
OTC monograph which may affect the safety of a product, how often is clinical or other
safety-related testing conducted?
# Answer

Responses %
1
Almost
always

20 44%
2
Most of the
time

15 33%
3 Sometimes

7 16%
4 Seldom

3 7%
5 Rarely

0 0%
Total 45 100%

184
Statistic Value
Min Value 1
Max Value 4
Mean 1.84
Variance 0.86
Standard Deviation 0.93
Total Responses 45

24. How often do companies evaluate risks in each of the following areas in relation to an
excursion from a non-final OTC monograph?
# Question Almost
Always
Commonly Sometimes Rarely Never Responses Me
an
1
Commercial/Marketing
Risks
33 10 6 3 0 52 1.60
2
Regulatory Compliance
Risks
35 13 3 1 0 52 1.42
3 Legal Risks 36 12 2 2 0 52 1.42
4 Financial Risks 24 17 9 2 0 52 1.79
5 Clinical Risks 15 17 16 3 0 51 2.14
6 Safety Risks 30 13 6 2 1 52 1.67
7 Product Quality Risks 18 18 8 4 2 50 2.08
8 Other Risks 2 1 6 0 13 22 3.95

Other Risks
None
Risks in company reputation
don't know
Risk to brand image

185
Statistic Commercial/
Marketing Risks
Regulatory
Compliance
Risks
Legal
Risks
Financial
Risks
Clinical
Risks
Safety
Risks
Product
Quality
Risks
Other
Risk
s
Min Value 1 1 1 1 1 1 1 1
Max Value 4 4 4 4 4 5 5 5
Mean 1.60 1.42 1.42 1.79 2.14 1.67 2.08 3.95
Variance 0.83 0.48 0.56 0.76 0.84 0.93 1.22 2.54
Standard
Deviation
0.91 0.70 0.75 0.87 0.92 0.96 1.10 1.59
Total
Responses
52 52 52 52 51 52 50 23

25. In your current or past experience, what is the overall impact of non-final OTC drug
monographs on OTC drug Industry operations?
# Answer

Responses %
1 Negative

4 7%
2
Somewhat
negative

24 44%
3 Neutral

15 28%
4
Somewhat
positive

10 19%
5 Positive

1 2%
Total 54 100%

186
Statistic Value
Min Value 1
Max Value 5
Mean 2.63
Variance 0.88
Standard Deviation 0.94
Total Responses 54

26. In your current or past experience, how important is the impact of non-final OTC drug
monographs on OTC drug industry operations?
# Answer

Responses %
1 Extremely important

5 9%
2 Very important

20 37%
3 Somewhat important

24 44%
4
Neither important nor
unimportant

5 9%
5 Unimportant

0 0%
Total 54 100%

Statistic Value
Min Value 1
Max Value 4
Mean 2.54
Variance 0.63
Standard Deviation 0.79
Total Responses 54

187
27. When an excursion is made from a non-final monograph on a commercialized OTC drug
product, are mitigation plans developed in advance for the monograph excursions to be
"corrected" once the monograph becomes final?
# Answer

Responses %
1 Almost always

9 17%
2 Commonly

22 42%
3 Sometimes

13 25%
4 Rarely

8 15%
5 Never

1 2%
Total 53 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.43
Variance 1.02
Standard Deviation 1.01
Total Responses 53

188
28. How much emphasis is placed on the amount of attention (news coverage, regulatory
comments, etc.) a non-final monograph may have received regarding a company's regulatory
and business strategy for an affected OTC drug product?
# Answer

Responses %
1 None

3 6%
2 Little

19 35%
3 Some

21 39%
4 Much

9 17%
5 Extensive

2 4%
Total 54 100%

Statistic Value
Min Value 1
Max Value 5
Mean 2.78
Variance 0.86
Standard Deviation 0.92
Total Responses 54

189
29. What is your opinion of how a non-final monograph, as opposed to a finalized
monograph, may affect product innovation?
# Answer

Responses %
1
Negative
effect

4 7%
2
Somewhat
negative
effect

17 31%
3 No effect

11 20%
4
Somewhat
positive effect

17 31%
5 Positive effect

5 9%
Total 54 100%

Statistic Value
Min Value 1
Max Value 5
Mean 3.04
Variance 1.32
Standard Deviation 1.15
Total Responses 54

190
30. Has any company you have worked for ever attempted to get FDA to finalize a non-
final monograph?
# Answer

Responses %
1 Yes

32 59%
2 No

22 41%
Total 54 100%

Statistic Value
Min Value 1
Max Value 2
Mean 1.41
Variance 0.25
Standard Deviation 0.50
Total Responses 54

31. Has any company you have worked for ever attempted to modify a non-final monograph
before finalization?
# Answer

Responses %
1 Yes

43 80%
2 No

11 20%
Total 54 100%

191
Statistic Value
Min Value 1
Max Value 2
Mean 1.20
Variance 0.17
Standard Deviation 0.41
Total Responses 54

32. What was the basis for the requested modification to the non-final monograph? Please
check all that apply.
# Answer

Responses %
1
New clinical
data

34 79%
2
New
ingredient data

22 51%
3
New
analytical
procedures

13 30%
4
New labeling
information

23 53%
5 Other

6 14%

192
Other
Logic!
Company data not fully considered by the agency
New dosage form
new application form
I know there was an attempt made; however, I was not apart of it, so I do not feel
comfortable providing feedback.

Statistic Value
Min Value 1
Max Value 5
Total Responses 43

193
33. What, if anything, would you change about the monograph system to improve it?
Text Response
enable "switches", after a certain period of time, to be included
Remove out of date information.
Give FDAthe resources to finalize it. It has been 50 years since 1962 statute, and 40 years
since monogrpah were first proposed. Science does march on.
Finalize as many monographs as possible.
The monograph system seems to have assumed a third tier status. Not much is happening
unless a Senator writes a letter or signs a bill.
Find a way to impose action timelines for decisions on submissions to monogrpah (both Fm
and non-FM)
the timescale for changes and use of International Regulatory status
Change the informally set deadlines for finalizing monographs to firm, observed deadlines of
three years or less, enforceable by withholding of agency appropriations.
Additional FDA funds needed to review additional data submissions and testimony to
support finalizing "old" non-final monographs.
delineate timelines for completion and implementation
TFMs should not be allowed to remain tentative for decades!
institute a user fee system to facilitate completion
Modify process to include new ingredients/dosage forms
nothing. the problems all stem from fda failure to finish it.
It should be short and words used are in accordance to the customer - laymen/ public
I would make it more straight forward, less cumbersome and more transparent.
I would not necessarily change it, but it has to move a lot faster than it does now. I am not
necessarily convinced that it is a high priority of the FDA and even if it was, I do not feel
there are enough resources allocated to complete it.
FDA honesty regarding timelines for "finalizing" specific monographs
Finalize monographs quicker so that formulators and regulatory personnel have a good
guidance to follow knowing that the guidance is based on what is safe and effective thus
minimizing cost of reformulation and labeling, etc.
inconsistency
Inclusion of "evergreen" guidances by reference so that new and improved analytical
techniques and safety testing methods can be implemented after a monograph is finalized
Set time requirements for finalizing monographs

194
FDA evaluation of product label compliance when NDC numbers are submitted. Frequent
non-compliance might drive FDA to prioritize monograph finalization.
clarify to industry that the status of the monograph final or not still impact how FDA will
audit the product. FDA follows the monograph final or not, so enforcement will occur in
some form for the non-compliant product.
Require finalization of monographs within a set period of time.
none
Get serious about completing the process. It has been active in the US for > 30 years.
I would ask for more resources to complete the task and assign a more definite timeline for
the completion of the monographs. The safety of the consumer is the main issue, secondarily
the lack of finality hampers the business climate for the establish companies and favors the
generic companies that we compete with.
Ensure each monograph is reviewed regularly and is still applicable and accurate based on
post marketing spontaneous and clinical data.
finish it!!
finish it up and install a standard way to be able to modify it in the future
Two things: monographs need to be created, evaluated, and approved in a timely fashion.
Equally important, there is no current mechanism that I'm aware of for timely updating (i.e.,
adding new ingredients, removing old ingredients, incorporating new test methodologies,
etc.). Currently, the monograph system is too slow and unable to keep up with the
advancements in medical life sciences.
The speed of finalizing and speed & openness to changes
Make it faster; more relevant. Make it easier to change-so there is room for innovation
From an industry point of view, I would do nothing to change the system.Over the course of
decades, ndustry has learned how to work the system.
Put concrete time limits to when they must be finalized.
Clear up any ambiguities that exist. Tighter controls.
Would like to see an easier way of getting new materials approved to the monograph.
Especially if they have been used around the world for years with no safety issues.
add a formal system so that when the monographs are first proposed there is a time limit for
industry and others to submit and then have an FDA finalization similar to NDA process;
would widen scope to add additional monographs once the outstanding monographs are
finalized; need follow up / amendment process to finalized monographs
Implement a final monograph approval system 1) that forces final approval within 2 yrs of
closing comment period. 2) permits modfication of to final monograph and provides for
reasonable phase-in period in order to not place financial burder on companies. Only
exception to phase-in period would be where evidence clearly demonstrates public safety is
at risk by not making modification.

195
shorten time for review and input to speed finalization
Facilitate inclusion of new active ingredients and active ingredient combinations. Above all,
finalize the monograph with a process in place to amend it when sufficient data exists to
support the change.
Complete it!
slow down the process of finalization
I enforce the cGMP compliance durning manufacture

Statistic Value
Total Responses 45

34. Would you agree to participate in a 15-20 minute phone interview to further discuss the
advantages and disadvantages of non-final OTC monographs? If so, please provide your
contact information.

Statistic Value
Total Responses 32

Abstract (if available)

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Asset Metadata

Creator Ramsey, Susan Valerie (author)

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

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 04/01/2013

Defense Date 03/08/2013

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

Tag Drugs,monographs,OAI-PMH Harvest,OTC

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances J. (committee chair), Davies, Daryl L. (committee member), Kaplan, Hilton (committee member), Loeb, Gerald E. (committee member)

Creator Email ramseyv@cbfleet.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-230191

Unique identifier UC11293639

Identifier usctheses-c3-230191 (legacy record id)

Legacy Identifier etd-RamseySusa-1501.pdf

Dmrecord 230191

Document Type Dissertation

Rights Ramsey, Susan Valerie

Type texts

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

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

Repository Name University of Southern California Digital Library

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