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ESTABLISHING CLINICAL EFFICACY OF BOTANICAL PRODUCTS
A SURVEY OF INDUSTRY VIEWS

by

Ali Reza Rejaei

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 2017

Copyright 2017 Ali Reza Rejaei

2
DEDICATION
This dissertation is dedicated to my loving sister Malehe who began her doctorate
education but her life was cut short and her dream remained unfulfilled. She taught me to
persevere, inspired me to be the best I can be at a time of adversity and aim for the moon.
If you miss, you will be among the stars, she said.

“Happiness is wanting what you have, not having what you want”
- Eckhart Tolle

3
ACKNOWLEDGEMENTS
I give my sincerest appreciation to my dissertation advisor, mentor, and now
friend, Dr. Frances Richmond. I thank Dr. Richmond for believing in me, for her
unconditional support, thoughtfulness, patience, motivation, and meticulous instruction. I
also thank her for expanding my boundaries, teaching me the importance of qualitative
research and encouraging me to take it to a new level. I could not have had a better
mentor and this work could not have been possible without her. I would also like to
express my gratitude to the rest of my thesis committee, Dr. Clemens, Dr. Rodgers, Dr.
Davies, and Professor Roberts for their guidance and insights that help strengthen this
work. I extend my thanks to Dr. Loeb for giving me insight into my work and Dr. Issa
for her support of putting the study together, Dr. Pacifici, and Dr. Smerkanich for their
availability and valuable discussion of clinical trials. I also thank the dedicated staff from
the USC Regulatory Science Department for their help throughout my studies. I like to
thank my colleagues at NIH-Dietary Supplement Practicum Dr. Joseph Betz and Dr.
Regan Bailey for their valuable discussion of dietary supplements regulations, Dr. Nandu
Sarma from USP Dietary Supplements and Dr. Taylor Wallace for being valued part of
my focus group and their valuable suggestions to improve my survey instrument. Lastly,
I thank Lynda and Steward Resnick for giving me the opportunity to pursue my dream.
Without their good intentions, this journey would have not been possible. I would like to
acknowledge the help of many professionals who took the time to help develop,
distribute, and complete this research survey.

4
TABLE OF CONTENTS
DEDICATION .................................................................................................................... 2
ACKNOWLEDGEMENTS ................................................................................................ 3
TABLE OF CONTENTS .................................................................................................... 4
LIST OF TABLES .............................................................................................................. 9
LIST OF FIGURES .......................................................................................................... 10
ABSTRACT ...................................................................................................................... 12
CHAPTER 1. OVERVIEW ...................................................................................... 13
1.1 Introduction .................................................................................................. 13
1.2 Statement of the Problem ............................................................................. 15
1.3 Purpose of the Study .................................................................................... 16
1.4 Importance of the Study ............................................................................... 17
1.5 Limitation, Delimitations, Assumptions ...................................................... 18
1.6 Organization of Thesis ................................................................................. 19
1.7 Definitions .................................................................................................... 20
CHAPTER 2. LITERATURE REVIEW .................................................................. 25
2.1 Introduction .................................................................................................. 25
2.2 History of Botanical Therapeutics ............................................................... 26
2.3 Botanical Product management and Regulation in the U.S. ........................ 28
2.3.1 Regulation of Dietary Supplements ................................................ 28

5
2.3.1.1 The Dietary Supplement Health and Education Act
(DSHEA) ........................................................................... 28
2.3.2 Regulation of Drugs........................................................................ 32
2.4 Concerns Regarding the Quality of Botanical Products .............................. 33
2.4.1 External Factors Affecting the Quality of Botanicals ..................... 34
2.4.1.1 Botanical products are grown in fields .............................. 34
2.4.1.2 Botanical products are often adulterated along the
sourcing path ...................................................................... 35
2.4.1.3 Botanical products are often deliberately adulterated
for economic gain .............................................................. 35
2.4.2 Establishing Identity of Active Components .................................. 37
2.4.3 Assessing Potency of Active Components ..................................... 39
2.5 Regulatory Response to Quality Issues ........................................................ 40
2.6 Concerns about Safety of Botanical Products .............................................. 45
2.7 Understanding Safety Problems ................................................................... 46
2.7.1.1 Adverse events can be caused by undeclared
ingredients ......................................................................... 48
2.7.1.2 Adverse events can be caused by drug
properties/toxicities ........................................................... 49
2.7.1.3 Adverse events can be caused by drug interactions ........... 51
2.8 Regulating Safety ......................................................................................... 52
2.9 Efficacy: Turning Botanical Products into Drugs ........................................ 53

6
2.10 Studying Clinical Trial Impediments ........................................................... 56
2.10.1 Resource Demands ......................................................................... 57
2.10.2 Regulatory Hurdles ......................................................................... 58
2.10.3 Product Development Challenges................................................... 60
2.10.4 Market Factors and Constrains ....................................................... 61
CHAPTER 3. METHODOLOGY ............................................................................ 63
3.1 Introduction .................................................................................................. 63
3.2 Development of the Initial Survey ............................................................... 63
3.3 Focus Group ................................................................................................. 64
3.4 Selection of Respondents ............................................................................. 64
3.5 Survey Delivery ........................................................................................... 66
3.6 Survey Analysis ........................................................................................... 67
CHAPTER 4. RESULTS .......................................................................................... 69
4.1 Results of the Focus Group .......................................................................... 69
4.2 Analysis of Survey Results .......................................................................... 70
4.3 Respondent Characteristic............................................................................ 72
4.4 Factors Impeding Clinical Trials .................................................................. 77
4.4.1 Financial Hurdles ............................................................................ 77
4.4.2 Regulatory Hurdles ......................................................................... 80
4.4.3 Market Constrain ............................................................................ 88
4.4.4 Product Development Challenges................................................... 91

7
4.4.5 Views on Cross-Topic and Additional Impediments ...................... 93
4.4.5.1 Concerns about repositioning supplements as drugs ......... 95
4.4.5.2 Cost of clinical trials .......................................................... 96
4.4.5.3 Challenges of Patentability. ............................................... 97
4.5 Cross Tabulations ....................................................................................... 102
4.5.1 Response Differences Between Different Type of Individuals
and Companies ............................................................................. 102
CHAPTER 5. DISCUSSION .................................................................................. 105
5.1 Introduction ................................................................................................ 105
5.2 Consideration of the Research Methodology ............................................. 105
5.2.1 Adequacy of Chosen Framework ................................................. 105
5.2.2 Selection of Survey Sample .......................................................... 106
5.2.3 Engagement of Survey Participants .............................................. 107
5.2.4 Survey Length and Construction .................................................. 109
5.2.5 Other Delimitations, Limitations and Assumptions ..................... 110
5.3 Impediments to Conducting Clinical Trial in the U.S. ............................... 110
5.3.1 Clinical Trials Hurdles .................................................................. 110
5.3.2 Financial and Market Constrains .................................................. 111
5.3.3 Regulatory Hurdles ....................................................................... 119
5.3.4 Product Development Constraints ................................................ 122
5.3.5 Inter-Company Alignment ............................................................ 124

8
CHAPTER 6. CONCLUSION................................................................................ 126
REFERENCES ............................................................................................................... 128
APPENDIX A. DRAFT SURVEY ........................................................................... 150
APPENDIX B. FINAL SURVEY............................................................................. 159
APPENDIX C. DESCRIPTIVE RESPONSES......................................................... 182

9
LIST OF TABLES
Table 1: Definition of Key Terms and Acronyms .............................................................21
Table 2: Number of Mandatory Events Reports (AERs) ...................................................47

10
LIST OF FIGURES
Figure 1:Dietary Supplement Sales in the U.S. .................................................................30
Figure 2: Factors Impeding Clinical Trial: ........................................................................57
Figure 3: Response Rate to Survey Questions ...................................................................71
Figure 4: Industry Profile ...................................................................................................73
Figure 5: Indicators of Company Size ...............................................................................74
Figure 6: Specializations of Respondents ..........................................................................76
Figure 7: Overview of Clinical Trial Challenges ...............................................................77
Figure 8: Company Clinical Trial Challenges ...................................................................79
Figure 9: Company Clinical Trial Challenges ...................................................................80
Figure 10: Familiarity of Respondents with Regulatory Areas of Focus ..........................81
Figure 11: Regulatory Claims Used by Supplement Companies.......................................82
Figure 12: Implementation of Clinical Trials for Different Marketing Aims ....................83
Figure 13: Appropriateness of Regulations .......................................................................84
Figure 14: Appropriateness of Regulations .......................................................................85
Figure 15: Appropriateness of Regulations .......................................................................87
Figure 16: Regulatory Overview Modification ..................................................................88
Figure 17: Market Incentives .............................................................................................89
Figure 18: Company Clinical Trial Motivation .................................................................90
Figure 19: Cost Coverage by Insurance .............................................................................91
Figure 20: Product Development Challenges Rated by Importance ..................................92
Figure 21: Comparative views on Incentives .....................................................................94
Figure 22: Market-oriented impediments to clinical trials ................................................95

11
Figure 23: Appropriateness of Regulations .......................................................................99
Figure 24: Appropriateness of path to regulate botanical products .................................100
Figure 25: Appropriateness of Governing Body for Dietary Supplements .....................101
Figure 26: Usefulness of Regulatory Guidance Documents ............................................102
Figure 27: Differences between responses to questions from individuals in
different job categories ............................................................................103
Figure 28: Differences between responses for individuals from companies of
different sizes ...........................................................................................104
Figure 29: Intercompany alignment .................................................................................125

12
ABSTRACT
In 1994, passage of the Dietary Supplement Health and Education Act (DSHEA)
provided a pathway by which botanical products could be marketed as dietary
supplements. This pathway shielded most botanicals from requirements to provide
evidence of efficacy and safety, but allowed them to claim health-giving effects. This
marketing route has become the preferred path for botanicals, so few have been studied in
rigorous clinical trials to establish their therapeutic potential and even fewer have been
developed as botanical drugs. This research study sought to explore the views of
regulatory affairs professionals in dietary supplement industry concerning the limitation
affecting the clinical study of botanical ingredients and their development as drugs. A
literature review first examined the challenges associated with assuring the quality and
safety of such products and the current state of efficacy testing. Based on this review a
framework to systematize areas of concern was established to guide development of a
survey instrument, that the survey instrument was reviewed by a focus group of industry
and academic experts to identify areas in which validity might be improved. It was then
disseminated to senior regulatory, marketing, and professionals knowledgeable about
dietary supplement and drug regulations and marketing. Results suggested that many
hurdles existed in financial, marketing, regulatory and product development domains.
The most important hurdle appeared to be the challenge of shielding a company that
pursues an expensive development program from competition from dietary supplement
manufacturers. In addition, results suggested that management often disagreed on the
need and approach for clinical trials in a way that impeded decision-making.

13
CHAPTER 1. OVERVIEW
1.1 Introduction
Botanical ingredients have been the main source of healing throughout the history
of mankind. Their usefulness as a medicine has been suggested from observations made
over thousands of years of practice, usually without a clear understanding of mechanism
of action or safety (Tang, Li, & Afseth, 2014). Often, crude plant components without
further processing or extraction procedures were used to treat a condition, so that even
the parts of the plant responsible for the therapeutic effect remained unknown.
However, as scientific methods have become capable of extracting and
characterizing compounds from plants, it became possible to develop new chemical
entities that had disease-modifying effects. These synthesized components could then be
modified to enhance their specificity for specific biochemical targets, and the use of
botanicals, with their more complex and hard-to-study multiple components, came to be
viewed as an inferior approach. By the end of the 20
th
century, the use of botanical
products as therapeutic agents was severely limited by law. Only drugs that could be
proven scientifically through a series of clinical trials and lengthy scrutiny by regulators
were permitted to make therapeutic claims. Instead, most botanicals are classified by
U.S. regulations as “dietary supplements”, permitted for health-improving but not
disease-modifying effects, if a history of relatively safe use suggested them to have
health-promoting effects. The trend away from botanical “drugs”, products with
permission to be marketed for disease-modifying effects, is apparent in the fact that only
two botanical drugs in the U.S. have been able to meet the required benchmarks for

14
efficacy and have thus far been approved despite the fact that 215 Investigational New
Drug applications (INDs) for botanicals were submitted from 2001-2008 (Wu et al.,
2010).
The U.S. approaches to botanical drug development are not characteristic of
views in many other cultures. The single-chemical, single-target approach to disease
treatment is not always viewed as the most appropriate and cost effective way to manage
some medical problems. Instead, many believe that plants in their more natural form may
have advantages. They argue that several compounds of merit might exist in a single
plant part and that the use of these compounds together might provide synergistic effects
(Chen et al., 2008). For example, ginseng root, that contains more than 28 ginsenosides,
is widely believed to boost immune function, improve metabolism, and possess anti-
aging properties (Wang & Ren, 2002). Further, some believe that the use of high doses
of single chemicals often can produce excessively strong effects that could be moderated
by using plants in a more natural form. For example, green tea has a long history of safe
use for human consumption yet major flavonoids of green tea extract such as purified
epigallocatechin-3-gallate (EGCG) have caused mitochondrial toxicity via their pro-
oxidation activities (Abdel-Rahman et al., 2011). These commonly held views have been
the basis for a thriving industry based on traditional medicines in some countries,
including China and India that together are home to more than 35% of the world’s
population.
Despite the strong support for botanical medicines elsewhere, it is unlikely that
Western medicine will be swayed to return to the use of natural botanical products on the
basis of historical use alone, without solid scientific evidence to affirm their safety and

15
effectiveness in treating a disease. Industry guidance for botanical drug issued in 2004
by U.S. FDA clarified the expectations for such botanical drugs (FDA, 2004a). Yet
acquiring the necessary evidence for such medicinal use has proven difficult because it
has been complicated by several factors. First, the quality of botanical product varies
significantly with season and manufacturing methods. Quality control problems persist
in even those countries that encourage and regulate herbal medicines despite abundant
literature about the toxic effects of their likely contaminants. Second, it is difficult to
know when botanical products are posing risks to safety. Adverse events are
underreported in countries that most commonly prescribe herbal remedies, presumably
due to lack of reporting activities, as noted by Government Accountability Office (GAO,
2013b). Those adverse events that are reported are often linked not to problems with the
natural constituents of the plant but to quality issues related to their conditions of growth
or preparation prior to sale. Thus, the types of data needed to provide a solid scientific
basis for the use of botanicals as drugs remain inadequate.
1.2 Statement of the Problem
The passage of the Dietary Supplement Health and Education Act (DSHEA) in
1994 allowed “disease” claims to be made for dietary supplements if they could be
supported by adequate clinical data. Further the U.S. FDA has provided guidance on
steps to be taken to validate a botanical product as a drug. Nonetheless, relatively little
well-controlled clinical research has been carried out on botanical ingredients. Further,
few of the products on which such studies have been initiated have progressed to the
point of being granted market approval as a drug. From 2001 to 2008 a total of 215

16
botanical INDs were submitted to the FDA (Wu et al., 2010) but to date the activity has
led to only two marketed drugs. A first approval was granted in 2006 for topical
Veregen® (sine catechins) for genital herpes and in 2012 for the oral drug, Crofelemer®
(Croton lechleri) to relieve symptoms of diarrhea in HIV patients. Why so few? What
are the challenges associated with attempts to progress botanical products into the
mainstream of pharmacologic therapeutics? We know that multiple impediments also
plague the development of synthetic drugs, but do not know if these same impediments
are typical for botanical drug development, or whether specific issues related perhaps to
regulatory, safety or financial constraints, are more important and perhaps prohibitive, for
companies attempting to develop botanical drugs. Inspection of the literature indicates
that most attention in this field has been paid to the legal and safety challenges associated
with adulteration and misbranding of different products, but no one appeared to have
investigated systematically the challenges perceived by industry to limit the testing of
botanical ingredients for efficacy in clinical trial setting.
1.3 Purpose of the Study
In this study, I traced the historical evolution of thought with regard to the use of
botanical drugs and then examined the current FDA regulations for drugs and dietary
supplement products in the United States. I then reviewed some of the literature that
illustrated current challenges associated with producing and marketing botanical products
of high quality for therapeutic applications. A four-element framework to base the
systematic study of these challenges was designed and subsequently used to base the
development of an electronically based survey instrument to probe the challenges

17
perceived by industry to develop botanical ingredients for disease-modifying
applications. To improve the face validity of the survey, a focus group of individuals
with different academic, regulatory and business backgrounds was convened before the
survey was disseminated to make improvements to it. The survey then used to obtain the
feedback of a sample of mid-level and senior professionals knowledgeable about the
dietary supplement industry, through their jobs in companies that manufacture and/or
distribute dietary supplement products or ingredients that are marketed with therapeutic
or health related claims. The survey explored their opinions about the regulatory,
scientific, financial resources and marketing challenges of developing botanical
ingredients with a particular emphasis on impediments associated with clinical trials,
where most of the efforts and costs of development are centered.
1.4 Importance of the Study
Botanical products have great potential for the future development of therapeutic
options around the world. An estimated 250,000 flowering plants and around 85,000
plant species have been documented for medicinal use (Tang et al., 2014), but only a
small fraction have been investigated for their potential therapeutic effects (Chen et al.,
2008). Botanical products are the primary source of healthcare treatments for many
under-developed countries, yet much of this use has evolved with little regulatory
oversight or safety and efficacy assessment. By investigating the challenges of
establishing the safety and efficacy of botanical ingredients in clinical trials, it was
possible to obtain better insights into the impediments limiting the development of
botanical drugs in the current regulatory environment. The results of this study should

18
help companies to develop a better strategy for establishing clinical efficacy for botanical
ingredients by allowing them to recognize and address the challenges in advance. It
should also help regulators to develop policies more conducive to botanical clinical
research. By using a defined framework to differentiate different types of constraints,
ambiguity may be reduced and insights may be gained that would help to modify and
improve frameworks for studying impediments to clinical trials more generally.
1.5 Limitation, Delimitations, Assumptions
This study is delimited to the study of regulations and views related to botanical
ingredients used in clinical trials in the U.S. The regulations of other countries are
introduced only to serve as models that might be considered by U.S. regulators as
alternative frameworks for improving botanical drug regulatory policy. It is further
delimited to the views of individuals currently or previously working in the regulatory,
legal, quality, food safety, and marketing functions in companies that manufacture or
distribute dietary supplements with potential structure/function, health or disease
modifying claims. These functions were chosen because individuals in these job
functions are most likely to understand and appreciate the challenges associated with
botanical drug development and substantiation. Surveys of other stakeholders, such as
consumers or regulators, could provide views that differ from that of industry personnel,
but those views have not been explored in this research.
Limitations of this study related in part to the use of survey instrument to address
all of the research questions. Because only a sample of experts in botanical ingredients
and dietary supplements can be surveyed, the validity of the results depended on the

19
extent to which these individuals represented the broader population of individuals in the
same job functions across the U.S. The study was also limited by my ability to develop
an effective and accurate survey instrument. The survey was evaluated by a focus group
of experts to ensure that it is as effective and free of bias as possible, but some level of
challenge may still remain. The study was also limited by the willingness of the
respondents to answer the survey questions honestly. The topic of the survey is directly
relevant to the success of the businesses that employ the respondents, so the responses
may be biased by the desire of these individuals to ensure continued company success.
The usefulness of the survey responses could also be limited by the experience and
regulatory knowledge of the respondents. The assumption was made that all survey
respondents were familiar with the definition of dietary supplement/botanical/herbal
ingredients and drugs as stated in the DSHEA and Food Drug & Cosmetic (FD&C) Act
and the regulatory approaches used by the FDA to regulate all the aforementioned
products.
1.6 Organization of Thesis
The qualifying materials for this study consist of five chapters. Chapter 1
provides a brief overview of the problem posed in DSHEA regulations in the U.S. and the
research that was conducted to understand the view of industry stakeholders. Chapter 2
describes the history of dietary supplements /herbal products and botanical drug
development efforts. It covers quality, safety and efficacy sequentially, to gain an initial
insight into the impediments of incorporating botanical ingredients in clinical setting in
the U.S. It compares dietary supplement and drug regulations in the U.S. and explores

20
alternative models for regulating dietary supplement and/or botanical drug development.
Finally, it outlines the framework that was used to base the survey research. Chapter 3
explains the methodology used to conduct the research study including the development
and use of survey instruments. Chapter 4 summarizes the results of the survey, and these
results are discussed in chapter 5.
1.7 Definitions
Dietary Supplements
A dietary supplement is a product intended for ingestion that contains a "dietary
ingredient" intended to add further nutritional value to (supplement) the diet. A "dietary
ingredient" may be one, or any combination, of the following substances: a vitamin a
mineral an herb or other botanical (FDA, 1994).
Prescription (Rx) Drug
A prescription drug is a drug product approved for marketing that can only be
obtained with a prescription from an appropriate health care practitioner.
Over-the-Counter (OTC) Drug
An OTC drug is a drug product marketed for use by the consumer without a
prescription from a health care practitioner (FDA, 2015d).
Botanical drugs
A botanical drug product is intended for use in the diagnosis, cure, mitigation,
treatment or prevention of disease in humans (FDA, 2004a).

21
 A botanical drug product consists of vegetable materials, which may include plant
materials, algae, macroscopic fungi, or combinations thereof.
 A botanical drug product may be available as (but not limited to) a solution (e.g.,
tea), powder, tablet, capsule, elixir, topical, or injection.
 Botanical drug products often have unique features, for example, complex
mixtures, lack of a distinct active ingredient, and substantial prior human use.
Fermentation products and highly purified or chemically modified botanical
substances are not considered botanical drug products (FDA, 2004a).
Herbal Medicine
Herbal medicine is the art or practice of using herbs and herbal preparations to
maintain health and to prevent, alleviate, or cure disease. A plant or plant part or an
extract or mixture of these used in herbal medicine (FDA, 2004a).
As used within this study, the following key terms and acronyms are defined in Table 1.

Table 1: Definition of Key Terms and Acronyms
Key Terms/acronyms Definition
ABC American Botanical Council
AE Adverse Event
AER Adverse Event Reporting
AHPA American Herbal Product Association
AM Annual Meeting

22
AMRM Analytical Methods and Reference Materials Program
API Active Pharmaceutical Ingredients
CARBON Centers for Advancing Research on Botanical and Other
Natural Products
CFR Code of Federal Regulations
cGMP current Good Manufacturing Practices
CMC Chemistry and Manufacturing Controls
CPM Chinese Proprietary Medicines
CPMP Proprietary Medical Product Committee
CRN Council for Responsible Nutrition
DMAA Dimethyamyl amphetamine
DSHEA Dietary Supplement Health and Education Act
EGCG Epigallocatechin-3-gallate
EMA European Medicine Agency
EMEA Europe Middle East Africa-part of EMA
ERG Eastern Research Group-Consulting
FD&CA Food Drug and Cosmetic Act
FDA Food and Drug Administration
FDLI Food Drug Law Institute
FPDI Food Protection and Defense Institute
FSMA Food Safety Modernization Act
GACP Good Agricultural Collection Practices

23
GAO U.S. Government Accountability Office
GCP Good Clinical Practices
GRAS Generally Recognized as Safe
HAS Health Science Authority - Singapore
HIPAA Health Insurance Portability Accountability Act
HIV Human Immunodeficiency Virus
HMPC Committee on Herbal Medicinal Products
ICH International Conference of Harmonization
ICSB International Conference on the Science of Botanicals
IND Investigational New Drug
IOM Institute of Medicine
IRB Institutional Review Board
MHRA Medicine and Healthcare Product Regulatory Agency
NBJ Nutrition Business Journal
NCCIH National Center for Complementary and Integrative
Health
NCE New Chemical Entity
NCI National Cancer Institute
NDA New Drug Application
NDI New Dietary Ingredient
NHANES National Health and Nutrition Examination Survey
NIH National Institute of Health

24
OCRA Orange County Regulatory Affairs
ODS Office of Dietary Supplement – Part of NIH
ODSP Office of Dietary Supplement Program– Part of CFSAN
OTC Over The Counter
QLN Quality Leadership Network
Rx Prescription drugs
TCM Traditional Chinese Medicine
USP United State Pharmacopeial Compendium
WHO World Health Organization

25
CHAPTER 2. LITERATURE REVIEW
2.1 Introduction
Botanical products and their derivatives have been used as both nourishment and
medicine throughout the history of mankind. Although some botanicals are consumed as
foods and others for their medicinal properties, the distinction between the two has never
been clear and some have been used for both purposes. Much is now known about the
nutritive value of many plant-based foods. However, only recently has effort been made
to validate scientifically the value of these products as medicines.
Plants have been used to treat a variety of illnesses for centuries; approximately 25% of
modern medicines have been developed from botanical extracts and components,
although many of these are never defined specifically as “drugs” (Balunas & Kinghorn,
2005). To be considered as a botanical drug, the product must be demonstrated to have a
clinically validated pharmaceutical action related to the spectrum of active compounds
produced by the plant (Sahoo, Manchikanti, & Dey, 2010). Unlike synthetic
pharmaceutical compounds whose singular active ingredient can be measured,
characterized, validated and standardized from one batch to another, botanicals with
multiple potentially active components are difficult to standardize, because their contents
of different constituents can vary significantly with seasonal variation, horticultural
conditions and quality control problems. Thus, many challenges must be overcome to
correlate the combined efficacy of a spectrum of botanical ingredients with their
therapeutic effects. In this chapter, I will briefly describe the history of use of botanical
therapeutics and the challenges that have been faced to assess their quality, safety and

26
efficacy. Finally, I will discuss what is known about the challenges faced by industry in
this area of development, as a basis for the research on industry attitudes and approaches
that will follow
2.2 History of Botanical Therapeutics
People have been using herbs for healing for at least 5000 years (Liu & Wang,
2008) for diseases as diverse as arthritis, cancer, asthma and allergies. Today, there are
more than 85,000 plant species that are reputed to have medical properties (Singh et al.,
2004). The World Health Organization (WHO) defines a herbal medicine as “a plant
derived material or preparation with therapeutic or other human health benefits which
contains either raw or processed ingredients from one or more plants” (WHO, 2008).
Within this definition can be differentiated subgroups of products that include raw or
processed herbal materials such as the unprocessed raw powder of botanical components,
or traditional formulations containing standardized herbal extracts or purified substances
often combined with excipients. The WHO essential medicine list includes 525 drugs of
which 11% are exclusively derived from plant origins. It has been estimated that 75% of
the world’s population use botanical products as their primary source of healthcare
treatment (Balunas & Kinghorn, 2005). In India, over 80% of the rural population use
indigenous herbal medicines; about 960 plant species are described in the Indian
Ayurveda alone (Sahoo et al., 2010).
Herbal medicines have a particularly rich history in Asia. In China, for example,
the use of herbal medicine can be recognized as early as 11th century BC (Bendiner,
1985a, 1985b), and the pharmacology of such products is documented in Chinese

27
pharmacopeiae dating back to first century BC (Shennong, 2007). However, the first
modern edition of the Chinese pharmacopeia, published in 1930, did not include
traditional Chinese herbs in its text. The second edition, published in 1963, had 446
commonly used traditional Chinese herbs and 197 preparations for traditional Chinese
medicine. A complete description of these products is beyond the scope of the thesis, but
the mere fact that so many are listed underlines the important role that such products have
had even in recent years. The 2010 (9
th
edition) covers most traditional Chinese
medicines as well as Western medicines and preparations, giving descriptions and
information on the standards of purity, testing, dosage, precautions, storage, and the
strength of each drug. It includes 4,567 total monographs, including 1,386 new
admissions and 2,228 revisions (Fan et al., 2012).
Herbal medicines are most commonly associated with Asian cultures, but with
accelerating global trade, Western medicine has also witnessed an increased consumption
of herbal medicines by consumers (Opara, 2004). This trend has been viewed with some
degree of concern by the regulatory and healthcare community. In part the concern has
related to the problematic control of quality of such products, with challenges as varied as
misidentification to contamination and even intentional adulteration. In part it arises
because insufficient knowledge exists regarding the safety and efficacy of botanical
preparations as medicinal agents. To some extent, laws and regulations in the U.S. have
been developed over the past three decades to categorize botanical products and to assure
their quality, safety and efficacy through guidelines on manufacturing and labeling.
These concerns, and the regulatory efforts to manage them, are discussed in more detail
in the following sections.

28
2.3 Botanical Product management and Regulation in the U.S.
In the U.S., botanical products are typically marketed as dietary supplements, and
are regulated as a subset of food. As a food product, the botanical is not allowed to make
any but the most-narrow of medicinal claims. Only two products (Veregen and
Crofelemer) are registered as drugs (Tang et al., 2014). Thus, most of today’s marketed
products will follow a prescribed set of regulations that are considered to be quite
moderate compared to typical drug regulations.
2.3.1 Regulation of Dietary Supplements
2.3.1.1 The Dietary Supplement Health and Education Act (DSHEA)
Dietary supplements in the U.S. are considered as a special category of food that
includes everything from vitamins and minerals to plant and even animal products. The
FDA describes a dietary supplement as (U.S.-103rd-Congress, 1994):
a product intended for ingestion that contains a "dietary ingredient"
intended to add further nutritional value to (supplement) the diet. A
"dietary ingredient" may be one, or any combination, of the following
substances:
 a vitamin
 a mineral
 an herb or other botanical
 an amino acid

29
 a dietary substance for use by people to supplement the diet by
increasing the total dietary intake
 a concentrate, metabolite, constituent, or extract
Dietary supplements may be found in many forms such as tablets,
capsules, softgels, gelcaps, liquids, or powders.
They are regulated under the Food Drug and Cosmetic (FD&C) Act of 1938 that
was amended in 1994 by DSHEA in response to the L-tryptophan disaster of 1989, in
which 38 deaths were reported as a result of impurities in ingredients supplied by the
Japanese wholesaler of the amino acid (Denham, 2011). Under DSHEA, dietary
supplement manufacturers and distributors were not required to provide evidence of
safety and efficacy prior to marketing a previously sold product because of their
presumably safe use historically (Sahoo & Manchikanti, 2013). Further, they were not
required to have FDA approval, unless they contained a New Dietary Ingredient (NDI).
In such a case, a 75-day notification was required for the new ingredient; this submission
outlined the scientific and clinical basis for considering that use would be safe (FDA,
1997). However, many have argued that these provisions have had minimal impact to
protect the safety of consumers because only a few ingredients are subject to this
provision. From 1994 to 2012 FDA received around 700 new dietary ingredient
notifications, a small subset of the 55,600 dietary supplements introduced to the
marketplace during that time period (Zakaryan & Martin, 2012).
Since the passage of DSHEA, the supplement industry has grown rapidly. Sales of
dietary supplements rose from $5.8 billion prior to 1994 to $17.1 billion in 2000 to $23.7

30
billion in 2007, and reached over $30 billion in 2011 (Bailey, Fulgoni, Keast, & Dwyer,
2012; Bailey, Gahche, Thomas, & Dwyer, 2013). Nutrition Business Journal (NBJ)
reported in July 2015 at the NBJ Summit (Dana Point, CA) that the dietary supplement
industry had grown in 2014 by 5.1% with annual sales reaching to $36.7 billion (Bradley,
2015b). In the FDA blog Acting Commissioner Dr. Stephen Ostroff states “the dietary
supplements industry is one of the fastest-growing in the world” posted on January 20,
2016 (FDAVoice, 2016).
Figure 1:Dietary Supplement Sales in the U.S.

Modified from NBJ Summit 2015, Dana Point, CA. Note the uneven spacing of
the dates that suggests an accelerating growth of the industry with time.
According to National Health and Nutrition Examination Survey (NHANES),
data presented at the Mary Frances Picciano Dietary Supplement Research Practicum
(2014) showed that more than two thirds of U.S. adults take dietary supplements, and one
third of U.S. children take at least one supplement daily (Bailey et al., 2013). Another
0
5
10
15
20
25
30
35
40
2000 2007 2011 2014
Dietary Supplement Sales; billions

31
survey conducted by Ipsos Public Affairs on behalf of Council for Responsible Nutrition
(CRN, 2014) identified that the numbers of dietary supplement products supporting this
market growth increased from 4,000 in 1994 to 75,000 in 2008 (Marcus & Grollman,
2012).
Under DSHEA dietary supplements can make three types of marketing claims;
nutrient content claims, structure-function claims and health claims. All of these three
types of claims can suggest health-giving effects to the consumer. A nutrient content
claim is one that identifies the nutrient content of dietary supplement, for example its
content of vitamin C or iron. It further can qualify that content according to its relative
content compared to nutritive needs, for example, a “good source of” a particular
nutrient, provided that the nutrient need is further described in relation to the incidence of
that specific nutritive deficiency. In the case of vitamin C, the incidence of its associated
deficiency disease, scurvy, is exceedingly low. Because such nutritive deficiencies are
relatively rare in the U.S., the usefulness of such content claims is relatively modest and
content claims are used infrequently.
Structure-function claims are the most common of the three claims types. They
relate the content of a nutrient, i.e. calcium, to some aspect of the structure or function of
human body, i.e. bone health. These claims might allow the consumer to draw inferences
about those health-giving effects as therapeutic agents, “calcium helps build strong
bones”, but cannot explicitly link that ingredient to the treatment or prevention, i.e.,
osteoporosis (FDA, 2000). The third type of claim, health claims, are the most strictly
regulated of all claims and require substantiation through clinical trials and a pre-
approval process. They can go further than structure-function claims by identifying a

32
stronger link between an ingredient and its ability to improve some aspect of health, i.e.
“calcium reduces the risk of osteoporosis”, but still prohibits claims of disease prevention
and mitigation, i.e. “prevents osteoporosis”(FDA, 2014b). Once such a claim is
submitted by an individual company and approved by the FDA, any other company that
makes the supplement becomes also free to use the claim on their product. FDA was
denied the authority to require approval of specific products if they follow the appropriate
labeling rules. DSHEA thus represented an uneasy compromise that required little
demonstration of efficacy, and created tension between FDA and industry over the value
of supplements (Kesselheim, Connolly, Rogers, & Avorn, 2015). It also failed, at least
in many eyes, to provide an effective framework for governing the manufacture and
ongoing oversight of dietary supplements, thus setting the stage for continuing challenges
of product quality and safety (Cohen, 2012a; Cohen, Maller, DeSouza, & Neal-Kababick,
2014; Marcus, 2015; Marcus & Grollman, 2012).
2.3.2 Regulation of Drugs
The alternative path to that of marketing a botanical product with actions on the
body is to pursue its development as a drug. The path to pharmaceutical drug
development is time- and resource-intensive. It requires toxicological and
pharmacological studies in animals, followed by human studies conducted in different
phases from small cohorts of healthy volunteers to large scale groups of patients with the
targeted disease. The trials must be conducted under Good Clinical Practices (GCP), as
defined by FDA guidance document (FDA, 1996), with systems in place to assess,
monitor and report adverse events. Scrupulous attention must also be paid to product
manufacture under cGMP procedures (FDA, 2010). As the product proceeds along its

33
development path, approvals must be sought from the FDA through the submission of
IND and NDA dossiers (FDA, 2015c). Thus, if a dietary supplement wants to become
qualified to make claims of disease prevention or treatment, it must carry out prospective
clinical trials to establish efficacy in the same way as a conventional drug. As a result,
the requirements for drug marketing are much more difficult, time-consuming and costly
than those for marketing a dietary supplement. These requirements and constraints are
discussed below by examining in more detail the challenges of assuring quality, safety
and efficacy.
2.4 Concerns Regarding the Quality of Botanical Products
Controlling the quality of medicinal agents has always been a significant area of
challenge for regulatory agencies and industry. It is difficult enough to assure the purity
and identity of high-value drugs, even when such products can be synthesized under
highly controlled conditions and with sophisticated quality assurance programs whose
costs can be borne by pricing those drugs at a premium. It can be much more difficult for
agriculturally sourced products that are variable in nature and do not command high
prices when sold. Factors affecting the quality of herbal products can be subcategorized
into external and internal factors. Internal factors are those associated with the inherent
composition of the plant itself that affects the quantities and pharmacological activities of
its phytochemicals. Plant synthesize a variety of phytochemicals such as flavonoids,
phenols, alkaloids and glycosides(Ernst, 2002b; Ernst & Pittler, 2002a). Controlling the
quantity and quality of such phytochemicals depends on careful choice and often genetic
breeding of plant genera that meet the specific needs of the user, a subject beyond the

34
scope of this dissertation. External factors include growing conditions, environmental
factors and manufacturing approaches that can further affect the chemical composition of
plant parts. These external factors also must be controlled, in order to obtain a consistent
product that can be used reliably in research or therapy.
2.4.1 External Factors Affecting the Quality of Botanicals
2.4.1.1 Botanical products are grown in fields
In order to foster agricultural yield, farmers must make decisions on the time of
planting and the use of herbicides and fertilizer that are best guesses related to the
unpredictable climatic and growing conditions that the plant will later experience. The
chemical makeup of a plant can be affected by environmental factors such as rainfall and
sun, soil condition, nutrients, as well as cultivation, processing, and storage conditions.
These can affect concentration of active components and therefore the chemical profiles
of plants and their derivatives (Ernst & Pittler, 2002b). Plants can also be challenged by
microbial exposure and heavy metal or pesticide contamination. Toxic heavy metals
levels such as arsenic, mercury and lead have been found quite frequently in Chinese
Proprietary Medicines (CPM) and Indian Ayurvedic medicines (Ernst, 2002a). This
contamination can occur if the plant is grown under inappropriate environmental
conditions where pollutants are present. Pesticide contamination of herbal preparations
from emerging markets has been relatively common. A study of pesticide residues in 280
herbal medicines by Xue and colleagues, for example, showed that 76% were
contaminated with at least one organochlorine such as pentachloronitrobenzene (PCNB),
aldrin, benzene hexachloride (BHC) and dichlorodiphenyltrichloroethane (DDT) (Xue,
Hao, & Peng, 2008). Similarly, in India, isomers of hexachlorocyclohexane (HCH) were

35
detected in all samples of Dashmoola, a common herbal preparation used for its
febrifugal properties (Rai et al., 2008). WHO has published guidelines for Good
Agricultural and Collection Practices (GACP) for medicinal plants in 2007 that to some
degree may reduce the natural variation and ensure consistency (WHO, 2007), but it is
unclear to what extent the farmers read and incorporate WHO guidelines.
2.4.1.2 Botanical products are often adulterated along the sourcing path
As products are harvested for sale, additional challenges to quality can present.
Perhaps that of most concern is the replacement of the desirable herb by misidentified or
lower quality ingredients, often but not always to maximize commercial return. For
example, in the United Kingdom (UK), unintentional substitution of Stephania tetrandra
by Aristolochia fangchi resulted in nephritis (Chan, 2003). Cases of medicinal drug
substitution have also been reported in India. In Ayurvedic nomenclature, Parpatta refers
to Fumaria parviflora, whereas in Siddha nomenclature, Parpatta refers to Mollugo
pentaphylla. These two herbs are often confused or unintentionally substituted in a
nation that follow these different types of practice and speak 72 different languages and
dialects (Mitra, Kannan, & Sundaram, 2007). Cases of misidentification have been
reported between Asian ginseng (Radix Ginseng) and American ginseng (Radix Panacis
Quinquefolii), which have similar morphology yet different chemical properties
(Dhandapani & Sabna, 2008).
2.4.1.3 Botanical products are often deliberately adulterated for economic gain
Not all adulteration is related to the innocent contamination of agricultural
products during growth or shipping. Many expensive Chinese herbs are in short supply,
so have often been substituted with fake or alternative herbs. Synthetic substances or

36
other active undeclared ingredients are also common adulterants to increase the apparent
strength or effectiveness of the plant materials. Deliberate adulteration of herbal products
with one or more synthetic drugs has been reported in many Asian countries that cultivate
and formulate finished preparations, mainly for Asian markets (Sahoo et al., 2010). In
the U.S., such substitution is also apparent, reflected, for example, in a recent FDA
warning letter to R. Thomas Marketing that identified sildenafil, the active ingredient in
Viagra®, as an undeclared adulterant to their “Herb Viagra”, “Black Ant” and “Real
Skill” dietary supplements (FDA, 2016b). Similar instances were also reported by the
Health Science Authority (HAS) in Singapore after they screened 3320 preparations of
Traditional Chinese Medicine and found nineteen synthetic drugs including sildenafil,
tadalsfil, verdenafil and other structurally modified analogues, all used to enhance male
potency (Yee, Chu, Xu, & Choo, 2005). Another example of deliberate adulteration was
that of “Tung Shueh” used for pain relief, adulterated with four undeclared drugs,
caffeine, diazepam, indomethacin and prednisolone that were considered the cause of
acute renal failure in users. Similarly, “Gu Ben Wan” used for the treatment of dry
cough, contained six undeclared drugs. “Wonder Pills” taken to manage weight loss
contained phenformin, a drug banned in Singapore (Yee et al., 2005). Elements
considered by most as undesirable contaminants may even be introduced in order to
achieve a specific therapeutic objective, as is the case for Zhusha (Cinnabaris) and
Xionghuang (Realgar), two products whose content of mercury and arsenic were seen to
be useful for their effects as topical drugs. Among the 572 preparations described in the
Chinese pharmacopeiae, 53 preparations include Zhusha and Xionghuang for a variety of
indications from carcinoma of uterine cervix to brain tumors (Lanling, 1992).

37
2.4.2 Establishing Identity of Active Components
Because of the potential that plant products might be misidentified, substandard or
contaminated, it becomes important to develop analytic methods to discriminate the
content of active ingredients in a particular sample of plant product. Herbal products are
different from synthetic drugs; a single plant extract may contain hundreds of many
different phytochemicals, each acting on physiological pathways with different affinities
and effects. For instance, each of the 28 ginsenosides identified in P. ginseng is
associated with a different therapeutic action (Zhang, Wider, Shang, Li, & Ernst, 2012).
The Chinese herbal medicine “Huang-qin” (scutellaria bacicalensis) has over 2000
compounds (Saxena, Cole, & Murch, 2007). From this complex mixture, the active
compound(s) responsible for therapeutic effect(s) is often unknown or is a combination of
many active compounds exerting their effect synergistically. The National Institutes of
Health (NIH) Botanical Research Expert Panel concluded that potential synergistic
interactions of drugs and botanicals are often postulated, but not confirmed. “New
methods and standards are needed to facilitate chemical characterization and to improve
the identification of possible biological actions and relevant interactions” (NIH, 2013).
In 2012, the top ten dietary supplements containing herbal products that were sold in the
United States were cranberry, garlic, saw palmetto, soy, ginkgo, milk thistle, black
cohosh, echinacea, St. John’s wort, and ginseng (Lindstrom, Ooyen, & Blumenthal,
2013). The main compounds responsible for their biological activities are either
unknown or disputed (Wu et al., 2010). However, in other cases, a class of related active
compounds is known to be responsible for biological activities. Catechins in tea are a
prime example of a class of compounds in which each individual compound is believed

38
to contribute to the overall effect, so that no single compound is responsible for the
observed biological activities (Kronenberg & Kennelly, 2013). Thus, using a single
marker can be insufficient to ensure identity, safety and efficacy of the product in its
totality. A multi-technique approach may therefore be required to establish “phyto-
equivalency” between batches of product. First developed in Germany, methods are
now available to “fingerprint” a botanical product sample using analytically defined
peaks so that the profile can be compared to the profile of a clinically proven reference
product (Kronenberg & Kennelly, 2013). This begs the question, however, of whether
the clinical reference standard is in fact the “best” representation of the potential
medicinal effects of such a botanical. Chemical markers defined by EMEA (EU, Middle
East, and Africa), a division of European Medicine Agency (EMA), as groups of
constituents of herbal medicine products have also been used for quality control purposes
even in the absence of known bioactivity or therapeutic effects related to the marker
compounds (HMPC, 2004). It is now common to use several identity markers such as
genomic and proteomic markers along with chemical profiling of constituents using
chromatographic techniques to complement morphological identifications of suitable
botanical products (Sahoo et al., 2010).
Even after suitable raw materials have been obtained, the pharmacological
activities of the active compounds may be altered by manufacturing processes such as
those needed for extraction or and purification. The manufacturing processes may
inadvertently modify the active ingredient to render it ineffective or cause it to become
more effective or even toxic. Excipients added to improve the flow properties, stability
and encapsulation process can also alter stability of many herbal products (Farnsworth &

39
Mahady, 2009). Variations in the temperature, light and humidity under which the
products are stored can also affect the product stability. These changes can be important
clinically.
2.4.3 Assessing Potency of Active Components
If we are to understand better how herbal products produce therapeutic effects, it
is important to start with well-characterized materials. In a clinical trial it is especially
important that consistency be maintained within and between batches used for the
duration of trial (Kronenberg & Kennelly, 2013). After such trials are over, it is then
important that same products, destined for market, are produced consistently within
established specifications for potency and stability. However, to date, it has been
challenging to assure that products have the potencies claimed on their product labels.
A study to evaluate the quality of 880 off-the-shelf products belonging to the top 10 U.S.
herbal supplement categories (according to sales volume) showed, for example, that 67%
of products containing echinacea and 57% of products containing ginkgo had contents of
active ingredients that did not match their labeled potency. Further, only 2 of 54 samples
of St. John’s wort had concentrations of the active ingredients, hypericin and
pseudohypericin, within 10% of that claimed on the product labels (Wolsko, Solondz,
Phillips, Schachter, & Eisenberg, 2005).
Much attention has been paid recently to the importance of standardization. In the
absence of official standards, one manufacturer may arbitrarily select one or more
compounds as its standard against which to be measured, whereas another might use a
different compound (e.g., 40% ellagic acid versus 5% punicalagin for pomegranate

40
extract) (Seeram et al., 2008). Standardization is particularly problematic for products
that are being used in clinical investigations. Over the past two decades there have been
more than 300 botanical clinical trials registered on the mandatory clinical trial
registration website, clinicaltrials.gov, in the U.S. (Kronenberg & Kennelly, 2013).
Amongst these trials, some apparently similar botanical research studies for the same
indication have had different results that could be due to the inherent variability of the
products under test, thus making interpretation of the data difficult.
Botanical research articles rarely specify the plant material used in the clinical
studies. A survey of product standardization by Timbo and colleagues showed that such
standardization is not typically established prior to starting a clinical trial (Timbo, Ross,
McCarthy, & Lin, 2006). The same study noted that many investigators believe that
having a simple certificate of analysis for their herbal products is an adequate level of
assurance. Stability of botanical products in the clinical trial over the research time
period is also of concern. For example, Kronenberg and colleagues (2013) raised issues
about the challenges of evaluating stability of plant extracts with hundreds of constituents
particularly when the active components that are responsible for clinical outcome of the
study are not well understood (Kronenberg & Kennelly, 2013). Thus, even if study
results exist, care must be taken to understand the state of the clinical trial materials that
may have influenced the results.
2.5 Regulatory Response to Quality Issues
Concerns over botanical quality have caused regulators globally to investigate the
potential challenges that these quality issues could pose to public health. In 2001, WHO

41
initiated a global survey of 191 member states in order to gain insight into concerns and
national policies related to the regulation of herbal products. They identified quality
issues related to use of herbal products including challenges related to compiled research
data, inconsistencies in quality control systems, and the limited education of healthcare
prescribers with regard to administration of herbal medicine (WHO, 2005). The survey
further showed that only 37% of member states had laws to regulate botanical products
and these systems of regulations were highly variable. Only 24% of responding member
states had established national pharmacopeiae for botanical products.
The interpretation of what constitutes a “quality” botanical is further complicated
by the way that the product is classed, because different classes have different quality
benchmarks and regulatory requirements. Amongst the countries that regulate herbal
medicine examined by WHO (2005), 68% were found to sell herbal medicines as over-
the-counter (OTC) drugs, and 35% treated herbal products as prescription medicines
(Rx); a percentage of these products are sold in either class depending on
national/regional regulations. Differences in classification are very important from the
point of view of quality management. When a product is marketed in the U.S. as a drug,
for example, the bar for quality is very high and is enforced by frequent internal audits as
well as biannual inspections by the FDA under regulations in 21 Code of Federal
Regulations (CFR) 210 and 211. For dietary supplements regulated under DSHEA,
manufacturers are responsible for the safety of the product before commercialization, but
the FDA rather than the manufacturer must assume the burden of proof that the marketed
product is unsafe. Thus, the FDA can only take action against an unsafe dietary

42
supplement manufacturer if the product can be proven to be harmful, as it did in the case
of sildenafil-laced “Herb Viagra”. However, contaminated product is not always easy to
identify, so contaminated products commonly remain on the market. For example, in
May 2010, GAO issued a report highlighting its discovery of trace amounts of at least
one potentially hazardous contaminant such as lead, mercury, cadmium or arsenic
concentrations in 37 of 40 tested herbal dietary supplements (GAO, 2010b). The GAO
report emphasized the need for regulating quality. It stated that “…weaknesses in the
regulatory system could increase the likelihood of unsafe products reaching the
market...”
Critics of DSHEA have pointed to numerous technical difficulties related to
assessment of the chemical constituents of botanical products under the current
regulatory regime. Each constituent requires its own unique method for chemical
analysis, and some of these methods may not even be developed or be available to those
testing the product (Kesselheim et al., 2015). Thus, FDA may have to allocate substantial
resources to identify such adulteration, and by the time of the identification, the product
may have been removed from the market, only to reappear under a different brand name.
Currently 20 different analogues of sildenafil for sexual potency have been recognized in
variety of dietary supplements (Cohen et al., 2014). Problems are not just restricted to
the use of sildenafil. For example, Cohen reported that 2 new analogues of
methamphetamine had been discovered in supplements in 2013; he further observed that
more than 500 dietary supplements have been reported to be adulterated with
pharmaceuticals of some kind (Cohen et al., 2014). The observations of quality problems
in dietary supplements have led Congress to make numerous attempts to tighten the

43
quality requirements for dietary supplements. In 2006, passage of the Dietary
Supplement and Nonprescription Consumer Protection Act required manufacturers to
report serious adverse events to the agency. One positive outcome of this requirement
would be to identify products whose adverse events profiles appeared out of character for
the product with which the adverse events were associated (U.S.-109
th
-Congress, 2006).
In February 2010, Sens. John McCain (R-AZ) and Byron Dorgan (D-ND) introduced S.
3002, the Dietary Supplement Safety Act of 2010. This bill would have required dietary
supplement manufacturers to disclose the ingredients in the dietary supplement. It also
would have given the FDA mandatory recall authority when a supplement was found to
be unsafe or harmful, and it would have required reports to the FDA of all adverse
effects, even those classed as non-serious (U.S.-111th-Congress, 2010b; Umhau, Garg, &
Woodward, 2012). However, bill S. 3002 met heavy resistance from industry, and later
was withdrawn. Trade groups credited Senators Hatch and Harkin for convincing
Senator McCain to withdraw the bill. Senator McCain released a March 4, 2010 letter
from Senator Hatch thanking him “for agreeing to withdraw your support for the
provisions of S. 3002 that I believe would do great harm to the dietary supplement
industry” (U.S.-111th-Congress, 2010b).
A more direct attempt to control the quality of dietary supplements was however
successful by using regulatory approaches. Regulations for Good Manufacturing
Practices (GMP) of Dietary Supplements were introduced in 2010 and these had a major
impact on the industry by requiring a large number of quality control measures not
previously considered to be applicable to dietary supplements. The Dietary Supplement
cGMP rule in 21 CFR part 111 (also known as the DS cGMP rule) requires persons who

44
manufacture, package, label, or hold a dietary supplement to establish and follow current
good manufacturing practice to ensure the quality of the dietary supplement and to ensure
that the dietary supplement is packaged and labeled as specified in the master
manufacturing record (FDA, 2010).
Enhancements to supplement quality were also secured in 2011 by the passage of
the FDA Food Safety and Modernization Act -FSMA (U.S.-111th-Congress, 2010a)
signed by President Obama on January 4, 2011. This Act gave the FDA new powers to
respond to food safety problems that included the ability to order a recall of dietary
supplements that could cause serious adverse health consequences or death, provided
FDA could prove “significant and unreasonable harm”. This new law enhanced the
requirements for tracking food ingredients from their sources, and put into place the
framework for a foreign vendor verification program. In addition, attention began to be
paid to the problems of importation of violative product.
The regulatory interventions described above illustrate a concerted effort to
increase the quality of dietary supplements. If botanical products were instead introduced
as drugs, these efforts would not be needed because the quality requirements for drugs
are already very rigorous as the result of multiple laws and regulations beginning in the
1960s with the Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act.
These efforts led to strict requirements for Good Manufacturing Practices as outlined in
CFR 210 and 211 (FDA, 2015a).
Currently both dietary supplements and drugs are governed by GMP regulations
(although the requirements for dietary supplements are not as strict as those for drugs).
Whether a botanical is marketed as a drug or dietary supplement, it now must be subject

45
to some form of identity and potency testing. In anticipation of such requirements, in
early 1990s, the U.S. Pharmacopeial Convention (USP) began the process of creating
botanical monographs that it published in the USP Dietary Supplement Compendium, to
provide industry and regulators with better benchmarks and standards for their quality
analyses (Dentali, 2010). However, these standards of quality have not yet been widely
incorporated in the industry (Zakaryan & Martin, 2012). Recently, the National Center
for Complementary and Integrative Health (NCCIH), a part of the NIH, has provided a
botanical guidance document to help manufacturers understand the requirements of
complex botanical research including characterization and identification of active and/or
other relevant marker compound(s) used for standardization (NCCIH, 2015). It renewed
the focus on the development of biomarkers that can be used to benchmark the
consistency and potency of botanical products in a way that will open the door for their
development as drugs as well as food products.
2.6 Concerns about Safety of Botanical Products
As expected, the increasingly popular use of botanical dietary supplements has
fueled a public safety debate regarding the health risks of such products to consumers.
Typically risks to health arise from two types of concerns (De Smet, 2000). First are
those associated with issues of quality such as plant misidentification, manufacturing
inconsistency, improper storage conditions, intentional adulteration, and contamination
from pesticides or manufacturing operations, discussed previously. Second are those
associated with the intrinsic characteristics of the botanical, such as its inherent toxicity,
its inappropriate use for specific medical conditions, and its interactions with other herbs

46
or prescription drugs (Jordan, Cunningham, & Marles, 2010). Safety issues were the
most important priority identified by NIH Botanical Research Expert Panel on April 29,
2013; “consideration should be given to clarification of safety concerns, both related to
toxic or adulterated products and to the products that interacts conventional
pharmacological agents” (NIH, 2013).
2.7 Understanding Safety Problems
Most of what we know about safety problems come from reports of serious
adverse reactions that are ultimately reported to regulatory agencies. A serious adverse
reaction to a marketed health product has been defined as “any undesirable experience
associated with the use of a medical product in a patient that involves death, or is life
threatening, that causes hospitalization, disability, permanent damage, congenital
anomaly or birth defects” (FDA, 2014c). This reporting system is far from perfect.
Mandatory Adverse Event (AE) reporting by manufacturers and distributors has only
recently been added as regulatory requirement in the U.S. by the passage of FSMA-2011,
and even now relies on feedback from consumers and health care professionals who are
well-known to underreport their negative experiences. This deficiency appears apparent,
for example, from a 2013 GAO report estimating that 55,000 dietary supplements were
on the market as of 2009 and half of the American population was taking these
supplements, but FDA received just 6,307 adverse event reports (AERs) from 2008
through 2011. By comparison, the FDA received more than 1.8 million AERs related to
prescription drugs from 2008 through 2011 (GAO, 2013c). Nonetheless, half of all FDA
class I recalls since 2004 were related to dietary supplements (Cohen et al., 2014). The

47
number of reported adverse reactions associated with dietary supplements in the U.S. has
been estimated to be less than 1% of the total that may actually occur (Cohen, 2012a;
Woo, 2007). In 2013 the GAO found that substantial underreporting of adverse events
persisted, with only about 1 in 50 complications reported to FDA (GAO, 2013a, 2013c).
The low incidence of AE reporting may reflect consumer perceptions that dietary
supplements are safe and that the reactions that they might experience come from other
causes (Jordan et al., 2010). This can be a particular problem because supplements are
often taken at the same time as drugs and with food products. Perhaps unsurprisingly
then, data published in March 2014 by FDA shows a decline rather than increase in the
number of AEs associated with dietary supplements compared to the prior year, despite
this tightening of adverse events reporting (Long, 2015). In 2014 FDA received 2,793
mandatory AERs linked to supplements, compared to 3,289 AERs in 2013 and slightly
below the 2012 number of 2,844 see Table 2 (Long, 2015).
Table 2: Number of Mandatory Events Reports (AERs)
Year Reported Mandatory AERs

13,378
2014 2793

Total number of mandatory
AERs from 2008 through 2014 2013 3289

2012 2844

3,832
2011 2037

Total number of voluntary AERs
from 2008 through 2014 that
indicated a supplement was
linked to the AE
2010 1014

2009 714

2008 687

Source: FDA - The 2008 through 2014 was obtained in May 2015

FDA acknowledges that post-market surveillance systems do not capture a full
picture of safety issues because not all adverse events are reported. According to an

48
investigation in 2014 by Atlanta Journal Constitution, only 5 out of 10 deaths linked to
controversial stimulant dimethyamyl amphetamine (DMAA) over three years were
reported to FDA (Cohen, 2012b; Long, 2015). Thus, a review of adverse event reporting
in the literature is not conclusive, and hardly addresses the safety issues of botanical
products, particularly when concomitant products are consumed. However, even when
the problems are known to the FDA, the challenges of assessing and acting on safety
concerns can be illustrated by examining the actions of FDA related to the dietary
supplement, ephedra. According to GAO, it took 10 years for the FDA to meet the
burden of proof to ban ephedra, a stimulant used in weight loss and bodybuilding
products, that was linked to at least 155 deaths and thousands of reported health problems
(GAO, 2009a).
2.7.1.1 Adverse events can be caused by undeclared ingredients
Numerous examples exist of herbal product adulteration linked to untoward safety
effects as described above (Ernst & Pittler, 2002b; Zhang et al., 2012). Undeclared drugs
and other ingredients found in herbal medicines are one form of adulteration that has
caused numerous safety problems. For example, the presence of undeclared Active
Pharmaceutical Ingredients (API), such as sildenafil to enhance male sexual potency and
sibutramine to promote weight loss, may injure consumers, particularly when the levels
of those drugs can be higher than allowed in prescription products (Jordan et al., 2010).
Another insight into the extensive nature of adulteration in dietary supplements comes
from evidence from FDA importation inspections. Zakaryan and colleagues analyzed a
report by GAO from FDA import data for the food category from 2002 to 2008, and
found that 38% of 3605 products refusals were related to adulteration in dietary

49
supplements. Another high percentage of refusals occurred because the companies failed
to label the product with the appropriate content of ingredients. Interestingly, about 1%
of total products imported into the United States are inspected by U.S. Custom Services
(De Carvalho et al., 2012; Zakaryan & Martin, 2012), so it might be assumed that many
marketed products have the same violative profiles of their intercepted counterparts.
2.7.1.2 Adverse events can be caused by drug properties/toxicities
The causality of an adverse event is also complicated by the inherent variability
of plant materials, the difficulty in assessing the potency of the botanical products, and
the relatively modest body of knowledge regarding the toxicological profiles of many
botanicals (Srinivasan, 2006). Over sixteen thousand suspected adverse events associated
with herbal products are present in the WHO database maintained by the Uppsala
Monitoring Center (WHO, 2016). Amongst these cases, incidents of poisoning related to
variations in the chemical composition of the herbal medicine have been reported (Liang,
2004).
The fact that some botanical products are potentially dangerous is recognized and
efforts have been made to restrict their use. In 1992, for example, the Proprietary
Medical Product Committee (CPMP) of European Commission published a list of 33
banned herbal drugs with serious threats to health (Sahoo et al., 2010). Further, Order
1997 of “Prescription Only Medicine” in the UK specified a list of 25 herbal products to
be supplied only by prescription because of their propensity to elicit toxic reactions
(MHRA, 2002); later the same organization requested all pyrrolizidine alkaloid products
to be withdrawn from UK market (Sahoo et al., 2010). The American Herbal Product
Association (AHPA) in 2003 issued an alert warning consumers about the use of comfrey

50
(Brinker, 2004; Consumer_Reports, 2004), an herb that contains pyrrolizidine alkaloids.
Nevertheless, the restrictions are often absent in some countries, particularly developing
countries. For example, medicinal plants in Indonesia used for women’s health care such
as disorders of pregnancy, leucorrhea, menstrual disorders and care during childbirth, are
often consumed directly or mixed in herbal medicine without much regard to safety
(Lestari, 2016).
FDA in the U.S. has reported undesirable cardiovascular effects from the use of
Chinese herbs containing ephedra to promote weight loss as described above; ephedra
was banned and subsequently removed by FDA from the marketplace (FDA, 2004b).
One important way to understand botanical product toxicity is by studying the
effects of botanical products with a well-characterized potency, and quality profile in
dose frequency clinical trials. Randomized controlled clinical trials have shown, for
example, that ephedra is linked to cardiovascular problems, and kava to hepatotoxicity
(Cuzzolin, Zaffani, & Benoni, 2006). NIH has recently taken a lead to fund botanical
research more systematically by creating five research centers each specialized in specific
area of research. Pennington Biomedical Research Center conducts botanical research on
Metabolic Syndromes, University of Illinois at Chicago focuses on Women’s Health, and
Phytochemistry, University of Illinois Urbana Champaign on breast cancer, University of
Missouri on prostate cancer, and Wake Forest University on genetic polymorphisms and
effects of botanical polyunsaturated fatty acids on inflammatory cells and conditions.
(NIH, 2015).

51
An important challenge that is not typical for conventional drugs is the difference
in toxicity that can be associated with whole plants versus isolated constituents. For
example, Stevia rebaudiana leaves contain a complex mixture of different diterpene
glycosides (SGs) which constitute 4-20% of the dry leaf weight (Kim & Kinghorn, 2002).
Stevia extract has been reported to be unsafe for human consumption by FDA whereas
purified diterpene glycosides (SGs) have been cleared the agency for safety and use in
food systems (Abdel-Rahman et al., 2011). Conversely, green tea has a long history of
safe use for human consumption in its relatively raw state, yet some major flavonoids of
green tea extract such as purified epigallocatechin-3-gallate (EGCG) have proven toxic to
mitochondria because of their pro-oxidation activities (Abdel-Rahman et al., 2011).
2.7.1.3 Adverse events can be caused by drug interactions
Another source of adverse events is the interaction between concurrently used
drugs and botanical products. For example, the active constituents of ginkgo (ginkgolic
acids), kava kava (desmethoxyangonin, methylsticin, dihydromethylsticin), and St.
John’s wort (hyperforin, quercetin) all inhibit the metabolism of drugs via the
cytochrome P450 pathway (Zou, Harkey, & Henderson, 2002). Concerns about herb-
drug interactions can also render certain drugs ineffective (Chen et al., 2008; Kanji et al.,
2012). An example of such interaction is that of warfarin and angelica sinensis (dong
quai) or salvia miltiorrhiza (danshen), that can affect the bioavailability and elimination
rate of warfarin if either herb is taken together with warfarin (Chan, Tan, Xin,
Sudarsanam, & Johnson, 2010; Tsai, Lin, Simon Pickard, & Mahady, 2012).

52
2.8 Regulating Safety
As discussed above, safety monitoring relies primarily on adverse events
reporting. Correlation of particular adverse event with a product is especially challenging
in those situations where the dietary supplement manufacturer has not been required to
submit any kind of marketing notification or submission to the FDA, either as a New
Dietary Ingredient (NDI) or a Generally Recognized as Safe (GRAS) notification (FDA,
2011). The FD&C Act requires that those who wish to market dietary supplements that
contain "new dietary ingredients" notify the agency about these ingredients (FDA,
2016a), but this has not been considered to be sufficiently effective. An important step
toward understanding adverse events was taken with the passage of the Dietary
Supplement and Nonprescription Consumer Protection Act in 2006 (U.S.-109
th
-Congress,
2006), with its requirement that supplement manufacturers, packers, and distributors
report serious adverse events associated with the use of dietary supplements (GAO,
2010a, 2013b). Subsequent regulations required that an adverse event report be filed
with FDA no later than 15 business days after it is received, and records of such events be
maintained for 6 years (FDA, 2014c; GAO, 2013b). Yet despite these regulatory efforts,
underreporting and inconsistency of reporting remains a serious concern (Long, 2015;
Zakaryan & Martin, 2012).
Effective adverse events monitoring requires large number of events to be
reported to the FDA, in order to identify a particular trend. Further, reports of less
serious consequences might be as important in creating a full profile of long term
toxicity, but submission of these types of lesser AEs are not required. Thus, the full

53
profile of AEs associated with each marketed product remains unidentified (Timbo et al.,
2006). Congress has been called to modify DSHEA to address many of the concerns and
loopholes, by requiring mandatory product registrations (Eichner, 2015) clarifying the
limited role of FDA in evaluating structure-function claims (Kesselheim et al., 2015),
developing more rigorous and standardized laboratory techniques to characterize dietary
supplement ingredients (Marcus, 2016; Marcus & Grollman, 2012, 2015) and
strengthening FDA’s authority to remove contaminated product swiftly (Cohen, 2014;
Dodge, Litt, & Kaufman, 2011).
A Dietary Supplement Labeling Act Bill S. 1425 was introduced on August 1,
2013, sponsored by Senator Dick Durbin (D-IL) and Richard Blumenthal (D-CT) that
would require supplement manufacturer to register their products with FDA and to
provide known safety information and adverse events on label, similar to drug products
(U.S.-113
th
-Congress, 2013). Bill S. 1425 therefore would have offered more safety
information, but still did not allow FDA to detect and remove dangerous supplements
from market place (Cohen, 2014; Marcus, 2016). Legislation was not enacted by the end
of a Congress and is now cleared from the books (U.S.-113
th
-Congress, 2015).
2.9 Efficacy: Turning Botanical Products into Drugs
The scientific basis for understanding therapeutic effects of botanical products is
surprisingly underdeveloped. Claims of supplement efficacy are based primarily on
empirical evidence gained over their long history of use, supplemented occasionally by a
relatively small number of clinical trials funded over the past few decades by
manufacturers (Marcus & Grollman, 2012, 2015). However, most of the observations

54
from such trials were obtained using products that did not have proper certifications of
test article identity. Further, little is known about efficacious dosage ranges that will
produce a therapeutic effect without toxicity. Thus, the results of those studies can be
open to question. However, it can be more difficult to develop a CMC dossier for
botanical drugs than it would be for a New Chemical Entity (NCE), where outcomes
typically depend on the potency of a single active component that can be readily
identified and quantified. Further, clinical trials are often made difficult by the challenges
of obtaining consistent high quality product. Product purity, economically motivated
fraud, unintentional substitutes, misbranding, environmental pollutants, microbial and
heavy metal contaminants must be considered as potential sources of variability that will
affect the conclusions drawn about the efficacy of botanical products (Schiff et al., 2006).
If quality challenges can be addressed, prospective randomized controlled trials
with meaningful end points are needed to establish the efficacy of herbal medicines.
Over 300 botanical INDs have been submitted to the FDA since guidance for botanical
drug development was issued in 2004 (Offit, 2012). However, the number of
publications and the numbers of approved NDAs are low and appear not to have
produced the scholarly or business outcomes that many of these clinical trials might lead
one to anticipate. Further, numerous clinical trials conducted by NIH have found no
benefit beyond placebo effect for a number of popular supplements including echinacea,
black cohosh, glucosamine, saw palmetto, ginseng, ginkgo biloba, isoflavones (Offit,
2012). Negative results in these and other trials can be difficult to publish and are
unlikely to result in marketable botanical drug products. However, new INDs continue to

55
be submitted, not only from domestic researchers, but also from groups overseas. For
example, as recently as December 25, 2015, the Shenzhen-based Yiling Pharmaceutical
Company announced via press release that its wholly owned subsidiary in the U.S.
received FDA approval to conduct trials for its oral herbal medicine, Lianhua-Qingwen,
compounded from 61 herbs and chemicals (Wang et al., 2014) for treating the common
cold and influenza virus.
Finally, some botanicals have a history of serious adverse events so cannot be
easily studied in clinical trials without risking the health of participants. Combining
foods with herbs or drugs may also confound attempts to measure efficacy in clinical
settings (Chan & Critchley, 1996). These limitations on clinical trials to date mean that
pharmacovigilance activities have often been the fallback anecdotal source of information
on efficacy, without the rigorous standards of clinical trials.
Nevertheless, the importance of systematic clinical trials of botanicals is not to be
underestimated. Currently consumers have only the health-improving claims on the
labeling provided by manufacturers for information about efficacy. These claims are
softened by a mandatory disclaimer to be placed on the label that "This statement has not
been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or
prevent any disease". However, a recent review of 17 published articles related to the
consumer understanding of this disclaimer concluded that the disclaimer had little impact
on consumer perception of supplements (Kesselheim et al., 2015). Structure-function
claims in particular are often misinterpreted to suggest more efficacy than warranted
amongst general consumers (France & Bone, 2005). According to a 2002 Harris Poll, a

56
majority of consumers believed that dietary supplements are reviewed and approved by
the government and a third of consumers believed that manufacturers were required to
report side effects on the labels of dietary supplements (Cohen, 2009). Dodge and
coworkers further showed in a study of college students that views of product safety but
not efficacy were lowered when the participants were made aware that FDA does not
approve dietary supplements. However, views on efficacy were lowered if participants
were educated about the use and significance of disclaimers (Dodge & Kaufman, 2007).
2.10 Studying Clinical Trial Impediments
Much has written about clinical trial impediments in the pharmaceutical arena
(Matthews, 2013), but similar research on impediments specific to botanical products
appears to be lacking. In a web search using the search term, “botanical product clinical
impediments”, over 482,000 results listed on January 17, 2016, were purported to be
relevant, but a review of the first 100 items were relatively non-specific; most identified
no specific impediments but rather alluded to the importance of doing more study of the
products, outlined FDA’s requirements for botanical trials, or noted the problems of
quality regarding botanical products. In addition, more than 100 papers listed in the
reference list or used for this research were reviewed to identify specific areas of
challenge for clinical trials, and some of the messages from those articles are identified as
quotes below. Some of these papers refer tangentially to impediments of various types;
most talked about the problems of product quality. However, it was not possible from
those sources to construct a clear, systematic picture of the relative importance of these
different types of hurdles and constraints. Nevertheless, it was possible to group the

57
hurdles mentioned in some papers and expert reviews in order to construct a framework
for the development of a survey to explore different types of hurdles more systematically.
From this analysis, all of the hurdles that were present in papers that were reviewed in
detail could be grouped into 4 principal themes (Figure 2).
Figure 2: Factors Impeding Clinical Trial:

2.10.1 Resource Demands
It is both difficult and expensive to establish the efficacy of herbal medicines in
prototypical clinical trials. A number of articles that were reviewed pointed to the fact
that dietary supplement companies typically do not have the financial resources and
scientific capabilities to carry out such demanding clinical trials. This challenge is
identified by Yeung and colleagues:

58
There are many problems associated with botanicals research, however.
These include procuring the study agents, selecting appropriate study
method and clinical trial design, navigating through regulatory obstacles,
and obtaining funding” (Yeung, Gubili, & Cassileth, 2008).
Resource constraints would also include the capability to carry out such trials
using the staffing present in the company, both in terms of numbers and competence.
Otherwise the company must be able to support the costs of outsourcing the trial to a
competent third-party like a clinical research organization. The resource capabilities
overlap to some degree with other sectors to be explored. For example, part of the
resource base is having the adequate capability to supply high-quality test products
(overlapping with product development) and knowing the regulatory requirements that
must eventually be met by the trial (overlapping with regulatory requirements).
Botanical dietary supplements, as compared with nutritional supplements
or single-component pharmaceutical drugs, are typically less-refined
preparations derived from bulk plant material and, as such, require a
modified approach to their development, production, and evaluation. An
integrated, multidisciplinary team of scientific and clinical investigators is
required in order to develop high quality phytomedicines and rigorously
evaluate their safety and efficacy.” (Piersen et al., 2004)
2.10.2 Regulatory Hurdles
Regulatory hurdles associated with clinical testing of botanicals were numerous,
and included the challenges of having the infrastructure to make submissions, including
electronic submissions, and the people with expertise in requirements and benchmarks
who are also able to discuss confidently the company’s needs and direction with the
FDA. This section overlaps with others as well. For example, an important part of a
clinical trial submission is providing a suitable description of the test articles and the
development of the CMC section of the IND. Some aspects of concern included the need

59
to validate analytical test methods for the botanical constituents, to conduct valid
toxicological testing and to design acceptable and meaningful clinical protocols.
FDA's guidance on botanical drugs removed some hurdles from the IND
process because botanicals have history of use in humans, but the
guidance did not ease the NDA process (NPI, 2012).
The current regulatory state of affairs regarding herbal medicines is sub-
optimal as it fails to spur rigorous research and development efforts into
herbal medicines. Due to the unfavorable regulatory climate, few U.S.
companies are engaged in developing drug products from herbal
medicines (Li, 2002).
Some authors have argued that the usefulness of the regulations themselves have not been
critically assessed and thus might be unnecessarily onerous.
One reason may be that regulations are often added as a reaction to
“something bad” happening, either to a participant or to a trial as a
whole. Such regulations are rarely evaluated to ensure that they are
having their intended effects rather than merely imposing additional
burdens (Fost & Levine, 2007).
Kramer and colleagues suggested a number of additional impediments related to
patient protection such as rules for the protection of human subjects and patient privacy.
Challenges are also associated with the need in some industry-sponsored trials to work
with multiple Institutional Review Boards (IRBs) and to respect restrictions related to
company policies (Kramer, Smith, & Califf, 2012). These all can slow trials down, cause
confusion, and create undue burdens when attempting to conduct appropriately controlled
clinical trials with meaningful endpoints. For example, the U.S. Health Insurance
Portability Accountability Act (HIPAA) requires a patient’s authorization to use health
related information for research unless IRB grants a waiver (Armitage et al., 2008). One
unintended consequence of HIPAA has been reported to be increased patients drop outs;

60
these dropped patients subsequently are not followed up and thus may not allow a
complete picture of long-term outcomes, such as survival and nonfatal myocardial
infraction (Fleming, 2011). Despite efforts by the Institute of Medicine (IOM) and the
National Cancer Institute (NCI) to develop standard contractual agreements and forms
between sponsors and research institutes, impediments to clinical trials persist due to the
concerns of investigators to avoid legal risk as reported by Kramer and colleagues
(Kramer et al., 2012).
Finally, the fact that multiple regulatory agencies can have jurisdiction over a
multicenter clinical trial has been reported to impede the conduct and efficiency of
clinical trial. Although efforts are being made to harmonize clinical trial standards, even
between the two most aligned constituencies, there are still differences in areas such as
adverse event reporting.
In such a setting, sponsors must adopt the most restrictive set of
regulations among participating countries; however, simply sorting out
requirements for a single trial can be logistically prohibitive. Although the
principles informing ICH GCP are reasonable, varied regional
interpretations regarding GCP implementation can be dauntingly complex
(Kramer et al., 2012).
A uniform research policy in herbal medicine is need of the hour. The
legal status of herbal ingredients varies from country to country (Kumar,
Mishra, & Gupta, 2010).
2.10.3 Product Development Challenges
Product development challenges remain a third impediment. Characterizing the
botanical product of interest through development of acceptable biomarkers and other
product standards and then assuring the consistency and stability products from batch to

61
batch for the duration of clinical trials are issues that have been repeatedly identified, as
discussed earlier in this chapter.
Nowadays, there is enormous requirement of safe and effective drugs in
the world. This has prompted scientists to revert back towards natural
resources as a potential source of therapeutics for treatment and
management of such chronic and fatal diseases. However, there are
certain serious challenges and limitations in this field including scale up
and commercialization of active compounds which allow only one in
thousand lead molecules to be developed as drug. (Sharma & Gupta,
2015)
Research on botanicals involves unique challenges as plant source
materials frequently vary in chemical content and may contain unwanted
pesticides, heavy metals, contaminant plant species, or other adulterants.
Ideally, a botanical formulation should be standardized, both chemically
and biologically, by a combination of analytical techniques and bioassays.
(Piersen et al., 2004)
Botanicals are an important new pharmacological strategy, which are
potentially exploitable in the oncological area but are characterized by a
number of problems still unresolved. Content variation of products is one
of the primary problems with botanicals and, consequently, there is a
concern about the therapeutic consistency in marketed batches.
(Fimognari et al., 2012)
2.10.4 Market Factors and Constrains
The competitive landscape defining the market for botanical drugs and
supplements are also identified by many as a key obstacle in pursuing a drug designation
for a botanical. The relative simplicity of the dietary supplement pathway reduces
substantially the up-front costs of entering the market by this route. Further, difficulties
of assuring patent protection for a product that has already a history of use and significant
publicly disclosed prior art would make it difficult to price products much above those of
competitors who have not done clinical trials. Without patent protection, the product

62
could easily be developed as a generic competitor by other manufacturers. This would
make it very difficult to recover the R&D expenditures invested in the clinical trials.
If patent protection for a traditional knowledge “invention” has been
sought, that protection can be contested…in that the invention is not novel
or inventive/innovative. Usually, a commercial advantage for an
“unprotectable” traditional phytotherapy product or phytotherapy is
established or enjoyed by way of a trade secret (insofar as this is possible)
or brand recognition (Ramzan, 2015).
The importance of these areas of challenge was also highlighted by an NIH
Botanical Research Expert Panel meeting in 2013 that identified a number of areas of
concern that could be fit under this umbrella, as indicated by the following excerpts from
its expert summary.
Efficacy studies need to be built upon strong biological hypotheses
developed through improved methodological approaches…Assessing the
chemical and biological properties of complex botanical dietary
supplements is a far more difficult challenge than that of a “single
chemical” entity drug (NIH, 2013).
Support the training of the next generation of investigators prepared to
lead and conduct interdisciplinary research on botanicals [is needed].
New methods or standards are needed to facilitate chemical
characterization and improve the identification of possible biological
action and relevant interactions (NIH, 2013).
In the research conducted here, questions were posed regarding the nature and
degree of impediments in these different categories. Also explored were whether other
constraints exist that are not captured by this framework or by the literature reviewed to
date. Of particular interest is the degree to which each type of impediment is a principal
factor affecting decisions to pursue clinical research

63
CHAPTER 3. METHODOLOGY
3.1 Introduction
The research has two parts, a detailed literature review, presented in chapter 2 and
not discussed further here, and an exploratory research survey. This exploratory study
used an on-line survey, to understand the views of individuals in companies that deal
with botanical products who are the most direct stakeholders in the conduct or outcome
of clinical research on botanicals.
3.2 Development of the Initial Survey
Questions for the survey instrument were developed based on the information obtained
from the literature review, discussion with dietary supplement professionals specified
above, and discussion with the research thesis committee from the USC International
Center for Regulatory Science. A few questions were moved, a descriptive one was
added, and many were refined for clarity during the Focus Group discussion. The survey
instrument focused primarily on four key areas based on the framework proposed in
chapter 2 that included a) resource demands, b) regulatory hurdles, c) product
development challenges, and d) market constraints. The survey was constructed using a
combination of closed/open formats such as “yes/no”, “choose one”, “scaled”, “rank-
order” and “open-ended” questions. Text boxes were provided to obtain further detailed
opinions that might not be captured by simple questions offering standardized choices.
Information from open text questions was examined closely for potential new
impediments not found in literature.

64
3.3 Focus Group
A focus group comprised of 9 individuals with different backgrounds in
academia, dietary supplement companies, and trade professional organizations was
convened on March 17, 2016 to review and provide appropriate feedback on the first
survey draft (appendix A). Three individuals participated via WebEx, and six were
present at the meeting.
The focus group assembled for 90 minutes. The goal of Focus Group was to
add/delete, clarify and optimize the questions posed in the survey. I moderated the Focus
Group. The Focus Group also suggested the expansion of the target population for the
survey to individuals consulting with companies in the target field. The results of Focus
Group were documented and incorporated into the first draft (appendix A) of the survey.
A final survey is provided in appendix B. To obtain the broadest set of responses possible
from qualified candidates, the respondent pool was not restricted to firms producing,
selling or distributing finished products, but also included companies that supply raw
materials to dietary supplement manufacturer or who manage manufacturing supply
chain. Consultants, law firms and academia working in the dietary supplement field,
were also included to get the broadest set of opinions.
3.4 Selection of Respondents
The targets for this survey were individuals currently or previously holding
positions in regulatory affairs, quality, sales, marketing and clinical research in
companies that manufacture, sell or distribute dietary supplements products. Consultants

65
including attorneys and academics who currently or previously worked with dietary
supplements companies were included in response to the suggestions of the focus group.
Respondents who met the inclusion criteria were identified from past and current
professional contacts and networks, and from social networking groups such as LinkedIn.
Individuals likely to be appropriate respondents often participate in professional
associations and industry meetings including but not limited to: Quality Leadership
Networks (QLN) food group, Orange County Regulatory Affairs (OCRA) meetings,
United State Pharmacopeial (USP) bi-annual food ingredients adulteration conference,
NIH-Dietary Supplement Practicum workshop, Council for Responsible Nutrition (CRN)
meetings, The Food and Drug Law Institute (FDLI) working groups, UCLA Resnick
Food and Law and Policy Symposia, The American Botanical Council (ABC), The
American Herbal Product Association (AHPA) meetings and International Conference
for the Science of Botanical (ICSB) held together with American Society of
Pharmacognosy meeting (ASP), where majority of academic research on botanical
products reference here presented along with policy makers and FDA Dietary
Supplement Office staff members. Some individuals were approached in person at
industry meeting and conferences, particularly the ICSB/ASP conference in April 2016,
after they expressed interest in the eventual results of the survey. Others were contacted
by email or telephone, to identify if they would be willing to participate in the survey. A
snowball technique in which interested respondents are encouraged to nominate other
participants was also useful to add additional respondents in order to expand the survey
population beyond immediate professional contacts.

66
3.5 Survey Delivery
Once the necessary changes were implemented, the survey was disseminated to
participants via the web-based survey platform, Qualtrics (http://www.qualtrics.com).
The target number of participants was 80, drawn from a pool of about 300 respondents to
which the survey was sent. Some participants were contacted by email prior to sending
the email link, to confirm their interest in participating.
The final version of the 33 questions survey titled “establishing clinical efficacy of
botanical products” was distributed on March 26, 2016 using the Qualtrics Mailer
function that managed email distribution by sending a unique survey link to each
participant. Included in the email was a short message to introduce the survey. An opt-
out link was provided in the email, a typical practice to reduce the likelihood that email
security software would block the email as SPAM. Survey participation was anonymous
and respondents were not to be recompensed for their time. Instead, I offered to email a
copy of the survey results upon completion of my dissertation submission and upon
request. If the respondents did not complete the survey within the allotted time frame of
four weeks, two staged reminders were sent via email weekly. As time went by and 50
new qualified participants were identified, a new panel was created and the survey link
was disseminated to the new participants, followed by more reminders and a thank you
note for their time and efforts. Further personal follow-up was needed in some cases to
encourage participation. At the end of the survey, each respondent was asked if he/she is
willing to participate in a 15-minute, informal phone interview. Regardless of response, a
final thank you email was sent to all participants. Results of the survey was collected and
stored electronically. The survey was open for 6 weeks, during the first 2 weeks 40

67
participants completed the survey. A reminder increased the responses to 45. A second
panel of additional 50 participants which was subsequently identified through referral and
recruitment at ICSB conference as described earlier were added which increased the
responses to 60 by week 4. Another reminder to all who have not taken the survey, or
have started but not completed the survey, was sent which increased the responses to 80
by week 5, a final reminder along with a thank you note was send to all 292 participants
prior to closing the survey on May 8, 2016 with 88 total responses were obtained in 6
weeks’ time. A breakdown of the results are as follows: 292 respondents received the
survey, 145 (50%) opened the survey, 99 (34%) started the survey and 88 (30%)
completed the survey. In spite of reminders some 11 participants who started the survey
did not complete it. A final 30% rate of completion (88/292) was recorded for my
survey.
3.6 Survey Analysis
The survey responses were analyzed as a population. It was sub-stratified to see
if differences are present amongst different groups of respondents (e.g., dietary
supplements manufacturers/distributors vs. marketing vs. regulatory and clinical research
professionals). Answers to categorical data is graphed, but only limited statistical
analysis is applied because the numbers are small for all but the most obvious
observations such as median and range. Continuous data was examined and where
appropriate averaged or analyzed with T-tests if two groups were to be compared. When
cross-tabulations were run to differentiate answers of different subgroups of respondents,
chi-square analysis was used to guide the identification of the few places where responses

68
seemed to show some degree of difference. However, the numbers for such analysis are
too small to be confident in the statistical validity of this non-parametric test, so the raw
data are instead shown where such comparisons are made.

69
CHAPTER 4. RESULTS
4.1 Results of the Focus Group
The draft survey tool was critiqued by the focus group prior to its dissemination.
Participants provided several ideas to improve the survey. They suggested that the survey
be expanded to include respondents in broader range of job functions beyond regulatory
affairs, sales and marketing and quality functions. This led me to include academics,
consultants and research investigators currently conducting or overseeing clinical
research on behalf of dietary supplement industry. In the latter category, I attempted to
include individuals working in Contract Research Organizations (CROs) who often run
clinical trials for dietary supplement industry clients. A few respondents were also
obtained by approaching qualified individuals in law firms and trade associations
representing the supplement industry.
Simplifications and modifications of subsequent questions were also suggested to
reduce the granularity of the Likert scale-type questions from 7-point to 5-point scales; to
add a “Cannot comment” and “N/A” option to some of the questions; and to rearrange the
order of the questions to improve flow. None of the participants expressed concern that
the survey exhibited bias or failed to address the research topic in sufficient detail. Most
focus group participants also provided written comments on pre-distributed hard copies.
Their comments and corrections were incorporated into the final version. A draft and
final version of the survey are included in Appendix A and B respectively. The focus
group also shared their views on methods to ensure sufficient participants in the survey.
One focus group member, for example, provided the name and contact information of

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former FDA employee with extensive supplement experience who would likely be
willing to participate in a phone interview.
4.2 Analysis of Survey Results
A total of 292 surveys were sent to potential participants. Half of the participants
opened the survey (145/292) within the first two weeks. Over one third of participants
(99/292) started the survey and most (89%; 88/292) completed the survey, equating to a
response rate of approximately 30%. Figure 3 shows the response rate for each of the 33
questions answered by 88 respondents. Twenty-seven (27) of 33 questions were
answered by all 88 respondents. Questions that were not answered by all respondents
were descriptive answers in text boxes. Question number 11 (15%) asked respondents to
identify other challenges not mentioned in the survey and question 18 (23%) solicited
views on impediments to the conduct of clinical trials. Questions 26 (68%) and 27 (56%)
allowed respondents to describe current challenges of botanical drug development, and
the rationale and future direction of botanical safety and efficacy trials respectively. A
more detailed summary of responses to the descriptive survey questions can be found in
Appendix C.

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Figure 3: Response Rate to Survey Questions

0 20 40 60 80 100 120
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Response Rate (%), n=88
Question Number

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4.3 Respondent Characteristic
The three figures that follow (Figures 4-6) illustrate demographic information
about the size and nature of the company’s commercial activities and the corporate level,
function, background of the participants. Respondents can be seen to come
predominately from companies that manufacture and/or distribute finished DS (55/125;
44%) or raw DS ingredients (29/125; 22%). Some respondents chose more than one
category to represent their company’s product offerings, as reflected in the fact that a
total of 125 responses were collected from 85 respondents. A small proportion of
respondents worked in academic and research institutions (17/125; 14%) or as
consultants (10/125; 8% ). Fourteen respondents (14/125; 11%) self-identified as
“other”, and defined their function as attorney representing the industry; dietary
supplement trade association staff and members; former policy makers; consumer
advocates; and freelance writers covering the dietary supplement industry. Nutritional
product lines were produced by the largest share of companies (41/141; 29%) but
botanical finished products (33/141; 23%) was second largest. Vitamin and minerals
(25/141; 18%), botanical raw materials (24/141; 17%), and “other” product types
(18/141; 13%) were also represented. Because the respondents could select more than
one option, the number of collected responses outnumbered the numbers of respondents.

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Figure 4: Industry Profile
More than one answer was offered by the same companies, as reflected in the fact
that 125 and 141 responses were collected from 85 respondents in A and B respectively.

A: “Which industry best describes your most recent employer or client? Please check all
that apply.” Dietary Supplement abbreviated – DS; Ingredients abbreviated – Ing

Number of Respondents

B: “Which category best represents the product assortment of your most recent
employer? Please check all that apply.”

Number of Respondents

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Respondents were distributed quite evenly across companies of different sizes. A
slightly higher proportion (33/85; 39%) worked for larger companies with more than
1000 employees than for small companies with fewer than 50 employees (28/85; 33%).
About one third of respondents were in companies offering 50 products or more (26/85;
31%), whereas a similar proportion (27/85, 32%) had no commercialized products. This
category would include for example, consultants, representatives of trade associations,
and academics. The remaining respondents worked for companies with small-sized
(12/85; 14%) or intermediate-sized product portfolios (12/85; 14%). A few respondents
(4/85; 5%) did not know the number of products offered by their respective employers.
Figure 5: Indicators of Company Size
A: “How many people currently work for your most recent employer or client?”, n=85

Number of Respondents

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B: “How many dietary supplement products does your company sell in the U.S. market?”
n=85

Number of Respondents

Respondents were employed in research and development (30/85; 35%),
regulatory affairs (13/85; 15%), sales and marketing (11/85; 13%), clinical research
(9/85; 11%) or quality (6/85; 7%). About one-fifth described their jobs as “Other”
(16/85; 19%), defined variously as management, consulting and legal representation by
some, but without further explanation by others. The job levels of respondents varied
widely. Most respondents had positions as the Director (23/84; 27%) or CEO/President
(16/84; 19%), but Associates (12/84; 14%), Managers (11/84; 13%) and Vice Presidents
(10/84; 12%) each also represented more than 10% of the respondents. A few
respondents described their levels as group leader (4/84; 5%) or “Other” (8/84; 10%).
These “other” categories included consultants, academics, trade associations and lawyers.

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Figure 6: Specializations of Respondents
A: “Which occupational category best describes your most recent employment?”, n=85

Number of Respondents

B: “Which job level best describes your corporate role?” n=84

Number of Respondents

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4.4 Factors Impeding Clinical Trials
4.4.1 Financial Hurdles
Respondents were asked to identify the relative importance of impediments of
different types on their conduct of clinical trials as suggested by the 4-element framework
on which this work has been structured. Most commonly respondents identified financial
resources as the main challenge that restricted the conduct of clinical trials on botanical
products (39/85; 46%). Regulatory hurdles, product development challenges and market
competition were rated most commonly as moderately to slightly challenging (Figure 7).

Figure 7: Overview of Clinical Trial Challenges
“How would you rate the impediments posed in the following areas when conducting
clinical trial on botanical products?.” n=85

Number of Respondents

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In order to capture areas impeding conduct of clinical trials other than those
suggested by the 4-element framework guiding the survey, respondents were offered a
descriptive “Other” option. The comments of respondents identified issues related to
internal alignment, clinical outcome measures and sourcing of raw materials:
In a large company like ours, the greatest challenge with respect to
conducting clinical trials is the inability to achieve internal alignment
between departments and among executives on exactly what it is we want
to accomplish with studies and what is the priority of this activity. There
are a number of other challenges, but these can be overcome if there is
internal alignment.
A dietary supplement is not targeting any disease, it is targeting
supplementing the missing components, which can enhance the health
conditions for a normal human population. So there are many factors need
to be considered, and there is no clinical symptom can be included in the
trial. It sole based on the current science and determined by statistical
analysis. So the scope of clinical trial of dietary supplement is critical to
succeed.
Most clinical trial outcomes are usually based on some type of pathology
or related outcome that may allow a regulator to interpret such outcomes
as a disease-related outcome and not a substantiation of a proposed s/f
claim.
It is difficult to develop a clinical study robust enough to support a
marketing claim strong enough to justify the added cost and product
concepts developed by marketing groups often contain claims that cannot
be legally made in the USA, even in the presence of clinical data to
support the claim. So the product may test favorably in a consumer study,
but if the claim language has to be modified, this can change the success
of the product on the market.
____________________________________________________________
Assurances of the source of botanical raw material is one impediments to
conducting proper clinical trial.
When constraints to clinical trials were ranked in another way, by offering six
options that might be important to facilitate the conduct of clinical trials directed at new

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drug development, the availability of financial support from other sources such as grants
(66/85; 78%) and biomarker validation (65/85; 76%) were ranked as important or very
important (numbers represent both important or very important summed) (Figure 8).
Other factors deemed to be relevant included changes in the current regulatory landscape
to facilitate conducting clinical trials for botanical products (66/85; 78%): training needs
(65/85; 76%), increased consumer demand for botanical drugs (64/85, 75%), and market
protection from competition (63/85; 74%).

Figure 8: Company Clinical Trial Challenges
“How important do you think that the following improvements would be in determining
whether companies with botanical products would conduct clinical trials to support new
product development?” n=85

Number of Respondents

To explore constraints further, respondents were asked to rank in degree of
importance, from very important to slightly important, about a broader array of
challenges that might make their companies reluctant to undertake clinical trials (Figure

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9). The factor considered to be most important appeared to be related to costs of
conducting clinical trials (“too expensive” 45/62; 73%). Responses for the other choices
were more mixed, but 4 options were still considered very important to moderately
important by the majority of respondents. These included: the need for statistical proof
of efficacy (24/58; 41%); lack of validated biomarkers (22/50; 44%); lack of botanical
standardization (20/51; 39%); and lack of a regulatory mandate requiring such trials to
establish efficacy (17/46; 37%).
Figure 9: Company Clinical Trial Challenges
“My company would be reluctant to undertake clinical trials to establish botanical
product efficacy because…: ”

Number of Respondents

4.4.2 Regulatory Hurdles
To explore in more detail the role of regulatory impediments, respondents were
first questioned about their degree of familiarity with common regulations and guidance
documents including the Food Drug and Cosmetic Act – FD&CA, the Nutritional

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Labeling and Education Act – NLEA, the Dietary Supplement Health and Education Act
– DSHEA, the New Dietary Ingredient notification process – NDI, the term Generally
Recognized as Safe – GRAS, the Investigational New Drug application– IND process,
the Over the Counter Drug monograph – OTC and the New Drug Application – NDA
process. The majority of respondents were “very familiar” with GRAS (61/84; 73%)
followed by DSHEA (54/84; 64%), and FD&CA (42/84; 49%). They were less familiar
with the IND, NDA and OTC regulations (Figure 10).
Figure 10: Familiarity of Respondents with Regulatory Areas of Focus
“Please indicate your level of familiarity with the following legal instruments/concepts”.
n=84

Number of Responses

Claims are an important aspect of regulatory strategy for dietary supplement
companies to convey the health giving effect of nutritional products. Respondents were
asked about the types of claims made by their company or client when marketing their

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supplements. Most respondents who answered this question reported that their companies
used nutrient content claims (53/62, 85%) and structure function claims (48/62, 77%) for
marketing purposes. Health claims were used less frequently (27/62; 44%), and disease
prevention claims were used rarely (2/62; 3%). The fact that companies used a mix of
claims is reflected in the total of 130 responses from 62 respondents.
Figure 11: Regulatory Claims Used by Supplement Companies
“Please indicate whether your company or client makes any of the following claims on
the label of dietary supplement products. Please check all that apply”. n=130

Number of Respondents
When asked if their company was considering clinical trials to prove product
efficacy, a majority (55/66; 83%) identified that their companies had considered and/or
planned clinical trials to establish efficacy of botanical products (Figure 12). However,
most of those who identified that they had carried out such trials identified that the goal
of those trials was to support health claims (41/66; 62%) rather than new drug claims

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(15/66; 22%). Notably a small group of respondents worked in companies where clinical
trials had not been considered as a way to establish efficacy of botanical products (11/66;
17%).
Figure 12: Implementation of Clinical Trials for Different Marketing Aims
“How engaged has your company been in considering to conduct clinical trials for
efficacy on a botanical product?” n=66

Number of Respondents
When asked about the suitability of regulations governing dietary supplements,
one third of respondents (29/85; 34%) believed that dietary supplements with health
claims are currently regulated appropriately, whereas a slightly smaller number (25/85;
29%) believed that health claims should be allowed only after FDA or a third-party has
established efficacy through arm’s length clinical trials, and an even smaller number of
respondents (15/85 18%) believed that dietary supplements with health claims should be
regulated as drugs. In contrast, a minority (12/85; 14%) expressed the view that health

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claims supported by existing literature should be allowed without FDA prior
authorization.
Figure 13: Appropriateness of Regulations
“A dietary supplement (DS) category has been created under DSHEA to supplement the
diet. Health Claims (HC) describe a relationship between a dietary supplement ingredient
and a reduction in risk of a disease or health-related condition. Which statement below
regarding dietary supplements with health claims best describes your view on this issue?”
n=85

To examine the Dietary Supplement Health Education Act further, respondents
were asked to provide their views on the appropriateness of DSHEA. A narrow majority
of respondents (46/83; 55%) believed that dietary supplements are currently regulated
appropriately, whereas a quarter (21/83; 25%) believed DSHEA is not sufficient as is,
and (16/83; 19%) believed that DSHEA is “okay” but needs to be modified. The
modification of DSHEA regulations is examined in later questions.

Number of Respondents

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Figure 14: Appropriateness of Regulations
“Do you think the current DSHEA is appropriate to regulate botanical dietary
supplements?” n=83

Number of Respondents

Respondents were given the opportunity to expand on their views in an open text
option. Some respondents who stated that DSHEA is not sufficient to regulate
supplements expanded their views by saying:
No proof of efficacy
Heterogeneous preparations, no specific model for highly purified
flavonoids versus whole food fruit pulp
There are too many products out there to be managed
Not enough clarity
No pre market regulations

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When respondents stated that DSHEA is “OK, but need to be modified”, the following
statements were made:
Market exclusivity for NDIs and products with approved health claims
To include quality, safety, efficacy requirements
Should be regulated and labeled the same way as food
Ability to make substantiated claims
Structure function claims are too vague, non-specific. These limitations
lead to all supplements making the same claims, whether or not they
deliver clinical studied doses or have been studied independently.

Respondents were further asked about elements that might be introduced to
improve the acceptability of a regulatory submission of safety or efficacy as part of
DSHEA (Figure 15). Amongst the most agreed-upon preferences were market
exclusivity (52/84; 62%), IP protection (50/84; 60%), and coverage by insurance (44/84;
52%). Respondents more commonly agreed than disagreed about the usefulness of
product reimbursement under insurance plans (40/84; 48%) and price protections (34/84;
40%). For all of the choices at least 10% of the respondents selected “do not know” and
one respondent added a comment:

If DSHEA were modified to include submission of regulatory dossier for
safety and/or efficacy substantiation, the industry would follow suit
because it would then be law.

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Figure 15: Appropriateness of Regulations
“If DSHEA were modified to include a submission of regulatory dossier for safety and/or
efficacy substantiation, which of the following would encourage the industry to follow
suit?” n=84

Number of Respondents

Pharmaceutical products have two regulatory routes to market, either through new
drug applications, or, for over-the-counter drugs, through adherence to a monograph.
Most respondents appeared to favor the monograph route as the preferential route (Figure
16); about half (35/67; 52%) selected “Somewhat agree” and an additional one third
(21/67; 31%) selected “Strongly agree”. Fewer than 10%, (6/67) selected “disagree
moderately” and “strongly disagree” when those two groups are combined.

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Figure 16: Regulatory Overview Modification
“I think that monograph requirements rather than a New Drug Application (NDA)
process would be more appropriate for botanical products.” n=67

Number of Respondents

4.4.3 Market Constrain
Market considerations also appear to play an important role in decisions to
conduct a clinical trial. When presented with a number of potential incentives,
respondents appeared to view the introduction of market exclusivity via patent protection
for tested botanical products as the most compelling option (47/156; 30%); while less
burdensome clinical trial rules (36/156; 23%) followed. Another market-associated
factor that might motivate supplement companies to conduct clinical trials was insurance
reimbursement of tested botanical products (29/156; 19%). Fewer respondents seemed to
feel that insufficient motivation by itself would be provided by the development of
monograph requirements (21/156; 13%), or the implementation of a process similar to
that for New Dietary Ingredient notification (17/156; 11%).

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Figure 17: Market Incentives
“Would any one of the following changes, made in isolation, be sufficient to cause you to
consider to undertake clinical trials? Please check all that apply”. n=156

Number of Respondents

Dietary supplement companies often lack resources to conduct clinical trials.
Respondents were therefore asked whether they would consider sharing the cost and
potential benefit of such endeavors with another similar company. Respondents favoring
such sharing (definitely yes plus probably yes, 27/60; 45%), were more frequent than
those with “no” answers (definitely no plus probably no 16/60; 27%).

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Figure 18: Company Clinical Trial Motivation
“Would your company /client consider sharing the cost of conducting a clinical
trial on a potential botanical product with a similar company, provided both parties
benefit from positive outcomes proportionally?” n=60

Number of Respondents
The absence of insurance coverage for botanical supplements appears to be an
issue as well. Over half of respondents (47/84; 56%) believe that botanical products with
health claims should have insurance coverage, and more than one-quarter had the even
stronger view that insurance coverage should extend to all marketed products (24/84;
29%). Less than 10% (7/84) disagreed that insurance coverage should be available for all
marketed supplements.

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Figure 19: Cost Coverage by Insurance
“Do you agree/disagree that botanical products prescribed by a physician should be
covered by health insurance as most drugs are?” n=84

Number of Respondents

4.4.4 Product Development Challenges
To understand product development impediments, participants were asked to rate
the difficulty of several requirements related to chemical characterization and
qualification. Areas of inquiry included the standardization of tested products, ability to
validate analytical methods, ability to assess purity and potency, ability to assure shelf
life and stability, and ability to find validated biomarkers (Figure 20). All five aspects of
botanical development were identified to be at least moderately difficult by most
respondents. From this list, “the selection and validation of appropriate biomarkers” was
viewed to be most difficult (24/85; 28%) whereas the ability to assure shelf-life and

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stability over the clinical trial period seemed to be easiest to achieve (29/85; 34%). One
respondent stated:
Finding an appropriate biomarker is almost impossible since plant
extracts contain a wide arrays of bioactive compounds.
Figure 20: Product Development Challenges Rated by Importance
“If your company decided to conduct a clinical trial, how difficult do you think that the
following aspects of botanical development would be?” n=85

Number of Respondents

An open text question asked, “If you are currently conducting clinical trial of a
botanical product, what do you consider to be your biggest problem?”
From the 20 participants (23%), who elaborated in detail, one respondent wrote:

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Greatest challenge is lack of internal alignment on the objective of studies
and the priority. After that, next challenge in studying botanical products
in clinical trials is what actual test material to use (composition) and what
that is to be based on. Botanical preparations vary widely, and which
specific preparation(s) to test is often not clear. How a company goes
about determining this can be challenging as the literature tends to be
incomplete when it comes to reporting the actual composition and
characteristics of the test materials used.
Other respondents wrote:
Cost of the clinical trial due to study population selection. Most
biomarkers used in the clinical trial are originally developed by disease
treatment or determination. Because of this, it is very difficult to measure
the level of biomarker change in healthy population. In order to achieve
this, a large sample size is needed and this can increase the cost of trial
significantly.
Showing efficacy within a reasonable timeline and budget, and there is a
lack of appropriate study design to showcase long term health promoting
supplements.
Research preparation standardization and inter subject variability
(gene/phenotype variances)
Investment not being IP protected
Finding participants and recruitments
4.4.5 Views on Cross-Topic and Additional Impediments
Although some of the views of respondents were quite easily sequestered according to
the four elements composing the governing framework used to base the survey, some
questions integrated different elements for comparison in a single question, or asked
about other types of impediments recognized by respondents. For example, Figure 21
shows the results of a question that explored the likelihood that various types of
incentives would motivate the conduct of clinical trials. The most common incentive,

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measured by combining “Very likely” and “Likely” options, was patent protection for
tested products (57/65; 88%) followed by FDA market exclusivity (54/65; 83%) and the
support of collaborative NIH activities (53/66; 75%). Availability of grants to pursue
New Drug development efforts (42/64; 66%), was seen to be more important than having
a generic drug process for tested botanical products (31/62; 50%).
Figure 21: Comparative views on Incentives
“Would your company/client consider conducting clinical trials on a botanical product if”

Number of Respondents

The importance of patent protection was again highlighted in a different question
that asked about the degree to which various factors would affect the decision to conduct
clinical trials. The most commonly selected hurdle from a list of 5 options was the lack
of IP protection (49/70; 70%). Lack of consumer interest in obtaining botanicals as drugs
rather than supplements garnered the same level of agreement as the challenge of pricing

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products at a higher value to cover development costs (45/70; 64%). Lack of insurance
coverage and lack of monograph standards (20/70; 30%) were equally scored as
significant hurdles by less than a third of respondents.
Figure 22: Market-oriented impediments to clinical trials
“Please indicate the degree to which you feel the following factors would affect your
decision to pursue conducting clinical trial on botanical products?” n=70

Number of Respondents
A series of open-text questions were asked to allow respondents to provide a more
descriptive option to express their views. When asked, “Why do you think out of 200
clinical trials currently conducted on botanical products little reach NDA stage”, 60
participents (68%) provided answers that were mostly grouped into 3 main themes. A
sampling of these answers is shown below, and the remainder are in Appendix C.
4.4.5.1 Concerns about repositioning supplements as drugs

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Dietary supplements are not drugs, therefore it is not appropriate to file
for an NDA on a product that is not a drug. To do so would prevent a
supplement company like ours to continue selling the product. It is
counterproductive. We conduct clinical trials on our products in order to
confirm the efficacy and safety of the products and to differentiate our
products from competitors, but we are still limited to the same generic
structure/function claims as every other company, ‘supports healthy
cognition in already healthy people' for example.
The NDA process is not clear to provide sufficient ROI
Because companies don't want to sell supplements as drugs. This would
limit accessibility.” “Supplement means for prevention, not for treatment,
so the potency is generally lower and less effective than drug. Because of
this, the cost of clinical trial will not be cheap. There are usually more
than one active ingredient in the dietary supplement so it is more
challenge to standardize the product. The cost of developing herbal drug
is not much different than developing a new drug and most dietary
supplement company may not have sufficient resources for doing this.”,
“lack of market protection”, “too expensive
4.4.5.2 Cost of clinical trials
Clinical study expense & poor clinical study design.
Costs. NDA stage enters ingredient into the drug sector, with much more
stringent regulations and associated costs involved. By limiting to dietary
ingredient and limited how claims are presented, there is a quicker return
on investment (ROI).
Lack of exclusivity Uncertain regulatory path Cost Lack of knowledge
concerning effect/sample size.
The clinical trials are too expensive and take too long to complete.
The hurdle for approval as a drug is too high.
Cost of running a trial. My clients do not have interest in marketing
products as drugs.

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It costs too much; the studies are inconclusive or negative; it takes too
long; DSHEA with some clever claim formulation permits an end run
since many consumers probably already associate certain supplements
with health effects.
4.4.5.3 Challenges of Patentability.
In the U.S. by definition dietary supplements are not drugs. If a ‘natural’
chemical or compound were to be developed as a drug, it would be
difficult to get it patented. A ‘use patent’ or “process patent’ may be
possible, but it is difficult to patent a naturally occurring compound.
The trials are started for marketing purposes. Stating to the public that a
product is under IND status is a selling point to the uneducated public.
Additionally, the burden of accumulating necessary data/evidence that the
clinical trials are appropriate to move to application status is too great.
That, coupled with the inability to receive a patent or exclusivity makes
moving to application for a license, either an NDA or BLA, pointless. If
you receive a license, everyone currently or in the future can now sell said
product and make the same claims without the cost of the regulatory path.
lack of market protection.
In a similar type of question, respondents were asked, “What are the main
impediments to conducting clinical trial at your company?”, Some comments from the 49
participents (56%) who elaborated in detail are included below, and the others are in
Appendix C:
Cost and concern on return of investment.
Cost. Why bother if you can state the "active" ingredient is already under
IND status.
The main impediments are knowledge of chemistry, manufacturing and
controls for a botanical product. A consistent source of supply and
fulfilling release criteria are big challenges. Assay development for
stability could be tricky. The other is to establish the regulatory strategy.
Costs, IP protection issues.

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Cost, time and lack of understanding of regulatory processes.
Cost, and to a lesser extent, time to develop.
Cost of clinical trials, ROI risk, and risk that a production will be deemed
an IND that can no longer be marketed as a supplement.” “Acceptance of
results vs return to company.
products are not a single ingredient. pharmacokinetics are not known
therefore difficult to suggest regimen. The variability of the effect is great,
product has very limited demonstrable measurable effects on testable end
points. stability unknown.
Showing efficacy within a reasonable timeline and budget, and there is a
lack of appropriate study design to showcase long term health promoting
supplements.
Protection of intellectual property rights to research. We do the research,
everyone else sells their product based upon our research.
Competitors borrow the information for their own product. Competitors
do not invest time or their own money to further the development of good
quality products.
Logistical coordination of all of the aspects of collecting data, biomarkers,
and analyses.
When asked “If DSHEA were to be modified to include submission of a
regulatory dossier for safety and/or efficacy substantiation, what would encourage the
industry to follow suit?”, two individuals provided answers:
If DSHEA were modified to include submission of regulatory dossier for
safety and/or efficacy substantiation, the industry would follow suit
because it would then be law.
Mandatory pre-market approval
When asked if botanical products should be held to the same standard as
pharmaceutical products with respect to clinical evidence of safety and efficacy, a

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majority (52/79; 66%) disagreed (Figure 23). However, most agreed that the current
regulatory environment encourages product adulteration (42/73; 57%), and that botanical
products, currently a subset of food, should be held to the same standards of food
regulation under NLEA (40/78; 51%). About half (37/78; 47%) also believed that
regulations associated with the current DSHEA are sufficient.

Figure 23: Appropriateness of Regulations
“Dietary Supplement Health Education Act – DSHEA does not require proof of safety
and efficacy for dietary supplements to be submitted to FDA prior to marketing. Please
indicate your level of agreement or disagreement with the following statements regarding
Botanical Products (BPs)” n=78

Number of Respondents
Respondents were asked about the regulatory framework under which Botanical
Products (BPs) carrying Health Claims (HC) should be governed (Figure 24) below.
Interestingly, a majority (47/70; 67%) agreed with the idea that a new monograph system
should be developed for botanical products with health claims. Leaving botanical

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products with health claims under DSHEA ranked as a second choice (45/68; 66%), with
regulating supplements without HC under NLEA (33/61; 54%) as a third. Lastly,
developing new regulations for botanical products carrying health claim was not a path
favored by most respondents (42/69; 60%).
Figure 24: Appropriateness of path to regulate botanical products
“In the U.S., OTC drugs are marketed by using a monograph or obtaining an approved
NDA. Do you agree or disagree with the following statement regarding the path to
regulate botanical products?”

Number of Respondents
Respondents were asked which of governing body would be most suitable to
oversee dietary supplements. The majority of respondents (45/84; 54%) agreed that
botanical products with health claims should remain under CFSAN. When asked
whether botanical products should be regulated as botanical drugs once efficacy is
established for a specific disease indication, more respondents (46/83; 55%) disagreed
than agreed. Furthermore, half of respondents (40/81; 50%) also disagreed with the idea

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of moving efficacious botanical products under the Division of Nonprescription Drug
Products - DNPD. Remaining options of either creating a new division to oversee
supplements or developing a New Dietary Ingredient process were spread quite evenly
across “agree”, “neither agree nor disagree” and “disagree” choices (Figure 25).

Figure 25: Appropriateness of Governing Body for Dietary Supplements
“In the U.S., botanical products are regulated under Center of Food Safety and Applied
Nutrition (CFSAN). Some manufacturers make health claims and/or structure-function
claims. Do you agree or disagree with the following statements?”

Number of Respondents

Finally, respondents were asked to give their views on the usefulness of certain
regulatory guidance documents and educational materials. The guidance describing Good
Manufacturing Practices – GMP (FDA, 2010) was found to be most useful (52/84; 62%),
followed by the Adverse Event Reporting document (FDA, 2014b) (31/84; 37%) and
Analytical Procedures and Method Validation guidance (FDA, 2000) (30/84; 36%). The

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bioavailability and bioequivalence studies guidance (FDA, 2003) (23/84; 27%), and last
Botanical Drug Products guidance (FDA, 2004) (18/84; 21%) were chosen as least useful
among guidance documents examined below.

Figure 26: Usefulness of Regulatory Guidance Documents
“Which of the FDA "Guidance for Industry" documents do you find most useful ?” n=84

Number of Respondents

4.5 Cross Tabulations
4.5.1 Response Differences Between Different Type of Individuals and Companies
In this study advantage was taken of the cross-tabulation capabilities of the
Qualtrics platform to examine whether individuals in different job categories or from
companies of different sizes would have different views on some of the issues with which
they were presented. Typically, little difference could be discerned when the responses
of individuals in different job categories were compared. Perhaps the question that
elicited the biggest difference is that shown in Figure 27 that asked about how the
respondent felt regarding the way that dietary products with health claims should be

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regulated. Even in this question, differences were subtle, but those in regulatory and
clinical jobs functions tended to favor current regulations or regulations as a drug,
whereas those in other departments tended to favor establishment of claims by using
existing literature or arm’s length clinical trials.
Figure 27: Differences between responses to questions from individuals in different
job categories
“A dietary supplement category has been created under DSHEA to supplement the diet.
Health claims describe a relationship between a dietary supplement ingredient and a
reduction on risk of a disease or health-related condition. Which statement below
regarding dietary supplements with health claims best describes your view on this issue?”

A comparison of responses from individuals in companies of different sizes also
suggested that company size did not greatly change the patterns of responses. One set of
questions that seemed to produce the greatest are shown below, but it is apparent that
responses of the smallest and largest companies had similar patterns of distribution.

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Figure 28: Differences between responses for individuals from companies of
different sizes
“If DSHEA were modified to include submission of a regulatory dossier for safety and/or
efficacy substantiation, which of the following would encourage the industry to follow
suit?”

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CHAPTER 5. DISCUSSION
5.1 Introduction
Dietary supplement regulations have created an uneasy compromise between
foods that are created for nourishment and drugs that are designed for disease prevention.
The creation of a “dietary supplement” category represented a departure from 1938
FD&C Act that blurred the line between foods and drugs. In the work presented here, the
often conflicting range of views on how to handle such products underlines the
complexity of the issues that have been created and the heterogeneity of this stakeholder
group. What follows is, first, a consideration of some of the delimitations and limitations
that should be kept in mind when considering the findings of this research. The results
themselves are then considered in light of previously available research, and their
implications for policy development are discussed.
5.2 Consideration of the Research Methodology
5.2.1 Adequacy of Chosen Framework
An important tool for exploring the research questions in this study was the use of
survey methods to capture the views of industry professionals knowledgeable about the
current regulatory and market environment for dietary supplement products. A good
survey often relies on the use of a conceptual framework so that empirical information
can be used more effectively to explore questions or test a hypothesis systemically
(Cunningham et al., 2015). In this study, a 4-element framework derived from
comprehensive literature search appeared to capture most of the concerns that were
identified in the literature of chapter 2. That these areas were significant was supported
by the findings that those same areas of concern appeared to be typical for the

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respondents in this study. When respondents were asked in open-text fields about other
types of concerns that might not have been explored fully, relatively few responses
pointed to issues that did not relate in some way to the areas covered by the framework.
Issues that did not fall under the areas suggested by the framework appeared to concern
management and organizational issues that also could also hinder clinical trials.
Particular issues included the inability to achieve internal executive alignment, to
converge on specific goals for the clinical research, and to agree on desired outcomes for
the research. Thus, organizational alignment might be another element to be added to the
framework.
5.2.2 Selection of Survey Sample
Identifying a suitable subset of respondents to represent a population of interest is
important to the success of a survey. Since this survey was directed at experts in
regulatory and marketing aspects of the U.S. dietary supplement industry, I had to find an
identifiable sample that corresponded closely enough to that target population to be
considered its surrogate (Rea & Parker, 2014). Originally, the respondent pool was
delimited to include only regulatory affairs, sales, marketing, and quality professionals
currently or previously working in companies that manufacture or distribute dietary
supplement products or ingredients in the United States. These job functions were
considered to be important because these individuals are most likely to understand and
appreciate the challenges of dietary supplement regulations. Focus group members
further suggested that the pool might usefully be broadened to include individuals in roles
that closely interact with dietary supplement professionals. A concern with broadening
the sample is its potential to smear the response patterns by mixing subpopulations with

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different viewpoints. However, to explore whether the views of individuals in different
job functions were similar, cross tabulations were carried out to see if differences could
be discerned between the answers of individuals in different job functions. The fact that
the responses of individuals in different job functions appeared similar when cross-
tabulated with various questions of interest suggested that the broader sampling did not
confound the results to any great extent. In fact, it may have strengthened the survey by
bringing together a broader representation of views from different subgroups of
professionals who are affected by these regulations, and work closely with dietary
supplement professionals or have a vested interest in the outcome of supplement
regulations. Their inclusion might help to increase representativeness and minimize
systematic omission or bias (Beebe et al., 2010; Rea & Parker, 2014).
5.2.3 Engagement of Survey Participants
An appropriately constructed survey must also be capable of providing results
from a reasonable and representative number of respondents within an acceptable period
of time. The use of the web-based tool, Qualtrics, allowed me to send the survey
simultaneously to a large panel of recipients. Compared to traditional paper-based
approaches, this web-based method had the added benefits of relatively low cost, high
convenience and greater speed. However, web-based surveys can have low response
rates (Cunningham et al., 2015). Thus, one concern when disseminating this survey was
whether the response rate would be high enough to justify a reasonable level of validity.
Survey response rates can be as low as 6% to a high of 75% (McMillan &
Sheehan, 1999). Thus, the response rate of 30% achieved here is not out of line with the

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rates of engagement identified by many other researchers in the health care field. For
example, Cunningham and colleagues conducted a web based survey of physicians and
concluded that an overall survey response rate of 35% was acceptable; however, response
rates varied by specialty (Cunningham et al., 2015). Further, response rates to e-mail
surveys are not stable over time. For example, Sheehan examined response rates in 31
email surveys in a range of disciplines between 1986 and 2000, and related those rates to
5 variables (year study was taken, number of survey questions, number of pre-notification
contacts, number of follow-up contacts, topic salience). He found that the year in which
the study was taken had the greatest effect on response rate (Sheehan, 2001). In the last
few years sampled by that study, between 1997 and 2000, response rates between 20-
35% were typical (Cunningham et al., 2015). The response rates of about 30% in this
study thus appear reasonable compared to those of others who have used web-based
methods.
Sheehan (2001) also pointed to the importance of pre-notification and follow-up
contacts in affecting survey response rates. Nevertheless, views regarding the usefulness
of pre-notification emails vary. Survey pre-notification has been reported to increase the
speed of recruiting respondents (Kaplowitz, 2004). However, repeated contact might be
regarded as an unsolicited and unwelcome intrusion unless the respondent already knows
the researcher (Rea & Parker, 2014). In this study, engaging the respondents in a pre-
survey conversation regarding the topic of the survey and obtaining their agreement to
participate appeared to increase the number of responses. Nevertheless, a number of
potential respondents failed to open the survey, for reasons that were difficult to assess.
One factor might stem from concerns that proprietary information about the product-

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development views of a company might become available to competitors. That concern
was real for at least one participant in the survey who started the survey but didn’t
complete it, and requested to be removed from the list (personal communication).
In this study much attention was paid to assuring that respondents were reminded
about responding to the survey. Post-notification emails slightly increased the response
rate each time a reminder was sent, as has been previously reported by others (Xie & Ho,
2013). It is not clear why some individuals failed to respond to those requests, despite
additional reminders. However, the individuals to whom the survey was directed are
known to have multiple conflicting time demands and are expected to prioritize activities
in order to satisfy job-related activities in a fast-paced industry. An external survey may
not be seen to be high on that priority list. This concern has been repeatedly voiced
elsewhere as a primary reason for low response rates (Romano, Sardella, & Alboni,
2016).
5.2.4 Survey Length and Construction
A final factor that has been repeatedly identified as a factor that may affect survey
participation is survey length. The views of our focus group appeared to be aligned with
the findings of Tomaskovic and colleagues (Tomaskovic, Leiter, & Thompson, 1999)
who concluded that a long survey discourages participants from finishing a survey. Thus,
care was taken to constrain survey length to 33 questions. In the present study, survey
length did not appear to be an important factor in respondent engagement according to
the findings that almost everyone who started the survey answered the questions through
to the end.

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5.2.5 Other Delimitations, Limitations and Assumptions
The extent to which we can give credence to the research results presented here
depends upon recognizing certain assumptions that were made prior to conducting the
research. In this study, we assumed that the recruited participants would be particularly
familiar with Dietary Supplement Health and Education Act - DSHEA and Nutritional
Labeling and Education Act - NLEA because these regulations are central to their
professional activities. If a respondent did not have a good understanding of these basic
regulations, he or she might give less accurate answers or even fail to respond to some
questions. This might contribute to non –response bias (Cohen, Rohde, & Yu, 2013). It
is therefore significant that most respondents indicated that they were knowledgeable
about these Acts. Another assumption that should be acknowledged is the assumption
that respondents would answer the questions honestly and without bias. It was clearly
not feasible to gauge the extent to which the answers of respondents represented their
own personal opinions, or whether they were expressed on behalf of their company
whose point of view the respondents felt obliged to reflect. Finally, this research did not
attempt to collect the options of the professionals outside United States. Because the
study was limited to the regulation of dietary supplements in the U.S., and did not seek
respondents of outside of DSHEA coverage, the views that were expressed might differ
from those in companies in other jurisdictions who might be importing into U.S.
5.3 Impediments to Conducting Clinical Trial in the U.S.
5.3.1 Clinical Trials Hurdles
Results of this study suggest that botanical product companies face several
hurdles, as might have been expected from the views captured by the literature review in

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chapter 2. What was not so clear from chapter 2 was the varying importance of these
hurdles. It is therefore important from a policy viewpoint to understand the biggest
challenges in these different areas if any headway is to be made in the development of
botanically-based drugs.
5.3.2 Financial and Market Constrains
Even though the framework in this study attempted to tease apart financial and
market-related hurdles as different elements for study, it was clear that they were
interrelated. Results from the survey appeared to confirm previously identified concerns
that the business model underlying drug development poses a huge challenge. Financial
hurdles by themselves appeared to be important, as might be expected given the very
high costs of completing a trial package appropriate to convert a dietary supplement to an
approvable drug. The Tufts Center for Drug Development Studies has previously
estimated that the average pre-tax cost of developing a drug is $2,558 million (DiMasi,
2014). Within this envelope, estimates for clinical trial costs to develop a single drug vary
widely according to indication, but numbers identified in the past 10 years all seem to
exceed millions of dollars (Hill & Rang, 2013). An attempt to expand on these costs was
published recently in Eastern Research Group-ERG report prepared for Health and
Human Services Secretary (Sertkaya, Birkenbach, Berlind, & Eyraud, 2014). That report
identified the highest average per-study costs across all phases to be pain and anesthesia
trials ($71.3 million) followed by ophthalmology ($49.9 million) and anti-infective
($41.3 million trials. Trials in dermatology, endocrinology, and gastroenterology had the
lowest overall costs across the same three phases. The factors that contributed most to
costs across all trial phases included clinical procedure costs (15 to 22 percent),

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administrative staff costs (11 to 29 percent), site monitoring costs (9 to 14 percent), site
retention costs (9 to 16 percent), and central laboratory costs (4 to 12 percent). Lengthy
timelines of clinical trials and difficulties in recruiting and retaining participants also
imposed costs in terms of resource allocation and business risk (Sertkaya et al., 2014).
The financial challenges associated with high clinical trial costs seem to be well-
recognized by respondents. About half of the respondents believed that financial
constraints impede botanical research and most agreed that financial support through
grants would enhance company’s ability to undertake botanical trials. Nevertheless, the
dietary supplement industry is relatively profitable (Bradley, 2015a), with sales reaching
to $37 billion in January 2015. Thus, it is likely that the only problem is not simply
finding money for trials. Rather it seemed clear that some of the strongest concerns
related to the difficulties of recouping the clinical trial investments. If there were to be a
path for monetizing those investments after the product came to market, it is likely that
some companies would find the investments more appealing. However, respondents
expressed the view that such investments cannot be recovered in the present market
environment because botanical drug sales cannot be adequately sheltered from
competition by dietary supplements based on the same products.
Are there any ways that these barriers can be overcome? To recoup the research
investment, the two most common tools identified by others are intellectual property
protection and the granting of some alternative form of market exclusivity by FDA
(Gallini & Scotchmer, 2002). These two elements are well-known to promote drug
innovation in the pharmaceutical industry. Patents allow recovery of expensive drug-

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development costs by protecting the new drug from competing generic products for 20
years from time that the patent was granted (FDA, 2014a). Market exclusivity offers a
related type of protection, by providing additional periods during which FDA does not
review and approve similar products for a set period of time, to reward the innovation
undertaken by branded drug developer (FDA, 2014a). Not surprisingly, then, the
incentives most favored by the majority of respondents were found to be related to
market exclusivity (62%) and IP protection (60%). It was also clear that most
respondents did not see a clear path if no such protections were to be offered.
The question arises, however, whether changes in the current rules governing
either patent protection or exclusivity would be possible to achieve. It is problematic to
protect natural products using patents for two reasons. First, to patent a product, it is
necessary that some aspect of the product be novel. Although it may be possible to
patent a novel manufacturing process or novel use of the product for a particular clinical
application, it is typically not possible to patent the chemical entity itself, since the
botanical has often been in known use for decades (Cardellina, 2002). Second, even if a
patent were to be obtained, enforcement of the patent becomes an issue, as discussed by
others (Gupta, 2004; Sharma & Gupta, 2015). It has been argued that many patents that
are filed and approved are worth nothing if infringement cannot be enforced (Grubb,
2012). For example, a recent clinical trial of wild berries has shown that the product can
improve memory and cognitive function (Krikorian et al., 2010). However, even if its
use were to be patented, nothing at the present time prevents a competitor producing a
similar berry extract for which it might claim a generic health and wellness claim related
to cognitive function on its label. Under current DSHEA regulations a safe harbor is

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offered for generic claims of brain wellness without safety or efficacy review (Meer &
Misner, 2005). This problem was apparent to respondents who suggested that no one
company would be likely to establish clinical efficacy if all other competitors could profit
from the investments of that company.
Market exclusivity was favored by a majority of respondents as a useful tool that
might incentivize clinical trials of botanicals. Current rules for drugs already allow
market exclusivity for a new product (FDA, 2014a). However, the rules for market
exclusivity applied to botanical drugs might suffer from the same limitation as that
discussed above for patent protection. Competitors could still work around the
exclusivity clause with general wellness claims unless FDA and the law courts were
prepared to enforce the exclusivity by vigorously pursuing any such competition.
Nevertheless, if more protection on the clinical investment were to be offered, this survey
suggests that more companies might be more willing to consider the conduct of clinical
trials with the goal of developing marketable botanical drugs. The current regulatory
process is not conducive to conduct of clinical trials for two reasons already discussed.
There is no protection offered nor a path to recoup the clinical investment apparent.
If it is politically too difficult or unsatisfactory to change the current
IP/exclusivity landscape, it may be necessary to look for other solutions to circumvent the
burden that developing an NDA would pose for a single company. One interesting
alternative is to develop a path for botanical drugs as over-the counter products with
relevant monographs. It was surprising that a majority (80%) of respondents appeared to
believe that a monograph process would be a more appropriate way to treat botanical
drug products than entering them into commerce by way of the NDA route. Such an

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approach has not been discussed in the literature as a way forward to motivate increased
development of botanical drugs. However, its appeal might be apparent when
considering the advantages of a monograph process. It would offer an established
unambiguous set of criteria to evaluate products making the same drug claims but
supplied from different companies (FDA, 2015d). Its requirements are relatively easy to
meet, and it would avoid the need for a drug submission prior to marketing, since OTC
products that meet monograph requirements do not have to gain premarket approval. As
suggested by Seiguer and Smith (Seiguer & Smith, 2005), industry likes to have clear
rules and guidance that remove the vagaries of variable interpretations. Further, given
that most of the botanical products have a relatively strong history of safe use and have
been purchased over the counter for a long time, the need for a full drug submission to
establish a risk profile seems harder to defend.
What is not so apparent if the monograph model were to be pursued is how the
information needed to substantiate the monograph would be developed. The monograph
development process as it currently stands was established to evaluate the safety and
effectiveness of OTC drug products marketed in the United States before May 11, 1972.
It has a three-phase public rulemaking process; each phase requires a Federal Register
publication and an opportunity for public discussion. The outcome of the process is the
set of standards and boundaries on an OTC therapeutic drug class (FDA, 2015d). These
“monographs” establish conditions under which certain OTC drug products are generally
recognized as safe and effective. Products containing active ingredients or indications
that are not covered by the monograph require an approved New Drug Application for
marketing.

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Such an approach would require a very different set of activities and players
because it would be necessary for some party to conduct the trials needed to establish the
background data to support the monograph. Some ideas about who that responsible party
might be could perhaps be gleaned from the opinions of respondents in this survey, who
had a range of views about the group that should establish the data to base efficacy
claims. One third of respondents felt that health claims should be allowed only after
FDA or a third party agency, such as NIH, has established efficacy through arm’s length
clinical trials. These views suggest one option- that at least some of the safety and
efficacy evidence to base a monograph should come from publicly funded activities
rather than the work of a company. Such suggestions would seem to have merit.
Botanical products are now widely used by the public, so that research into such products
could be argued to be in the public interest. Publicly funded research would allow all
companies and society to benefit from the outcomes of that research. However, such a
bank of publicly available data seems a long way off. A recent search in PubMed for
published botanical monographs indicates that only a handful of botanical monographs
exist for individual plant species (Holstein, 2015), and a systematic effort to provide the
data for monograph development is not evident.
Although the U.S. does not have a botanical monograph system, such approaches
do exist in other countries., most notably the EU. According to Qu and colleagues, there
are 109 herbal medicine monographs in European Community (Qu et al., 2014). Further
ideas about how to develop a botanical monograph system could come from that previous
European experience. There, a herbal monograph (formerly known as Community herbal
monograph) is evaluated by The Committee on Herbal Medicinal Products (HMPC), one

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of EMA’s subcommittees. The monograph contains the HMPC's scientific opinion on
safety and efficacy data about an herbal substance and its preparations intended for
medicinal use (HMPC, 2016). The HMPC evaluates all available information, including
non-clinical and clinical data, but also documented long-standing use and experience in
the EU. The monographs provide all information necessary for the use of a medicinal
product containing a specific herbal substance or preparation. Article 16a (1) (d), of
Directive 2004/24/EC currently requires a 15-year period of use in the EU Community as
a proof for safety. For some botanicals, such a history should not be difficult to establish.
For others, access to scientific data to support the safety of the product may be a possible
solution to overcome the hurdle presented by the normal requirement that such products
show a long history of safe medicinal use in the community (Qu et al., 2014). In the EU,
some herbal monographs fall into a category of “traditional” use that is based on
“plausible efficacy”. This category may also provide a potential alternative way to
advance the use of herbal medicines.
The efforts to develop monograph standards would have an additional benefit
seen to be important to survey respondents here, specifically the need to reduce product
adulteration that can be a particular challenge for developing drugs of all kinds. The
types of research needed to establish a monograph would increase knowledge about good
candidates to be developed as qualified markers and good analytic methods to assess the
quality of the botanical ingredients for all manufacturers. Because OTC products would
be governed by stricter quality requirements suitable for drugs rather than dietary
supplements (reflected in 21CFR 210-211 versus 21CFR 111), an OTC path would also
increase the height of the barrier to entry for unscrupulous botanical manufacturers.

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The development of monographs might be one of a few different ways in which
better cooperation between the public and private sector might contribute to better
knowledge of botanical therapeutics. Another step in the direction of cooperation is seen
in recent attempts to develop a library of authenticated Chinese medicine in the U.S.
(Eisenberg et al., 2011). Similar approaches have had some success across the border
where therapeutic effects of Mexican medicinal botanical products have been detailed in
a publicly available database created by a joint effort between government institutions
and the private sector (Lozoya, 1994).
A more aggressive set of joint activities would be the development of efficacy
studies through collaborations between companies and governmental research entities,
such as NIH. Government support through grants or other forms of assistance could
encourage supplement companies with manufacturing facilities based in the U.S. to
consider undertaking research to establish efficacy claims and share data more publicly.
Further, the involvement of governmental or academic groups with no financial interest
would increase public confidence in the results, if they were to be positive. Such
collaborations have not been common in the U.S. If they were to take place, the most
likely government agency to promote such collaboration might be the Office of Dietary
Supplements Program at the FDA (FDA, 2015b), where beginning efforts in this
direction can be recognized. For example, the Office of Dietary Supplements Program
(ODSP) could collaborate with the NIH- Centers for Advancing Research on Botanical
and Other Natural Products (CARBON) Program (NIH, 2015), whose purpose is to
promote collaborative, transdisciplinary research on the safety, effectiveness, and
mechanisms of action of botanical dietary supplements with strong potential to benefit

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human health. The primary research of these Centers is focused on preclinical research
that will inform future clinical studies (NCCIH, 2015; NIH, 2016). Clinical development
of these botanical products would seem to be a logical step to take place in collaborations
with private companies interested in pursuing a specific target indication, similar to the
pharmaceutical model. Such a model might well be popular with industry. In this
survey, a majority of respondents seemed to feel that collaboration with research
institution such as NIH to validate clinical data was an attractive idea.
5.3.3 Regulatory Hurdles
Challenges from a financial and market viewpoint appear in the view of the
respondents to be compounded by concerns about regulatory requirements and
restrictions. In this arena, respondents expressed opinions that were somewhat
unexpected. Their views on the use of an OTC route rather than an NDA process to
develop monographs have already been discussed. Other interesting findings were the
often mixed views on DSHEA as an instrument to govern botanical products. Most
respondents agreed that CFSAN should remain the governing body for dietary
supplements, but about half appeared to favor the rules associated with NLEA rather than
DSHEA as a vehicle to regulate those supplements. It is not clear what prompted dietary
supplement professionals to express a preference for NLEA over DSHEA. NLEA
mandates that manufacturers of foods ensure safety and wholesomeness of food products
prior to marketing, and to do this the regulations often impose stricter requirements.
Under NLEA, for example, FDA has authority to recall a product that it deems unsafe for
human consumption (U.S.-101st-Congress, 1990). Under DSHEA (U.S.-103rd-
Congress, 1994), however, FDA has to prove beyond reasonable doubt that the

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supplement is harmful to consumers before it is removed from the marketplace (FDA,
1994). DSHEA requirements that FDA prove that a product is unsafe therefore put the
burden of proof on FDA and make it much more difficult to remove products from the
market (Cohen, 2012a, 2014; GAO, 2009b; Wallace, 2015)
Another observation that was somewhat unexpected was related to the often
pessimistic views of respondents about the degree to which DSHEA could assure public
health. We might expect that consumers and public interest groups would be critical of
DSHEA to assure supplement safety. Consumers are spooked by incidents such as the
high profile case in which the NY Attorney General’s office accused four major
supplement retailers (GNC, Target, Walgreens and Walmart) on February 3
rd
, 2015 of
selling fraudulent and potentially dangerous herbal supplements, demanding that they
remove such products from their shelves (Schneiderman, 2015). DNA tests found that
some store brand supplements did not contain the ingredients as advertised (Wang, 2015).
However, in this study, the impression was gained that industry respondents were also
concerned. This impression was supported by the findings that a majority (57%) of
industry respondents also felt that DSHEA regulations encourage adulteration of dietary
supplements, and less than half believed that DSHEA offers more consumer access.
Although the traditional pharmaceutical risk assessment model may not be applicable to
dietary supplements (Cohen, 2012a, 2012b), some enhanced form of public protection
from adulteration and misuse seems to be supported by many respondents. One approach
might be that advocated by Kapoor and Sharfstein, that has been called an “access with
safety” approach. In this approach, they suggest that the focus of product management
should be on safety, by implementing a number of measures. These include:

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Registration of all dietary supplements to permit easier enforcement
against rough products, a stronger disclaimer explaining the limited role
of FDA in evaluating structure/function product claims, the establishment
of standard laboratory techniques for characterization of products, and
more clear authority for the agency when safety concerns arise…(Kapoor
& Sharfstein, 2016).
Concerns about product safety reiterate some of the views expressed by several
presenters at the 16
th
Annual Oxford International Conference on the Science of
Botanicals (ICSB) earlier this year (ICSB, 2016a). For example, one presenter offered a
report on supplement industry initiatives to enhance botanical GMPs and supplier quality
in light of elaborate and intentional adulteration schemes of overseas manufacturers
whose supplements are being imported into the U.S. (ICSB, 2016b). At the same time, it
must also be acknowledged that other respondents in this study did not recognize a need
for more rigorous regulations and oversight. Rather, they suggested that a better
enforcement scheme, rather than an increase in regulation, might serve the industry more
effectively. That such an approach is also regarded as important by government is clear
from presentations from the FDA-Office of Dietary Supplement Program at the ICSB
meeting. Their future priorities included such initiatives as protecting the public health,
ensuring the integrity of product identity, publication of new NDI guidance and
enforcement of GMP compliance in order to combat adulteration of supplements (ICSB,
2016c).
The degree of familiarity of respondents with different regulations related to
product quality was also interesting to explore because the results can inform educators
and trainers about areas in which more training might be helpful. The fact that most
respondents were familiar with GRAS might be expected, because the self-affirmed

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GRAS process is a common regulatory pathway to self-compliance and might be
expected to be used by a large proportion of companies for at least some botanical
products. Familiarity with DSHEA was higher than with NLEA, which in turn was
higher than familiarity with OTC regulations. The lower familiarity with OTC
regulations is interesting, given that many expressed support for the option of using an
OTC pathway as a route to commercialization as discussed above. Respondents were
also found to be less familiar with IND and NDA regulations. Perhaps this unfamiliarity
is understandable if most manufacturers have not attempted to pursue clinical trials or
drug commercialization.
5.3.4 Product Development Constraints
A final element of the framework used to guide the research here was concerned
with impediments associated with product development. This element would include
limitations on the ability to produce a botanical with sufficient purity, consistency and
specificity to be used comparably for clinical studies in different patients or different
sites. The challenges of quality have been discussed previously as posing particular
problems for botanicals (Pan et al., 2014; Zhang et al., 2012). Researchers like Schilter
and colleagues have additionally discussed the type of research data that would be needed
to guide the safe use of botanical ingredients, and offered advice on the development of
risk assessment strategies consistent with due diligence under existing food regulations
(Schilter et al., 2003). Product specifications, composition and characterization of
standardized and authentic materials, and documented history of previous use are
discussed as challenges for product development efforts. Respondents in this study
appeared to share the concerns of those previous authors; challenges associated with

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identifying and standardizing suitable biomarkers and developing analytical methods to
validate those standards were noted by respondents to hinder botanical developmental
efforts. The concerns of scientists and respondents here are also shared by governmental
agencies. Improving these capabilities has been a focus for research directed both by the
FDA, Office of Dietary Supplements Program-ODSP (FDA, 2015b) and the National
Institutes Health, Office of Dietary Supplements-ODS (NIH, 2015). Perhaps the most
specific of those initiatives is the Dietary Supplement Analytical Methods and Reference
Materials Program (AMRM), that was established in 2002. This program is responsible
for the development and dissemination of reliable analytical methods and reference
materials and for outreach efforts to improve analysis of dietary supplements and nutrient
biomarkers (NIH, 2002). Other options for research funding and private partnerships also
exist at various levels. For example, eight academic research centers associated with
NIH currently work on collaborative efforts focused on promoting the safety and
effectiveness of botanical products that have a high potential to benefit human health
under its 5-year Strategic Plan of 2015-2020 (NIH, 2016). These Centers aim to identify
and characterize botanicals according to the bioavailability and bioactivity of their
chemical components, and explore their mechanisms of action through pre-clinical and
clinical activities. A full accounting of those initiatives is beyond the scope of this
dissertation, but much more information can be found in documents describing the
CARBON program (see for example, (NCCIH, 2015; NIH, 2015, 2016).
The characterization and validation of biomarkers suitable for clinical use is
perhaps the most obvious opportunity for industry and research institutions to work

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together. Khan argues that many botanical research studies cannot be considered as
scientifically valid unless the tested product has been authenticated and characterized in
order to ensure consistency of product tested over time (Khan, 2006). Clinical studies
may state that they used standardized material, but often that standardization has simply
been determined with an analytical test. Although chemical standardization is important,
its utility is limited for botanical products because the starting material may not be well-
characterized botanically (Khan, 2006).
5.3.5 Inter-Company Alignment
Most of the concerns identified by respondents and discussed above have already
been mentioned at least anecdotally in the previous literature, but another type of
constraint had not been so obvious. This concerns the internal decision-making processes
of management at dietary supplement companies. Respondents drew attention to the
difficulties of achieving internal alignment between departments and among executives
on exactly what it is to be accomplished when a development strategy is created. The
challenges inherent in prioritizing clinical projects, clarifying objectives in each area of
interest, and anticipating potentially unclear or negative outcomes can create an
environment that fuels internal conflicts among divisions. Perhaps the absence of
attention to this potential hurdle in the literature is not surprising; most of the work
published previously that was related to the challenges of botanical drug development has
been written by individuals concerned about the scientific hurdles. The papers were often
authored by individuals who either had an academic role or whose position in business
required that they protect internal company practices and activities that would be
considered proprietary, embarrassing or confidential. However, it adds one more area of

125
challenge to a development path already faced with other important impediments, any
one of which could be used by executives to question clinical testing of botanical
products already in their portfolio.
Figure 29: Intercompany alignment

Internal Alignment
Regulatory
Hurdles
Product
Development
Challenges
Market
Constraints
Resource
Demands

126
CHAPTER 6. CONCLUSION
In December, 2015, FDA created the Office of Dietary Supplement Programs
(ODSP), elevating the program from its previous status as a division under the Office of
Nutrition Labeling and Dietary Supplements (FDA, 2015b). This new initiative would
seem to be a step in the right direction to recognize botanicals as important health-related
products. To date, however, the major goal of this office appears to be directed at the
removal of problematic supplements from the marketplace rather than the proactive
development of research programs to establish an understanding of product efficacy. The
detailed structure of this new office and the identification of its priorities remain to be
announced, so that it is not clear if this Office might also become a conduit for changes
that could help compliant products become drug products. Certainly, such governmental
activities seem to be important if the richness of botanical products are to be developed
into medicines. Results here strongly suggest that the current regulatory system is not
well-constructed to motivate supplement companies to take botanicals through the
expensive regulatory path to NDA submission. They further suggest that such
development will not progress effectively unless the incentive structure is changed
through modifications of IP protection or market exclusivity. Even if that were to be
possible, the incentives would remain weak because of the way that supplements are
marketed currently; under DSHEA most botanical products can be placed on the market
with claims that imply health giving effects without substantiation of efficacy. Thus,
many companies may not see a justification for the additional work.

127
Botanical products have been part of the human diet for centuries. They have been
widely used in other countries as a source of medicine, where the various national
authorities have taken different routes to establish a regulatory path to manage their
commercialization (Miroddi, Mannucci, Mancari, Navarra, & Calapai, 2013). Unless and
until we see a great increase in consumer demand for safer and more efficacious
supplements in the U.S., no regulatory changes are likely to occur. This work would
suggest that policymakers and the public should not expect that industry will be the place
in which clinical trials for botanical efficacy will occur in this environment. However,
advancements in the science might be motivated by developing an intermediate way of
introducing botanicals as drugs, such as the use of the existing monograph system

128
REFERENCES
Abdel-Rahman, A., Anyangwe, N., Carlacci, L., Casper, S., Danam, R. P., Enongene, E..
Walker, N. J. (2011). The safety and regulation of natural products used as foods
and food ingredients. Toxicol Sci, 123(2), 333-348.
Armitage, J., Souhami, R., Friedman, L., Hilbrich, L., Holland, J., Muhlbaier, L. H., . . .
Van Nie, A. (2008). The impact of privacy and confidentiality laws on the
conduct of clinical trials. Clin Trials, 5(1), 70-74.
Bailey, R. L., Fulgoni, V. L., Keast, D. R., & Dwyer, J. T. (2012). Examination of
vitamin intakes among US adults by dietary supplement use. J Acad Nutr Diet,
112(5), 657-663.e654.
Bailey, R. L., Gahche, J. J., Thomas, P. R., & Dwyer, J. T. (2013). Why US children use
dietary supplements. Pediatr Res, 74(6), 737-741.
Balunas, M. J., & Kinghorn, A. D. (2005). Drug discovery from medicinal plants. Life
Sci, 78(5), 431-441.
Beebe, T. J., Rey, E., Ziegenfuss, J. Y., Jenkins, S., Lackore, K., Talley, N. J., & Locke,
R. G. (2010). Shortening a survey and using alternative forms of prenotification:
impact on response rate and quality. BMC Med Res Methodol, 10, 50.
Bendiner, E. (1985a). Medicine in China. Validating the venerable and investigating the
new. Hosp Pract (Off Ed), 20(6), 7-8.
Bendiner, E. (1985b). Medicine in China. Validating the venerable and investigating the
new. Hosp Pract (Off Ed)Hosp Pract (Off Ed), 20(6), 7-8.

129
Bradley, J. (2015a). The US Supplement Industry is $37 Billion. Nutrition Business
Journal. Retrieved from http://www.nutraingredients-usa.com/Markets/NBJ-The-
US-supplement-industry-is-37-billion-not-12-billion Accessed Oct. 10, 2016
Bradley, J. (2015b). The US Supplement Industry is $37 Billion. Nutrition Business
JournalNutrition Business Journal. Retrieved from http://www.nutraingredients-
usa.com/Markets/NBJ-The-US-supplement-industry-is-37-billion-not-12-billion
Accessed Oct. 10, 2016
Brinker, F. (2004). Coming clean on supplements designated by "Dirty Dozen". AHC
Media. Retrieved from https://www.ahcmedia.com/articles/3071-coming-clean-
on-supplements-designated-the-8216-dirty-dozen-8217 Accessed Oct. 26, 2016
Cardellina, J. H. (2002). Challenges and opportunities confronting the botanical dietary
supplement industry. J Nat Prod, 65(7), 1073-1084.
Chan. (2003). Some aspects of toxic contaminants in herbal medicines. Chemosphere,
52(9), 1361-1371.
Chan, & Critchley, J. A. (1996). Usage and adverse effects of Chinese herbal medicines.
Hum Exp Toxicol, 15(1), 5-12.
Chan, Tan, M., Xin, J., Sudarsanam, S., & Johnson, D. E. (2010). Interactions between
traditional Chinese medicines and Western therapeutics. Curr Opin Drug Discov
Devel, 13(1), 50-65.
Chen, S. T., Dou, J., Temple, R., Agarwal, R., Wu, K. M., & Walker, S. (2008). New
therapies from old medicines. Nat Biotechnol, 26(10), 1077-1083.
Cohen, P. A. (2009). American roulette--contaminated dietary supplements. N Engl J
Med, 361(16), 1523-1525.

130
Cohen, P. A. (2012a). A false sense of security? The U.S. Food and Drug
Administration's framework for evaluating new supplement ingredients. Antioxid
Redox Signal, 16(5), 458-460.
Cohen, P. A. (2012b). DMAA as a dietary supplement ingredient. Arch Intern Med,
172(13), 1038-1039.
Cohen, P. A. (2014). Hazards of hindsight--monitoring the safety of nutritional
supplements. N Engl J Med, 370(14), 1277-1280.
Cohen, P. A., Maller, G., DeSouza, R., & Neal-Kababick, J. (2014). Presence of banned
drugs in dietary supplements following FDA recalls. JAMA, 312(16), 1691-1693.
Cohen, P. A., Rohde, F., & Yu, W. (2013). Building Wave Response Rates in a
Longitudinal Survey. Field Methods, 25(4), 361-387.
Consumer_Reports. (2004). Dangerous supplement still at large. Retrieved from
http://consumersunion.org/pub/0504%20DietarySup.pdf Accessed Oct. 25, 2016
CRN. (2014). The Dietary Supplement Consumer Report. Council for Responsible
Nutrition. Retrieved from http://www.crnusa.org/CRNconsumersurvey/2014/
Accessed Jan. 31, 2016
Cunningham, C. T., Quan, H., Hemmelgarn, B., Noseworthy, T., Beck, C. A., Dixon, E.,
. . . Jetté, N. (2015). Exploring physician specialist response rates to web-based
surveys. BMC Med Res Methodol, 15, 32.
Cuzzolin, L., Zaffani, S., & Benoni, G. (2006). Safety implications regarding use of
phytomedicines. Eur J Clin Pharmacol, 62(1), 37-42.
De Carvalho, L. M., Cohen, P. A., Silva, C. V., Moreira, A. P., Falcão, T. M., Dal Molin,
T. R., . . . Martini, M. (2012). A new approach to determining pharmacologic

131
adulteration of herbal weight loss products. Food Addit Contam, 29(11), 1661-
1667.
De Smet, P. A. (2000). Overview of herbal quality control. Drug Information Journal,
34, 323-327.
Denham, B. E. (2011). Dietary supplements--regulatory issues and implications for
public health. JAMA, 306(4), 428-429.
Dentali, S. J. (2010). Successful botanical research requires botanical expertise. Clin
Pharmacol Ther, 87(2), 149-151.
Dhandapani, R., & Sabna, B. (2008). Phytochemical constituents of some Indian
medicinal plants. Anc Sci Life, 27(4), 1-8.
DiMasi, J. A. (2014). Pharmaceutical R&D performance by firm size: approval success
rates and economic returns. Am J Ther, 21(1), 26-34.
Dodge, T., & Kaufman, A. (2007). What makes consumers think dietary supplements are
safe and effective? The role of disclaimers and FDA approval. Health Psychol,
26(4), 513-517.
Dodge, T., Litt, D., & Kaufman, A. (2011). Influence of the dietary supplement health
and education act on consumer beliefs about the safety and effectiveness of
dietary supplements. J Health Commun, 16(3), 230-244.
Eichner, A. (2015). Adulterated dietary supplements threaten the health and sporting
career of up-and-coming young athletes. Drug Testing and AnalysisDrug Testing
and Analysis: Published online in Wiley Online Library.
Eisenberg, D. M., Harris, E. S., Littlefield, B. A., Cao, S., Craycroft, J. A., Scholten, R., .
. . Clardy, J. (2011). Developing a library of authenticated Traditional Chinese

132
Medicinal (TCM) plants for systematic biological evaluation. Fitoterapia, 82(1),
17-33.
Ernst, E. (2002a). Ayurvedic medicines. Pharmacoepidemiol Drug Saf, 11(6), 455-456.
Ernst, E. (2002b). Spotlight on herbal medicine. Pharmacoepidemiol Drug Saf, 11(7),
585-586.
Ernst, E., & Pittler, M. H. (2002a). Herbal medicine. Med Clin North Am, 86(1), 149-161.
Ernst, E., & Pittler, M. H. (2002b). Risks associated with herbal medicinal products.
Wien Med Wochenschr, 152(7-8), 183-189.
Fan, T. P., Deal, G., Koo, H. L., Rees, D., Sun, H., Chen, S., . . . Chan, K. (2012). Future
development of global regulations of Chinese herbal products. J Ethnopharmacol,
140(3), 568-586.
Farnsworth, N. R., & Mahady, G. B. (2009). Research highlights from the UIC/NIH
Center for Botanical Dietary Supplements Research for Women's Health: Black
cohosh from the field to the clinic. Pharm Biol, 47(8), 755-760.
FDA. (1994). Dietary Supplements Regulations. Guidance for Industry. Retrieved from
http://www.fda.gov/food/dietarysupplements/default.htm Accessed Feb. 4, 2016
FDA. (1996). Good Clinical Practices GCP. Guidance for Industry. Retrieved from
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073122.pdf Accessed
Jan. 3, 2016
FDA. (1997). New Dietary Ingredients Notification Process. Retrieved from
http://www.fda.gov/Food/DietarySupplements/NewDietaryIngredientsNotificatio
nProcess/default.htm Accessed Dec. 25, 2015

133
FDA. (2000). Structure/Function Claims. Retrieved from
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInf
ormation/ucm103340.htm Accessed June 20, 2015
FDA. (2004a). Botanical Drug Products. Guidance for Industry. Retrieved from
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/ucm070491.pdf Accessed Jan. 31, 2016
FDA. (2004b). FDA Prohibits Sales of Dietary Supplements Containing Ephedra.
Retrieved from
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm1082
42.htm Accessed Jan. 31, 2016
FDA. (2010). Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements. Guidance for Industry.
Retrieved from
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInf
ormation/DietarySupplements/ucm238182.htm Accessed Jan. 31, 2016
FDA. (2011). Generally Recognized as Safe. Guidance for Industry. Retrieved from
http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/ Accessed Dec.
25, 2015
FDA. (2014a). Frequently Asked Questions on Patents and Exclusivity. FDA drug
development and approval process. Retrieved from
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079031.htm
Accessed Oct. 3, 2016

134
FDA. (2014b). Qualified Health Claims. Guidance for Industry. Retrieved from
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinform
ation/ucm053832.htm Accessed Jan. 31, 2016
FDA. (2014c). Reporting Serious Adverse Events. Guidance for Industry. Retrieved
from http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm
Accessed Jan. 6, 2015
FDA. (2015a). Current Good Manufacturing Practices For Finished Pharmaceuticals.
Guidance for Industry. Retrieved from
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFR
Part=211 Accessed Jan. 17, 2016
FDA. (2015b). FDA Creates the Office of Dietary Supplement Programs and Announces
New Nutrition Office Leadership. Constituent Updates. Retrieved from
http://www.fda.gov/Food/NewsEvents/ConstituentUpdates/ucm478303.htm
Accessed July 27, 2016
FDA. (2015c). New Drug Application. Guidance for Industry. Retrieved from
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedan
dapproved/approvalapplications/newdrugapplicationnda/default.htm Accessed
Jan. 4, 2016
FDA. (2015d). Over-the-Counter (OTC) Drug Monograph Process. Guidance for
Industry. Retrieved from
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope
dandApproved/ucm317137.htm Accessed August 21, 2016

135
FDA. (2016a). Dietary Supplements: New Dietary Ingredient Notifications and Related
Issues. Draft Guidance for Industry. Retrieved from
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinform
ation/dietarysupplements/ucm257563.htm Accessed Oct. 25, 2016
FDA. (2016b). R Thomas Marketing LLC In Conjunction with Just Enhance LLC Issues
Nationwide Recall of Black Ant, Herb Viagra, Real Skill, Weekend Prince,
African Black Ant And Stree Overlord Along With Multiple Other Products Due
To Undeclared Sildenafil. Retrieved from
http://www.fda.gov/Safety/Recalls/ucm481054.htm Accessed Oct. 19, 2016
FDAVoice. (2016). Making Progress in Protecting Consumers from Unsafe Supplements.
Posted on January 20, 2016 by FDA Voice. Retrieved from
http://blogs.fda.gov/fdavoice/index.php/2016/01/making-progress-in-protecting-
consumers-from-unsafe-
supplements/?source=govdelivery&utm_medium=email&utm_source=govdeliver
y Accessed Jan. 25, 2016
Fimognari, C., Ferruzzi, L., Turrini, E., Carulli, G., Lenzi, M., Hrelia, P., & Cantelli-
Forti, G. (2012). Metabolic and toxicological considerations of botanicals in
anticancer therapy. Expert Opin Drug Metab Toxicol, 8(7), 819-832.
Fleming, T. R. (2011). Addressing missing data in clinical trials. Ann Intern Med, 154(2),
113-117.
Fost, N., & Levine, R. J. (2007). The dysregulation of human subjects research. JAMA,
298(18), 2196-2198.

136
France, K. R., & Bone, P. F. (2005). Policy makers' paradigms and evidence from
consumer interpretation of dietary supplements labels. J. Consum. Aff., 39(27),
27-51.
Gallini, N., & Scotchmer, S. (2002). Intellectual Property, when is it the best incentive
system? In J. L. a. S. Adam B. Jaffe & Stern (Eds.), Innovation Policy and the
Economy (Vol. 2, pp. 51-78). National Bureau of Economic Research: MIT Press.
GAO. (2009a). Dietary Supplements: FDA Should Take Further Actions to Improve
Oversight and Consumer Understanding, U.S. Government Accountability
Office. GAO-09-250;Dietary Supplements: FDA Should Take Further Actions to
Improve Oversight and Consumer Understanding, GAO-09-250;. U.S.
Government Accountability Office. Retrieved from
http://www.gao.gov/products/GAO-09-250 Accessed Jan. 31, 2016
GAO. (2009b). Dietary Supplements: FDA Should Take Further Actions to Improve
Oversight and Consumer Understanding, GAO-09-250;. U.S. Government
Accountability Office. Retrieved from http://www.gao.gov/products/GAO-09-250
Accessed Jan. 31, 2016
GAO. (2010a). Dietary Supplement Safety Act. GAO-S.3002. U.S. Government
Accountability Office. Retrieved from https://www.gpo.gov/fdsys/pkg/BILLS-
111s3002is/pdf/BILLS-111s3002is.pdf Accessed Feb. 4, 2016
GAO. (2010b). Herbal Dietary Supplements: Examples of Deceptive or Questionable
Marketing Practices and Potentially Dangerous Advice.-10-662T. U.S.
Government Accountability Office. Retrieved from
http://www.gao.gov/products/GAO-10-662T Accessed Jan. 31, 2016

137
GAO. (2013a). Dietary Supplements - FDA may have opportunities to expand its use of
reported health problems to oversee products. GAO 13-244. U.S. Government
Accountability Office. Retrieved from http://www.gao.gov/products/GAO-13-244
Accessed Jan. 31, 2016
GAO. (2013b). Dietary Supplements Adverse Events Mandatory Reporting. U.S.
Government Accountability Office. GAO-03-1042TDietary Supplements Adverse
Events Mandatory Reporting. GAO-03-1042T. U.S. Government Accountability
Office. Retrieved from http://www.gao.gov/products/GAO-03-1042T Accessed
Jan. 31, 2016
GAO. (2013c). Dietary Supplements Adverse Events Mandatory Reporting. GAO-03-
1042T. U.S. Government Accountability Office. Retrieved from
http://www.gao.gov/products/GAO-03-1042T Accessed Jan. 31, 2016
Grubb, P. (2012). Intellectual Property in Drug Discovery and Development. Drug
Discovery and Development, 275-284. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1002/0471266949.bmc040.pub2/pdf
Accessed Oct. 25, 2016
Gupta, R. K. (2004). Surge in US patents on botanicals. Nat Biotechnol, 22(6), 653-654.
Hill, R., & Rang, H. (2013). Drug Discovery & Development. Elsever: Churchill
Livingstone.
HMPC. (2004). Committee on Herbal Medicinal Products. Directive 2001/83/EC.
Retrieved from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_c
ontent_000264.jsp Accessed Feb. 4, 2016

138
HMPC. (2016). European Union monographs and list entries. Committee on herbal
medicinal products. Retrieved from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_
content_001132.jsp&mid=WC0b01ac0580033809 Accessed Oct. 25, 2016
Holstein, N. (2015). Monograph of Coccinia (Cucurbitaceae). PhytoKeys(54), 1-166.
ICSB. (2016a). 16th Oxford ICSB/5th Interim ASP. International Conference on the
Science of Botanicals. Retrieved from http://oxfordicsb.org/index.php/past
Accessed Oct. 6, 2016
ICSB. (2016b). A Report On Industry Initiatives To Enhance Botanical GMPs And
Supplier Quality, session 8a. International Conference on the Science of
Botanicals. Retrieved from http://oxfordicsb.org/index.php/16th-agenda/agenda3
Accessed Oct. 9, 2016
ICSB. (2016c). CFSAN FDA Dietary Supplement Regulatory Overview. International
Conference on the Science of Botanicals. Retrieved from
http://oxfordicsb.org/images/PDF/16th/Welch_ICSB_2016.pdf Accessed Oct. 20,
2016
Jordan, S. A., Cunningham, D. G., & Marles, R. J. (2010). Assessment of herbal
medicinal products: challenges, and opportunities to increase the knowledge base
for safety assessment. Toxicol Appl Pharmacol, 243(2), 198-216.
Kanji, S., Seely, D., Yazdi, F., Tetzlaff, J., Singh, K., Tsertsvadze, A., . . . Ansari, M. T.
(2012). Interactions of commonly used dietary supplements with cardiovascular
drugs: a systematic review. Syst Rev, 1(1), 26.

139
Kaplowitz, M. D. (2004). A comparison of web and mail survey response rate. Public
Opinion Quarterly, 68, 94-101.
Kapoor, A., & Sharfstein, J. M. (2016). Breaking the gridlock: Regulation of dietary
supplements in the United States. Drug Test Anal, 8(3-4), 424-430.
Kesselheim, A. S., Connolly, J., Rogers, J., & Avorn, J. (2015). Mandatory disclaimers
on dietary supplements do not reliably communicate the intended issues. Health
Aff (Millwood), 34(3), 438-446.
Khan, I. A. (2006). Issues related to botanicals. Life Sci, 78(18), 2033-2038.
Kim, N. C., & Kinghorn, A. D. (2002). Highly sweet compounds of plant origin. Arch
Pharm Res, 25(6), 725-746.
Kramer, J. M., Smith, P. B., & Califf, R. M. (2012). Impediments to clinical research in
the United States. Clin Pharmacol Ther, 91(3), 535-541.
Krikorian, R., Shidler, M. D., Nash, T. A., Kalt, W., Vinqvist-Tymchuk, M. R., Shukitt-
Hale, B., & Joseph, J. A. (2010). Blueberry supplementation improves memory in
older adults. J Agric Food Chem, 58(7), 3996-4000.
Kronenberg, F., & Kennelly, E. J. (2013). Phytochemical identity and stability of herbal
products: challenges for clinical research. Maturitas, 76(4), 291-293.
Kumar, R., Mishra, A., & Gupta, R. (2010). Problems associated with clinical trials of
Ayurvedic medicines (Vol. 20). Revista Brasileira de Farmacognosia.
Lanling, P. (1992). Experience in Treating Cancers With Traditional Chinese Medicine.
(pp. 408-447). Shanghai, China: Shandong Science and Technology Press.

140
Lestari, A. (2016). Review of traditional use, pharmacological effects and toxicity of
medicinal plants for women's health in Indonesia. Asian Journal of
Pharmaceutical and Clinical Research, 9(1), 41-46.
Li, W. (2002). Botanical Drugs: The Next New New Thing. Harvard DASH repository.
Digital Access to Harvard Dashboard. Retrieved from
https://dash.harvard.edu/handle/1/8965577 Accessed Jan. 5, 2016
Liang, Y. Z. (2004). Quality control of herbal medicines. J Chromatogr, 812(1-2), 53-70.
Lindstrom, C., Ooyen, P., & Blumenthal, M. (2013). Herb supplements increase 5.5% in
2012. The Journal of the American Botanical Council. Retrieved from
http://cms.herbalgram.org/herbalgram/issue99/hg99-
mktrpt.html?ts=1477502860&signature=a936330472ccc0c34fbacd4957421374
Accessed Oct. 25, 2015
Liu, Y., & Wang, M. W. (2008). Botanical drugs: challenges and opportunities:
contribution to Linnaeus Memorial Symposium 2007. Life Sci, 82(9-10), 445-449.
Long, J. (2015). Mandatory AERs fall, but questions of underreporting remain. Natural
Product Insider Report, 38-39.
Lozoya, X. (1994). Two decades of Mexican ethnobotany and research in plant drugs.
Ciba Found Symp, 185, 130-140; discussion 140-152.
Marcus, D. M. (2015). Dietary supplements: What's in a name? What's in the bottle?
Drug Testing and Analysis: Published online in Wiley Online Library.
Marcus, D. M. (2016). Dietary supplements: What's in a name? What's in the bottle?
Drug Test Anal, 8(3-4), 410-412.

141
Marcus, D. M., & Grollman, A. P. (2012). The consequences of ineffective regulation of
dietary supplements. Arch Intern Med, 172(13), 1035-1036.
Marcus, D. M., & Grollman, A. P. (2015). Toxicity of botanical medicines: An
overlooked global health problem. Am J Public Health, e1-e2.
Matthews, G. L. (2013). Disease modification: promising targets and impediments to
success. Rheum Dis Clin North Am, 39(1), 177-187.
McMillan, S. J., & Sheehan, K. B. (1999). Response variation in e-mail survey: An
exploration. J. of Advertising and Research, 39(4), 45-54.
Meer, M., & Misner, S. (2005). Labeling of dietary supplements. Journal of Functional
Foods, 4, 3-4.
MHRA. (2002). Safety of Herbal Medicinal Products. Medicine and Health care Products
Regulatory Agency. Medicines and Healthcare products Regulatory Agency.
Retrieved from www.mhra.org.uk Accessed Jan. 3, 2016
Miroddi, M., Mannucci, C., Mancari, F., Navarra, M., & Calapai, G. (2013). Research
and development for botanical products in medicinals and food supplements
market. Evid Based Complement Alternat Med, 2013. Retrieved from
https://www.ncbi.nlm.nih.gov/pubmed/23606886
Mitra, S. K., Kannan, R., & Sundaram, R. (2007). Pharmacognostical and
physicochemical characteristics of roots of lesser known medicinal plant
caesalpinia digyna rottl. Anc Sci Life, 26(3), 35-39.
NCCIH. (2015). Policy of Natural Product Intergrity. National Center for
Complementary and Integrative Health. Retrieved from
https://nccih.nih.gov/research/policies/naturalproduct.htm Accessed Jan. 4, 2016

142
NIH. (2002). Dietary Supplement Analytical Methods and Reference Materials Program.
National Institute of Health. Retrieved from
https://ods.od.nih.gov/Research/AMRMProgramWebsite.aspx Accessed Oct. 12,
2016
NIH. (2013). NIH Botanical Research Expert Panel Meeting. National Institute of Health.
Retrieved from
https://nccih.nih.gov/sites/nccam.nih.gov/files/2013BREPreport.pdf Accessed
Jan. 15, 2016
NIH. (2015). NIH Centers for Advancing Research on Botanical and Other Natural
Products (CARBON) Program. NIH-NCCIH collaboration. Retrieved from
https://ods.od.nih.gov/Research/Dietary_Supplement_Research_Centers.aspx
Accessed September 2, 2016
NIH. (2016). NIH-Wide Strategic Plan. National Institute of Health. Retrieved from
https://www.nih.gov/sites/default/files/about-nih/strategic-plan-fy2016-2020-
508.pdf Accessed Oct. 6, 2016
NPI. (2012). Botanical Drug Market Hampered by Regulations. Natural Product Insider
Report. Retrieved from
http://www.naturalproductsinsider.com/news/2012/12/botanical-drug-market-
hampered-by-regulations.aspx Accessed Jan. 5, 2016
Offit, P. A. (2012). Studying complementary and alternative therapies. JAMA, 307(17),
1803-1804.
Opara, E. I. (2004). The efficacy and safety of Chinese herbal medicines. Br J Nutr,
91(2), 171-173.

143
Pan, S. Y., Litscher, G., Gao, S. H., Zhou, S. F., Yu, Z. L., Chen, H. Q., . . . Ko, K. M.
(2014). Historical perspective of traditional indigenous medical practices: the
current renaissance and conservation of herbal resources. Evid Based Complement
Alternat Med, 2014, 525340.
Piersen, C. E., Booth, N. L., Sun, Y., Liang, W., Burdette, J. E., van Breemen, R. B., . . .
Farnsworth, N. R. (2004). Chemical and biological characterization and clinical
evaluation of botanical dietary supplements: a phase I red clover extract as a
model. Curr Med Chem, 11(11), 1361-1374.
Qu, L., Zou, W., Zhou, Z., Zhang, T., Greef, J., & Wang, M. (2014). Non-European
traditional herbal medicines in Europe: A community herbal monograph
perspective. J Ethnopharmacol.
Rai, V., Kakkar, P., Singh, J., Misra, C., Kumar, S., & Mehrotra, S. (2008). Toxic metals
and organochlorine pesticides residue in single herbal drugs used in important
ayurvedic formulation - 'Dashmoola'. Environ Monit Assess, 143(1-3), 273-277.
Ramzan, I. (2015). Phytotherapies: Efficacy, Safety, and Regulation Phytotherapies.
Hoboken, New Jersey: John Wiley & Sons Inc.
Rea, L. M., & Parker, R. A. (2014). Designing and Conducting Survey Research: A
Comprehensive Guide (Fourth Ed. ed.). San Francisco, CA Jossey-Bass.
Romano, M. F., Sardella, M. V., & Alboni, F. (2016). Web health monitoring survey: A
new approach to enhance the effectiveness of telemedicine systems. JMIR Res
Protoc, 5(2), e101.
Sahoo, N., & Manchikanti, P. (2013). Herbal drug regulation and commercialization: an
Indian industry perspective. J Altern Complement Med, 19(12), 957-963.

144
Sahoo, N., Manchikanti, P., & Dey, S. (2010). Herbal drugs: standards and regulation.
Fitoterapia, 81(6), 462-471.
Saxena, P. K., Cole, I., & Murch, S. J. (2007). Approaches to quality plant based
medicine. Dordrecht, The Netherlands: Springer,.
Schiff, P. L., Srinivasan, V. S., Giancaspro, G. I., Roll, D. B., Salguero, J., & Sharaf, M.
H. (2006). The development of USP botanical dietary supplement monographs,
1995-2005. J Nat Prod, 69(3), 464-472.
Schilter, B., Andersson, C., Anton, R., Constable, A., Kleiner, J., O'Brien, J., . . . Walker,
R. (2003). Guidance for the safety assessment of botanicals and botanical
preparations for use in food and food supplements. Food Chem Toxicol, 41(12),
1625-1649.
Schneiderman. (2015). Attorney General Schneiderman Asks Major Retailers To Halt
Sales Of Certain Herbal Supplements As DNA Tests Fail To Detect Plant
Materials Listed On Majority Of Products Tested. Retrieved from
http://www.ag.ny.gov/press-release/ag-schneiderman-asks-major-retailers-halt-
sales-certain-herbal-supplements-dna-tests Accessed May 19, 2016
Seeram, N. P., Zhang, Y., McKeever, R., Henning, S. M., Lee, R. P., Suchard, M. A., . . .
Heber, D. (2008). Pomegranate juice and extracts provide similar levels of plasma
and urinary ellagitannin metabolites in human subjects. J Med Food, 11(2), 390-
394.
Seiguer, E., & Smith, J. J. (2005). Perception and process at the Food and Drug
Administration: obligations and trade-offs in rules and guidances. Food Drug Law
J, 60(1), 17-32.

145
Sertkaya, A., Birkenbach, A., Berlind, A., & Eyraud, J. (2014). Examination of clinical
trials cost and barriers for drug development. Retrieved from
https://aspe.hhs.gov/sites/default/files/pdf/77166/rpt_erg.pdf Accessed Aug 30,
2016
Sharma, S. B., & Gupta, R. (2015). Drug development from natural resource: a
systematic approach. Mini Rev Med Chem, 15(1), 52-57.
Sheehan, K. B. (2001). E-mail survey response rates: A review. Journal of Computer-
Mediated Communication, 6(2), 0-0.
Shennong, Q. (2007). Chinese Pharmacopeia first documented herbal product.
kaleidoscope.cultural-china. Retrieved from http://kaleidoscope.cultural-
china.com/en/196Kaleidoscope8524.html Accessed Jan.10, 2015
Singh, U. P., Singh, D. P., Maurya, S., Maheshwari, R., Singh, M., Dubey, R. S., &
Singh, R. B. (2004). Investigation on the phenolics of some spices having
pharmacotherapeuthic properties. J Herb Pharmacother, 4(4), 27-42.
Srinivasan, V. S. (2006). Challenges and scientific issues in the standardization of
botanicals and their preparations. United States Pharmacopeia's dietary
supplement verification program--a public health program. Life Sci, 78(18), 2039-
2043.
Tang, T. Y., Li, F. Z., & Afseth, J. (2014). Review of the regulations for clinical research
in herbal medicines in USA. Chin J Integr Med, 20(12), 883-893.
Timbo, B. B., Ross, M. P., McCarthy, P. V., & Lin, C. T. (2006). Dietary supplements in
a national survey: Prevalence of use and reports of adverse events. J Am Diet
Assoc, 106(12), 1966-1974.

146
Tomaskovic, D., Leiter, J., & Thompson, S. (1999). Organizational survey nonresponses.
Administrative Science Quarterly, 39(3), 439-457.
Tsai, H. H., Lin, H. W., Simon Pickard, A., & Mahady, G. B. (2012). Evaluation of
documented drug interactions and contraindications associated with herbs and
dietary supplements: a systematic literature review. Int J Clin Pract, 66(11),
1056-1078.
U.S.-101st-Congress. (1990). Nutrition Labeling and Education Act. Retrieved from
https://www.congress.gov/bill/101st-congress/house-bill/3562 Accessed Oct. 25,
2016
U.S.-103rd-Congress. (1994). Dietary Supplement Health and Education Act. S. 784
Dietary Supplement Health and Education Act of 1994. Retrieved from
https://www.govtrack.us/congress/bills/103/s784 Accessed Oct. 25, 2016
U.S.-109
th
-Congress. (2006). Dietary Supplement and Nonprescription Drug Consumer
Protection Act of 2006. Public Law 109-462, 109th Congress. Retrieved from
https://www.congress.gov/109/plaws/publ462/PLAW-109publ462.pdf Accessed
Feb. 5, 2014
U.S.-111th-Congress. (2010a). Food Safety Modernization Act. Retrieved from
https://www.govtrack.us/congress/bills/111/s510/summary Accessed Oct. 25,
2016
U.S.-111th-Congress. (2010b). Sen. John McCain, Remarks on S. 3002, Congressional
Record, 111th Congress, February 22, 2010. Retrieved from
https://www.govtrack.us/congress/bills/111/s3002 Accessed Feb. 4, 2016

147
U.S.-113
th
-Congress. (2013). S. 1425 (113th) Dietary Supplement Labeling Act of 2013,
Bill Introduced. The text of the bill below is as of Au g1, 2013 (I ntroduced).
Retrieved from https://www.govtrack.us/congress/bills/113/s1425/text# Accessed
Feb. 4, 2016
U.S.-113
th
-Congress. (2015). S. 1425 (113
th
) Dietary Supplement Labeling Act of 2013.
This bill was introduced on August 1, 2013, in a previous session of Congress but
was not enacted. Retrieved from
https://www.govtrack.us/congress/bills/113/s1425 Accessed Oct. 20, 2016
Umhau, J. C., Garg, K., & Woodward, A. M. (2012). Dietary supplements and their
future in health care: commentary on draft guidelines proposed by the Food and
Drug Administration. Antioxid Redox Signal, 16(5), 461-462.
Wallace, T. C. (2015). Twenty Years of the Dietary Supplement Health and Education
Act--How Should Dietary Supplements Be Regulated? J Nutr, 145(8), 1683-1686.
Wang. (2015). New York Attorney General targets mislabeled herbal supplements.
npr.org. Retrieved from http://www.npr.org/2015/02/03/383578263/new-york-
attorney-general-targets-mislabeled-herbal-supplements Accessed Oct. 12, 2016
Wang, & Ren, J. (2002). Current status and future direction of Chinese herbal medicine.
Trends Pharmacol Sci, 23(8), 347-348.
Wang, Zhong, Y., Zhang, Y., Liu, J. P., Wang, Y. F., Jia, W. N., . . . Gao, X. M. (2014).
A network analysis of the Chinese medicine Lianhua-Qingwen formula to identify
its main effective components. Mol Biosyst.

148
WHO. (2005). National policy on traditional medicine and regulation of herbal
medicines. Report of a WHO global survey. Retrieved from
http://apps.who.int/medicinedocs/en/d/Js7916e/#Js7916e Accessed Feb. 3, 2016
WHO. (2007). Guidelines on good agricultural and collection practices (GACP) for
medicinal plants. World Health Organization, Geneva. Retrieved from
http://apps.who.int/medicinedocs/en/d/Js4928e/ Accessed Jan. 31, 2016
WHO. (2008). Traditional medicines. Traditional and complementary medicine.
Retrieved from http://www.who.int/topics/traditional_medicine/en/ Accessed Jan.
10, 2015
WHO. (2016). Uppsala Monitoring Center. World Health Organization. Retrieved from
http://www.who-umc.org/ Accessed Oct. 26, 2016
Wolsko, P. M., Solondz, D. K., Phillips, R. S., Schachter, S. C., & Eisenberg, D. M.
(2005). Lack of herbal supplement characterization in published randomized
controlled trials. Am J Med, 118(10), 1087-1093.
Woo, J. J. (2007). Adverse event monitoring and multivitamin-multimineral dietary
supplements. Am J Clin Nutr, 85(1), 323S-324S.
Wu, K. M., Dou, J., Ghantous, H., Chen, S., Bigger, A., & Birnkrant, D. (2010). Current
regulatory perspectives on genotoxicity testing for botanical drug product
development in the U.S.A. Regul Toxicol Pharmacol, 56(1), 1-3.
Xie, Y., & Ho, S. C. (2013). Prenotification had no additional effect on the response rate
and survey quality: a randomized trial. J Clin EpidemiolJ Clin Epidemiol, 66(12),
1422-1426.

149
Xue, J., Hao, L., & Peng, F. (2008). Residues of 18 organochlorine pesticides in 30
traditional Chinese medicines. Chemosphere, 71(6), 1051-1055.
Yee, Chu, Xu, & Choo. (2005). Regulatory control of Chinese Proprietary Medicines in
Singapore. Health Policy, 71(2), 133-149.
Yeung, K. S., Gubili, J., & Cassileth, B. (2008). Evidence-based botanical research:
applications and challenges. Hematol Oncol Clin North Am, 22(4), 661-670,.
Zakaryan, A., & Martin, I. (2012). Regulation of Herbal Dietary Supplement: Is there a
better way. Drug Information Journal, 46(5), 532-544.
Zhang, J., Wider, B., Shang, H., Li, X., & Ernst, E. (2012). Quality of herbal medicines:
challenges and solutions. Complement Ther Med, 20(1-2), 100-106.
Zou, L., Harkey, M. R., & Henderson, G. L. (2002). Effects of herbal components on
cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci, 71(13),
1579-1589.

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APPENDIX A. DRAFT SURVEY

151

152

153

154

155

156

157

158

159
APPENDIX B. FINAL SURVEY

Ali Rejaei botanical efficacy survey

The following survey seeks to understand the views of the dietary supplement industry
with regard to factors affecting the conduct of clinical trials on botanical products in the
United States. It is part of research associated with the Doctor of Regulatory Science
degree at the University of Southern California. Your candid answers are important to the
success of this study and are completely anonymous. Toward the end of the survey, there
will be an option to voluntarily participate in a follow-up phone interview. You can have
the results upon request once survey is closed. Thank you in advance for your
participation.

Q1 Which industry best describes your most recent employer or client? Please check all
that apply.
 Manufacturer of finished dietary supplement products (1)
 Distributor of finished dietary supplement products (2)
 Manufacturer of raw dietary supplement ingredients (3)
 Distributor of raw dietary supplement ingredients (4)
 Academia, institution, school, research center (5)
 Consultant (6)
 Other (7) ____________________

Q2 Which occupational category best describes your most recent employment?
 Sales and Marketing (1)
 Quality Control/Assurance (2)
 Regulatory Affairs (3)
 Clinical Research (4)
 Research & Development (5)
 Other (6) ____________________

Q3 Which job level best describes your corporate role?
 Associate, specialist (1)
 Group leader (2)
 Manager (3)
 Director (4)
 Vice President (5)
 CEO/President (6)
 Other (7) ____________________

160
Q4 Which category best represents the product assortment of your most recent employer?
Please check all that apply.
 Botanical finished products (1)
 Raw materials /ingredients (2)
 Vitamins and minerals (3)
 Nutritional products (4)
 Other (5) ____________________

Q5 What is the company size of your most recent employer/client in terms of number of
employees?
 1-49 (1)
 50-499 (2)
 500-999 (3)
 >1,000 (4)
 I don't know (5)

Q6 How many dietary supplement products does your company/client sell in the U.S.
market?
 none (1)
 1-9 (2)
 10-19 (3)
 20-49 (4)
 >50 (5)
 I don't know (6)

161
Q24 Please indicate your level of familiarity with the following legal instruments or
concepts. Please check all that apply.
Unfamiliar (1)
Somewhat Familiar
(2)
Very Familiar (3)
Food Drug &
Cosmetic Act - FDCA
(1)
  
Nutrition and Health
and Education Act -
NLEA (2)
  
Dietary Supplement
Health Education
Act – DSHEA (3)
  
New Dietary
Ingredient
notification - NDI (4)
  
Generally
Recognized As Safe -
GRAS (5)
  
Investigational New
Drug - IND (6)
  
Over the counter
Drug Monographs -
OTC (7)
  
New Drug
Application - NDA
(8)
  

Q25 Please indicate whether your company or client makes any of the following claims
on the label of dietary supplement products. Please check all that apply.
 Nutrient Content Claims (1)
 Structure/Function Claims (2)
 Health Claims (3)
 Disease prevention Claims (4)
 None of the above (5)
 I don't know (6)

162
Q8 If your company decided to conduct a clinical trial, how difficult do you think that the
following aspects of botanical development would be?
Easy (1)
Moderately
difficult (2)
Very
Difficult (3)
Impossible
(4)
N/A or
cannot say
(5)
Standardization of
tested product (1)
    
Ability to validate
analytic methods
(2)
    
Ability to assess
purity/potency (3)
    
Ability to assure
shelf-life, stability
(4)
    
Selection/validation
of appropriate
biomarkers (5)
    
Other (6)     

163
Q11 How would you rate the impediments posed in the following areas
when conducting clinical trials of botanical products?

Not
challenging
at all (1)
Slightly
challenging
(2)
Moderately
challenging
(3)
Very
challenging
(4)
N/A (5)
Limits on
financial
/staff
resources (1)
    
Regulatory
and DSHEA
hurdles (2)
    
Product
development
challenges
(3)
    
Concerns
about market
competition
(4)
    
Other (5)     

Q37 If you identified "other" or want to expand on your answer, please enter in the text
box below

164
Q9 How important do you think that the following improvements would be in
determining whether companies with botanical products would conduct clinical trials to
support new product development?

Very
important (1)
Important (2)
Slightly
important (3)
Not at all
important (4)
N/A (5)
Availability of
financial
support from
grants (1)
    
Enhanced
training
opportunities
for staff
regarding the
conduct of
trials (2)
    
Changes in
regulatory
environment
to facilitate
trials (3)
    
Increased
consumer
demand for
botanical
drugs (4)
    
Marketing
protection
from
competition
(5)
    
Improved
and qualified
methods for
biomarker
validation (6)
    
Other (7)     

165
Q15 How engaged have your company been in considering to conduct clinical trials for
efficacy on a botanical product?
Agree (1) Disagree (2) I don't know (3)
We have never
considered the idea
of conducting
clinical trials to
demonstrate
efficacy (1)
  
We have considered
but rejected the
decision to conduct
clinical trials before
we started any
planning (2)
  
We have had
planning meetings
that never
progressed to an
Investigational New
Drug (IND)
application (3)
  
We have had INDs
for trials to establish
sufficient evidence
to support a
structure-function
claim (4)
  
We have pursued
clinical trials to
gather sufficient
evidence to support
a health claim (5)
  
We have pursued
clinical trials to
position a botanical
product as a drug (6)
  

166
Q16 My company would be reluctant to undertake clinical trials to establish botanical
product efficacy because:

167

Very
important
(1)
Moderately
important (2)
Slightly
important
(3)
Not at all
important
(4)
N/A (5)
Our staff is not
sufficiently
knowledgeable
about the
conduct of
clinical trials
(1)
    
Our staff is not
sufficiently
knowledgeable
about IND
regulations
and
submissions
(2)
    
Statistical
proof of
efficacy would
require
unreasonably
large
participant
cohorts (3)
    
We cannot
standardize or
botanical
product with
sufficient rigor
to satisfy
FDA’s
requirements
(4)
    
We do not
have validated
biomarkers to
assure control
of product
potency (5)
    

168
Such trials
would be more
expensive than
warranted by
potential
market return
(6)
    
Lack of
regulatory
requirements
to mandate it
(7)
    

Q20 Would any one of the following changes, made in isolation, be sufficient to cause
you to consider to undertake clinical trials? Please check all that apply.
 Less burdensome clinical trial rules (1)
 75-day review of New Dietary Ingredients (NDI) by regulators (2)
 Introduction of market exclusivity / patent protection (3)
 Insurance reimbursement of tested botanicals (4)
 Monograph requirements as OTC products (5)
 Other (6) ____________________

Q10 A dietary supplement category has been created under DSHEA to supplement the
diet. Health claims describe a relationship between a dietary supplement ingredient and a
reduction in risk of a disease or health-related condition. Which statement below
regarding dietary supplements with health claims best describes your view on this issue?
 Dietary supplements with health claims should be regulated as drugs (1)
 Dietary supplements with health claims are currently regulated appropriately (2)
 Health claims supported by existing literature should be allowed even without FDA prior
authorization (3)
 Health claims should be allowed only if FDA or third party agency has established efficacy
through arm's length clinical trials. (4)
 Other (5) ____________________

Q13 Do you agree/disagree that botanical products prescribed by a physician should be
covered by health insurance as most drugs are?
 Agree for all marketed products (1)
 Agree only for botanicals with authorized health claims (2)
 Disagree for all marketed supplements (3)
 Other (4) ____________________

169
Q40 If you are currently conducting a clinical trial of a botanical product, what do you
consider your biggest problem?

Q14 Would your company /client consider sharing the cost of conducting a clinical trial
on a potential botanical product with a similar company, provided both parties benefit
from positive outcomes proportionally?
 Definitely yes (1)
 Probably yes (2)
 Might or might not (3)
 Probably not (4)
 Definitely not (5)
 I do not know (6)

Q18 I think that monograph requirements rather than an New Drug Application (NDA)
process would be more appropriate for botanical products.
 Strongly agree (1)
 Somewhat agree (2)
 Neither agree nor disagree (3)
 Somewhat disagree (4)
 Strongly disagree (5)
 cannot answer (6)

170
Q21 Would your company/client consider conducting clinical trials on a botanical
product if:

171

Very
likely (1)
Likely (2)
Neutral
(3)
Unlikely
(4)
Very
Unlikely
(5)
N/A (6)
FDA offered
market
exclusivity
(similar to
drugs) to a
company/client,
if the outcome
were to be
positive? (1)
     
Grants were
available to
pursue a New
Drug
Application
(NDA) on any of
your marketed
products? (2)
     
It were to be
possible to
pursue a
generic drug
application
(Abbreviated
New Drug
Application,
ANDA) for any
of your
botanicals? (3)
     
The patent
office offered
patent
protection to
your company
for the tested
product? (4)
     

172
NIH agreed to
collaborate
with you to
validate the
data, provided
positive
outcome? (5)
     

Q22 Please rank which of the following would best ensure monetary return on your
clinical trial investment?
______ IP protection (1)
______ Market exclusivity (2)
______ Health insurance reimbursements (3)
______ Shared development costs (4)
______ Other (5)

Q23 Please indicate the degree to which you feel the following factors would affect
your decision to pursue conducting clinical trial on botanical products?
Agree (1)
Neither agree
nor disagree (2)
Disagree (3) I don't know (4)
Lack of IP
protection (1)
   
Lack of
monograph
standards (2)
   
Lack of
consumer
interest (3)
   
Lack of
insurance
coverage (4)
   
Need to price
product beyond
range
acceptable to
consumer (5)
   

173
Q26 Do you think the current DSHEA is appropriate to regulate botanical dietary
supplements?
 DSHEA is appropriate to regulate botanicals (1)
 DSHEA is NOT sufficient to regulate dietary supplements because: (2)
____________________
 DSHEA is OK but needs to be modified to include (3) ____________________

Q27 Dietary Supplement Health Education Act – DSHEA does not require proof of
safety and efficacy for dietary supplements to be submitted to FDA prior to marketing.

174
Please indicate your level of agreement or disagreement with the following statements
regarding Botanical Products (BPs)

175
Agree (1)
Neither agree
nor disagree (2)
Disagree (3) I don't know (4)
Current DSHEA
regulations are
sufficient (1)
   
Botanical
products should
be held to the
same standards
of food
regulation under
Nutrition
Labeling and
Education Act (2)
   
Botanical
products should
be held to the
same standards
as
pharmaceuticals
with respect to
clinical evidence
requirements of
safety and
efficacy (3)
   
The current
environment
regulating
botanical
products
encourages
product
innovation, and
easy consumer
access (4)
   

176
The current
environment
regulating
botanical
products
encourages
product
adulteration,
misidentification
(5)
   

Q38 There are currently more than 200 clinical trials being conducted for dietary
supplements but very few reach the New Drug Application (NDA) stage. Why do you
think that this situation exists?

Q28 If your employer /client is considering to conduct a clinical trial, but is not engaged
yet, what are the main impediments in your point of view?

177
Q29 In the U.S., OTC drugs are marketed by using a monograph or obtaining an
approved NDA. Do you agree or disagree with the following statement regarding the path
to regulate botanical products?
Agree (1)
Neither agree
nor disagree (2)
Disagree (3) I don't know (4)
Botanicals that
make health
claims should
follow NLEA
food
regulations
regarding
authorized
claims (1)
   
Botanicals that
make health
claims should
continue to
follow DSHEA
regulations (2)
   
Botanicals that
make health
claims should
follow existing
OTC
monograph
regulations (3)
   
BPs that make
health claims
should follow
new or generic
drug
regulations (4)
   
A new
monograph
system should
be develop for
botanical
products (5)
   

178
Q30 In the U.S., botanical products are regulated under Center of Food Safety and
Applied Nutrition (CFSAN). Some manufacturers make health claims and/or structure-
function claims. Do you agree or disagree with the following statements?

179
Agree (1)
Neither agree
nor disagree (2)
Disagree (3) I don't know (4)
Botanicals with
health claims
should remain
under FDA's
Center for Food
Safety and
Applied
Nutrition -
CFSAN (1)
   
Botanicals with
health claims
should move to
Division of
Nonprescription
Drug Products
(DNPD) (2)
   
Botanicals with
health claims
deserve their
own new
division within
FDA (3)
   
Botanicals with
health claims
should follow
the New Dietary
Ingredients
(NDI)
notification
process (4)
   
Botanicals
should not make
health claims.
Once they prove
efficacy, they
should be
regulated as
new botanical
drugs (5)
   

180

Q31 If DSHEA were modified to include submission of regulatory dossier for safety
and/or efficacy substantiation, which of the following would encourage the industry to
follow suit?
Agree (1)
neither agree
nor disagree (2)
Disagree (3) I don't know (4)
Market
exclusivity (1)
   
IP protection (2)    
Coverage by
insurance (3)
   
Price protection
(4)
   
Product
reimbursement
(5)
   
Other (6)    

Q41 If you identified "other" or want to expand on your answer, please enter in the text
box below.

181
Q35 Which of the following FDA "Guidance for Industry" documents do you find most
useful ?

Extremely
useful (1)
Moderately
useful (2)
Slightly
useful (3)
Neither
useful nor
useless (4)
N/A (5)
Botanical Drug
Products
Guidance (1)
    
Good
Manufacturing
Practices
Guidance (2)
    
Adverse Event
Reporting for
Dietary
Supplements
Guidance (3)
    
Analytical
Procedures
and Methods
Validation
Guidance (4)
    
Bioavailability
and
Bioequivalence
Studies
Guidance (5)
    

Q33 Would you agree to participate in a 15-20 minute phone interview to discuss the
impact of DSHEA regulations on conducting clinical trials of dietary supplement
products in order to justify safety and efficacy? if yes, please provide contact information

182
APPENDIX C. DESCRIPTIVE RESPONSES

Q9 - How important do you think that the following improvements would be in
determining whether companies with botanical products would conduct clinical
trials to support new product development?
changes in regulatory environment regarding approved claims
clinical trial design

Q10 - A dietary supplement category has been created under DSHEA to supplement
the diet. Health claims describe a relationship between a dietary supplement
ingredient and a reduction in risk of a disease or health-related condition. Which
statement below regarding dietary supplements with health claims best describes
your view on this issue
supported with specific testing to the formulas not just literature on
ingredients but on that formula
Permissible health claims for a dietary ingredient should be provided by
FDA
Health claims should still require FDA authorization, but the framework
should be revised to include more incentives (such as exclusivity) for
companies that make the investment.
Q11 - How would you rate the impediments posed in the following areas when
conducting clinical trials of botanical products?
Other
supply chain
creating non disease s/f claims
Homeopathic Product
Time constraints
meet demands for efficacy claims

183
scope of trial
Internal alignment on purpose and priority of conducting clinical studies

Q13 - Do you agree/disagree that botanical products prescribed by a physician
should be covered by health insurance as most drugs are?
agree for competent human trial evidenced based products
Agree for DS that are appropriately documented by 3d party audit for
GMP compliance
Agree, but also for trained professionals like acupuncturists, who actually
are more qualified.
Agree for all marketed products with existing literature supporting
efficacy and/or clinical trials on the finished product.
Healthcare coverage should not be a function of claims; what is needed is
standardization of products. Without that, physicians cannot know what
they are prescribing and consumers cannot know what they are getting.

Q22 - Please rank which of the following would best ensure monetary return on
your clinical trial investment?
Not clear how to answer this Q
Ip
n/a
stronger benefit claims
published monograph to enforce in the industry
N/A
Q26 - Do you think the current DSHEA is appropriate to regulate botanical dietary
supplements? DSHEA is NOT sufficient to regulate dietary supplements because:
no proof of efficacy

184
heterogenous preparations, no specific model for highly purified
flavonoids versus whole food fruit pulp
There are too many products out there to be managed
Not enough clarity
no pre market regulation
it does not require GMPs for ingredient suppliers
unknown safety and efficacy
we need clinical trials and GMP controls to assure safe and effective
products
Needs proof of safety and efficacy
meeting official standards is not mandatory. Industry is not using
validated methods
cant answer fairly
it is not stringent enough
insufficient oversight to prevent unauthorized claims and sales of
ineffective products
Insufficient standards and test methods
No scientific framework to support S/F claims; Proprietary blends should
not be allowed.
Many dietary supplement manufacturers do not fully comprehend the
DSHEA or even the CFR laws for dietary supplements. Even if all cGMP
guidelines are followed there still is room for error that could potentially
be harmful or even fatal to an unsuspecting consumer. Supplements
should be required to demonstrate safety before being released to the
public. I disagree that dietary supplements need to show efficacy before
being marketed as I feel there is a general lack of good research in this
arena due to funding.

185
Limits efficacy because of regulatory hurdles are too high for next step.

DSHEA is OK but needs to be modified to include
Market exclusivity for NDIs and products with approved health claims
quality, safety, efficacy requirements
should be regulated and labeled the same way as food
ability to make substantiated claims
Structure function claims are too vague, non-specific. These limitations
lead to all supplements making the same claims, whether or not they
deliver clinical studied doses or have been studied independently.
Monographs
pre-market registration
ability to communicate clinical results, even if disease related
see above regarding health claims.
verifiable means of substantiation for health claims, perhaps through
regulatory action
FDA product registration as in Canada
Efficacy and safety
Pre-market notification of all products to FDA, minimum quality
standards esp for botanical products, and greater supply chain
transparency.
increase approval rate on NDI application
Q28 - If your employer /client is considering to conduct a clinical trial, but is not
engaged yet, what are the main impediments in your point of view?

186
Cost, cost, cost. Lack of market exclusivity. Limited claims can be made
that may not produce a competitive product in the marketplace.
Funding
Cost. Why bother if you can state the "active" ingredient is already under
IND status.
return on investment not clear
conducting clinical study does not mean successful outcome
Cost.
Cost and time
The clinical protocol and design to adequately support the botanical
product claims.
Non-profit status, complexity of IRB.
Too expensive. No protection. Difficult to show affect.
money ROI
Primarily financial cost for a well-controlled study with adequate p values
etc.
N/a
N/A
The main impediments are knowledge of chemistry, manufacturing and
controls for a botanical product. A consistent source of supply and
fulfilling release criteria are big challenges. Assay development for
stability could be tricky. The other is to establish the regulatory strategy
ROI
expense consumer relevance/interest

187
N/a
n/a
Cost, and to a lesser extent, time to develop.
Cost of clinical trials, ROI risk, and risk that a production will be deemed
an IND that can no longer be marketed as a supplement.
Trial costs and lack of acceptance of results
Cost
money, lack of market research, personnel resources are limited; no new
discoveries.
Cost of conducting a well-designed study that will have meaningful data
(positive or not).
already engaged in clinical trials.
Cost and ability to use the data for marketing.
We are not involved in the design or conduct of clinical trials.
Cost.
cost and timing, ability to recruit a large number of volunteers.
N/A
n/a
Cost vs benefit
Cost of a quality clinical trial
Funding. Timeline. Consumer mindset. Knowledge of the process.
Costs, IP protection issues.

188
Biomarkers
Cost vs. market return.
Cost and complexity
strict regulation regarding to efficacy and safety
Strong enough copy based on ingredient clinical trials costs much less,
and is low-risk enough work with.
Lack of internal alignment among executives.
Cost, time and lack of understanding of regulatory processes
products are not a single ingredient. pharmacokinetics are not known
therefore difficult to suggest regimen. The variability of the effect is great,
product has very limited demonstrable measurable effects on testable end
points. stability unknown
Acceptance of results vs return to company
Cost
Available resources and sponsor willing to support the study
Cost vs benefit. Cost is too high benefit too low.
cost and concern on return of investment

Q37 – How would you rate the impediments posed in the following area when
conducting clinical trials of botanical products. If you identified "other" or want to
expand on your answer, please enter in the text box below
assurances of the source botanical raw material
quality and accuracy in source materials

189
Most clinical trial outcomes are usually based on some type of pathology
or related outcome that may allow a regulator to interpret such outcomes
as a disease-related outcome and not a substantiation of a proposed s/f
claim
Homeopathic Products are currently under scrutiny by the FDA.
We don't currently work with botanicals nor do we conduct clinical trials
All of the items listed are challenging, but all can be overcome. One major
barrier, however, is the time required to conduct clinical trials, primarily
the challenges to get them approved by an IRB. Many IRBs believe that a
dietary supplement requires an IND, but of course, if you get an IND for
your supplement, you have moved your product into the drug category
where it does not belong,
Australian TGA control the list of botanicals which h can be used for
medicine formulations. Mangosteen (Garcinia Mangostana) ls not listed.
What with the mountain of lab tests and more recently human clinical
trials it isn’t enough to satisfy them for listing. A recent double blind
placebo clinical trial for our proprietary mangosteen powder for
schizophrenia showed a marked improvement against pharmaceutical
medication It seems that the establishment is being governed and
controlled by Big Pharma. We are now being examined to find out why
and how it works via another 3 yr study on 150 people.
Product concepts developed by marketing groups often contain claims that
cannot be legally made in the USA, even in the presence of clinical data to
support the claim. So the product may test favorably in a consumer study,
but if the claim language has to be modified, this can change the success
of the product on the market.
Even with positive/favorable trial results, it can be very difficult to link
these results into meaningful claims and marketing materials. From my
perspective, this is mainly due to the difficulties associated with claim
substantiation, and the risks associated with reliance on small or
preliminary studies (which are far more practical to conduct).
Additionally, it seems that clinical studies are, at times, designed without
an end goal from a claims and marketing perspective. This type of
exploratory science is important because it builds and expands upon
existing/good science. However, when business-driven goals are not
realized, this can make the science seem less meaningful.

190
I am a lawyer and so my company does not offer any products like herbal
supplements
It is difficult to develop a clinical study robust enough to support a
marketing claim strong enough to justify the added cost
A dietary supplement is not targeting any disease, it is targeting
supplementing the missing components, which can enhance the health
conditions for a normal human population. So there are many factors need
to be considered, and there is no clinical symptom can be included in the
trial. It sole based on the current science and determined by statistics
analysis. So the scope of clinical trial of dietary supplement is critical to
the succeed.
In a large company like ours, the greatest challenge with respect to
conducting clinical trials is the inability to achieve internal alignment
between departments and among executives on exactly what it is we want
to accomplish with studies and what is the priority of this activity. There
are a number of other challenges, but these can be overcome if there is
internal alignment.

Q38 - There are currently more than 200 clinical trials being conducted for dietary
supplements but very few reach the New Drug Application (NDA) stage. Why do
you think that this situation exists?
Problems in defining the test product and producing it consistently.
Botanicals have more modest effects than highly purified synthesized
molecules so the clinical benefits are less impressive. Clinical design is
more challenging if the botanical has multiple ingredients that work
together to provide a measurable outcome. If you change the amount of
one component you can't predict the dose response. What markers can be
used for defining efficacy is difficult for mixtures.
Poor competence at clinical trial design Inadequate degrees of
standardization Inadequate funding to facilitate adequately powered trials

191
The trials are started for marketing purposes. Stating to the public that a
product is under IND status is a selling point to the uneducated public.
Additionally, the burden of accumulating necessary data/evidence that the
clinical trials are appropriate to move to application status is too great.
That, coupled with the inability to receive a patent or exclusivity makes
moving to application for a license, either an NDA or BLA, pointless. If
you receive a license, everyone currently or in the future can now sell said
product and make the same claims without the cost of the regulatory path.
poor performance in a randomized controlled trial model versus older off
patent and competing drug options already on the market
Efficacy of the botanicals itself may now show in a short term clinical trial
design
Costs. NDA stage enters ingredient into the drug sector, with much more
stringent regulations and associated costs involved. By limiting to dietary
ingredient and limited how claims are presented, there is a quicker return
on investment (ROI).
The clinical trials are too expensive and take too long to complete
There is not a single answer to this question. The reasons may be related
to the safety, efficacy, quality or financial concerns.
Variations in institutional standards for NDA.
Too expensive. No protection.
researchers not trained in botany and botanical research end goals are
not realistic or valid or meaningful
Do not know; such issues are confidential within FDA
$
NA
Most are research only INDs
Difficult to prove sufficient efficacy on disease

192
Most of the studies have to be registered in clinicaltrials.gov even if the
company is not pursuing the NDA path. Also, getting a botanical to the
market, from a chemistry perspective is not easy. The one good thing is
that initial clinical trials to determine proof of concept can be performed
usually without toxicology requirements.
ROI
too many hurdles for compliance
Lack of exclusivity Uncertain regulatory path Cost Lack of knowledge
concerning effect/sample size
Lack of evidence of efficacy.
They are not looking to make health claims.
The expense
In the U.S. by definition dietary supplements are not drugs. If a "natural"
chemical or compound were to be developed as a drug, it would be
difficult to get it patented. A "use patent" or "process patent" may be
possible, but it is difficult to patent a naturally occurring compound.
Dietary supplements are not drugs, therefore it is not appropriate to file
for an NDA on a product that is not a drug. To do so would prevent a
supplement company like ours to continue selling the product. It is
counterproductive. We conduct clinical trials on our products in order to
confirm the efficacy and safety of the products and to differentiate our
products from competitors, but we are still limited to the same generic
structure/function claims as every other company, "supports healthy
cognition in already healthy people' for example.
Big Pharma are influencing government control
not enough research has been done on the supplements to grant NDA
stage
consumer interest in the product fades, monetary problems, product does
not work as well as initially thought.

193
Lack of marketing advantage in selling an dietary supplement as a drug.
Dietary supplements are not intended to be drugs.
The consumer does not want to take pharmaceuticals. Dietary
Supplements support healthy lifestyles without the invasion of
pharmaceutical companies.
Most are not interested in NDA; prefer Dietary Supplement status.
The hurdle for approval as a drug is too high.
lack of market protection
The NDA process is not clear to provide sufficient ROI.
Burdensome and antagonistic situation
Not necessary for completion of these trials in order to market the
product. The additional cost is not justified for the ROI.
Cost and failure rates are both high.
I think this may be due to the fact that companies do not want to be
accused of marketing a drug if they have the product already on the
market as a dietary supplement
It costs too much; the studies are inconclusive or negative; it takes too
long; DSHEA with some clever claim formulation permits an end run
since many consumers probably already associate certain supplements
with health effects
dietary supplements do not necessarily need to be new drugs. instead can
support the claims being made on allowable dietary supplement
ingredients
Many companies are not in a position to market and sell drug products.
Cost of running a trial. My clients do not have interest in marketing
products as drugs.

194
Probably due to many regulations to reach that stage
The cost-benefit equation does not allow for further investment. The cost
and complexity involved with execution of an NDA outweigh the potential
future benefit.
There are a number of reasons this situation exists. Funding is probably
the primary reason as many dietary supplement companies lack the
capital to be able to invest in Phase I, II, and III clinical trials. Also add to
this the risk that the supplement fails to show efficacy, safety, or has
adverse side effects and it simply isn't worth the investment for most
companies. The dietary supplement industry is fast-paced with firms
constantly competing and updating formulas in order to gain an edge. The
time-sink of running a clinical trial through to the NDA stage is too much
to stay competitive. Also many consumers of dietary supplements could
care less which companies have clinical trials as their logic indicates that
an herb is just an herb regardless of it's guaranteed potency or active
ingredients. This type of logic among the consumers really defeats much of
the motivation for creating proof of efficacious botanicals or dietary
supplements.
Because companies don't want to sell supplements as drugs. This would
limit accessibility.
Lack of biomarkers to gauge moderate health benefit success that could be
helpful over a long period of time. Long clinical trials are excessively
expensive. Want to be able to assess moderate health benefits and
biomarkers do not exist at this time.
Inability to confirm the clinical trial results through peer reviews
Cost and complexity
Because dietary supplement is regulated as food.
The general supplement industry is not interested in entering the drug
market. I cannot speak to general botanical research.
Lack of exclusivity and IP protection results in poor return on investment
(ROI) and contributes to commoditization which erodes margins. In short,
today it does not make business sense to invest heavily in R&D for
supplements.

195
Clinical study expense & poor clinical study design
botanical ingredients are not easy to standardize to support efficacy
Have to test on Healthy Individuals
Not necessary.
Training on the scientists involved in the clinical trial having sufficient
knowledge base to successfully complete the study. When data is available
the availability of standards can impair the adequate interpretation of the
data.
Inadequate IP protection
Many reasons for this. Supplement means for prevention, not for
treatment, so the potency is generally lower and less effective than drug.
Because of this, the cost of clinical trial will not be cheap. There are
usually more than one active ingredient in the dietary supplement so it is
more challenge to standardize the product. The cost of developing herbal
drug is not much different than developing a new drug and most dietary
supplement company may not have sufficient resources for doing this.

Q40 - If you are currently conducting a clinical trial of a botanical product, what do
you consider your biggest problem?
Dollar cost of conducting the trial
research preparation standardization and inter subject variability
(gene/pheno type variances)
Showing efficacy within a reasonable timeline and budget, and there is a
lack of appropriate study design to showcase long term health promoting
supplements.
finding participants
Logistical coordination of all of the aspects of collecting data, biomarkers,
and analyses.
Consistency of release specifications and source of supply

196
Recruitment
We conduct clinical trials on our finished products and one of the biggest
problems we have had is with the protocol approval by the IRB. There is a
tremendous amount of confusion on the part of the IRB and in some cases,
the FDA, university researchers, CROs and other dietary supplement
companies as to the differences between an IND, a NDI, GRAS and other
designations. We are voluntarily conducting clinical trials on our finished
products, yet these studies are delayed due to a lack of clear guidelines
and a lack of education. We are not required to conduct clinical trials in
order to conduct studies, yet when we set out to voluntarily do the extra
research on our products, we actually get increased scrutiny from
regulatory bodies such as the IRB and the FDA. If we want more
companies to conduct clinical trials to support the efficacy of supplements,
we need to make it easier to conduct such trials
We had our proprietary mangosteen powder used by a university in a TGA
5 yr clinical study. Even though the markers were significant against a
placebo and pharmaceutical medication it is not sufficient to appease the
TGA. Bloody frustrating!
Competitors borrow the information for their own product. Competitors
do not invest time or their own money to further the development of good
quality products.
Protection of intellectual property rights to research. We do the research,
everyone else sells their product based upon our research.
N/A
Deciding which specific health claim the trial can support, and deciding
whether FDA will find this support/substantiation sufficient. It can be
quite challenging to determine whether FDA will view a statement as a
supported structure function claim vs. as an unauthorized health claim or
disease claim. FDA should provide a more clear and less burdensome
pathway to establish authorized health claims. They should also offer
either exemptions or more leeway towards claims which have been
authorized or favorably reviewed by other authoritative bodies (EFSA,
Health Canada, etc.)
Money
limits on resources

197
Investment not being IP protected.
n/a
Regulation
Greatest challenge is lack of internal alignment on the objective of studies
and the priority. After that, next challenge in studying botanical products
in clinical trials is what actual test material to use (composition) and what
that is to be based on. Botanical preparations vary widely, and which
specific preparation(s) to test is often not clear. How a company goes
about determining this can be challenging as the literature tends to be
incomplete when it comes to reporting the actual composition and
characteristics of the test materials used.
cost of the clinical trial due to study population selection. Most
biomarkers used in the clinical trial are originally developed by disease
treatment or determination. Because of this, it is very difficult to measure
the level of biomark change in healthy population. In order to achieve this,
a large sample size is needed and this can increase the cost of trial
significantly.
Q41 – If DSHEA were modified to include submission of regulatory dossier for
safety and /or efficacy substantiation, which of the following would encourage the
industry to follow suit. If you identified "other" or want to expand on your answer,
please enter in the text box below
Mandatory pre-market approval
If DSHEA were modified to include submission of regulatory dossier for
safety and/or efficacy substantiation, the industry would follow suit
because it would then be law.

Abstract (if available)

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