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FDA influence on advisory committees through documentation: a content analysis and survey of industry views

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Content

FDA INFLUENCE ON ADVISORY COMMITTEES THROUGH
DOCUMENTATION:
A CONTENT ANALYSIS AND SURVEY OF INDUSTRY VIEWS

by

William P. Leitner

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

August 2015

Copyright 2015 William P. Leitner

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DEDICATION
To Michelle, my beautiful wife, who loves and supports me regardless of how “big
picture” I am. Thank you for giving me the strength and inspiration to finish my
dissertation despite life’s many obstacles.

To Madison, my little bundle of joy, who acted as my alarm clock every morning at
4AM, and dozed next to me on the couch as I worked on my thesis.

To my loving family for giving me the foundation to pursue my academic endeavors and
encouraging me to finish my doctorate.

To my loyal bulldogs, Hugo and Ace, you guys have been with me since the beginning
and have spent many an hour by my side next to the fireplace as I plug away at my thesis.

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ACKNOWLEDGEMENTS
I would like to thank everyone who has supported and encouraged me in making this
dissertation a reality. I would like to thank Dr. Richmond for her continued support
throughout my dissertation and the doctoral program. She had an uncanny ability to know
just the right thing to say to help motivate me. She is the MVP of doctoral advisors and I
couldn’t have done it without her support. I would also like to thank Jim DiBiasi, one of
the foremost experts on advisory committee meetings, who helped make this research
possible by giving me access to 3D Communications database of advisory committee
meetings and for always making himself available to provide feedback. I would also like
to thank my thesis committee members, Dr. Gerald Loeb, Dr. Eunjoo Pacifici, and Jim
DiBiasi for providing many valuable comments and insight that improved the
presentation and contents of this thesis. Finally, I’d like to acknowledge the help and
support of the staff of the Regulatory Science Program, and for Randa always assisting
with formatting.

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TABLE OF CONTENTS
DEDICATION .................................................................................................................... 2
ACKNOWLEDGEMENTS ................................................................................................ 3
TABLE OF CONTENTS .................................................................................................... 4
LIST OF TABLES .............................................................................................................. 9
LIST OF FIGURES .......................................................................................................... 10
ABSTRACT ...................................................................................................................... 13
CHAPTER 1. OVERVIEW OF THE STUDY ......................................................... 15
1.1 Introduction .................................................................................................. 15
1.2 Statement of the Problem ............................................................................. 18
1.3 Purpose of the Study .................................................................................... 19
1.4 Significance of the Study ............................................................................. 21
1.5 Delimitations, Limitations and Assumptions ............................................... 21
CHAPTER 2. LITERATURE REVIEW .................................................................. 24
2.1 Background .................................................................................................. 24
2.2 Advisory Committees for Drugs .................................................................. 27
2.3 Advisory Committees for Biologics ............................................................ 34
2.4 Advisory Committees for Medical Devices ................................................. 38
2.5 Regulatory Framework around FDA Advisory Committees ....................... 43
2.5.1 Laws ................................................................................................ 44

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2.5.2 Regulations ..................................................................................... 47
2.5.3 Guidance Documents ...................................................................... 50
2.5.3.1 FDA GUIDANCE DOCUMENT ONE AND TWO --
Financial Conflict of Interest ............................................. 51
2.5.3.2 FDA GUIDANCE DOCUMENT THREE -- Voting
Procedures .......................................................................... 52
2.5.3.3 FDA GUIDANCE DOCUMENT FOUR – Public
Availability of Information Given to Advisory
Committee Members .......................................................... 52
2.5.3.4 FDA GUIDANCE DOCUMENT FIVE -- When FDA
Convenes an Advisory Committee .................................... 53
2.5.3.5 FDA GUIDANCE DOCUMENT SIX -- Public
Comment Procedure at Advisory Committee Meetings .... 53
2.6 Sequence of Events in Setting up an Advisory Committee ......................... 54
2.7 Advisory Committee Members and Process Flow ....................................... 55
2.7.1 Advisory Committee Membership .................................................. 55
2.7.2 Flow of Activities during an Advisory Committee Hearing ........... 57
2.7.2.1 Introductions/Conflict of Interest ....................................... 59
2.7.2.2 Questions Posed to the Committee .................................... 59
2.7.2.3 Sponsor Presentation / Q&A for the Sponsor .................... 61
2.7.2.4 FDA Presentation / Q&A for the FDA .............................. 61

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2.7.2.5 Open Public Comment Period ........................................... 62
2.7.2.6 Committee’s Discussion and Questions from the
Committee .......................................................................... 62
2.8 Current Concerns related to Advisory Committees ..................................... 63
2.9 Influence in the Social Science Literature ................................................... 70
CHAPTER 3. METHODOLOGY ............................................................................ 75
3.1 Introduction .................................................................................................. 75
3.2 Characterization of the Briefing Books ....................................................... 77
3.3 Content Analysis .......................................................................................... 77
3.4 Survey Analysis ........................................................................................... 78
CHAPTER 4. RESULTS .......................................................................................... 81
4.1 Summary of Reviewed Briefing Books ....................................................... 81
4.2 Characterization of FDA Medical Device Briefing Books .......................... 82
4.2.1 Length of FDA Briefing Books ...................................................... 82
4.2.2 Number of Tables and Figures ........................................................ 83
4.2.3 Explanation of Rationale for Presentation to the Advisory
Committee ....................................................................................... 84
4.2.4 Inclusion of Additional Analyses .................................................... 85
4.2.5 Explanation of Post-Approval Study (PAS) Inclusion.................... 86
4.2.6 Content of the Introduction ............................................................. 86

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4.2.7 Variability in Comment Format ...................................................... 89
4.2.8 Number of FDA Comments ............................................................ 92
4.3 Content Analysis of FDA Medical Device Briefing Books ......................... 93
4.3.1 Classification of FDA Comments ................................................... 93
4.3.2 Comments on the Approvability of the Medical Device ................ 95
4.3.3 Other Types of Comments .............................................................. 97
4.3.4 The Use of the Word “Concern” In FDA’s Comments .................. 98
4.4 Relationship between FDA Concerns and Advisory Committee Votes .... 100
4.5 Analysis of Survey Results ........................................................................ 104
4.5.1 Information on Survey Respondents ............................................. 104
4.5.2 Views of Respondents Regarding Briefing Books ....................... 107
CHAPTER 5. DISCUSSION .................................................................................. 118
5.1 Summary .................................................................................................... 118
5.2 Consideration of Methods .......................................................................... 118
5.3 Consideration of Results ............................................................................ 125
5.3.1 Characterization of Briefing Books .............................................. 125
5.3.1.1 Length of Briefing Books ................................................ 125
5.3.1.2 Formatting Inconsistencies between Reviewing
Divisions .......................................................................... 127
5.3.1.3 Comments Included in the Briefing Books ...................... 130

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5.3.2 Summary of Findings and Recommendations .............................. 134
REFERENCES ............................................................................................................... 136

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LIST OF TABLES
Table 1: Drug Advisory Committees Organized by Specialty .....................................30
Table 2: Biologics Advisory Committees Organized by Specialty ..............................36
Table 3: Medical Device Advisory Committees Organized by Specialty ....................40
Table 4: Laws, Regulations & Guidance Documents for FDA Advisory
Committees ................................................................................................43
Table 5: Steps to Convene an Advisory Committee .....................................................55
Table 6: Medical Device Advisory Committees (April 2010 – April 2013) ................76
Table 7: Summary of the Coding Scheme and Example ..............................................78
Table 8: Frequency of Medical Device Advisory Committee Meetings ......................81
Table 9: The Use of Comments Explained in the Introduction of the FDA
Briefing Book.............................................................................................87
Table 10: Examples of the Multiple Comment Formats Used by FDA .........................91
Table 11: Examples of the Different Types of Comments .............................................93
Table 12: Question 13: Do you have anything that you would like to share? ..............117

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LIST OF FIGURES
Figure 1: Key Dates in the Development of Drug Advisory Committees .....................26
Figure 2: Key Dates in the Development of Biologics Advisory Committees ..............34
Figure 3: Key Dates in the Development of Medical Device Advisory
Committees ................................................................................................37
Figure 4: Sample Advisory Committee Agenda ............................................................58
Figure 5: Sample FDA Advisory Committee Question .................................................60
Figure 6: Potential Sources of Bias Introduced Into Advisory Committees ..................64
Figure 7: Frequency of Medical Device Advisory Committee Meetings ......................82
Figure 8: Length of Medical Device FDA Medical Device Briefing Books .................83
Figure 9: Average Number of Tables and Figures in Medical Device Briefing
Books .........................................................................................................84
Figure 10: Number of FDA Comments Organized by Division ......................................92
Figure 11: Number of Comments on Approvability in the FDA Briefing Books ............96
Figure 12: Number and Types of Concerns per Briefing Book .......................................98
Figure 13: Number of Times FDA Uses the Word “Concern” in Their
Comments ................................................................................................100
Figure 14: Relationship between FDA Concerns and Advisory Committee Votes .......101
Figure 15: Relationship between FDA’s use of the Word “Concern” and
Advisory Committee Votes......................................................................102
Figure 16: Proportion of ‘Yes’ Votes and the Number of Concerns .............................103

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Figure 17: Proportion of ‘Yes’ Votes and the Number of Times FDA Uses the
Word “Concern” ......................................................................................104
Figure 18: Advisory Committee participation by respondents ......................................106
Figure 19: Question 3: What is the ideal length of the FDA Briefing Materials? .........107
Figure 20: Question 4: If you participated in more than one advisory meeting,
do you feel that the format of the FDA Briefing Materials was
consistent? ................................................................................................108
Figure 21: Question 5: If you participated in more than one advisory meeting,
do you feel that the type of content of the FDA Briefing Materials
was similar? .............................................................................................109
Figure 22: Question 6: In the Introduction section of the FDA briefing materials,
guidance is typically provided as described below. .................................110
Figure 23: Question 7: Do FDA briefing materials help you in forming your
opinion on the risk-to-benefit ratio of the medical device? .....................111
Figure 24: Did you feel that the FDA communicated its opinion on the risk-to-
benefit of the medical device in the briefing materials that you
have reviewed?.........................................................................................112
Figure 25: Question 9: Below is an example of comment that the FDA included
in one set of briefing materials.................................................................113
Figure 26: Question 10: Below is an example of a recommendation that FDA
included in one set of briefing materials. .................................................114

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Figure 27: Question 11: In March 2010, the FDA issued a press release with
changes to the Medical Device Advisory Committee process. In
the release, they stated they would no longer comment on the
approvability of the medical device to the advisory committee. In
your experience, to what extent does FDA follow this guidance? ..........115
Figure 28: Question 12: Do you think that restrictions on the ability of FDA to
comment on the approvability of a device is a progressive or
retrogressive step in supporting the work of advisory committees? ........116

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ABSTRACT
The primary role of an FDA advisory committee is to provide independent, expert
scientific advice to support FDA’s evaluation of specific drugs, biologics, or medical
devices. The FDA briefing book, which serves as a significant conduit for
communication between the FDA and the advisory committee, may have the potential to
influence advisory committee members by virtue of its format and content. FDA briefing
books between April 2010 and April 2013 were analyzed to identify if document content
and format were notably different between the different medical device divisions of the
FDA. In addition, using methods of content analysis, the study evaluated whether the
FDA commented on the approvability of the medical device and whether the tone and
content of the briefing materials conveyed FDA’s opinion on the risk-to-benefit profile of
the device. Further, a survey of advisory committee members was undertaken to evaluate
if briefing book content was considered to be influential in how the committee member
felt about the risk-to-benefit profile of the medical device. The research identified that the
content and format of the briefing books varied between the different medical device
divisions suggesting no overarching process for creating a briefing book. In addition, the
comments included in the briefing book often included opinions, concerns, and even
recommendations to advisory committee members. It was identified that FDA directly or
indirectly commented on the approvability of the medical device in five different briefing
books. The survey showed that advisory committee members felt that comments
expressing negative FDA opinions or concerns were at least somewhat influential, and

14
that the briefing book as a whole generally used text and tone that conveyed FDA’s
opinion with regard to the risk-to-benefit profile of the product under review.

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CHAPTER 1. OVERVIEW OF THE STUDY
1.1 Introduction
The U.S. Food and Drug Administration (FDA) regulates more than 150,000 marketed
drugs and medical devices. The list of covered products gradually lengthens each year
through the addition of some subset of the nearly 3,000 investigational new drugs under
development at any one point in time (FDA 2011). Before they are added to the list, new
candidate medicines and medical devices must be scrutinized for risks and benefits by a
specialized review team at the FDA. However, even the most knowledgeable FDA staff
members composing these teams often recognize the value of supplementing their
medical and scientific experience with input from “special government employees”, hired
to provide additional counsel to further their goals to provide safe and effective products
through rigorous scientific review. These outside advisers make up the FDA’s advisory
committees.
Advisory committees to the FDA have a number of functions. Their primary role is to
“provide independent expert advice to the agency on scientific, technical, and policy
matters related to the development and evaluation of FDA-regulated products” (FDA
2008a). For specific products, advisory committees consider the available data and
provide scientific and medical judgments on safety, efficacy, and appropriate use.
Committees may also be asked to participate in the agency’s decision-making process as
the agency considers broader regulatory and scientific issues. Advisory committee

16
meetings can occur during any stage of a product’s review process or, if necessary, when
post-marketing issues arise. The opinions of the advisory committee are taken very
seriously. Nevertheless their recommendations are advisory in nature; all final decisions
on both policy and technical matters are made by FDA (Ackerley, Eyraud et al. 2009).
FDA advisory committees were first used in the 1960s, when rapidly expanding
technology in pharmaceutical development led to a growing opinion among scientists and
public health experts that the FDA could perform its mission to protect the safety of the
public more effectively by using outside scientific experts. The agency extended its use
of such committees in the early 1970s to the review of biologics, and following the
Cooper report of 1970, to assist with the risk based classification of medical devices
(Rettig, Earley et al. 1992). With the passage of the Federal Advisory Committee Act in
1972, Congress formally recognized the value of seeking advice from non-government
employees. The regulation appears today in the Code of Federal Regulations (CFR),
Title 21, Part 14. It characterizes an advisory committee as follows:
An advisory committee has a fixed membership, a defined purpose of providing
advice to the agency on a particular subject, regular or periodic meetings, and an
organizational structure, for example, a chairman and staff, and serves as a
source of independent expertise and advice rather than as a representative of or
an advocate for any particular interest (FDA 1999).
The agency describes the purpose of advisory committees in very general terms. It
advocates their use when:
the Commissioner concludes, as a matter of discretion, that it is in the public
interest for a standing or ad hoc committee (advisory committee or committee) to
hold a public hearing and to review and make recommendations on any matter

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before FDA and for interested persons to present information and views at an
oral public hearing before the advisory committee (FDA 1999).
Advisory committees sometimes play a role in the early stages of product development
and in the evaluation of post marketing issues but their primary function is to evaluate
applications for marketing approval – new drug applications (NDAs) for drugs, biological
license applications (BLAs) for biologics, and pre-market approvals (PMAs) for medical
devices.
Advisory committees play a critical role in the approval process. Although the advice of
the committees is not binding on the FDA, the recommendations of the committee are
regarded as a strong predictor of the actions that the agency will take. For example, in a
study by Zuckerman (2006) that reviewed medical device advisory committee voting
patterns between 1998 and 2005, 94% of the devices recommended for approval were
subsequently approved by the FDA. As a result, FDA advisory committees have become
highly visible to the public, the Congress, the media, and the financial investment
community as a bellwether of product approval or disapproval. A committee meeting
involving a particularly controversial product or matter can draw an audience of 300 to
400 individuals that typically includes members from the investment community,
competitors, media, and patient advocates.
Membership on advisory committees must be “fairly balanced”, as open and inclusive as
possible according to the Federal Advisory Committee Act. Committee membership is
expected to include ethnic, gender, and geographic diversity, and at the same time to have

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individuals such as clinicians and researchers with recognized expertise and judgment in
a specific field. Most members of FDA’s Drug Advisory Committees are physician-
scientists whose specialties or research involve the types of products under review. Other
members might include statisticians, epidemiologists, nutritionists, and toxicologists. The
FDA also insists on having access to industry and public perspectives. Thus, nearly all
committees include industry and consumer representation (Pub. L. 92-463 1972).
1.2 Statement of the Problem
The primary role of an FDA advisory committee is to provide independent, expert
scientific advice to the agency that will support its evaluation of specific drugs, biologics,
and medical devices at any stage of consideration by the agency. To assure this
independence, the committee should be free from influence by the sponsor of the product
under consideration and from any other entities or persons who have a vested interest in
the outcome of the process. Most attention in the past has been focused on the potential
conflicts of interest and undue influence exerted by medical product companies.
However, this undue influence could also come from the FDA. A previous criticism of
FDA’s behavior toward advisory committees is that they seek to control or influence an
outcome that is aligned with its interests or opinions. The charge of “undue influence” is
often made about the wording of the questions posed to a committee (Rettig, Earley et al.
1992), and the preliminary analysis of the sponsor’s data published in the FDA briefing
book. Leading questions and poorly balanced analyses of the sponsor’s data could

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unduly influence an advisory committee, which is intended to be an independent voice in
the FDA approval process.
In 2008, the FDA published a guidance document on advisory committees. The guidance
included best practices to reduce the potential for bias during an advisory committee
meeting. The guidance advised “that the question presented for a vote should have
minimal qualifiers, not be leading, and should avoid the use of double or triple
negatives”, in an effort “to help maximize the integrity, consistency and utility of
advisory committee voting results”, (FDA 2008b). Further, the Institute of Medicine
(IOM) recommended in their report published in 1992 on FDA advisory committees that
the agency should remain neutral during advisory committee meetings.
As a general proposition, the IOM committee believes that FDA staff
members should conduct themselves at advisory committee meetings in
ways that avoid the appearance of exerting undue influence over the
committee. Agency presentations to a committee should focus on the
critical evaluation of data but should not withhold or disguise expressions
of agency concerns with an application. The tone of agency presentations
should be professional, thorough, and dispassionate, and agency staff
should not dominate or appear to dominate committee discussions (Rettig,
Earley et al. 1992).
However, it is not clear the extent to which this instruction is being followed, and to what
extent the advisory committees are able to serve as arms’ length advocates.
1.3 Purpose of the Study
Prior to all medical device advisory committee meetings, the FDA publishes briefing
materials referred to on the FDA website as an FDA Executive Summary and also

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commonly known as a FDA briefing book, which includes analyses of the sponsor’s data.
In 2010, the FDA released a statement, in which they said that they would no longer
comment on the approvability of the medical device in their analysis, and would no
longer present a “unified, consensus analysis”. Rather they would present a range of
scientific opinions (FDA 2010a).
The FDA briefing book is one of the few documents reviewed by the majority of the
committee members, as identified by 3D Communications in their publication on how
FDA advisory committee members prepare and what influences them. Their survey
findings showed that approximately 98% of committee members said their vote was
“very much” or “quite a bit” influenced by the FDA briefing documents (McIntyre 2012).
This study characterized the FDA briefing documents published on the FDA website
between April 2010 and April 2013 by the different FDA medical device divisions within
the Office of Device Evaluation, in terms of the absence or presence of potentially
influential statements or inferences in the text and tone of the language. The 30 medical
device advisory committee meetings included in the collection of source material was
studied to identify if the briefing book content and format was notably different between
the different divisions within the FDA. Also, using methods of content analysis, the study
identified whether the FDA directly commented on the approvability of the medical
device and whether the tone of the comments suggested support or disapproval of the
product. Further, a survey of advisory committee members who participated in at least
one of the meetings was undertaken to evaluate if the FDA analysis of the briefing

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documents, or FDA’s comments in the briefing documents, was in his or her view
influential in how the advisory committee member felt about the risk to benefit profile of
the medical device.
1.4 Significance of the Study
This study contributes to a small but important body of research concerned with FDA
advisory committees. Thus far, most research performed in this area evaluates the
disclosure of financial conflict of interest and voting patterns of members; the strengths
and weaknesses of the FDA advisory committee process; and the use of advisory
committees by FDA. This study appears to provide the first objective analysis to evaluate
FDA’s neutrality when they serve as an intermediary to transmit data to the advisory
committees for their unbiased review. The results may assist in identifying weaknesses in
the medical product approval process. If such weaknesses are found to exist, the results
would provide information of value to the FDA as an evaluative tool to assess the
effectiveness of policy implementation. It might further guide policy development and
ultimately improve the advisory committee process.
1.5 Delimitations, Limitations and Assumptions
Advisory committees are formed to assist the approval process for specific drugs,
biologics, and medical devices. This study is delimited in its focus to medical devices in
the United States, which are handled by the Center for Devices and Radiological Health
(CDRH). This study is further delimited to those advisory committee meetings that took

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place between April 2010 and April 2013. This study will focus primarily on FDA
briefing books, and will not extend to other types of materials that might be provided by
other sources, and will not extend to verbal or written interactions of other kinds such as
emails to individual participants in the advisory committees. In addition, the survey
portion of this study will be delimited to professionals who have participated in at least
one medical device advisory committee meeting, and are identified in 3D
Communications Database of advisory committee members.
As with any study using content analysis methods, the strength of conclusions will be
affected by the ability of a reviewer to code and interpret the data accurately and
consistently. As an exploratory study, its conclusions will be limited to the study of
documents from a modest subset of FDA advisory committees, and these may not
represent adequately the advisory committee process as a whole, and particularly the
nature of content in briefing documents from advisory committees in other branches of
the FDA. In the future, the study would have to evaluate a larger sample of advisory
committees across multiple FDA divisions, to assure the external validity of any findings
of this study with respect to the advisory committee process across all branches of the
FDA. The number and availability of advisory committee members who will respond to
the survey limit the survey portion of the study. Research such as this dealing with
sensitive topics may be limited by the willingness of the respondent to share sensitive
information. The study may also have limitations related to the degree of skill and
experience of the researcher with this type of research. The results presented here will

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therefore be preliminary and should be viewed as a starting point in a more detailed
consideration and analysis of FDA advisory committees.

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CHAPTER 2. LITERATURE REVIEW
2.1 Background
FDA is responsible for protecting the public health by assuring the safety,
efficacy and security of human and veterinary drugs, biological products,
medical devices, foods, cosmetics, and products that emit radiation. They
are also responsible for advancing the public health by helping to speed
innovations that make medicine more effective, safer, and more affordable
and by helping the public to acquire the accurate, science-based
information that they need to use medicines and foods to maintain and
improve their health (FDA 2012a).
With such a broad charter, the FDA has come to rely on experts outside of the agency to
obtain independent advice on scientific, technical and policy matters. Public advisory
committees are used widely throughout the federal government for a variety of purposes.
They may be ad hoc or standing committees, which can be classified further as policy
advisory committees and technical advisory committees. Policy advisory committees
advise on broad and general matters whereas technical advisory committees deal with
specific technical or scientific issues that may relate to regulatory decisions (FDA 1999).
This study will focus on certain aspects of conduct in standing technical advisory
committees that make recommendations to the FDA on the approvability of a medical
device.
FDA advisory committee meetings are crucially important for companies that have
invested years of effort and millions of dollars in research, development, and clinical
trials, for a product that might promise billions of dollars in potential revenue once
marketed. In 2012, Eli Lilly posted on the company’s corporate blog, during the Super

25
Bowl, that the average cost of bringing a drug to market is $1.3 billion, a price that would
buy 371 Super Bowl ads, 16 million official NFL footballs, two pro football stadiums, the
pay of almost all NFL football players, and every seat in every NFL stadium for six
weeks in a row (Herper 2012). Other estimates from academic sources estimate drug
development costs to be between $500 million to more than $2 billion for each new drug
(DiMasi, Hansen et al. 2003, Adams 2006, Dickson 2009). Thus, when advisory
committee meetings are called, companies expend considerable effort to prepare the best
case possible to support the approval of their products. To prepare for an advisory
committee meeting, companies will put together dedicated teams that start working
months prior to the meeting on the messaging and communication activities that will be
delivered the day of the hearing. They often hire outside expert consulting companies to
develop a professionally designed set of activities that will help them to prepare for the
meeting.
Advisory committee meetings are risky for drug and device companies because
“independent evaluations” by experts, which are developed in a one-day meeting, can be
relatively subjective but nevertheless influential with regard to approvability of the
product under consideration. Thus, much that has written about advisory committees has
focused on improvements to the FDA advisory committee process and also the voting
habits of advisory committee members, many of whom can have potential conflicts of
interest. However, little has been written about the influence of the FDA on advisory
committees. In the literature review below, I will first examine the history of advisory

26
committees, starting with their inception and evolution. Then the regulatory framework
surrounding advisory committees, including the laws, regulations, and guidance
documents by which they operate, will be discussed in detail. A third section will provide
a detailed discussion of the advisory committee process, including the multiple parts of a
committee hearing. Finally, the literature will conclude with a consideration of the
current state of advisory committee decision-making and unanswered questions that will
be a focus for the research in subsequent chapters.
Figure 1: Key Dates in the Development of Drug Advisory Committees

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2.2 Advisory Committees for Drugs
The FDA has used drug advisory committees since the early 1960s, although the early
advisory committees were different in structure and function than those configured
currently. The first drug advisory committees were created to help satisfy a particular
requirement of the 1962 drug amendments to the Food, Drug, and Cosmetic Act (Pub.L.
87-781) that increased regulatory oversight to assure the safety of new pharmaceutical
products. The history of these amendments has been documented repeatedly elsewhere.
Briefly, they were written in response to a tragedy in Europe in which the use of a drug
sold under the brand name, Kevadon, more commonly known as Thalidomide in the US,
led to of a constellation of related children’s birth defects that included phocomelia, a
rare condition characterized by missing or highly-malformed limbs. When the adverse
effects of Thalidomide were discovered in Europe, the drug was undergoing clinical
evaluation in the US, and had yet to be approved for sale (Stepp 1999). Nevertheless,
concerns that this type of drug could have easily slipped into clinical use and commerce
spurred Congress to enact the US Kefauver Harris Amendment, or “Drug Efficacy
Amendment”. The amendment served to strengthen the current regulations around drug
safety and for the first time required drug manufacturers to demonstrate effectiveness of
their drug prior to marketing (FDA 2012c).
The Drug Efficacy Amendment had a number of new requirements. One that was
particularly salient to this thesis was its requirement that the FDA reevaluate the nearly
4,000 prescription drugs that had been approved between 1938 and 1962 on the basis of

28
safety alone. In those early years, the Food, Drug, and Cosmetics Act (Pub. L. 75-717)
permitted the marketing of drugs on the basis of relatively modest tests of safety; there
was no regulatory requirement to prove efficacy. The Drug Efficacy Amendment raised
the regulatory bar by requiring that drugs provide “substantial evidence” of the drug’s
efficacy for a marketed indication. The FDA contracted with an external group, the
National Academy of Sciences-National Research Council (NAS-NRC), to evaluate the
effectiveness of these 4000 historically approved drugs (Rettig, Earley et al. 1992), in
what came to be known as the Drug Efficacy Study. Several medical advisory boards
were created to provide the needed medical and scientific expertise to evaluate the drugs.
The new medical advisory boards were confronted with a huge challenge - 3,000 to 4,000
marketed products whose applications had been filed between 1938 and 1962 and would
have to be reevaluated for effectiveness (Rettig, Earley et al. 1992). A Policy Advisory
Committee (PAC), consisting of representatives from academic and professional
medicine, pharmacology, industry, and medical sociology, was established to develop
guidelines to govern the submission of data and the evaluation of the drugs under review.
Then, 180 specialists were assembled into thirty different advisory committees, each
responsible to evaluate drugs in one of 60 categories of therapeutic effect, that together
covered all of the drug applications received between 1938 and 1962 that were to be
reviewed over a three year period beginning in 1966. Each advisory committee reviewed
approximately 150 reports (Stepp 1999).

29
The Policy Advisory Committee, along with the chairman from each of the thirty panels,
assigned the drugs to be reviewed by each panel. The panels, early precursor models for
advisory committees, sought evidence of drug efficacy from data provided in four main
sources: 1) briefs submitted by the sponsor of the drug; 2) additional evidence directly
solicited from the sponsor; 3) files from the FDA; and 4) medical literature brought in by
the expert panelists. Each individual claim for a drug was evaluated separately. Thus,
each panel was required to make thousands of decisions about the validity and
appropriateness of many pieces of scientific data regarding the drug under study, and
ultimately to produce an overall decision regarding the drug’s efficacy. Drugs were
classified as effective, probably effective, possibly effective, or ineffective. The reports
were advisory in nature and FDA retained the authority to disagree with the report (Edsall
1985).
The advisory committees that followed the Drug Efficacy study established the
foundation for the current advisory committee process, but some notable differences
could be recognized between early and current FDA practices related to advisory
committee activities. When the Drug Efficacy study advisory committees were
configured, the FDA had no role in selecting panel members, the makeup of the
committee was not disclosed, and the established procedures were much less stringent
than those used today (Rettig, Earley et al. 1992). In the late 1960s, in response to the
increased use of advisory committees by the federal government, Congress held a series
of hearings to examine the use of federal advisory committees by the executive branch.

30
Based on the outcome of the investigation, the House Committee issued
recommendations that were incorporated into a bill introduced in 1971 to regulate
advisory committees. In 1972, the Federal Advisory Committee Act (FACA) was signed
into law. It formalized the process for establishing, operating, overseeing, and
terminating federal advisory committees (Pub. L. 92-463 1972).
Drug advisory committees continued to change over the years. Small modifications were
made to the structure and procedural approaches of the committees. For example,
consumer representatives were added to the committees in the late 1970s. In addition,
standing rather than ad hoc advisory committees were implemented, to create a more
structured and cohesive process. The number of standing drug advisory committees
continued to grow and FDA currently has seventeen standing drug advisory committees
shown in Table 1 (FDA 2012d).
Table 1: Drug Advisory Committees Organized by Specialty
CENTER FOR DRUG EVALUATION AND RESEARCH
Advisory Committee Purpose Date
Established
Anesthetic and Life
Support Drugs Advisory
Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
the field of anesthesiology and surgery.
May 1, 1978
Anti-Infective Drugs
Advisory Committee
Reviews and evaluates available data
concerning the safety and effectiveness
of marketed and investigational human
drug products for use in the treatment of
infectious diseases and disorders.
October 7,
1980

31
Advisory Committee Purpose Date
Established
Antiviral Drugs
Advisory Committee
Reviews and evaluates available data
concerning the safety and effectiveness
of marketed and investigational human
drug products for use in the treatment of
acquired immune deficiency syndrome
(AIDS), AIDS-related complex (ARC),
and other viral, fungal, and
mycobacterial infections.
February 15,
1989
Arthritis Advisory
Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
arthritic conditions.
April 5, 1974
Cardiovascular and
Renal Drugs Advisory
committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
cardiovascular and renal disorders.
August 27,
1970
Dermatological and
Ophthalmic Drugs
Advisory Committee
Reviews and evaluates available data
concerning the safety and effectiveness
of marketed and investigational human
drug products for use in the treatment of
dermatologic and ophthalmic conditions
October 7,
1980
Drug Safety and Risk
Management Advisory
Committee
Reviews and evaluates data on risk
management plans, provides active
surveillance methodologies, trademark
studies, methodologies for risk
management communication, and
related issues.
May 31, 1978
Endocrine and
Metabolic Drugs
Advisory Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
endocrine and metabolic disorders.
August 27,
1970
Reproductive Health
Drugs
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
March 23,
1978

32
Advisory Committee Purpose Date
Established
the practice of obstetrics, gynecology,
and related specialties.
Gastrointestinal Drugs
Advisory Committee
Reviews and evaluates data on the
safety effectiveness of marketed and
investigational human drugs for use in
gastrointestinal diseases.
May 3, 1978
Oncologic Drugs
Advisory Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
treatment of cancer.
September 1,
1978
Peripheral and Central
Nervous System Drugs
Advisory Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
neurological disease.
June 4, 1974
Psychopharamcological
Drugs Advisory
Committee
Reviews and evaluates data on the
safety and effectiveness of marketed and
investigational human drugs for use in
the practice of psychiatry and related
fields.
June 4, 1974
Pulmonary – Allergy
Drugs Advisory
Committee
Reviews and evaluates data on the
safety and effectiveness of marked and
investigational human drugs for use in
the treatment of pulmonary disease and
diseases with allergen and/or
immunologic mechanisms.

February 17,
1972
Advisory Committee for
Pharmaceutical Science
and Clinical
Pharmacology
The committee shall provide advice on
scientific, clinical and technical issues
related to safety and effectiveness of
drug products for use in treatment of a
broad spectrum of human diseases.
Jan 22, 1990

33
Advisory Committee Purpose Date
Established
Nonprescription Drugs
Advisory Committee
The committee reviews and evaluates
available data concerning the safety and
effectiveness of nonprescription human
drug products.
August 27,
1991

34
Figure 2: Key Dates in the Development of Biologics Advisory Committees

2.3 Advisory Committees for Biologics
A biological product is defined as a “virus, therapeutic serum, toxin, antitoxin, vaccine,
blood component or derivative, allergenic product, or analogous product…applicable to
the prevention, treatment, or cure of a disease or condition of human beings” (FDA
2009). Biological products are amongst the first therapeutic products to be regulated by
the federal government. The first regulations of biological products resulted from the
Biologics Control Act of 1902, which was prompted by two incidents in which children
died from contaminated vaccines. The Act delegated the regulation of biologics and the
research necessary to support such regulation to the US Treasury Department’s Hygienic
Laboratory of the Public Health and Marine Hospital Service. The Hygienic Laboratory

35
evolved into the Center for Biologics Evaluation and Research (CBER) (FDA 2002),
which was under the authority of the National Institute of Health (NIH) (Stepp 1999).
In 1972, Congress adopted the Consumer Safety Act, which transferred authority for the
regulation and review of biologics from the NIH to the FDA, and prompted the formation
of the Bureau of Biologics. The FDA was compelled to apply the requirements to
demonstrate safety and effectiveness implicit from the 1962 “Drug Efficacy”
Amendment, described earlier, to its newly acquired catalogue of biological products.
The resulting reexaminations became known as the “Biologics Review”. Biologics, like
drugs before them, were grouped into multiple categories. Manufacturers were contacted
to provide supporting data, and six standing advisory committees were created to review
the materials that were received (Stepp 1999). The committees were responsible to assure
that biologics met efficacy standards, but also evaluated safety more directly in the
context of the data that it was given.
As the FDA worked with the newly formed Biologics Advisory Committees, it became
apparent that standing advisory committees were needed on an ongoing basis for the
approval of new biologics as they sought commercial registration in the future. After the
committees finished their one-time review of existing biologics, the agency restructured
the original committees. The charter of the committees was also changed to include
certain new tasks: to give ongoing advice about new products; to advise on general
problems that occurred with both marketed and experimental products; and to review
intramural research (Rettig, Earley et al. 1992).

36
The FDA currently has five standing Biologics Advisory Committees. The first
committee to be formed was the Vaccines and Related Biological Products Advisory
Committee, established in 1979. Three more were established in the 1980s to deal with
allergenic products, cell, tissue and gene therapy products and blood products
respectively. The final committee was established in the mid-1990s to evaluate products
that could transmit spongiform encephalopathies, as shown in Table 2 (FDA 2010c).
Table 2: Biologics Advisory Committees Organized by Specialty
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
Advisory Committee Purpose Date Established
Vaccines and Related
Biological Products
Advisory Committee
Reviews and evaluates data on the
safety and effectiveness of vaccines
intended for use in the diagnosis,
prevention, or treatment of human
disease.
December 31,
1979
Allergenic Products
Advisory Committee
Reviews and evaluates data on the
safety and effectiveness of allergenic
biological products intended for use
in diagnosis, prevention, or treatment
of human disease.
July 9, 1984
Cellular, Tissue, and Gene
Therapies Advisory
Committee
Reviews and evaluates available data
relating to the safety, effectiveness,
and appropriate use of human cells,
human tissues, gene transfer
therapies and xenotransplantation,
implantation, infusion, and transfer in
the prevention and treatment of a
broad spectrum of human diseases
and in the reconstruction, repair or
October 28,
1988

37
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
Advisory Committee Purpose Date Established
replacement of tissues for varied
conditions.
Blood Products Advisory
Committee
Reviews and evaluates data on the
safety and effectiveness, and
appropriate use of blood products
intended for use in the diagnosis,
prevention, or treatment of human
disease.
May 13, 1980
Transmissible Spongiform
Encephalopathies
Advisory Committee
Reviews and evaluates available
scientific data concerning the safety
of products which may be at risk for
transmission of spongiform
encephalopathies having an impact
on the public health.
June 21, 1995

Figure 3: Key Dates in the Development of Medical Device Advisory Committees

38
2.4 Advisory Committees for Medical Devices
The FDA was given the authority to regulate medical devices in 1938 under the Federal
Food, Drug, and Cosmetic Act (Pub. L. 75-717). The 1938 Act defined “devices” as:
An instrument, apparatus, implement, machine, contrivance, implant, in vitro
reagent, or other similar or related article, including any component, part, or
accessory, which is
(1) recognized in the official National Formulary, or the United States Pharmacopeia,
or any supplement to them,
(2) intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other animals, or
(3) intended to affect the structure of any function of the body of man or other animals,
and which does not achieve its primary intended purposes through chemical action
within or on the body of man or other animals and which is not dependent upon
being metabolized for the achievement of its primary intended purposes.

Under this act, the FDA had the authority to challenge medical devices that were
“misbranded” or “adulterated”. However, for much of the twentieth century,
manufacturers were not required to demonstrate safety and effectiveness prior to
marketing a device.
In 1969, President Richard Nixon called for a thorough study of medical device
management to determine areas in which specific legislation might be needed. Under the
leadership of Dr. Theodore Cooper, Director of the National Heart and Lung Association,
a study group was formed to the review the adequacy of premarket regulations for
medical devices. This report came to be known as the Cooper report (Study Group on
Medical Devices (Cooper Committee) 1970). The report recognized the variety and
complexity of the medical devices that were coming to market and recommended a risk
based classification system, with the highest risk devices requiring premarket approval

39
(Chapman 1994). The report recommended that standing advisory committees be
established as part of the approval system.
The passage of the Medical Device Amendments of 1976 later made several changes to
the 1938 Food, Drug and Cosmetics Act. The amendments established three regulatory
classes for medical devices, in which Class III devices had the highest risk and Class I
devices, had the lowest. It also mandated the creation of permanent advisory committees
for two purposes: 1) to classify medical devices, in order to carry out the ongoing
requirements to classify new devices and 2) to assist with the evaluation of class III
medical devices that require premarket approval. The advisory committees were to be
configured with a chairman, industry members, nonvoting consumer members, and
experts that were qualified in the particular types of devices assigned to that committee.
The secretary shall point to each panel established under paragraph (1) persons
who are qualified by training and experience to evaluate the safety and
effectiveness of the devices to be referred to the panel and who, to the extent
feasible, possess skills in the use of, or experience in the development,
manufacture, or utilization of, such devices. The secretary shall make
appointments to each panel so that each panel consist of members with
adequately diversified expertise in such fields as clinical and administrative
medicine, engineering, biological, and physical sciences, and other related
professions. In addition, each panel shall include as nonvoting members a
representative of consumer interests and a representative of interest of the device
manufacturing industry (Pub. L. 94-295 1976 ).
The advisory committee process was again modified following passage of the Safe
Medical Devices Act (SMDA) of 1990 (Pub. L. 101-629 1990). The act did not change
the original committee mandates of the 1976 amendments, but gave the agency more
flexibility in the use of advisory committees. Prior to the act all pre-market approvals

40
were required to be reviewed by advisory committees. The new act made such reviews
optional so that the committees could focus their precious, and expensive, energies on the
most innovative technologies that had greater risks. The FDA currently has eighteen
advisory committees, configured by area of specialty, as shown in Table 3 (FDA 2012e).
Table 3: Medical Device Advisory Committees Organized by Specialty

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
Advisory Committee Purpose Date
Established
Anesthesiology and
Respiratory Therapy
Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational devices for use in
anesthesiology and respiratory therapy.
April 14, 1984
Circulatory System
Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational devices for use in the
circulatory and vascular systems.
April 14, 1984
Clinical Chemistry and
Clinical Toxicology
Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in vitro devices for
use in clinical laboratory medicine
including clinical toxicology, clinical
chemistry, endocrinology and oncology.
April 14, 1984
Dental Products Panel Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational products for use in
dentistry, endodontics or bone
physiology relative to the oral and
maxillofacial area.
April 14, 1984
Ear, Nose, and Throat
Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
April 14, 1984

41
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
Advisory Committee Purpose Date
Established
and investigational ear, nose, and throat
devices.
Gastroenterology –
Urology Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational gastroenterology,
urology and nephrology devices.
April 14, 1984
General and Plastic
Surgery Devices Plane
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational general and plastic
surgery devices.
April 14, 1984
General Hospital and
Personal Use Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational general hospital,
infection control and personal use
devices.
April 14, 1984
Hematology and
Pathology Devices Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in-vitro devices for
use in clinical laboratory medicine
including pathology, hemotology,
histopathology, cytotechnology and
molecular biology.
April 14, 1984
Immunology Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in-vitro devices for
use in clinical laboratory medicine
including oncology, immunology and
allergy.
April 14, 1984
Medical Devices Dispute
Resolution
Provides advice to the Center Director
on complex or contested scientific issues
between the FDA and medical device
sponsors, applicants, or manufactures
relating to specific products, marketing
April 27, 1999

42
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
Advisory Committee Purpose Date
Established
applications, regulatory decisions and
actions by FDA, and agency guidance
and policies. The Panel makes
recommendations on issues that are
lacking resolution, are highly complex in
nature, or results from challenges to
agency decisions or actions.
Microbiology Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in-vitro devices for
use in clinical laboratory
April 14, 1984
Molecular and Clinical
Genetics Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in-vitro devices for
use in clinical laboratory medicine
including clinical molecular genetics.
November 1,
1999
Neurological Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational devices for use in the
neurological system.
April 14, 1984
Obstetrics – Gynecology
Device
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational in-vitro devices for
use in clinical laboratory medicine
including clinical and molecular genetics.
April 14, 1984
Ophthalmic Device Panel Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational devices for use in the
eye.
April 14, 1984
Orthopedic and
Rehabilitation Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational orthopedic and
rehabilitation devices.
April 14, 1984

43
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
Advisory Committee Purpose Date
Established
Radiological Devices
Panel
Reviews and evaluates data concerning
the safety and effectiveness of marketed
and investigational diagnostic or
therapeutic radiological and nuclear
medicine devices.
April 14, 1984
2.5 Regulatory Framework around FDA Advisory Committees
The Food and Drug Administration’s website describes the laws, regulations, and
guidance documents that provide the framework for FDA’s advisory committee program
(FDA 2012f). Some of these laws and regulations establish standards for convening
advisory committees and reviewing potential conflicts of interest, among other things.
FDA has also developed specific guidance documents that describe FDA
recommendations and policy related to their interactions with advisory committees.
Table 4: Laws, Regulations & Guidance Documents for FDA Advisory
Committees
LAWS DATE
Federal Advisory Committee Act October 1972
Government in the Sunshine Act September 1976
Food and Drug Administration Amendments Act (FDAAA) of
2007
September 2007

44
REGULATIONS DATE
5 CFR 2640 – Interpretation, Exemptions and Waiver Guidance
Concerning 18 U.S.C 208 (Acts Affecting a Personal Financial
Interest)
January 2007
5 CFR 2635.502 Impartiality in Performing Official Duties January 2008
Public Hearing Before a Public Advisory Committee (Code of
Federal Regulation, 21 CFR Part 14)
April 2008
GUIDANCE DOCUMENTS DATE
Public Availability of Advisory Committee Members’ Financial
Interest Information and Waivers – Final Guidance
March 2012
Procedures for Determining Conflict of Interest and Eligibility for
Participation in FDA Advisory Committees - Final Guidance
August 2008
Voting Procedures at Advisory Committee Meetings – Final
Guidance
August 2008
Preparation and Public Availability of Information Given to
Advisory Committee Members – Final Guidance
August 2008
When FDA Convenes an Advisory Committee – Draft Guidance August 2008
The Open Public Hearing at FDA Advisory Committee Meetings –
Final Guidance
December 2010

2.5.1 Laws
The development of the current system of advisory committees as they are configured
today has evolved gradually with experience and public pressure. In the early 1970s,
members of Congress had two primary concerns with regard to advisory committees.
First, they were concerned about widely held public perceptions that many advisory
committees were inefficient and redundant. Second, they recognized that advisory
committees were not viewed by some as being able or willing to represent the public

45
interest. Committee proceedings were at that time often not made public, so that their
actions lacked transparency (Ginsberg 2009). The Federal Advisory Committee Act
(FACA) was therefore established to create a framework for the current advisory
committee process. By passing the Act in 1972, Congress acknowledged the benefits of
using advisory committees to obtain expert views drawn from business, academic,
governmental and other spheres. It established the first requirements to have a system that
could manage and oversee advisory committees to ensure impartial and relevant
expertise. FACA required that the advice provided by advisory committees be objective
and accessible to the public, and that committee membership be “fairly balanced in terms
of the points of views represented.” (Pub. L. 92-463 1972) .
In addition, the passage of FACA helped to assure a certain level of transparency in the
advisory committee process that was not present previously. Notices of meetings were
required to be published in advance in the Federal Register. All papers, records, and
minutes became subject to the requirements of the Freedom of Information Act, so that
the public could access them. FACA also contained general guidelines for membership,
requiring committees to be “fairly balanced in terms of the points of view represented and
the functions to be performed” (Ginsberg 2009).
FACA legally defined how advisory committees would operate and added new emphasis
on open meetings, and these protections were increased in 1976 when Congress enacted
the Government in the Sunshine Act (Pub.L. 94-409 1976), designed to provide the
public with information relevant to their decision-making while protecting the rights of

46
individuals and the ability of the Government to carry out its responsibilities. The act
reinforced the policy that the “public is entitled to the fullest practicable information
regarding the decision making process of the Federal Government” (Pub.L. 94-409
1976). The importance of all of these new rules for advisory committee function was
reflected in statements by FDA Commissioner Donald Kennedy, who in 1978,
commented:
Governmental decisions, particularly regulatory decisions, should be passed on
publicly available information... This premise underlies the Freedom of
Information Act, the Federal Advisory Committee Act, and the Government in the
Sunshine Act. In enacting each of these statutes, the Congress implemented a
basic principle of our political system: that people affected by governmental
decision have a right to the basis on which they are made. Anyone who questions
the wisdom of a regulatory decision should be able to examine the factual
foundation of the decision (FDA 2010b).
In the 1970s Congress was concerned with the ability of committees to represent the
public rather than private interests. This has also been the subject of more recent
reexamination. In 2006, the Journal of the American Medical Association published an
article by Lurie and colleagues, titled Financial Conflict of Interest Disclosure at FDA
Drug Advisory Committee Meetings. The article noted that several advisory committee
members participated in advisory committee meetings that were passing judgment on
products to which they were linked financially. In its evaluation of advisory committees
held between 2001 and 2004, they reported that sixty-six percent of all meetings included
at least one advisory committee member with a financial conflict (Lurie, Almeida et al.
2006).The publicity given to advisory committee members with financial ties to
pharmaceutical companies helped to drive changes to the advisory committee process,

47
which resulted in 2007 with the passage of a new law. The Food and Drug
Administration Amendments Act (FDAAA) of 2007 (Public Law 110-85 2007)
introduced new initiatives to increase the transparency of the advisory committee process.
This new multifaceted law represented a significant expansion of FDA’s authority.
Amongst its eleven titles were requirements to change the drug approval process, clinical
trials, and promotional materials.
The title of particular relevance to this discussion was Title VII. Under Title VII:
Conflicts of Interest, the law made changes to the conflict of interest rules governing
advisory committees. In an effort to increase transparency, these changes addressed the
way that FDA recruited advisory committee members, and the circumstances under
which conflict of interest exceptions could be granted. The changes made to the advisory
committee process required that all individuals under consideration for appointment to an
advisory committee must disclose to the committee’s executive secretary all financial
interests that would be affected by the actions of the advisory committee. Under the law,
the FDA was then instructed to reduce the number of “conflict of interest” waivers by 5%
each year starting in 2007, progressively over the succeeding four years (Public Law 110-
85 2007). FDA was further instructed to disclose the waivers to the public 15 days prior
to the meeting by posting them on their website.
2.5.2 Regulations
Typically, laws written in the US are relatively high-level, and are delegated to a
government department or agency so that the intent can be described in regulations that

48
specify the rules and standards for compliance with the law. The primary standards for
developing and working with an advisory committee are laid out in regulations described
in Title 21 Part 14, Public Hearing Before a Public Advisory Committee, of the Code of
Federal Regulations (FDA 1999). The regulation includes nine subparts, designated A
through I. Subpart A, General Provisions, describe how public advisory committees are
defined under the Federal Advisory Committee Act. Subpart B, Meeting Procedures,
describes the hearing process, and will be described in detail in the next section.
Subpart C, Establishment and Renewal of Advisory Committees, establishes the
parameters related to the creation, renewal, and termination of an advisory committee.
Subpart D, Records of Meetings and Hearings before Advisory Committees, describes
requirements for administrative records and advisory committee records. Subpart E,
Members of Advisory Committees, describes the qualifications of members and the
nomination process to select a member of an advisory committee. Subpart F, Standing
Advisory Committees, provides a list of standing advisory committees. Finally, Subpart
G and H describe the special rules specific to the Technical Electronic Products Radiation
Safety Standards Committee and Color Additive Advisory Committee, respectively.
Additional guidance is provided by other regulations. Both 5 CFR 2635.502, Impartiality
in Performing Official Duties, and 5 CFR 2640, Interpretation, Exemption and Waiver
Guidance Concerning 18 U.S.C 208 (Acts Affecting a Personal Financial Interest),
address potential financial conflicts of interest for advisory committee members. The

49
Code of Federal Regulations 5 CFR 2635.502 uses a broad description when describing a
potential conflict of interest. It states:
Where an employee knows that a particular matter involving specific
parties is likely to have a direct and predictable effect on the financial
interest of a member of his household, or know that a person with whom
he has a covered relationship is or represents a party to such matter, and
where the person determines that the circumstances would cause a
reasonable person with knowledge of the relevant facts to question his
impartiality in the matter, the employee should not participate in the
matter unless he has informed the agency designee of the appearance
problem and has received authorization from the agency designee.
The topic of financial conflicts of interest of members serving on FDA advisory
committees has received increased scrutiny over the past several years (Steinbrook 2005,
Kondro 2006, Lurie, Almeida et al. 2006, Zuckerman 2006). Most of these discussions
centered on the potential ability of financial contributors to sway the views of advisory
committee members in favor of the entity providing the financial support. However, hard
evidence that financial interests will “buy” the support of the advisory committee
members has not yet been presented. In fact, several studies that have evaluated the
financial interests of committee members with respect to drug companies have not been
able to develop a case to show substantial impact of such conflicts on the guidance and/or
vote that the member renders to the FDA regarding the approvability of the drug, device,
or biologic. One of the most comprehensive studies in the literature performed by
Ackerley and colleagues (Ackerley, Eyraud et al. 2009), actually showed that advisory
committee members with financial ties to pharmaceutical companies tend to vote against
the financial interest of those companies. The study was based upon data collected for
CDER meetings held between January 2001 and the first quarter of 2008. Data was

50
compiled from publicly available advisory committee transcripts, agendas, rosters, and
minutes from the FDA website. For committee members granted waivers, the author
obtained information from FDA regarding the nature of the financial interest.
2.5.3 Guidance Documents
Although regulations help to clarify legal expectations, they often provide too little detail
regarding particular policies, procedures or benchmarks for those who must understand
and implement some of their requirements. Guidance documents are therefore written by
the agency to whom enforcement is delegated, to describe current thinking on a
regulatory issue (FDA 2012b). In 2008, FDA released four such final guidance
documents and one draft document, which elaborated on the policies and procedures for
the management of its advisory committees. The guidance documents were produced as
part of an effort to bring greater transparency and public awareness to the work of
advisory committees by imposing stricter limits on financial conflict of interest for
committee members, enhancing voting procedures, and disclosing more information
pertaining both to the qualifications and conflicts of advisory committee members and to
specific matters considered at advisory committee meetings. To date, FDA has released a
total of six guidance documents related to advisory committees, including the four
released in 2008.

51
2.5.3.1 FDA GUIDANCE DOCUMENT ONE AND TWO -- Financial Conflict of
Interest
Two of the guidance documents, Guidance for the Public, FDA Advisory Committee
Members, and FDA Staff: Public Availability of Advisory Committee Members Financial
Interest Information and Waivers (FDA 2012g), and Guidance for the Public, FDA
Advisory Committee Members, and FDA Staff on Procedures for Determining Conflict of
Interest and Eligibility for Participation in FDA Advisory Committees (FDA 2008a),
address the topic of financial conflict of interest.
The guidance suggested that FDA would adopt stricter criteria when granting a conflict
of interest waiver in an effort to achieve the goal set forth in the Food and Drug
Administration Act of 2007 (FDAAA) of reducing the number of granted waivers. FDA
instituted a cap of $50,000 as the maximum personal financial interest that an advisor
could hold in all companies affected by a particular meeting. If the personal financial
interest of an advisor, his/her spouse and minor children were to be greater than $50,000,
he or she would not be allowed to participate in the meeting. If the conflict were to be
less than $50,000, the FDA had the option to grant a waiver, but would do so only if they
identify a critical need for the area of expertise of that advisor. All waivers issued by
FDA would have to disclose the conflict of interest and the reason why the expert was
essential for the work of the committee. This information would then be posted on the
FDA’s website prior to the particular meeting in question.

52
2.5.3.2 FDA GUIDANCE DOCUMENT THREE -- Voting Procedures
The guidance document: Guidance for FDA Advisory Committee Members and FDA
Staff: Voting Procedures for Advisory Committee Meetings (FDA 2008b), addresses
methods that might be used to govern voting by committee members, in order to avoid
the perception that votes were manipulated. Previously, members of advisory committees
were called upon sequentially by the committee chair and asked to announce his/her vote
verbally to the rest of the committee. However, this sequential method was criticized as
potentially contributing to “voting momentum” (Callander 2007) in which voters may be
influenced, even subconsciously, by the opinions of those who voted before them. The
guidance recommended the use of simultaneous voting, in which all members vote at
once. Guidance was also provided on the way that questions, in which members voted on
were worded. The guidance recommended that the questions presented for a vote should
have minimal qualifiers, should not be leading, and should avoid the use of double or
triple negatives.
2.5.3.3 FDA GUIDANCE DOCUMENT FOUR – Public Availability of Information
Given to Advisory Committee Members
The guidance document: Preparation and Public Availability of Information Given to
Advisory Committee Members (FDA 2008c), addresses how and when the public can gain
access to briefing documents and background information provided to advisory
committee members in advance of the meeting. The guidance document identifies the
intent of FDA to post briefing documents on its web site no later than 48 hours before the
meeting is scheduled to occur. It also provides details on preparing and submitting

53
documents to FDA for inclusion in the briefing documents and recommends a timetable
that sponsors should follow when submitting such documents. It also explains how the
documents will be reviewed to determine which parts can be released to the advisory
committee and public, in order to restrict the release of proprietary information.
2.5.3.4 FDA GUIDANCE DOCUMENT FIVE -- When FDA Convenes an Advisory
Committee
The draft guidance document: Guidance for the Public and FDA Staff on Convening
Advisory Committee Meetings (FDA 2008d), proposes new criteria to clarify when the
FDA should refer a matter to an advisory committee. In certain circumstances, the FDA
is required to refer a matter to an advisory committee. In most situations, however, the
FDA can exercise discretion to determine if a meeting of an advisory committee is
warranted. The FDA would use the following criteria:
1. Is the matter at issue of such significant public interest that it would be highly
beneficial to obtain the advice of an advisory committee as part of the agency’s
regulatory decision-making process?
2. Is the matter at issue so controversial that it would be highly beneficial to obtain the
advice of an advisory committee as part of the agency’s regulatory decision-making
process?
3. Is there a special type of expertise that an advisory committee could provide that is
needed for the agency to fully consider a matter? (FDA 2008d).

2.5.3.5 FDA GUIDANCE DOCUMENT SIX -- Public Comment Procedure at
Advisory Committee Meetings
The guidance document: Guidance for The Open Public Hearing at FDA Advisory
Committee Meetings (FDA 2010e), addresses the conduct during the public comment
period of an advisory committee meeting. Most advisory committee meetings include a
session in which the public can participate in order to present relevant information.

54
Participants could include members of the general public, individuals or spokespersons
from the regulated industry (except the sponsor whose product is under review),
consumer advocacy groups and professional organizations, societies, or associations. The
guidance provides instructions on how to request a time to speak and how the FDA staff
should respond to those requests.
2.6 Sequence of Events in Setting up an Advisory Committee
Applying the laws, regulations, and guidance documents described above, Table 5 depicts
the sequence of events when setting up an advisory committee, how many days prior to
the meeting it occurs and the applicable regulation or guidance document.

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Table 5: Steps to Convene an Advisory Committee

2.7 Advisory Committee Members and Process Flow
How then do advisory committees currently operate? What follows is a more detailed
description of the configuration and operation of a typical FDA technical advisory
committee, extracted from the aforementioned regulations and guidance documents.
2.7.1 Advisory Committee Membership
As part of FDA’s effort to recruit qualified experts to serve on advisory committees, FDA
requests nominations of individuals to serve as members. Nominations originate from
professional societies, industry, consumer and patient advocacy groups, the individual

56
himself or other interested persons. FDA looks for candidates who are technically
qualified experts in their field and have experience interpreting complex data (FDA
2010d).
A typical advisory committee includes a chairperson, several academic medical advisors
and clinicians, a consumer representative, and an industry representative. External
experts can be part of the committee if expertise in a particular area is needed. Within
every advisory committee, the FDA strives to assure gender, ethnic, and geographic
diversity wherever possible.
The position of Chair is considered to be one of the most important roles. The Chair is
tasked with making sure that the goals of the meeting are met and with keeping the
meeting running on time and on track. The Chair will often clarify the questions that the
FDA poses to the committee, and also helps to clarify the comments made by the
committee, if necessary. The Chair is responsible to correct misinformation and solicit
opinions from all members of the committee. This is particularly important when the
committee is addressing very specific questions on which committee members have
limited experience or expertise (Brass 2012).
The Academic Medical Advisors and Clinicians are roles typically filled by medical
doctors with a specialty related to the drug or device of interest and by experts with a
PhD in a particular specialty. Often the specialists are experts on the condition for which
the company’s drug or device is indicated. Their primary role is to provide independent

57
advice that will contribute to the quality of the agency’s regulatory decision-making and
lend credibility to the product review process (FDA 2011).
The Consumer Representative is chosen to represent the consumer’s point of view, and
is typically a technically qualified professional with specific links to consumer advocacy
groups or patient representatives. Their role is to present “real world” concerns of the
patient who is to be the potential recipient of the new product (FDA 2011). The consumer
representative does not always have a vote on the committee.
The Industry Representative addresses global concerns for industry, but does not
specifically represent his/her employer. The individual is expected to discuss an issue
before the committee from the perspective of the affected industry and not to present the
narrower views of any individual organization. These members are non-voting members
who usually serve a four-year term.
2.7.2 Flow of Activities during an Advisory Committee Hearing
Advisory committees are typically highly orchestrated events with several different
activities. Figure 4 shows a sample agenda of an advisory committee meeting and the
approximate time allotment for each part of the meeting.

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Figure 4: Sample Advisory Committee Agenda

59
2.7.2.1 Introductions/Conflict of Interest
Most advisory committee hearings last one day and begin with the FDA introductions. In
an effort to be transparent, the FDA posts disclosure statements regarding conflicts of
interest and waivers on the FDA website prior to that meeting date. Also, the designated
Federal Officer for the advisory committee reads a conflict of interest statement at the
beginning of the meeting. This statement includes information on which members, if any,
were granted a waiver, the type of waiver, and the nature of the disqualifying financial
interest for which the waiver was granted (Ackerley 2007).
2.7.2.2 Questions Posed to the Committee
The FDA will ask the advisory committee a series of scientific questions that may deal,
for example, with issues such as whether the safety of a drug is properly characterized for
patients or whether a new device would provide meaningful benefit for patients. These
questions create a framework that guides the discussion of the drug or device and
establishes the boundaries around the questions on which the committee will vote.
Frequently the questions posed to the committee focus on areas that are important to the
FDA or require additional clarification (3D Communications 2008). Figure 5, for
example, shows sample questions that the FDA presented to a sponsor in 2010.

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Figure 5: Sample FDA Advisory Committee Question

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2.7.2.3 Sponsor Presentation / Q&A for the Sponsor
The sponsor of the product under scrutiny is typically invited to make a presentation of
sixty minutes, although up to 90 minutes may be allotted with prior permission by the
FDA. The presentation is focused on data and arguments as to why the drug or device
under consideration should be approved. In addition, the presentation will include the
company’s position on the risk/benefit of its product and its response to previous FDA
questions and concerns (Biedenbach 2006). Typically, committee members refrain from
asking questions during the presentation or will limit their questions to brief, clarifying
interruptions. The sponsor’s presentation is subsequently made available to the public on
the FDA website.
2.7.2.4 FDA Presentation / Q&A for the FDA
The medical reviewer, along with other FDA officials, will present the FDA’s analysis of
the data that was provided as part of the marketing application under review. The length
of the presentation typically matches the time allowed for the sponsor. The content on
which this presentation will focus can differ from that discussed in the sponsor’s
presentation. The presentation by the FDA is considered to be public information and is
posted on the FDA’s website shortly before the meeting. Companies may receive the
FDA discussion and questions on which the committee will vote a few weeks prior to the
meeting and will see the slides to be presented by the FDA 30-60 minutes prior to the
start of the meeting when they become available to the public (3D Communications
2008).

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2.7.2.5 Open Public Comment Period
The public comment period allows members of the public, consumer advocacy groups,
professional organizations, and societies to speak during the meeting. The public
comment period usually lasts one hour, and those wishing to speak must sign up in
advance. Interested persons may present data, information, or views, orally or in writing,
on the issues before the committee. After they have spoken, the chair may ask them to
remain if the committee wishes to question them further. Then the Chair will recognize
unscheduled speakers if time allows. Only the advisory committee may question speakers
during the open public hearing. The more controversial the product under review, the
more lively the public comment period is likely to be. This is an important part of the
hearing, because it allows the committee members to hear the concerns of stakeholders
and may raise issues to which members might refer to in their deliberations.
2.7.2.6 Committee’s Discussion and Questions from the Committee
Following all of the presentations and public comments, the committee then has several
hours to discuss the data and to question both the sponsor and FDA. The sponsor will
have a team of experts including core presenters, consultants, content experts, and slide
retrieval teams, all of whom may help to provide a full and accurate response to questions
from the committee. The company is expected to respond to all questions asked by
advisory committee members. At the end of the discussion and question period, the
advisory committee votes on the questions initially posed by the FDA.

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2.8 Current Concerns related to Advisory Committees
The previous sections outline the governmentally defined principles, rules, and initiatives
that have been taken to ensure that FDA has access to specialized advice about product
concerns. Advisory committees also have an important role to counterbalance the
tendency for a single agency to make approval decisions unilaterally. For the committees
to do their work well, care must be taken to ensure their objectivity and breadth. Prior to
FACA there had been approximately 5000 federal advisory committees, many of which
operated in secret. Members of the public felt that the “unchecked proliferation” of
advisory committees and their closed methods of operation were creating a ‘fifth arm of
government’ standing outside the networks of democratic control (Jasanoff 1990). FACA
established procedures for the committees and mandated that all committees had to be
authorized by Congress, by the President, or by an agency head and had to have written
charters. Other provisions included requirements for open meetings with advanced notice
of the time and place, detailed transcripts, and public participation (Steinbrook 2004).
All of the changes associated with FACA were designed to increase the transparency of
the advisory committee process, and create a more systematic process for the agency to
solicit feedback from independent experts. In the research specifically proposed in this
thesis, the way that FDA and advisory committees interact to maintain objectivity is of
key interest. Close inspection of FACA reveals three potential areas in which bias could
presumably be introduced and over which special care must be taken when managing the
construction and activities of the committees. As shown in Figure 6, bias can be

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introduced into the advisory committee process by 1) permitting advisory committee
members to have conflicts of interest, 2) creating an unfair balance in the choice of
membership, and 3) using inappropriate influence to sway the views of the advisory
committee members. Over the past two decades a number of scholars and political
analysts have discussed extensively the first two sources of influence, those of unfair
balance and conflict of interest, as discussed below. The third has received relatively
little attention from the scholarly or trade community, and will be the subject of this
thesis. In the review below, the literature relating to the first two elements of bias will be
described. The relatively meager literature associated with the third will be introduced,
first by describing how influence is generally considered to be exerted over social groups
and then more specifically how this will be studied in the exploratory research proposed
here.
Figure 6: Potential Sources of Bias Introduced Into Advisory Committees

1) unfair balance
3) inappropriate
influence
2) conflict of
interest

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1) Committee membership: One of the first criticisms leveled at the advisory committee
process from its inception was the issue of balanced membership, as discussed briefly above.
With respect to the concern about membership, the Federal Advisory Committee Act advises that
“standards and uniform procedures should govern the establishment, operation, administration,
and duration of advisory committees”. To achieve this end, it first identifies the importance of
assuring balance in the committees. To quote the Act, the FACA expects:
The membership of the advisory committee to be fairly balanced in terms of the
points of view represented and the function to be performed by the advisory
committee (Pub. L. 92-463 1972).
What it does not specify are explicit standards for evaluating or measuring whether
committees are “fairly balanced”. The criteria described in the law provide little
operational guidance to the agency regarding the nomination and selection of advisory
committee members. On the surface, most advisory committees are considered “fairly
balanced” because they contain a diverse group of experts. Nevertheless, allegations
have been made that the composition of advisory committees has been manipulated in the
past. For example, in 2004, Steinbrook observed that the Bush administration may have
compromised the advisory committee system by manipulating it and seeking scientific
advice that matches the administration’s own views. The Union of Concerned Scientists,
a nonprofit advocacy group, alleged that the Bush Administration appointed unqualified
persons with industry ties or with ideological agendas, stacking advisory committees, and
opposing the appointment of qualified experts (Shulman 2004, Steinbrook 2004).

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Another criticism is that the agency may “stack” committee composition by holding a
few positions vacant in which key individuals sympathetic with the position of the FDA
can be added. Such actions are possible because committee members serve staggered
terms and are reappointed on a rolling basis. A lag in the process of choosing new
committee members for those who have rotated off can create temporary vacancies on an
advisory committee that can be filled by sympathetic “ad hoc’ members. One or two
strategic appointments, or the appointment of temporary committee members, may
change the outcome of the vote (Love 2010). An example of this concern was raised in
2009, when the Wall Street Journal reported on ReGen’s Menaflex knee implant device.
The article reported that after repeated rejections of the product by internal FDA
reviewers, who were concerned with the efficacy of the product, the FDA convened a
panel of experts to review the manufacturer’s claims (Mundy 2009 ). The eight-person
committee included five temporary sports-medicine experts from outside of the FDA’s
regular pool of orthopedic-device experts. In addition, none of the FDA reviewers who
had previously criticized Menaflex were asked to speak at the meeting. The advisory
committee found the device to be at least as effective as other knee implants on the
market. Jay Mabrey, the chief of orthopedic surgery at Baylor University and chairman
of the FDA advisory committee that considered Menaflex stated: “In retrospect, I think
they [the FDA] were stacking the committee to get the decision the company wanted.”
Another example is provided by consideration of the advisory committee asked to
comment on the diet drug, dexfenfluramine, later marketed as Redux. Two months after
the advisory committee recommended disapproving the drug, the FDA convened another

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meeting of the same group to reconsider the drug. No additional data was presented, but
several critical members from the first advisory committee meeting could not attend, and
the drug was approved in their absence (Avorn 2007).
2) Conflict of interest: Perhaps the area that has received the most attention from
scholars and trade community over the last few decades is that of conflict of interest on
committees. Voting and non-voting committee members are designated as special
government employees (SGEs) and are subject to laws governing Federal employees.
Specifically, 18 U.S.C. 208 (Acts Affecting a Personal Financial Interest) prohibits
committee members from participating in matters where they or their family members
have a disqualifying financial interest, unless the member meets the requirements for a
waiver of conflict of interest and such a waiver is granted. Waivers may be granted if the
advisory committee member has an area of expertise that is considered to be important to
the committee, so that the benefit to the committee outweighs the potential risk from the
conflict of interest. Nevertheless, some have alleged that conflicts of interest lead to
inherent bias in the recommendations made to FDA. At least three well known
newspapers have published highly influential articles regarding the potential bias
associated with conflicts of interest of advisory committee members. In 1999, David
Willman of the Los Angeles Times printed an article about a meeting that discussed the
safety of troglitazone, in which two advisory committee members had “significant ties”
to the sponsoring company (Willman 1999). In 2000, Dennis Cauchon (Cauchon 2000) of
USA Today, reviewed drug-related meetings between January 1, 1998 and June 30, 2000,

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and found that 92% of all FDA Drug advisory Committees had at least one voting
member with a conflict of interest and that 33% of the experts had a conflict at the 102
meetings dealing with a specific product. In 2005, Stephanie Saul of the New York Times
published an article on an advisory committee evaluating the cardiovascular toxicity of
the diabetes drug muraglitazar. The advisory committee failed to include a cardiologist in
part due to a conflict of interest held by the committee’s sole cardiologist (Saul 2005).
The newspaper articles raised awareness and created controversy around conflict of
interest rules, but lacked the credibility that might be associated with articles published in
medical journals. Further, the articles could not address the key issue of whether the
financially conflicted individuals affected the voting outcome of the committees. The
concern was addressed more systematically, in 2006, when Lurie and coworkers (Lurie,
Almeida et al. 2006) investigated the relationship between disclosure of financial
conflicts of interest and voting behavior among FDA advisory committee members. The
study found that “there was no relationship between conflict rate and voting outcome” of
advisory committees. However, it did find that each member with a conflict had a ten
percent greater likelihood to vote in favor of the drug that was under evaluation. The
study concluded, however, that if all advisory committee members with conflicts were
excluded, the voting outcome for all product meetings would have been unchanged.
Little scientific evidence and data is present currently in the literature to support the view
that conflicts of interest are influencing the recommendations of FDA scientific advisory
committees. Yet, a few outside groups that disagree with the outcomes reached by the

69
advisory committee continue to be vocal opponents of the advisory committee process
and conflict of interest rules (Bailey 2008). In 2009, under contract to the US Food and
Drug Administration, Eastern Research Group, Inc. (ERG) once again assessed the
relationship between financial conflict of interest disclosure and voting patterns at FDA
advisory committee meetings (Ackerley, Eyraud et al. 2009). In concordance with Lurie
and colleagues, ERG found no statistically significant relationship between disclosed
conflict rates and voting outcome. The study concluded that it could find no evidence to
suggest a relationship between voting patterns in support of a particular interest by those
who acknowledged a financial interest in a sponsor or competitor company among FDA
standing and temporary advisory committee members.
3) Information provided to the committee: The FACA also addresses the way that
information is provided to the committee, because biased or incomplete briefing materials
could affect the ability of the committee to make a reasoned decision. The Act states that
the management procedures of committees should:
contain appropriate provisions to assure that the advice and recommendations of
the advisory committee will not be inappropriately influenced by the appointing
authority or by any special interest, but will instead be the result of the advisory
committee’s independent judgment (Pub. L. 92-463 1972).
Compared to the foci on committee composition and financial conflict of interest as
potential sources of committee bias, relatively little appears to have been written about
the bias that could be introduced if the materials supplied to the committee by the FDA
were to be slanted or opinionated or how this may influence advisory committees. To
understand how influence might be exerted, it is helpful to examine the multiple

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mechanisms by which influence is considered to be exerted more generally, in the social
science literature.
2.9 Influence in the Social Science Literature
The study of persuasion and influence has attracted scholars for hundreds of years, dating
back to the Greek Philosopher Aristotle who first laid out the principles of persuasion
thousands of years ago in Rhetoric, wherein he articulated the process of logical
persuasive argument (Heimes 1998). In that work he describes the three modes of
persuasion: 1) when the speaker is deemed to be credible through his or her speech
2) when the speech stirs emotions 3) when the speech proves a truth by means of a
persuasive argument.
However, the scientific study of influence in western sources is often thought to take
origin around the time of World War II, when a social psychologist named Carl Hovland
was contracted by the U.S. Armed Forces to bolster the morale of soldiers. It was
Hovland’s job to conduct experiments on the effectiveness of training and information
programs that were intended to influence the motivation of men in the American armed
forces. This research appeared to be amongst the first to apply true experimental
techniques to study the persuasive effects of propaganda. It showed that changes in
opinion are significantly related to the trustworthiness of the source in communication.
The more “trustworthy” the source, the more likely the source was to exert influence of
an individual or group (Hovland 1951).

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For years scientists have studied communication settings like group discussions or
governmental meetings to understand better the causal mechanism(s) that underlie
influence. These discussions of influence are not isolated to a single discipline. Research
has been performed to develop voting models in physics (Callander 2007), cascade
models in epidemiology (Castellano 2010), attitude influence in psychology (Watts
2007), and information exchange models in economics (Friedkin 2010). A review of the
many different models of influence is beyond the scope of the work presented here. Most
are developed for situations rather different from the one that is of interest in this thesis
where we are interested in the way that influence might be exerted by the transfer of
information from the regulatory agency to the advisory committee. From this group of
models, however, there are two that seem most applicable to the present work: the Social
Impact Theory of Latane and the Six Key Principles of Influence of Cialdini.
The Social Impact Theory was developed by Bibb Latane in 1981. It is a theory that uses
mathematical equations to predict the level of “social impact” exerted by one person onto
another in a specific social situation. Latane described social impact as a phenomenon in
which people affect one another in a manner that is proportional to a multiplicative
function of the strength, immediacy, and the number of sources. The three principles of
social impact include:
• Strength – Strength is a measure of the amount of influence, power, or intensity
the target perceives the source to possess.

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• Immediacy – Immediacy is related to the relationship between the involved
parties and is measured by how close the target is to the source of the influence
(in space and time) at the time of the influence attempt.
• Number – The number is measured by how many people there are in the group.
Impact grows in approximate proportion to the square root of the number of
people involved (Latane 1996).
The six principle model of Robert Cialdini, like that social influence model of Latane,
has several factors that he believes to be important in determining the strength of
influence. This work appears to articulate much of the current thinking on the science
of influence and persuasion today. The model of Cialdini lists six basic social and
psychological principles, as follows:
• Reciprocity – Reciprocity is related to the desire to return favors and pay
back debts. This trait can lead to feelings of obligation, to offer concessions or
discounts.
• Commitment – Commitment is related to the deep desire to be consistent. For
this reason, once an individual has committed to something, that individual is
then more inclined to go through with the commitment.
• Social Proof – Social proof relies on people’s sense of “safety in numbers”.
People see actions as more appropriate when others are doing it.

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• Liking – Liking relies on the principle that individuals are more likely to be
influenced by individuals who they like. Likability comes in many forms –
sharing similarities, being complimented, or just a sense of trust.
• Authority – Authority is described by having a sense of duty or obligation to
individuals in positions of authority.
• Scarcity – Scarcity uses the principle that an individual desires objects when
their availability is limited, or when one stands to lose the opportunity to
acquire them on favorable terms (Cialdini 2003).
In many of these respects, the FDA is in a privileged position of influence. It is certainly
regarded as a strong and immediate source of power, with considerable authority.
Further, committee members are often chosen by the FDA and may have a desire to be
liked. They may feel that their position on the advisory committee is a “scarce” and
prestigious opportunity, which to some extent might be regarded as a “favor” to be
reciprocated. Thus, it is especially important that the FDA recognize its influential
position and take care in its briefing documents and written opinions not to encourage
“confirmation bias”, defined as “the seeking or interpreting of evidence in ways that are
partial to existing beliefs, expectations, or a hypothesis in hand” (Nickerson 1998).
The FDA appears to recognize that its staff members have the inherent power to
influence advisory committees with their opinions. In 2010, the FDA sent out a news
release announcing it would change the way its experts review and discuss data. The
changes were prompted by an increasing number of medical device advisory committee

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meetings in the prior year and a desire to have a more transparent process. Excerpts from
the news release stated:
There are many issues involved in the FDA’s review of a medical device.
Historically, the FDA’s presentations to panels include comments on
approvability. With the changes, the FDA’s presentation will continue to include
reviews of the agency’s data analysis, but will no longer include comments on
approvability.” “Before the changes, the agency’s medical device reviewers
presented a unified, consensus analysis of supporting data. Now, the reviewers
will present together with data and analysis, the range of scientific opinion in the
group. This move will allow more in-depth discussion on safety and effectiveness
and risk versus benefit of the device under consideration (FDA 2010a).
However, to my knowledge, no systematic analysis has been carried out to investigate
whether the instructions of the FDA to its staff have in fact been implemented effectively.
No literature could be found that examined the way that FDA staff members interact with
the advisory committees, and whether their interactions might have the potential to
influence advisory committee decisions. Of particular concern would be the nature of the
briefing documents given to the committee. The FDA briefing document was chosen to
review, because it is one of the few documents examined by the majority of the
committee members, as identified by 3D Communications, in their publication on how
FDA advisory committee members prepare and what influences them (McIntyre 2012).
Thus, a reasonable first approach to deal with this question would be to conduct a content
analysis of FDA briefing documents prepared for the advisory committees in order to
assess the nature of the materials provided and the degree of fair balance and impartiality
in them.

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CHAPTER 3. METHODOLOGY
3.1 Introduction
This study characterized FDA briefing documents, provided to medical device advisory
committee members, which were published on the FDA website between April 2010 and
April 2013. The 30 medical device advisory committee meetings (Table 6) included in
the collection of source material were studied to identify if briefing document content and
format was notably different between the different divisions within the FDA. Also, using
methods of content analysis, the study identified whether the FDA directly commented
on the approvability of the medical device and whether the tone of the comments
suggested support or disapproval of the product. Further, a survey of advisory committee
members that participated in one of the meetings was undertaken to evaluate if the FDA
analysis of the briefing documents, or FDA’s comments in the briefing documents,
influenced the way that advisory committee member felt about the risk to benefit profile
of the medical device.

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Table 6: Medical Device Advisory Committees (April 2010 – April 2013)

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3.2 Characterization of the Briefing Books
The 30 medical device advisory committee meetings included in the source material
collection were characterized to identify if briefing document content and format were
notably different between the different divisions within the FDA. Information such as
length, inclusion of an introduction, number of FDA comments included in the document,
if the FDA included any of their own analyses, and if they included a conclusion, were
collected and summarized according to the reviewing division responsible for the briefing
book.
3.3 Content Analysis
After the FDA briefing books were characterized, the content analysis was performed. A
reviewer (Bill Leitner) with over ten years of experience in the medical device industry
reviewed the comments that the FDA included in the briefing materials and coded them
as being related to the ‘safety’ or ‘effectiveness’ of the medical device; those comments
not related to safety or effectiveness were coded as ‘other’. Comments were further
classified as either a ‘concern’ if the FDA communicated a concern or ‘neutral’ if no
concern was communicated. A second reviewer (Jim DiBiasi) inspected representative
coding sequences in the initial briefing book to ensure agreement with the classification
method and to assure that comments were coded accurately. Once the briefing book
assessments were complete and the number and types of concerns were totaled, the
advisory committee votes were compared to the number of concerns included in the

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briefing book and the results were tabulated. Table 7 provides a summary of the coding
scheme and an example.
Table 7: Summary of the Coding Scheme and Example
Classification of FDA Comments
1) All comments are classified as being related to the ‘safety’, ‘effectiveness’, or
‘other’ as described below.
Safety – If the comment includes the word “safety” or mentions adverse event,
device failure, health risk, developmental risk, etc.
Effectiveness – If the comment includes the words “efficacy” or “effectiveness” or
mentions primary endpoint, success, performance, etc.
Other – If the comment refers to non-clinical data, pre-clinical data, background
information, study design, regulatory history, etc.
2) All comments are further classified as being a “concern” or “neutral”.
Concern – If the comment includes the word “concern” or communicates a concern
with the medical device without using the word concern.
Neutral – If the comment does not include the word “concern” or doesn’t
communicate a concern with the medical device.
Classification Example
MelaFind did not significantly reduce the number of biopsy ratio when compared
to the examining dermatologist. ….Note that the FDA review team does not
believe this is a clinically significant difference. In addition, this difference in
biopsy reduction comes at the expense of MelaFind missing one melanoma
when compared to the examining dermatologist. (Effectiveness – Concern)

3.4 Survey Analysis
A survey of advisory committee members who participated in at least one of the meetings
was undertaken to evaluate if the FDA analysis of the briefing documents, or FDA’s
comments in the briefing documents, influenced how the advisory committee members
felt about risk-to-benefit profile of the medical device. Prospective advisory committee

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members were evaluated from a proprietary database (KOLLEAD®) of 3D
Communications that includes publicly available information regarding more than 2000
individuals who have been or currently are FDA advisory committee members. This
information includes both biographical information (e.g., education, academic positions,
research interests, publications, editorial boards, and task forces for developing treatment
guidelines) and advisory committee-related information (e.g., which therapeutic
committees on which they have served, their general attendance, and transcripts of
pertinent advisory committee discussions, including member views and votes on
particular products).
A web-based survey was constructed using the electronic survey tool, Qualtrics
(www.Qualtrics.com). The survey was designed to be completed within 5 to 10 minutes
to facilitate participation. The draft survey was scrutinized by several individuals from
industry. It also included an expert on survey development as well as individuals with
advisory committee experience. The feedback was incorporated to produce a final survey
that was distributed to advisory committee members in the KOLLEAD database.
Respondents were assured of anonymity. To encourage participation, a personal note
was sent to the potential respondent to identify the purpose of the survey and confirm
their appropriateness and interest in participating. All respondents were reviewed to
ensure no respondents submitted more than one survey response. The results of the
survey were analyzed using simple statistics such as averages and standard deviations,

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but more advanced statistics that rely on large numbers of responses were not possible
with this exploratory dataset.

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CHAPTER 4. RESULTS
4.1 Summary of Reviewed Briefing Books
The 30 FDA briefing books published by FDA between April 2010 and April 2013 were
distributed across 18 different advisory committees, and described a breadth of products
from cosmetic products such as injectable dermal fillers to life-saving or sustaining
devices such as a melanoma detector and a stent (Table 8). The Circulatory System
Advisory Committee had the most meetings with twelve during the time span whereas
the Orthopedic and Radiological Advisory Committees had the fewest, only 2, during that
same period.
Table 8: Frequency of Medical Device Advisory Committee Meetings
Advisory Committee Number of Briefing Books
Circulatory System 12
Neurologic 5
Ophthalmic 3
Gastroenterology and Urology 3
General and Plastic Surgery 3
Orthopedic and Rehabilitation 2
Radiological 2

As shown in Figure 7, meetings were relatively evenly spaced during the three year
window. Six meetings were held in 2010, twelve meetings in 2011, nine meetings in

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2012, and three meetings in first half of 2013. October 2011 had the most meetings, with
three, while fifteen months, including the August months in this period, had no meetings.
Figure 7: Frequency of Medical Device Advisory Committee Meetings

4.2 Characterization of FDA Medical Device Briefing Books
4.2.1 Length of FDA Briefing Books
The length of FDA briefing books varied between reviewing divisions. The average
length of the FDA briefing books surveyed here was 70 pages, but individual books
ranged from as many as 385 pages to as few as 29 pages. The Ophthalmic Briefing Books
averaged 179 pages, whereas the Radiological Briefing Books averaged 34 pages. The
briefing books of the remaining five committees were all close to an average of 60 pages.
0
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3
4
5
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May-10
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Jun-11
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Apr-13
Number of Meetings

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Figure 8 shows the breakdown of briefing book by the number of pages. Divided into
bins of 20 pages, the highest proportion of briefing books (37%) were 41 to 60 pages
long, and only three were over 100 pages long.
Figure 8: Length of Medical Device FDA Medical Device Briefing Books

4.2.2 Number of Tables and Figures
Tables and figures were included in all FDA briefing books, regardless of reviewing
division and product. The average number of tables was 30 and the average number of
figures was 9. The Solesta Briefing Book had the highest number of tables (72) and the
Retinal Prosthesis System Briefing Book had the highest number of figures (27) (Figure
9). Briefing books created by the Gastroenterology and Urology Division had the highest
average number of tables (43 tables each) and by the Circulatory and Ophthalmic
Divisions had the highest number of figures (12 each). The number of tables and figures
appeared to correlate loosely with the length of the briefing books.
0
2
4
6
8
10
12
0-20 21-40 41-60 61-80 81-100 101-120 121-140 >140
Number of Briefing Books
Number of Pages
Average - 70.0
SD - 62.9
Min - 29
Max - 385

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Figure 9: Average Number of Tables and Figures in Medical Device Briefing
Books

4.2.3 Explanation of Rationale for Presentation to the Advisory Committee
In a small number of briefing books, the FDA included a rationale near the beginning of
the book to explain why the product was referred to the advisory committee. For
example, in the MelaFind Briefing Book, the FDA included the following rationale:
Rationale for Bringing P090012 to the General and Plastic Surgery
Devices Panel. The FDA review team is presenting the PMA P090012 to
the General and Plastic Surgery Devices Panel for panel deliberation of
the safety and effectiveness of the MelaFind device based upon the results
from the clinical study. The device is being taken to panel since MelaFind
is a first of the kind device and the sponsor has requested a panel. FDA
may refer the PMA to a panel on its own initiative, and will do so upon the
sponsor’s request of an applicant, unless the FDA determines that the
application substantially duplicates information previously reviewed by a
Panel. The timing of this Panel as requested by the sponsor depends upon
FDA review and assessment of the information preparedness.
However, in 22 (73%) of the 30 briefing books, FDA provided no explanation regarding
their rationale for recommending the product to the advisory committee. There appears to
0
5
10
15
20
25
30
35
40
45
Number of Tables and Graphs
Number of Tables
Number of Figures

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be some consistency in the presence or absence of explanations from one division to
another. With the exception of the Gastroenterology-Urology Division, where one
briefing book included an explanation as to why the FDA recommended the product to
advisory committee and one did not, the remaining briefing books either did or did not
contain explanations depending on the division that wrote the briefing book. The
Circulatory System, Neurologic, and Ophthalmic Briefing Books did not explain in their
briefing books why the product was recommended to the advisory committee, whereas
the Orthopedic and Rehabilitation and Radiological Briefing Books did.
4.2.4 Inclusion of Additional Analyses
The FDA relies heavily on the sponsor’s analysis of its own data; however, in the
majority (83%) of the briefing books the FDA included additional analyses. Often this
additional data comes from analyses done at the request of the Agency by the sponsor.
For example, in the expanded indication for Abbott Vascular’s RX Acculink Carotid
Stent System, the FDA requested additional analyses of the primary endpoint; these were
conducted by the sponsor and included in the FDA’s briefing book. In some instances the
FDA performs the analysis within the Agency. In the Solesta Briefing Book, FDA
conducted additional analyses of the primary effectiveness endpoint that included the
addition of baseline medication dosages. While the majority of the FDA briefing books
contained additional analyses, it was noted during the review that two of the briefing
books without such analyses came from the Gastroenteroloy-Urology Division.

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4.2.5 Explanation of Post-Approval Study (PAS) Inclusion
In most briefing books, the FDA included a note to the advisory committee members at
the beginning of the Post-Approval Study section explaining that the inclusion of a PAS
section should not be interpreted to mean that FDA has made a decision on the
approvability of the PMA. For example, in the Pipeline Embolization Briefing Book, the
FDA included the following rationale:
NOTE TO PANELISTS: FDA’s inclusion of a section/discussion on a post-
approval study (PAS) in this executive summary should not be interpreted to mean
that FDA has made a decision on the approvability of this PMA. The presence of
post-approval study plans or commitments does not in any way alter the
requirements for premarket approval. A recommendation from the Panel on
whether the data demonstrates reasonable assurance on device safety and
effectiveness must be based solely on the premarket data. The issues noted below
are FDA’s comments regarding potential post-approval studies.
In 9 (33%) of the 27 briefing books that contained a PAS section (three did not include a
PAS in the briefing book), no such explanation regarding the relationship between PAS
study and approvability was present. The nine briefing books were from the following
advisory committees divisions: Circulatory System (4), Gastroenterology-Urology (1),
General and Plastic Surgery (1), Neurology (1), Ophthalmology (1), and Radiology (1).
Thus, no clear pattern between the presence or absence of such explanations appeared to
exist between divisions.
4.2.6 Content of the Introduction
The FDA includes an Introduction in all of the briefing books. Generally the Introduction
included a description of the product, regulatory history, and background on the clinical

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study. In some of the briefing books, the FDA included additional text to explain that it is
seeking the input from the advisory committee and will have comments that highlight the
areas in which it is seeking feedback. An example of the language included in the
Medtronic Cardiac Resynchronization Therapy Defibrillator, for example, reads:
FDA's comments to the panel are identified throughout the document
starting with the text "FDA Comment" and encompassed by a border (see
example below). The text in these sections is intended to highlight
relevant findings, potential discussion topics, and questions for the panel.
In addition, a summary of these comments is provided in Section 11:
Summary of FDA's Comments.
Table 9 lists the briefing books and describes whether the FDA includes instructional
language for the advisory committee in the Introduction section of the briefing book.
Such language could not be found in the Introduction or any other section of 13 of 30
briefing books. The use of such language appears to vary by division. The briefing books
for Gastroenterology-Urology, Neurologic, Ophthalmic, and Orthopedic and
Rehabilitation Divisions do not typically contain explanations related to FDA comments;
only two exceptions, in one of the circulatory and one of the ophthalmic briefing books
were found. In contrast such language was typical for briefing books from the
Circulatory, General/Plastic Surgery and Radiological Divisions.
Table 9: The Use of Comments Explained in the Introduction of the FDA
Briefing Book
Product Advisory Committee Yes No
RX Acculink Carotid Stent System Circulatory System X
SAPIEN Transcatheter Heart Valve Circulatory System X
Berlin Heart Circulatory System X

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Product Advisory Committee Yes No
PTX Drug-Eluting Peripheral Stent
System Circulatory System X
Synergy Ablation System Circulatory System X
Ablation Frontiers Cardiac Ablation
System Circulatory System X
Cardiac Resynchronization Therapy
Defibrillators Circulatory System X
Champion HF Monitoring System Circulatory System X
Ventricular Assist System Circulatory System X
Subcutaneous Implantable
Cadioverter Defibrillator Circulatory System X
SAPIEN Transcather Heart Valve Circulatory System X
MitraClip Delivery System Circulatory System X
Solesta Gastroenterology-Urology X
LAP-BAND Gastroenterology-Urology X
Reflux Management System Torax Gastroenterology-Urology X
MelaFind General and Plastic Surgery X
Restylane General and Plastic Surgery X
MarginProbe System General Plastic Surgery X
NovoCure Ltd Neurologic X
Pipeline Embolization Device Neurologic X
Wingspan Stent System Neurologic X
CoAxia NeuroFlo Catheter Neurologic X
RNS System for Epilepsy Neurologic X
iStent Trabecular Micro-Bypass Stent Ophthalmic X
Retinal Prosthesis System Ophthalmic X
Toric Accommodating Posterior
Chamber Intraocular Lens Ophthalmic X
AMPLIFY rhBMP-2 Matrix Orthopedic and Rehabilitation X

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Product Advisory Committee Yes No
Augment Bone Graft Orthopedic and Rehabilitation X
3D Digital Breast Tomosynthesis
(DBT) System Radiological X
Selenia Dimensions 3D System Radiological X
4.2.7 Variability in Comment Format
Similarities appeared to exist in the formatting of comments presented in different
briefing books from the same division. For example, the Circulatory Division generally
italicized and boxed their comments and started them with “FDA Commentary”, whereas
the General and Plastic Surgery Division started their comments with “FDA Review
Team’s Comments” and the Ophthalmology Division generally italicized their comments
but did not call them out as an “FDA Comment”. Most briefing books had comments
throughout the document, but a small number of briefing books limited their comments to
specified areas of the briefing book. For example, in two of the General and Plastic
Surgery Briefing Books, comments were only included in certain sections of the briefing
book and were denoted with “FDA Review Team’s Comments on …..”. Comments were
generally used to draw attention to areas of concern. For example, in the MelaFind
Briefing Book, the FDA included the following comment:
The FDA review team also believes that the clinical data in Protocol 20061 does
not support the proposed indications for use of MelaFind for the detection of
early melanomas on all atypical lesions since the data is limited to the enrolled
atypical lesions suspicious for melanoma.

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Although most FDA comments communicated concerns to the advisory committees,
some briefing books also used comments to let the advisory committee know that the
FDA did not have a concern with a particular aspect of the PMA. For example, in the
AtriCure Synergy Ablation System Briefing Book, the FDA included the following
comment at the end of the Pre-Clinical and Animal Studies section of the briefing book:
FDA Commentary: FDA has no remaining concerns with regard to pre-clinical
testing of the device.
Table 10 shows the variability between the formatting of the FDA comments by
providing examples pulled from the subset of briefing books reviewed in this thesis.

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Table 10: Examples of the Multiple Comment Formats Used by FDA

NOTE TO PANEL: The panel will be asked to address the issue of how closely the enrolled
population represents the US population which would be eligible to receive treatment and whether
there are any concerns regarding imbalances between patient groups in terms of baseline
characteristics. (Gastroenterology-Urology, Solesta, December 2, 2010)

The Panel will be asked to consider the proposed indication for use and discuss whether it is
supported by the data in the PMA. (Neurological, NovoCure, March 17, 2011)
The panel will be asked to discuss whether the data from the clinical trial support the safety and
effectiveness of the PED for the proposed indication for use, including whether the terminology for
the target anatomic region of the internal carotid artery adequately describes the region studied.
(Neurological, Pipeline Embolization Device, March 18, 2011)

FDA Review Team’s Comments on the Primary Effectiveness Outcome: (General and Plastic
Surgery, Restylane, April 26, 2011)
FDA Commentary: FDA has no remaining concerns with regard to pre‐ clinical testing of the device.
(Circulatory System, AtriCure Synergy Ablation System, October 26, 2011)

FDA Comment
The panel is being asked to comment on the proposed labeling (indications and claims) that would be
solely based on the clinical data and results from the REVERSE and RAFT studies submitted by the
sponsor. (Circulatory System, Cardiac Resynchronization Defibrillator, December 7, 2011)

FDA Commentary: FDA has no remaining concerns at this time with regards to pre-clinical testing of
the device. (Circulatory System, CardioMEMS HF Monitoring System, December 8, 2011)

FDA Comment: FDA has no remaining concerns regarding the pre-clinical bench testing.
(Circulatory System, Transcatheter Heart Valve, June 13, 2012)

Due to differences in device design and study populations, FDA considers the Argus II IDE study
described in Section 7.2 below to be the primary basis for the evaluation of safety and probable benefit.
(Ophthalmic, Argus II Retinal Prosthesis, September 28, 2012)

The panel members will be asked to comment on the clinical significance of the 90 day stroke-related
mortality rate, given the associated statistical caveats. (Neurologic, CoAxia NeuroFlo Catheter,
November 1, 2012)

The Panel will be asked to consider the proposed indications for use and discuss whether they are
supported by the data in the PMA. (Neurologic, RNS System for Epilepsy, February 23, 2013)

FDA Comment: FDA has no remaining concerns regarding the pre-clinical bench testing.
(Neurologic, MitraClip Delivery System, March 20, 2013)

Reviewer Comments: Of note, there were no control eyes for these accommodative substudies and the
methodology was not validated. (Ophthalmic, Trulign Toric Accomodating Posterior IOL, April 8, 2012)

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4.2.8 Number of FDA Comments
The number of comments that the FDA included in the briefing books was inconsistent,
ranging between 5 and 54 with an average of 25. The General and Plastic Surgery
Briefing Books had the highest number of comments with an average of 41 comments,
whereas the Neurologic Briefing Books had the lowest number of comments with an
average of 13 comments. The remaining briefing books all had comments with averages
ranging from 19 to 36. Figure 10, shows the breakdown of briefing books by the number
of comments.
Figure 10: Number of FDA Comments Organized by Division

0
10
20
30
40
50
60
SAPIEN Transcatheter Heart…
Berlin Heart
PTX Drug-Eluting Peripheral…
Synergy Ablation System
Ablation Frontiers Cardiac…
Cardiac Resynchronization…
Champion HF Monitoring System
RX Acculink Carotid Stent System
Ventricular Assist System
Subcutaneous Implantable…
SAPIEN Transcather Heart Valve
MitraClip Delivery System
Solesta
LAP-BAND
Reflux Management System…
MelaFind
Restylane
MarginProbe System
NovoCure Ltd
Pipeline Embolization Device
Wingspan Stent System
CoAxia NeuroFlo Catheter
RNS System for Epilepsy
iStent Trabecular Micro-Bypass…
Retinal Prosthesis System
Toric Accommodating Posterior…
Augment Bone Graft
AMPLIFY rhBMP-2 Matrix
Selenia Dimensions 3D System
3D Digital Breast…
Number of Comments
Circulatory
Gastro.
Plastic Surg.
Neurologic
Ophthalmic
Orthopedic
Radiol.

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4.3 Content Analysis of FDA Medical Device Briefing Books
4.3.1 Classification of FDA Comments
As described in Table 11, FDA comments can generally be organized into one of four
different categories: comments communicating that the data is acceptable; comments that
express concerns; comments that are neutral; and comments that are recommendations.
Concerns are those comments in which FDA directly or indirectly states a concern or
issue with data, trial design or product. Neutral comments are neither negative nor
positive in their language and simply draw committee member’s attention to an item,
often to get feedback. Infrequently, comments in the briefing books take the form of a
suggestion or recommendation to advisory committee members.
Table 11: Examples of the Different Types of Comments
Comments stating that FDA has a Concern
FDA’s mission is to protect and promote the Public Health and the FDA review team
has significant concerns this device has not studied adequately for its current
indications for use and therefore puts the health of the public at risk. (Mela Find)
FDA has examined the appropriateness and success of each step required to make the
Sponsor’s proposed comparative analyses and has concluded that significant problems
exist in each step.
FDA has concerns whether the balance of false negative results and false positive
results is sufficiently acceptable to allow approval of the device for its Intended Use
(Margin Probe)
FDA is concerned about the overall safety profile of the System. (Cardiac Ablation
System)
The patient examples listed above underline FDA’s concern regarding the bias
associated with the ‘As Treated’ analysis by the sponsor. (Sapien Transcatheter)

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Comments stating that FDA Does not have a Concern
FDA review team finds this adequate and has no further questions.
FDA has no comments or concerns regarding any of the non-clinical data presented.
FDA has no remaining concerns regarding the pre-clinical bench testing.
The safety population of 107 subjects excluding only subject treated with the device
were included in the sponsor’s safety population which FDA considers acceptable.
(Pipeline Embo)
Neutral Comments
For the new enrollment study, the applicant has chosen a non-inferiority margin of 5%
for the sight-threatening adverse events. The Panel will be asked about the
appropriateness of this assumption. (Glaukos Stent)
The Panel will be asked to consider the proposed indication for use and discuss
whether it is supported by the data in the PMA. (NovoCure)
Panel will be asked to comment on the appropriateness of the applicant’s defined PP
population. (NovoCure)
Based on the study results at Week 8, the FDA statistician calculated that if 100
patients were injected, a little over 50 patients would be Responders. FDA will request
Panel Comment on the potential effectiveness of Restylane use for lip augmentation.
(Restylane)
Comments in the form of a Recommendation
Therefore, FDA recommends that the MitraClip CDS continue to remain available to
this vulnerable patient population as an investigational device so that Abbott Vascular
can conduct the COAPT and European trials in optimal manner. PMA approval is not
appropriate at this time as major questions of safety and effectiveness, as well as the
overall benefit-risk profile for this device, remain unanswered for the regulatory
standards set forth in 21 CFR 860.7. (MitraClip)
The FDA review team sees both studies as service as exploratory studies for the actual
risk benefit of this device, and recommends a new primary study for the actual
indications for use of the device. With this background, we will be asking for the panel
to provide formal input on a series of questions related to these points. (MelaFind)
Enrollment and follow-up: Given the short window of observation, it is unlikely that
most pancreatic cancers potentially associated with BMP were captured. A longer
follow-up time is recommended. (Amplify Med)
Also, with many of the secondary endpoints, the sponsor has presented results on mean
percentage change from baseline instead of mean change from baseline. The mean
percentage change across groups can be misleading because it often appears that

95
Solesta is very much better than Sham in percentage change, but when one examines
the actual mean value, it is not by a great amount. Therefore, we recommend that the
panel focus on actual change not percentage change when comparing groups. (Solesta)
4.3.2 Comments on the Approvability of the Medical Device
Of the 30 briefing books, 5 (17%) commented on the approvability of the medical device.
These briefing books contained language that either commented directly on the
approvability of the device or questioned the approvability through strongly worded
concerns that would call into question the safety and effectiveness of the device. The
following are examples in which the FDA commented directly on the approvability of the
medical device, from the MelaFind and MitraClip Briefing Books.
FDA’s mission is to protect and promote the Public Health and the FDA review
team has significant concerns this device has not been studied adequately for its
current indications for use and therefore puts the health of the public at risk.
(MelaFind)
Therefore, FDA recommends that the MitraClip CDS continue to remain
available to this vulnerable patient population as an investigational device so that
Abbott Vascular can conduct the COAPT and European trials in optimal manner.
PMA approval is not appropriate at this time as major questions of safety and
effectiveness, as well as the overall benefit-risk profile for this device, remain
unanswered for the regulatory standards set forth in 21 CFR 860.7. (MitraClip)
The following are three examples in which the FDA commented indirectly on the
approvability of the medical device, taken from the briefing books of the Augment Bone
Graft, Toric Intraocular Lens, and Cardiac Ablation System respectively.
If the number of such protocol violators and withdrawals is high, the FDA will
question the overall quality of the trial and its execution. FDA has advised the
sponsor that it has not provided an accurate “all evaluated” patient accounting,
and that the number of withdrawals, especially those patients who are one year
post-treatment withdrawn for problems that occurred intraoperatively,
significantly impacts the ability to determine true study success, and thereby
device safety and efficacy. (Augment Bone Graft)

96
Reviewer’s Comment: Bausch + Lomb is seeking approval for lens models with
11.5 and 12.0 mm optics However, we believe that the 12.0 mm lens may not be
comparable to the 11.5mm with regard to the rotational stability. Since only a
small number of subjects were implanted with the 12.0 mm optic lens (in violation
of the approved protocol), FDA does not believe adequate data were provided to
establish the rotational stability of this lens model. (Toric Accommodating
Posterior Chamber IOL)
FDA is concerned about the overall safety profile of the System. When using an
analysis that includes all safety events observed in the trial for subjects that
underwent at least one study procedure, 38 subject with at least one serious
device/procedure related event out of 176 patients (133 Ablation Arm Subjects +
43 crossover subjects) were observed for an overall safety assessment rate of
21.6%. (Cardiac Ablation System)
In 3 of the 5 briefing books in which FDA commented on the approvability, such
comments were made more than once (Figure 11).
Figure 11: Number of Comments on Approvability in the FDA Briefing Books

0
1
2
3
4
5
6
7
8
9
Toric
Accomodating
Posterior Chamber
IOL
Cardiac Ablation
System
Augment Bone
Graft
MelaFind MitraClip Delivery
System
Number of Comments
on Approvability

97
4.3.3 Other Types of Comments
Not all comments made strong inferences about approvability but gave other forms of
input to the committee. All of FDA’s comments were examined and those comments that
expressed concerns were identified and further categorized as a concern about safety,
effectiveness, or other. The category of ‘Other’ included such areas as trial design,
preclinical data, or regulatory issues, for example. Figure 12 shows the number of
comments expressing concern by briefing book. The MelaFind, MarginProbe System,
and MitraClip Delivery System Briefing Books had the highest number of total concerns
with each having over 40 concerns. The majority of the concerns were related to the
effectiveness of the device. On the other end of the spectrum, the Pipeline Embolization,
RNS System for Epilepsy, and Selenia Dimensions 3D System Briefing Books all
contained no comments reflecting concerns.

98
Figure 12: Number and Types of Concerns per Briefing Book

4.3.4 The Use of the Word “Concern” In FDA’s Comments
FDA comments that contained the word “concern” were analyzed further to identify
those instances in which a relationship to the product was present. Below are two
examples of such comments.
FDA has ongoing concerns with the possible toxicity of this product as well as the
ability of the studies to data to demonstrate reasonable safety and effectiveness
and will describe these concerns in this summary. (Augment Bone Graft)
FDA has concerns that although the sponsor met their endpoint based on the
current definition, the NTTV endpoint as assessed in the current submission is not
appropriate due to inclusion of shavings from all surgical procedures. The
0
5
10
15
20
25
30
35
40
45
50
SAPIEN Transcatheter Heart Valve
Berlin Heart
PTX Drug-Eluting Peripheral Stent System
Synergy Ablation System
Ablation Frontiers Cardiac Ablation System
Cardiac Resynchronization Therapy Defibrillators
Champion HF Monitoring System
RX Acculink Carotid Stent System
Ventricular Assist System
Subcutaneous Implantable Cadioverter…
SAPIEN Transcather Heart Valve
MitraClip Delivery System
Solesta
LAP-BAND
Reflux Management System Torax
MelaFind
Restylane
MarginProbe System
NovoCure Ltd
Pipeline Embolization Device
Wingspan Stent System
CoAxia NeuroFlo Catheter
RNS System for Epilepsy
iStent Trabecular Micro-Bypass Stent
Retinal Prosthesis System
Toric Accommodating Posterior Chamber…
Augment Bone Graft
AMPLIFY rhBMP-2 Matrix
Selenia Dimensions 3D System
3D Digital Breast Tomosynthesis (DBT) System
Number of Concerns
# S a f e ty C o n c e r n s
# E f f e c ti v e n e s s C o n c e r n s
# O th e r C o n c e r n s
Circulatory
Gastro.
Plastic Surg.
Neurologic
Ophthalmic
Orthopedic
Radiol.

99
shavings taken at later surgical procedures confound the effect of false positive
readings by the device that lead to additional shavings. (MarginProbe System)
Figure 13 shows the use of the word “concern” by briefing book. The Augment Bone
Graft and MitraClip Delivery System Briefing Books had the highest use of the word
“concern” in their comments, with 26 and 24, respectively. When looking at the average
number of times that the word “concern” is used in briefing books by division, the
Orthopedic and Rehabilitation and General and Plastic Surgery Advisory Divisions had
the two highest averages with 20 and 16, respectively, whereas the Ophthalmic and
Radiological Committees each averaged only 3.

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Figure 13: Number of Times FDA Uses the Word “Concern” in Their Comments

4.4 Relationship between FDA Concerns and Advisory Committee Votes
Figure 14 plots the number of FDA concerns per briefing book in relation to the outcome
of the advisory committee vote. Regression analysis suggests a modest trend for ‘Yes’
votes to decrease and the ‘No’ votes to increase as the number of FDA concerns
increases. The graph also shows that ‘Abstain’ votes appear to be independent of the
number of FDA concerns. Figure 15 plots the number of time the FDA uses the word
“concern” in relationship to the outcome of the advisory committee vote. The figure
suggests that ‘No’ votes increase and ‘Yes’ votes decrease in relation to the number of
times FDA uses the word “concern” in the briefing book.

0
5
10
15
20
25
30
RX Acculink Carotid Stent…
SAPIEN Transcatheter Heart…
Berlin Heart
PTX Drug-Eluting Peripheral…
Synergy Ablation System
Ablation Frontiers Cardiac…
Cardiac Resynchronization…
Champion HF Monitoring…
Ventricular Assist System
Subcutaneous Implantable…
SAPIEN Transcather Heart Valve
MitraClip Delivery System
Solesta
LAP-BAND
Reflux Management System…
MelaFind
Restylane
MarginProbe System
NovoCure Ltd
Pipeline Embolization Device
Wingspan Stent System
CoAxia NeuroFlo Catheter
RNS System for Epilepsy
iStent Trabecular Micro-…
Retinal Prosthesis System
Toric Accommodating…
Augment Bone Graft
AMPLIFY rhBMP-2 Matrix
Selenia Dimensions 3D System
3D Digital Breast…
Circulatory
Gastro.
Plastic Surg.
Neurologic
Ophthalmic
Radiol.
Orthopedic

101
Figure 14: Relationship between FDA Concerns and Advisory Committee Votes
The number of FDA concerns are plotted along the X-axis, while the votes, ‘Yes’, ‘No’,
or ‘Abstain’ are plotted along the Y-axis.

0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
VOTES
Number of FDA Concerns
'Y', 'N', 'A' Votes and Number of Concerns
Yes - Votes
No - Votes
Abstain - Votes

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Figure 15: Relationship between FDA’s use of the Word “Concern” and
Advisory Committee Votes

To evaluate further the relationship between the number of concerns and advisory
committee votes, the proportion of ‘Yes’ votes was calculated and graphed against the
number of concerns. The proportion was calculated by dividing the number of ‘Yes’
votes by the total number of ‘Yes’, ‘No’, and ‘Abstain’ votes (Y/(Y+N+A)) for each
advisory committee (Figure 16). The proportion of ‘Yes’ votes tended to decrease with
increasing number of concerns. The R-squared value suggests a very weak relationship
between the number of concerns and the proportion of ‘Yes’ votes. The regression
equation suggests that the proportion of ‘Yes’ votes tends to decrease by 0.38 percentage
points for each additional expression of concern.

0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30
VOTES
Number of Times FDA Says the Word "Concern"
'Y','N', 'A' Votes and Number of "Concerns"
Yes - Votes
No - Votes
Abstain - Votes

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Figure 16: Proportion of ‘Yes’ Votes and the Number of Concerns

Figure 17 shows the relationship between the proportion of ‘Yes’ votes and the number
of times FDA uses the word “concern” specifically in relationship to the product. Similar
to the relationship described in Figure 16, the proportion of ‘Yes’ votes decreases as the
number of concerns increase. Although the R-squared value is higher than described
above, the correlation still does not suggest a strong relationship; for each additional
“concern”, the proportion of ‘Yes’ votes is predicted to decrease by 1.13 percentage
points.
y = -0.0038x + 0.8058
R² = 0.062
0.00
0.20
0.40
0.60
0.80
1.00
1.20
0 5 10 15 20 25 30 35 40 45 50
Proportion of 'Yes' Votes
Number of Concerns
Proportion of 'Yes' Votes = (Y/(Y+N+A))

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Figure 17: Proportion of ‘Yes’ Votes and the Number of Times FDA Uses the
Word “Concern”

4.5 Analysis of Survey Results
4.5.1 Information on Survey Respondents
The survey of advisory committee members was sent to 254 individuals who were
committee members in the studied period; 107 (42%) surveys were opened and
37 respondents completed more than 75% of the questions, equating to a response rate of
approximately 15%. Of these 37 respondents (Figure 18A), 6/37 (16%) had participated
in one advisory committee meeting, 7/37 (19%) in two meetings, 5/37 (14%) in three
meetings and 16/37 (43%) in four or greater than four meetings. A few respondents
(3/37; 8%) could not recall.
y = -0.0113x + 0.8364
R² = 0.1731
0.00
0.20
0.40
0.60
0.80
1.00
1.20
0 5 10 15 20 25 30
Proportion of 'Yes' Votes
Number of "Concerns"
Proportion of 'Yes' Votes = (Y/(Y+N+A))

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The Circulatory System Advisory Committee had the highest number of meetings during
the studied period (Figure 18B) and was also the most common advisory committee on
which respondents served. The least common of the specified committees was the
Radiological Advisory Committee with only five respondents serving on it, and ‘other’
was selected four times representing additional choices for the Hematologic (2),
Microbiology, and Cellular, Tissue, and Gene Therapy Advisory Committees.

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Figure 18: Advisory Committee participation by respondents
A: Question 1: In how many Medical Device Advisory Committee meetings have
you participated in since April 2010?

B: Question 2: Check all Medical Device Advisory Committees on which you served
as a SGE, between April 2010 through April 2013.

0%
5%
10%
15%
20%
25%
30%
N=37
10
7
8
7
3
7
5
4
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 2 3 >4 I do not recall
7
5
N=37
6
16
3

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4.5.2 Views of Respondents Regarding Briefing Books
The views of respondents with respect to the briefing book were first explored. When
asked about the preferred length of the briefing book (Figure 19), 13 (35%) of 37
respondents indicated that less than 50 pages was ideal, 4 (11%) felt 51 to 100 pages was
ideal, 1 (3%) felt 101 to 150 pages was ideal, 4 (11%) felt the ideal length was greater
than 150 pages, and 15 (41%) had no preference.
Figure 19: Question 3: What is the ideal length of the FDA Briefing Materials?

Asked if the format of the FDA Briefing Book was consistent between advisory
committee meetings (question 4, Figure 20), 4 (11%) of the respondents identified ‘a
great deal’ of consistency between briefing books, 21 (57%) identified ‘quite a bit’ of
consistency, 4 (11%) felt the briefing books were ‘somewhat’ consistent, 1 (3%)
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
< 50 Pages 51 - 100 Pages 101 - 150 Pages > 150 Pages I have no
preference
4
1
4
13
15
N=37

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identified ‘very little’ consistency, 4 (11%) respondents did not recall, and 3 (8%) of the
respondents could not answer because they did not participate in more than one meeting.
Figure 20: Question 4: If you participated in more than one advisory meeting, do
you feel that the format of the FDA Briefing Materials was consistent?

Question 5 (Figure 21) asked if the committee members who attended more than one
meeting felt that the ‘type of content’ in the FDA briefing materials was similar from one
briefing book to the next. Three (8%) of the respondents reported ‘a great deal’ of
consistency in the content of the briefing books, and 22 (61%) reported ‘quite a bit’ of
consistency. Six (17%) felt the content was ‘somewhat’ consistent, 1 (3%) identified
‘very little’ consistency, and 4 (11%) did not recall.

0%
10%
20%
30%
40%
50%
60%
A Great
Deal
Quite a Bit Somewhat Very Little Not at All I do not
recall
I did not
participate
in more
than 1
meeting
4
N=37
3
1
4
21
4

109
Figure 21: Question 5: If you participated in more than one advisory meeting, do
you feel that the type of content of the FDA Briefing Materials was
similar?

When respondents were asked by question 6 (Figure 22) if the guidance in the
Introduction Section of the briefing book was helpful in focusing their reviews, most
seemed to appreciate the guidance. Fifteen (41%) of the respondents felt that the
guidance helped ‘a great deal’ and 12 (32%) that it helped ‘quite a bit’ in focusing their
review. Seven (19%) felt the guidance was ‘somewhat’ helpful and 3 (8%) of the
respondents did not recall.

0%
10%
20%
30%
40%
50%
60%
70%
A Great
Deal
Quite a Bit Somewhat Very Little Not at All I do not
recall
I did not
participate
in more
than 1
meeting
22 N=36
3
6
1
4

110
Figure 22: Question 6: In the Introduction section of the FDA briefing materials,
guidance is typically provided as described below.
FDA’s comments to the panel are identified throughout the document starting
with the text “FDA Comment” and encompassed by a border. The text in these
sections is intended to highlight relevant findings, potential discussion topics, and
questions for the panel. In addition, a summary of these comments is provided in
Section 11: Summary of FDA’s Comments.
Do you think that such an Introduction is helpful for focusing your review?

Question 7 (Figure 23) asked respondents if the FDA briefing materials were helpful in
forming their opinion on the risk-to-benefit ratio of the medical device. Ten (27%) of the
respondents felt the FDA briefing materials helped ‘a great deal’, 13 (35%) felt that it
helped ‘quite a bit’ 10 (27%) felt that it helped ‘somewhat’, 3 (8%) that it helped ‘very
little’, and 1 (3%) felt that it was ‘not at all’ helpful in forming an opinion.
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
A Great Deal Quite a Bit Somewhat Very Little Not at All I do not recall
7
12
15
3
N=37

111
Figure 23: Question 7: Do FDA briefing materials help you in forming your
opinion on the risk-to-benefit ratio of the medical device?

Most respondents felt that the FDA communicated its opinion on the risk-to-benefit of
the medical device in the FDA briefing materials to at least some extent (Question 8,
Figure 24). Five (14%) of the respondents felt the FDA communicated their opinion ‘a
great deal’, 16 (43%) felt the FDA communicated their opinion ‘quite a bit’, 9 (24%) of
the respondents felt the FDA ‘somewhat’ communicated their opinion, 1 (3%) of the
respondents felt the FDA communicated their opinion ‘not at all’, and 3 (8%) of
respondents did not recall if FDA communicated their opinion.
0%
5%
10%
15%
20%
25%
30%
35%
40%
A Great Deal Quite a Bit Somewhat Very Little Not at All
1
3
10
13
10
N=37

112
Figure 24: Did you feel that the FDA communicated its opinion on the risk-to-
benefit of the medical device in the briefing materials that you have
reviewed?

Questions 9 and 10 respectively (Figure 25 and Figure 26) asked whether specific
examples of FDA language taken from briefing books could influence their decision on
the approvability of the medical device. When the language expressed significant
concerns with the adequacy of the study data and therefore risk to public health, three
(8%) of the respondents said that such an example would be ‘extremely influential’,
13 (35%) said that it would be ‘very influential’, 16 (43%) that it would be ‘somewhat
influential’, 4 (11%) that it would be ‘slightly influential’, and 1 (3%) that it would be
‘not at all influential’.

0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
A Great Deal Quite a Bit Somewhat Very Little Not at All I do not recall
16
9
5
3
1
3
N=37

113
Figure 25: Question 9: Below is an example of comment that the FDA included in
one set of briefing materials.
FDA’s mission is to protect and promote the Public Health and the FDA review
team has significant concerns this device has not been studied adequately for its
current indications for use and therefore puts the health of the public at risk.
Do comments such as that above influence your decision on the approvability of the
medical device?

Question 10 (Figure 26) asks a similar question about an FDA comment in which it
expressed concerns that the product was not yet ready for commercial approval. Three
(8%) of the respondents said that such an example would be ‘extremely influential’,
16 (43%) that it would be ‘very influential’, 14 (38%) of the respondents that it would be
‘somewhat influential’, 3 (8%) that it would be ‘slightly influential’, and 1 (3%)
respondent that it would be ‘not at all influential’.

0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Extremely
Influential
Very Influential Somewhat
Influential
Slightly Influential Not at all
Influential
3
13
16
4
1
N=37

114
Figure 26: Question 10: Below is an example of a recommendation that FDA
included in one set of briefing materials.
Therefore, FDA recommends that the MitraClip CDS continue to remain
available to this vulnerable patient population as an investigational device so that
Abbott Vascular can conduct the COAPT and European trials in optimal manner.
PMA approval is not appropriate at this time as major questions of safety and
effectiveness, as well as the overall benefit-risk profile for this device, remain
unanswered for the regulatory standards set forth in 21CFR 860.7.
Do recommendations such as that above influence your decision on the
approvability of the medical device?

Respondents had mixed views on the extent to which the FDA followed the guidance by
refraining from comment on the approvability of the medical device to the advisory
committee (Question 11, Figure 27). Eight (22%) of the respondents said that FDA
follows the guidance ‘a great deal’, 10 (28%) that they would follow the guidance ‘quite
a bit’, 15 (42%) that they followed it ‘somewhat’, 2 (6%) that they followed it ‘very
little’, and 1 (3%) that they follow the guidance ‘not at all’.
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Extremely
Influential
Very Influential Somewhat
Influential
Slightly
Influential
Not at all
Influential
3
1
14
16
3
N=37

115
Figure 27: Question 11: In March 2010, the FDA issued a press release with
changes to the Medical Device Advisory Committee process. In the
release, they stated they would no longer comment on the
approvability of the medical device to the advisory committee. In your
experience, to what extent does FDA follow this guidance?

Question 12 (Figure 28) asked respondents whether they thought that the restrictions on
the ability of the FDA to comment on the approvability of a device is a progressive or
retrogressive step in supporting the work of advisory committees. Ten (27%) responded
that the guidance was a ‘progressive/positive step’, whereas 14 (38%) responded that it
was a ‘retrogressive/negative step’, and 13 (35%) had ‘no opinion’.
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
A Great Deal Quite a Bit Somewhat Very Little Not at All
8
10
15
2
1
N=36

116
Figure 28: Question 12: Do you think that restrictions on the ability of FDA to
comment on the approvability of a device is a progressive or
retrogressive step in supporting the work of advisory committees?

Ten (27%) of the respondents also took advantage of the opportunity to share additional
information using a provided text-box. A few of the comments requested clarification on
a specific question, but most provided feedback or insight into the advisory committee
process.

0%
5%
10%
15%
20%
25%
30%
35%
40%
Progressive / Positive Step No Opinion Retrogressive / Negative
Step
13
14
10
N=37

117
Table 12: Question 13: Do you have anything that you would like to share?
Comment 1 I mainly sit on drug advisory committees. FDA leadership provides
guidance to the committee. I find their expert opinion very useful.
Comment 2 There is a dissociation of the FDA with the real world of medicine.
Comment 3 On the second to last question, I would have responded "I don't
know" if that was available. I checked 4 instead because my
experience is that the FDA follows it own procedures.
Comment 4 The process is pretty good. You should ask them about their work on
risk tolerance versus benefit in survey data to patients.
Comment 5 It is a shame that there is no effort to integrate the company and FDA
materials, so that you do not have to fish through the entire two
packets to get to the core issue of contention and agreement.
Comment 6 I could not answer the second to last question since I do not have
enough experience with this change.
Comment 7 Item 6, re Introduction is inadequate, depending on what you want to
know. Is it the fact that it is and Introduction, is it the practice of
making comments "throughout the document" or is it making any
such comments at all?
Comment 8 In general the panel consists of very opinionated experts, I don't think
FDAs convey opinion matters much. For example the first Atritech of
2014 (or maybe late 2013) when I dont think FDA favored approval,
the trial didn't meet endpoints, and the panel voted something like
13-0 or 13-1 to approve.
Comment 9 The impact of the FDA recommendations, in the past, have been
impacted by the preparation of the presenter of these
recommendations. The presenter MUST be well prepared to answer
questions regarding the methodology for arriving at the opinion that is
expressed. I have participated in a number of panels where FDA
comments were overridden by the panel consensus.
Comment 10 FDA should comment with respect to the particulars of the product
being reviewed.

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CHAPTER 5. DISCUSSION
5.1 Summary
The primary role of an FDA advisory committee is to provide independent, expert
scientific advice to support FDA’s evaluation of specific drugs, biologics, or medical
devices at any stage of consideration. To assure this independence, the committee should
be insulated from any potential influence from the sponsor of the product under
consideration as well as from any other entities or persons with a vested interest in the
outcome of the process. In principle, the FDA itself might be considered to be a vested
party, so efforts have been made to ensure that the FDA does not compromise
impartiality of the committee. The goal of this exploratory study is to examine whether
FDA briefing book, which serve as a significant conduit for communication between the
FDA and the advisory committee, has the potential to influence advisory committee
members prior to the meeting by virtue of their format and content.
5.2 Consideration of Methods
The primary method by which FDA conveys information to the advisory committee prior
to the meeting is through briefing materials published by the FDA in the form of a
briefing book. The analyses performed in this exploratory study were delimited to the
briefing book; they did not extend to other types of materials that were provided by other
sources, and did not extend to verbal or written interactions of other kinds such as emails
to individual participants in the panel or transcripts of the advisory committee meetings.

119
The briefing book was considered to be a reasonable beginning point to understand the
manner and effect of formal communications between the FDA and the advisory
committees because this is the primary and most detailed document used by advisory
committee members to prepare for the meeting (McIntyre 2012). Despite its potential as
a source for both information and influence, there appears to be no previous study to
characterize FDA briefing materials, and thus appears to be a good starting point for the
research here. If this study were to be expanded, additional documents that could be
reviewed might include the materials and verbal exchanges occurring during the advisory
committee meetings, including the FDA presentation and transcripts of each meeting.
The study is further delimited in scope and time. It examines briefing books given to
advisory committees that were concerned with the approval of medical devices in the
United States through FDA’s Center for Devices and Radiological Health (CDRH). It is
further delimited to advisory committee meetings held from April 2010 to April 2013.
This timeframe was specifically chosen because it followed a public statement by the
Center for Devices and Radiological Health (CDRH) announcing that they would no
longer comment on the approvability of medical devices during advisory committee
meetings (FDA 2010a). However, this limitation restricts the study to only about 30
meetings of medical device advisory committees. Its results may not adequately
represent the content of briefing documents prepared for advisory committees in other
branches of the FDA. In particular, the Center for Drug Evaluation and Research (CDER)
has a different format for their briefing books and a slightly different advisory committee

120
process. In the future a more complete picture might be obtained by conducting a similar
study on materials for a broader sample of advisory committees across multiple FDA
divisions, to assure the external validity of these findings for the advisory committee
process across all branches of the FDA.
Several asymmetries and limitations should be considered when attempting to interpret
the results of this study. The individual reviewing divisions of CDRH had different
numbers of advisory committee meetings during the studied period, so that the results
will be most influenced by observations from those divisions with the highest number of
meetings and therefore the highest number of briefing books. For example, the
Circulatory Systems Advisory Committee met 12 times, whereas the Orthopedic and
Radiological Committees only met twice each. Further, some medical device advisory
committees did not meet at all and are not represented in the study group.
As with any study based on content analysis, the validity of the conclusions is limited by
the ability of the reviewer to develop an appropriate coding structure (Folger 1984) and
to sort the data into appropriate categories in a way that is robust, reproducible and free
of bias (Potter 1999). The use of coding strategies in qualitative studies is a well-
established way of grouping like observations in document types as varied as interview
transcripts, participant field notes, journals, documents, literature, and e-mail
correspondence (Strauss 1987). A strong analysis depends on careful development of a
unique, fit-for-purpose coding strategy that must be derived from initially subjective
examinations of the materials under study by the researcher. This stage, known as

121
theoretical sampling, allows for the coding categories to be applied and tested, and often
will generate additional categories and revisions to the original categories (Strauss 1987).
Coding strategies are vulnerable to bias, both in the selection of observations considered
to be important to capture, and the placement of those observations into an appropriate
grouping by the application of the coding approach. In this study, the analytic approach
was much less subjective than it often is in social science studies, because the coding
method was relatively simple, straightforward to apply and easily related to questions that
were asked in the research. The specific coding criteria for this study were established
after reviewing several briefing books and comparing comments and formats from the
different reviewing divisions. The comments in the briefing books were then divided into
only three categories related to safety, effectiveness, or other and were further sub-
classified only by signifying whether or not FDA expressed a “concern” as part of the
comment. This secondary decision was relatively straightforward because the FDA
would frequently use the word “concern” when communicating a concern in the
comment, thus limiting the need for interpretation. Nevertheless, I took advantage of a
strategy often employed in more complex or subjective studies, in which a second
examiner repeats the analysis in a small sample to assure the reproducibility of the results
(Hruschka 2004). The very high level of consensus that was observed when a second
individual with appropriate experience repeated the analysis on sampled documents
provided a high level of confidence in the coding decisions on the whole collection of
more than 2,100 pages of documentation.

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Characterizing the structure and comments in briefing books was much easier than
understanding how the comments made by the FDA would influence the decision-making
of the advisory committee members. By supplementing the document analysis by more
direct interrogation of some advisory committee members, it was hoped that more insight
could be gained into this difficult question. The use of multiple methods to evaluate FDA
briefing books can contribute to the strength of the study by triangulating the
observations (Kohlbacher 2006). However, limitations are also associated with the
survey method, related to the representativeness of the sampled respondent pool and the
passage of time since the committee members reviewed the briefing book. Both potential
limitations may influence the results presented here.
It can be very difficult to assure a large respondent pool when the number of affected
individuals is inherently small, as is the case here. An average advisory committee was
found in this study to have about 11 members, and some of these committees did not
even meet in the timeframe covered by this study. By using an email survey, however, it
was at least possible to assure that all members of the relevant committees were offered
the opportunity to participate. This avoided the often-cited disadvantage of selection bias
that is of concern when a survey cannot be distributed in a way that allows adequate
representation of the population under study (Atkinson 2001). Nevertheless, much has
been written about the problems that can limit the responses of those who are
approached. For example, extrapolating the survey results can be problematic if only
certain respondents have a valid email address, access to the internet, and the technical

123
proficiency to fill out an online survey (USGS 2013). Thus care had to be taken to
consider sources of problems related to the technology. In this study of highly trained
medical doctors and scientists, I did not anticipate that respondents would not have the
tools or skills to complete an email survey. What did however seem to limit this survey
was the use of spam filters by many email systems. Care was taken in the wording for the
subject line of the email to minimize the chance the email would be identified as spam by
the computer. Nevertheless, such a possibility may have affected the response rate here.
Another concern was the possibility that individuals could have multiple addresses or
nonworking email addresses and might receive the survey more than once or not at all.
Nevertheless, when reviewing the unique identifier on Qualtrics of those that took the
survey, no respondents submitted more than one survey response.
In any survey, it is anticipated that not all potential applicants will provide responses. It is
a particular challenge to secure the assistance of healthcare professionals who are
typically busy and difficult to interest in participating. Short surveys are known to elicit
higher response rates (Bhattacherjee 2012), so the survey was kept to 10 questions that
could be completed in five to ten minutes. In addition, non-respondents were sent a
follow-up request in an effort to increase the response rate. Nevertheless, the survey
dataset was limited by the number and availability of advisory committee members who
were willing to respond to the survey. In this instance, the responses of 37 individuals
who completed the survey equated to a response rate of about 15%, lower than the 32%
response rate that Watt et al (2002) reported as an average for online surveys, but higher

124
than some professional surveys whose response rates are in the single digits (Kaplan
2002). Possible contributing factors to the modest response rate may have been the fact
that the survey dealt with sensitive topics which may have limited the willingness of the
respondent to share sensitive information. Respondents may also be reluctant to
participate in a survey that asks the respondent to recall specific information after
advisory committee meetings that in some cases occurred 2-3 years previously. On the
other hand, the fact that the survey was anonymous may have helped to increase the
response rate and assure that the respondents felt safe to express their views honestly. An
advantage of an anonymous survey rather than an interview is that advisory committee
members do not have direct contact with an interviewer and may be less likely to be
affected by interviewer bias (Phellas 2011). However, the survey approach is limited in
its ability to probe deeper into areas that might prove interesting. In this respect,
interviews might have had certain advantages because the interviewer could have been
able to clarify questions that the respondent has not understood and could have probed to
obtain further elaboration of replies. It was clear from the many replies in the text box
provided for comments that future studies might profit from more in-depth interviews of
committee members.
Another limitation of the study is related to the degree of skill and experience of the
researcher with this type of research. Despite this potential limitation and despite the
exploratory nature of this work, the results presented here do provide more insight than
has previously been available and gives a good starting point and benchmark for later

125
detailed consideration and comparative analysis of documentary interactions with FDA
advisory committees.
5.3 Consideration of Results
5.3.1 Characterization of Briefing Books
Prior to this study, little had been written about the organization of FDA briefing
documents. Thus many of the observations here provide basic information about
document content and format. The results suggest that the briefing books are not
organized in a highly consistent manner, especially between reviewing divisions. These
differences include, but are not limited to the length of the briefing book, whether FDA
includes a description of why the medical device was sent to advisory committee, and the
format and use of comments by the FDA.
5.3.1.1 Length of Briefing Books
In the present study, briefing books were found to vary in length from 29 to 385 pages. Is
the highly varying length of the briefing book of any particular relevance? Based upon
the literature review, only one document, Preparation and Public Availability of
Information Given to Advisory Committee Members (FDA 2008c), is publicly available
and discusses the structure of the briefing book. However, the document aims primarily
to provide a sponsor of a new medical product with guidance on creating and submitting
their briefing materials, and does not detail the approach of the FDA to the operational
development of the book. In fact, the FDA acknowledges that briefing materials will

126
vary in length and content, “…the type and amount of information included generally
will depend on the type of product or issues to be discussed.” Based upon the complexity
of the medical device and the clinical study, one would expect some variation in the
length of the FDA briefing materials. Nevertheless, it seems surprising that so much
variation was seen in the briefing books that were studied. One factor that certainly
appears to affect overall length is the volume of materials supplied by the sponsor. While
FDA includes some original content in the briefing books, it relies heavily on the content
and analyses provided in the Sponsor’s briefing book. Another contributing factor may be
stylistic and procedural variations that are associated with different reviewing divisions.
Most FDA briefing books contain at a minimum the following sections: Introduction,
Background Information, Non-Clinical Data, Clinical Study Description, Clinical Study
Results, and Post-Approval Study. However, examples of unique elements such as the
presence of an entire section of FDA concerns, titled “FDA Review Team’s Summary of
Clinical and Statistical Concerns”, in one briefing book and a section on “FDA
Recommendations” to the advisory committee in another, were particularly interesting
not only because they lengthened the book but because they seemed to defy the policies
of FDA to insulate the advisory committee.
After identifying that briefing books varied in length, it seemed useful to understand
whether the length of those books was of any significance to advisory committee
members who had the task of reading and analyzing those materials, and whether there
seemed to be an “ideal” length for the document. Perhaps surprisingly, a large proportion

127
(41%) of the respondents did not have a preference on the length of the briefing book. It
is not clear however, whether respondents were less concerned because they rely heavily
on certain shorter parts of the book, such as the Executive Summary, and use the rest of
the book for reference, by navigating to certain sections using its table of contents, for
example, or whether they feel that books should simply vary according to the complexity
and volume of materials that seem relevant for the particular review. When a preference
was stated, it was most commonly for a length under 50 pages. A preference for shorter
books by more than a third of respondents may not be surprising. Advisory committees
are composed largely of medical doctors and scientists, whose busy schedules might be
expected to limit the time available to prepare for the meeting. Those preparations must
include not only the review of the FDA briefing book but also the Sponsor’s briefing
book. Interestingly, a few respondents (11%) were at the other end of the scale and
preferred the briefing book to be over 150 pages. The reasons for the divergence in
preference would be interesting to explore in the future.
5.3.1.2 Formatting Inconsistencies between Reviewing Divisions
The FDA has flexibility in referring a medical device to an advisory committee but is not
required to explain that decision in the briefing book. The draft guidance, Guidance for
the Public and FDA Staff on Convening Advisory Committee Meetings (FDA 2008d),
states that the FDA is not legally compelled to refer a matter to advisory committee, but it
may nevertheless choose to do so voluntarily when one of the following criteria are met:
(a) when the matter at issue is a significant public interest (b) when the matter at issue is

128
highly controversial (c) when there is a special type of expertise that an advisory
committee could provide that the FDA is lacking. The guidance document goes on to
state that the FDA recognizes that advisory committee meetings demand significant
resource commitments by advisory committee members, sponsors and other public
participants, as well as by the FDA itself, and thus should be reserved for important
matters. It therefore makes sense that a decision of such importance should be explained
in the briefing book so that advisory committee members can better understand the
reason that the committee was called. For example, the FDA provided the following
detailed description in the Augment Bone Graft Briefing Book:
Rationale for Presentation to the Panel: The FDA presents this PMA to the
Orthopedic and Rehabilitation Devices Advisory Committee for the following
reasons:
• The Augment Bone Graft is the first combination product utilizing rh-PDGF-BB to be
indicated for use as an alternative to autograft in hindfoot and ankle fusion
procedures that require supplemental graft material, including tibiotalar,
tibiocalcaneal, talonavicular, and calcaneocuboid fusions.
• FDA has ongoing concerns with the possible toxicity of this product as well as the
ability of the studies to demonstrate reasonable safety and effectiveness and will
describe these concerns in this summary.
It was therefore interesting to find that most briefing books included no explanation of
why the product was referred to a meeting of the advisory committee. Because this study
limited its examinations to the FDA briefing book, it is not possible to know whether
advisory committee members were given this information from the FDA in some other
way. However, its presence or absence appeared to depend on the typical practice of the
division developing the briefing book. The inconsistencies from one medical device
reviewing division to another suggests that internal procedures may exist to create

129
briefing books within the individual divisions, but no standardized internal procedure
appears to be shared between them. It might be useful for the FDA to examine its
internal processes to determine whether benefits would accrue from providing the
rationale for convening the meeting in all medical device briefing books as a standard
procedure.
Another finding suggesting division to division variability was the inconsistency in the
way that comments were formatted. In some books, the comments are bolded, while in
others they are italicized, boxed, or left in a normal typeface. Some comments start with
an identifier such as “FDA Note” or “Comment”, but others do not. Some comments are
placed after the text, whereas other comments are interposed within the text where they
can be more challenging to identify. The format in many cases appeared to depend on the
originating division. It again suggests that the formatting rules for briefing books are
largely dictated by the individual reviewing divisions acting independently and without
an overarching process or procedure at the level of CDRH as a whole. The finding that
most advisory committee members viewed the formatting and content as at least
somewhat consistent between briefing books may reflect the fact that advisory committee
members typically serve only within a single reviewing division, where style is more
consistent that it is across divisions. Another possibility is that the differences noted
above were not significant enough for the advisory committee members to recall, since
some of the meetings under consideration took place as long as five years prior to survey
administration.

130
5.3.1.3 Comments Included in the Briefing Books
The comments that FDA includes in the briefing books are intended to “highlight
relevant findings, potential discussion topics, and questions for the panel”. In a little over
half of the briefing books the FDA was found to have explained the use and methodology
of the comments included in the briefing book in the Introduction Section. While this
piece of information may not be critical to the activities of the advisory committee, it was
seen to be a useful piece of information by the large majority of advisory committee
respondents.
FDA briefing books were found in this study to have many interposed comments, and
some of these comments expressed FDA concerns. This observation raises a central
question: Are the comments appropriate when they go beyond the communication of
data and instead directly or indirectly state a concern with data, trial design or product?
Conversely, is it appropriate for FDA to tell advisory committee members when the data
is acceptable and they do not have a concern? It must be acknowledged that comments
using neither negative nor positive language were more common than positive or
negative comments. However, these latter comments, as well as the even more loaded
suggestions or recommendations, can potentially have an impact on a committee
member’s opinion of a product. We know from the research of McIntyre (McIntyre
2012) that the FDA briefing book is the primary document used by advisory committee
members in their preparation for a meeting. The fact that 89% of the respondents said that
the FDA briefing book was ‘a great deal’, ‘quite a bit’, or ‘somewhat’ helpful in forming

131
their opinion on the risk-to-benefit of the medical device supports the observations of
McIntyre. It reinforces the potential importance of opinions included by the FDA in their
briefing book and further demonstrates the privileged position that FDA can have on the
outcome of an advisory committee meeting by shaping the information provided to its
members.
To better understand the relationship and the possible influence that the FDA can have
over advisory committee members, one can look at two models of influence discussed in
Chapter 3, Six Key Principles of Influence (Cialdini 2003) and Social Impact Theory
(Latane 1996). The Social Impact Theory states that the influence of a person or
organization depends on its perceived strength or authority, the immediacy of its
influencing actions, and the number of available sources of influence. FDA may occupy a
particular position of power or importance with respect to advisory committee members
because those members are chosen by the FDA, and because several FDA personnel will
be in immediate contact with the advisory committee members throughout the committee
meeting. Further, the briefing book has a potentially strong influence because of its
immediate relationship to the meeting and because of the fact that relatively few other
materials are used by the committee to prepare for the meeting. All of these factors
suggest that FDA might be in a position to have substantial influence over this “arms-
length” body.
Cialdini’s Six Key Principles of Influence highlight elements - reciprocity, commitment,
social proof, liking, authority, and scarcity- that reiterate ideas introduced by the Social

132
Impact Theory. The theory suggests that FDA is in a position of “authority” because it
selects the members of advisory committees; such positions are “scarce” and prestigious,
and the selection process is highly selective. As a result, members may have a desire to
“reciprocate” to the FDA for selecting them for the advisory committee. In addition, FDA
may influence advisory committees through “confirmation bias”, defined as “the seeking
or interpreting of evidence in ways that are partial to existing beliefs, expectations, or a
hypothesis in hand” (Nickerson 1998). Nevertheless, it could be argued that advisory
committee members are highly capable individuals who typically “know their own
minds”. Thus the question remains: To what extent do the inclusion of strongly worded
comments and recommendations in the FDA Briefing Book influence advisory
committees?
Insight into this question was difficult to gain simply by examining the relationship
between the nature of comments in the briefing book and the voting patterns on that
product by the committee. Voting outcomes can reflect a multiplicity of influences.
Unsurprisingly, then, only a modest statistical relationship is in evidence between the
number of comments in briefing books and the voting patterns of the committees; that
relationship suggested that the proportion of ‘Yes’ votes decreased by 0.38 percentage
points with each concern and 1.13 percentage points when only those comments that
explicitly used the word ‘concern’ were used in the analysis. For this reason, it seemed
relevant simply to ask the committee members about the extent to which a strongly
worded concern or recommendation would tend to influence them. The fact that most

133
advisory committee members felt that such comments would be influential suggests that
FDA should exercise great care with such comments.
Another interesting observation was the variability observed in the number of comments
in the briefing books, with the inclusion of more comments typical for products whose
approval appeared to be less well supported by FDA. For example, the MelaFind Briefing
Book had the highest number of comments reflecting concern, and these concerns
included an explicit recommendation not to approve the product. Three other briefing
books with a high number of comments are the Augment Bone Graft, Margin Probe
System, and MitraClip Delivery System Briefing Books. FDA recommended against
approval in two of the three briefing books, and adopted a largely negative tone in the
third. In contrast, briefing books with few to no comments included the iStent, LAP-
BAND, Pipeline Embolization Device, PTX Drug Stent, and Restylane, devices that
appeared to have been approved with relative ease. The range in the number of concerns
that the FDA included in the briefing books appeared therefore to be related to the FDA
opinion on whether the medical device should be approved. These results are consistent
with the affirmative responses of most advisory committee members when asked if they
felt that the FDA included their opinions on risk-to-benefit relationships in the briefing
books.
Although FDA stated in 2010 publicly that they would no longer comment on the
approvability of the medical device to advisory committee members, it is apparent from
this analysis that such comments continue to be made. Not only were 5 of 30 briefing

134
books found to include comments on approvability, but strongly worded concerns were
also found in several others. In addition, the FDA has stated in a press release (FDA
2010a) that they would make greater efforts to include a range of scientific opinions in
their analyses. Trying to quantify the different scientific opinions included in the briefing
books is a complex undertaking that was beyond the scope of this research, and might be
an interesting, albeit difficult topic to be addressed as part of follow-on research.
5.3.2 Summary of Findings and Recommendations
A review of the literature and the results suggest that the FDA briefing book is an
important document supporting the preparation of advisory committee members for the
meetings. While each reviewing division seems to have its own process for creating a
briefing book, there does not appear to be a consistent overarching process followed by
different divisions of the Center for Devices and Radiological Health (CDRH). It would
seem prudent that the CDRH consider the introduction of practices that would allow the
reviewing divisions enough flexibility to tailor the content and analyses to the different
types of products, while still using a consistent approach to the formatting and type of
information in the briefing book. High quality briefing books that are consistent in
formatting and content would seem to benefit both the FDA as well as the advisory
committee members, both for their immediate as well as archival roles.
One practice that could profit from particular scrutiny is the way that comments are used
in the briefing book. While FDA’s comments are intended to highlight certain areas of
the briefing book, they often go beyond that intended scope, to include opinions,

135
concerns, and even recommendations to advisory committee members. Some of the
comments that the FDA includes in the briefing books are not in compliance with the
intention of the Federal Advisory Committee Act that states the committee should:
contain appropriate provisions to assure that the advice and recommendations of
the advisory committee will not be inappropriately influenced by the appointing
authority or by any special interest, but will instead be the result of the advisory
committee’s independent judgment (Pub. L. 92-463 1972).
This conclusion is reinforced by views of advisory members that leading comments
expressing negative FDA opinions or concerns are at least somewhat influential, and that
the book as a whole generally uses text and tone elements that convey FDA opinions with
regard to the risk-to-benefit character of the product under review. We know from the
review of the briefing documents that the FDA directly or indirectly commented on the
approvability of the medical device in five different briefing books.
These observations may stimulate FDA to review its internal processes for the
development of briefing documents and to implement a more standardized methodology
that increases the consistency of formatting and content between medical device divisions
as well as purging loaded comments and directive recommendations from its briefing
materials. A more consistent and robust process might include a quality inspection step to
ensure that briefing documents comply with applicable statutes, regulations, guidance,
and procedures. Although the results presented here are preliminary and should be
viewed as a starting in a more detailed consideration and analysis of FDA advisory
committees, these findings can provide some initial guidance for policymakers on this
important issue.

136
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Abstract (if available)

Abstract The primary role of an FDA advisory committee is to provide independent, expert scientific advice to support FDA’s evaluation of specific drugs, biologics, or medical devices. The FDA briefing book, which serves as a significant conduit for communication between the FDA and the advisory committee, may have the potential to influence advisory committee members by virtue of its format and content. FDA briefing books between April 2010 and April 2013 were analyzed to identify if document content and format were notably different between the different medical device divisions of the FDA. In addition, using methods of content analysis, the study evaluated whether the FDA commented on the approvability of the medical device and whether the tone and content of the briefing materials conveyed FDA’s opinion on the risk-to-benefit profile of the device. Further, a survey of advisory committee members was undertaken to evaluate if briefing book content was considered to be influential in how the committee member felt about the risk-to-benefit profile of the medical device. The research identified that the content and format of the briefing books varied between the different medical device divisions suggesting no overarching process for creating a briefing book. In addition, the comments included in the briefing book often included opinions, concerns, and even recommendations to advisory committee members. It was identified that FDA directly or indirectly commented on the approvability of the medical device in five different briefing books. The survey showed that advisory committee members felt that comments expressing negative FDA opinions or concerns were at least somewhat influential, and that the briefing book as a whole generally used text and tone that conveyed FDA’s opinion with regard to the risk-to-benefit profile of the product under review.

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Asset Metadata

Creator Leitner, William P. (author)

Core Title FDA influence on advisory committees through documentation: a content analysis and survey of industry views

School School of Pharmacy

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Publication Date 08/04/2015

Defense Date 04/22/2015

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

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Advisor Richmond, Frances J. (committee chair), DiBiasi, Jim (committee member), Loeb, Gerald E. (committee member), Pacifici, Eunjoo (committee member)

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