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Preclinica

A BioTechniques® Publication

Volume 2, No. 2 March/April, 2004

Looking Through a Window of the Food and Drug


Administration: FDA's Advisory Committee System
Linda Ann Sherman
Director, Advisory Committee Oversight & Management Staff, Food and Drug Administration,
Rockville, MD, USA
Reprinted with permission from Preclinica 2(2): 99-102 (March/April 2004)

The U.S. FDA is one of the most recognized necessitated the establishment of a strong advisory
and respected federal agencies in the world. It committee system within the FDA. Scientific
is responsible for food safety policy and for the advisory committees complement the Agency’s
regulation of more than 150,000 marketed medi- scientific expertise by bringing cutting-edge re-
cal products. Not only does the Agency review search, patient and patient caregiver concerns,
new investigational products, but it also continues and industry and consumer advocacy viewpoints
its oversight for the entire life cycle of the prod- to the table for discussion.
uct from its preclinical development phase to its
continued presence in the marketplace. Given the FDA OVERVIEW
exponential explosion of scientific discoveries over
the last century, how does this relatively small gov- The mission of the FDA is to protect the pub-
ernment agency remain current on all emerging lic health by ensuring the safety, efficacy, and se-
technologies to appropriately evaluate the cutting- curity of human and veterinary drugs, biological
edge scientific medical developments that are pre- products, medical devices, the nation’s food sup-
sented to it for approval? Within the Agency’s sci- ply, cosmetics, and products that emit radiation.
entific armamentarium, one of its most important The FDA is also responsible for advancing the
resources is the FDA advisory committee system. public health by helping to speed innovations that
Extensive use of most of the federal advisory make medicines and foods more effective, safe,
process began shortly after the Second World War and affordable, and helping the public get the ac-
when it became apparent that the use of public curate, science-based information. The FDA is
meetings, as functional parts of governmental divided into the six Centers (Center for Biologics
agencies, improved communication and citizen Evaluation and Research, Center for Devices and
acceptance of new statutes and regulations. The Radiological Health, Center for Drug Evaluation
FDA did not initially take full advantage of the and Research, Center for Food Safety and Applied
advisory committee process, because the post-war Nutrition, Center for Veterinary Medicine, and
administration believed that the FDA’s experts the National Center for Toxicological Research),
were capable of making appropriate independent the Office of the Commissioner, and the Office
regulatory decisions. However, over the decades, of Regulatory Affairs (FDA’s enforcement arm).
rapidly changing complex technology, additional Approximately 10,000 individuals work at the
legislation, and increased consumer activism have Agency: this includes physicians, nurses, dentists,

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Commentary
Regulatory Forum

microbiologists, chemists, pharmacists, toxicolo- having public discussions of controversial topics


gists, statisticians, biopharmaceutists, engineers, by the world’s experts, the Agency staff, and the
economists, and administrators. Agency’s stakeholders (industry and consum-
The public entrusts the FDA to safeguard its ers). Every meeting also serves to keep consumers
health and safety by making timely and credible abreast of the latest developments in the industry
independent scientific decisions on products as well as affords them the opportunity to com-
that it regulates. In the most recent past, it has ment in an open public hearing session.
been challenged by such multifaceted topics as The FDA has 30 advisory committees, 18
variant Jacob-Creutzveldt disease, silicone breast device panels, 8 chartered subcommittees, and
implants, hormone replacement therapy, ephe- 1 committee that it administers on behalf of the
dra, gene therapy, vaccine efficacy, allogeneic Office of the Secretary, Department of Health
islet cell transplantation, blood donor deferrals, and Human Services (DHHS). The commit-
and emergency contraception. Just how does the tees are divided along product lines (e.g., food,
Agency fulfill its mission of answering difficult devices, drugs, and biologics) and body systems
scientific questions? When a pre-market new (e.g., cardiovascular or gastrointestinal prod-
drug application (NDA) is submitted, a team of ucts). Committees are either mandated by leg-
reviewers examines “the sum of its parts.” The islation (five) or established at the discretion of
chemist examines the sponsor’s new product the Department of Health and Human Services.
chemistry and manufacturing specifications, Each committee, save two statutory committees,
the toxicologist looks at the preclinical animal is chartered for 2 years. If, at the end of 2 years,
or in vitro studies, and the physician reviews the the Agency or the DHHS determines that an ad-
data of the pivotal clinical studies. A compre- visory committee no longer serves a useful pur-
hensive discussion of the FDA review process is pose or that it might be better incorporated in
beyond the scope of this article, but the simplest another committee’s mission, it is terminated.
description of the FDA review is that it is a com- A regular review is necessary because committee
prehensive audit. Consider a protocol in which meeting costs are high. In the fiscal year 2003,
a determination of cure or failure requires a 1- the cost of the FDA’s committee process conser-
month posttreatment clinical assessment. The vatively cost taxpayers over $8 million for 80+
sponsor determines that the cure rate or efficacy meetings.
is 88% or that eight of nine (8/9) persons were In accordance with the Federal Advisory Com-
cured, one person failed treatment (1/9), and mittee Act of 1972 and to maximize their effec-
one patient was not evaluated because he did not tiveness, the FDA’s committees are balanced both
return for the 1-month posttreatment evalua- demographically and scientifically. Committees
tion. If the clinical reviewer determines that the are composed of respected academicians, clini-
reason for the lack of follow-up was due to dis- cians, consumer advocacy group representatives,
ease progression, the FDA will reassess the cure industry representatives, and patients or their
rate as 80% or eight (8/10) cures and two (2/10) caregivers. Nominations for scientists originate
failures. Different judgments may become topics from professional societies, industry, consumer
of discussion at an advisory committee meeting. groups, prior members, or the individual himself.
In contrast to the scientific experts selected by the
THE WINDOWS Commissioner of Food and Drugs or his desig-
nee, peers select their own stakeholder (consumer
The advisory committees’ role is to offer the and industry) representatives. Concerted efforts
FDA the very best advice possible on related ques- are made to ensure that each FDA advisory com-
tions posed by the Agency on a product of regu- mittee or panel mirrors the population of Amer-
lated industry. It is important to understand that ica. With appropriate representation of age, race,
the committee’s function is to give advice; however, sex, ethnicity, geographic, and other factors, a
the Agency is not bound to follow that advice. voice is available to speak for multiple population
The FDA’s advisory committees lend cred- characteristics that are impacted as a new medical
ibility to the FDA decision-making processes by product is being evaluated.

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Regulatory Forum

Upon selection, all members, except those there are few individuals who can match the level
representing industry, become special govern- of expertise in the field of these distinguished
ment employees (SGEs), subject to multiple scholars. It is in an instance such as this that a
criminal statutes including 18 U.S.C. section waiver might be sought. It is much more difficult
208 and the Emoluments Clause of the Constitu- to find relief for an individual’s intellectual bias.
tion. Members serve overlapping terms for up to In fact, the FDA Modernization Act of 1997 spe-
4 years and are rarely renewed to guarantee fresh cifically prohibits members of biologics or drug
points of view. A Chair facilitates the meeting therapeutic advisory committees from reviewing
and influences conversation such that a discus- matters related to their own work. The waiver cri-
sion neither deviates from the topic nor is mo- teria document (WCD) is an algorithmic guidance
nopolized by any one member. Chairpersons are that shows how FDA staff manages issues related to
generally selected from existing committee mem- potential financial conflicts of interest. More can
bers with leadership skills after they have served be learned about financial disclosure by reading
at least 2 years on a committee. the FDA’s WCD on the web (http://www.fda.gov/
oc/advisory/conflictofinterest/intro.html).
FINANCIAL DISCLOSURE AND Interestingly, much criticism has been and
INTELLECTUAL BIAS continues to be levied against members for their
inevitable financial holdings related to industry.
To be credible as well as useful, the advisory It is of note that these matters are often trivial
committee of a regulatory agency such as the FDA (i.e., less than 1% of an individual’s net worth)
must demonstrate that its members are free of or peripheral to an individual’s departmental
financial or intellectual biases. A financial inter- colleague’s grant from a competitor’s spon-
est is an interest imputed to a person, his spouse, sor. Nonetheless, all interests are reviewed and
minor child, or employer in which a regulatory evaluated by the Agency’s Ethics and Integrity
decision can result in a potential financial gain staff. In the year 2001, the Agency was asked by
or loss. Intellectual bias is more difficult to de- its stakeholders to provide more disclosure of the
fine. It usually means that the individual has been financial interests. To understand how current
involved in the clinical development process of members would feel about revealing more infor-
the new medical product. Before every meeting, mation publicly, a survey was conducted of its then
each member must disclose information related to 400+ members. Surprisingly, the members were
financial holdings and professional activities re- in favor of revealing more about their potential
lated to the product(s) or its competitor(s) that are conflicts; the members believed that more disclo-
subjects of the meeting. The difficulty the Agency sure would demonstrate to the public that their
faces in trying to hire SGE members to serve on an meeting recommendations were objective. As a
FDA advisory committee is that by definition the result, the FDA established a new policy whereby
world’s experts who are engaged in cutting-edge information relating to the nature and magnitude
bench science, clinical research, and independent of an SGE’s waived potential conflict of interest
consulting work are the very same individuals that for a product to be discussed is read into the pub-
are sought after by regulated industry. Fortunate- lic record. For more information on the disclo-
ly, there is relief from this conundrum in the stat- sure guidance, consult the web at http://www.fda.
utes, particularly 18 U.S.C. section 208. Basically, gov/oc/guidance/advisorycommittee.html. The
if the Agency’s need for a particular individual’s Agency aims for transparency in all its processes
expertise outweighs his or her potential financial and the advisory committee system is one window.
conflict, the Commissioner or his designee may
grant a waiver so that the individual may partici- PASSING THROUGH THE LOOKING-GLASS
pate. He may fully participate or be asked to par-
ticipate in a limited fashion. The decision for full The advisory committee system is a mechanism
or limited participation depends on the level of in which a private citizen can make a difference by
financial conflict. The FDA has had Nobel Prize his or her participation in a government process.
winning faculty as members on its committees; To meet the criteria as a committee member, one

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Commentary
Regulatory Forum

must be a technically qualified expert who is able to ommended that the risk/benefit ratio supported
interpret the complex data presented. He is either a restricted marketing of Lotronex for the treat-
an academician and/or a member of an advocacy ment of women with severe, diarrhea-predomi-
group or the industry. However, every meeting has nant IBS who fail to respond to conventional
an opportunity for all citizens—a required mini- IBS therapy. The FDA followed the committees’
mum of 60 minutes for an open public hearing ses- recommendation and approved a supplemental
sion—in which any person may make a presentation NDA. This story illustrates the power of the ad-
of scientific fact or personal experience. In one of visory committees and how the Agency utilizes
our most recent controversial meetings on breast the open, integrative process and its participants
implants, the FDA offered the public an 8-hour to make its regulatory decisions.
opportunity to present testimony to the committee
and over 140 individuals participated. BEING PART OF THE PROCESS
The approval of Lotronex™ (alosetron HCl),
a product for the treatment of irritable bowel The FDA highly values the service of its ad-
syndrome (IBS), serves as an example of how the visory committee members and the relationship
advisory committee process contributes to the the process affords with consumers and indus-
FDA through the use of the advisory committee try. The system allows for full participation and
experts, the power to be heard by patient advo- empowers the FDA’s stakeholders to assist in the
cates and other stakeholders, and the transpar- regulatory decision-making process. For more
ency of the Agency’s processes. Prior to its initial information on the FDA’s advisory committees
approval, several mild complications associated or how to participate, consult the FDA web site
with alosetron HCl usage were discussed at a 1999 at http://www.fda.gov/oc/advisory/default.htm or
open public gastrointestinal advisory commit- contact the Advisory Committee Oversight and
tee meeting. After its approval in early 2000, a Management Staff at 301-827-1220.
second meeting was held in mid-2000 to discuss
increased reports of more serious side effects. Address correspondence to:
By November 2000, the FDA was seriously con-
cerned and the sponsor voluntarily withdrew the Linda Ann Sherman
product. Patients with severe cases of IBS ap- Director, Advisory Committee & Management Staff
pealed to the agency, because many had experi- Food and Drug Administration
enced relief without side effects. In April 2002, 5600 Fishers Lane, HF-4
in a well-attended and emotional meeting of the Rockville, MD 20857, USA
gastrointestinal and drug safety and risk manage- e-mail: lsherman@oc.fda.gov
ment advisory committees, the committees rec-

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