Food and Drug Administration Advisory Committees (1992)

On July 1, 1992, the Food and Drug Administration (FDA) had a total of 41 technical advisory committees or panels that supported the work of the three centers responsible for the evaluation and regulation of drugs, biologics, and medical devices.^* In 1991, these committees met a total of 67 times, usually for two days per meeting, for an average of 3.2 meeting days per year. They typically consist of seven to nine members each, none of them employees of the FDA, who are supported by FDA professional staff and by a number of consultants. In this report, we refer to these advisory committees and their administrative support as the FDA's advisory committee system.

FDA technical advisory committees play an important, multifaceted role in the development and evaluation of new drugs, biologics, and medical devices. Although they are involved to some extent in the early stages of product development, and sometimes in postmarketing issues, their primary use lies in assisting the FDA to evaluate specific applications for marketing approval—new drug applications (NDAs) for drugs and biologics, product licensing agreements (PLAs) for biologics, or pre-market approvals (PMAs) for medical devices.

In addition, FDA advisory committees help the agency develop general guidelines regarding scientific and technical issues related to the agency's broader regulatory responsibilities, most often for biologics and less often for drugs and devices. In the case of the Center for Biologics Evaluation and Research, they review intramural research programs and personnel.

Although the advice of advisory committees is not binding on the FDA, the recommendations of a committee are widely regarded as a predictor of agency action. As a result, FDA advisory committees have become highly visible to the public, the Congress, the media, and the financial investment community. A committee meeting involving a particularly controversial matter may draw an audience of 300 to 400 individuals, including FDA staff,

sponsor employees, observers from competitor firms, the national and trade press, including cable and network television, and investment advisors.

The importance and visibility of FDA advisory committees make this study a timely effort. The Institute of Medicine (IOM) committee that conducted it hopes that its analyses and recommendations will be useful to the agency and to the public in helping the FDA fulfill its responsibilities to the American people.

The study originated in remarks made by Dr. David A. Kessler, the Commissioner of Food and Drugs, at a meeting of the IOM's Forum on Drug Development in March 1991. Before his appointment as Commissioner in late 1990, Dr. Kessler had chaired the Subcommittee on Drugs and Biologics of the Department of Health and Human Services (DHHS) Advisory Committee on the Food and Drug Administration (known as the Edwards Committee, after its chairman, former Commissioner Dr. Charles E. Edwards). In that capacity, Dr. Kessler had heard testimony that challenged the credibility of the FDA's advisory committee system, and, to the Forum members, he expressed the desire to make more effective use of these committees.

The resulting interaction between the IOM and the FDA led to this study. That interaction began when the FDA requested that the IOM examine the optimal use of FDA advisory committees in the evaluation of drugs, biologics, and medical devices. The agency also asked the IOM to consider their use in relation to agency management and agency accountability.

In response, the IOM appointed a committee to conduct the study. Its members brought expertise in medical research; development of drugs, biologics, and medical devices; design and conduct of clinical trials; medicine, surgery, and nursing; regulation of drugs, biologics, devices, consumer products, and health care services; administration of medical research, health care financing, and the delivery of health care services; and health and science policy research. Three members of the IOM committee currently serve on FDA advisory committees, two others have served in the past, and three were previously involved as FDA officials in the design of the current system.

In the early months of the study, two meetings were held between the committee chair, Dr. Laurence E. Earley, and the Commissioner, the second involving the acting president of the IOM and senior IOM staff. These meetings were held to clarify certain questions about the scope and purpose of the study. Then, when the study committee convened for its first meeting

on December 6–7, 1991, it heard a personal presentation from Commissioner Kessler of his views on the study.

The Commissioner made three major points at the December meeting. First, he indicated that the improved use of advisory committees was one of several management improvement initiatives that he was undertaking. Consequently, he asked for a report that would provide him and the FDA with operational guidance. Second, he expressed his hope for the deep involvement in this study of FDA senior staff, a hope that has been realized in committee deliberations and in the study's data collection efforts. Finally, he emphasized the importance of the IOM committee's addressing the process for controlling financial conflict of interest because it was affecting the operations of the advisory committee system.

The purposes of the IOM study that arose out of the initial FDA request, the concerns of Commissioner Kessler, and the deliberations of the study committee are the following:

• To understand the FDA's process of product development and evaluation so that the IOM committee could recommend how best to use advisory committees in the context of the FDA's overall mission, policies, and procedures.

• To understand how FDA advisory committees are used in the three centers responsible for the evaluation of drugs, biologics, and medical devices.

• To provide the FDA with operational guidance regarding the selection of advisory committee members and the operation and management of the advisory committee system.

• To study and analyze the impact on the use of advisory committees of financial conflict of interest statutes, regulations, and administrative practices, and the related issue of scientific bias.

• To consider the use of advisory committees for improving agency management and increasing agency accountability.

This study examines the use by the FDA of technical advisory committees in the review of therapeutic and diagnostic medical products—drugs,

biologics, and devices.^* Prior studies have usually dealt with FDA advisory committees that are used for the evaluation of drugs or sometimes drugs and biologics; they have seldom included medical devices. This study encompasses the use of advisory committees by the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH).

The study considers the use of policy advisory committees only in passing. It does not examine any advisory committees serving the Center for Food Safety and Applied Nutrition, the Center for Veterinary Medicine, or the National Center for Toxicological Research. The study also excludes the Board of Tea Experts, a technical advisory committee created by the Tea Importation Act of 1897 to advise the Commissioner regarding standards for imported teas.

Other limitations of the study should be mentioned here. This was a relatively short study by IOM standards. The contract ran from September 23, 1991, until October 22, 1992, during which the committee met only four times. As a result of this timetable, the IOM committee focused its attention on matters that it considered to be of greatest concern to the agency and to the advisory committees themselves, with two consequences worth noting here.

First, although the committee's report (in Chapter 6, ''Ensuring Committee Integrity'') deals with both financial conflict of interest and intellectual bias, the former receives the lion's share of attention and for very practical reasons. The committee was asked by the FDA to consider the problems of regulating the potential financial conflict of interest of advisory committee members, mainly because these issues were threatening to impair the agency's ability to use advisory committees. Moreover, the existing statutes regulating conflict of interest deal solely with financial conflict.

Second, intellectual bias, which is important in its own right, was considered by the committee but received less commitment of committee time than did financial conflict. For one thing, the legal principles operative in this context are a matter of some uncertainty. The statutes governing conflict of interest do not address intellectual bias. And although the Federal Advisory Committee Act does require that advisory committee membership be "fairly balanced," the meaning of this for technical advisory committees cannot be specified easily in advance of a specific meeting agenda. Even though intellectual bias has yet to generate for the FDA the administrative difficulties that have characterized the matter of financial

conflict of interest, the IOM committee recommends that agency begin now to address this issue.

In recent years, research universities and scientific journals have been among the institutions actively pursuing the general issues related to intellectual bias. But the treatment of bias by scientific regulatory agencies in relation to advisory committees remains undeveloped. A study of greater scope (than just the FDA) and of greater duration would have been required to plough this new ground.

In general, advisory committees are the major way by which the FDA obtains independent technical and scientific advice. Other means for obtaining such advice include workshops, symposia, consultants, and extensive, often informal, contacts among agency professionals and the scientific and medical communities. Although this report focuses on advisory committees, the IOM committee recognizes and endorses the appropriate use of these other means of obtaining independent expert advice.

The IOM committee believes that it is essential for the FDA to systematically acquire independent external scientific advice. The scope of the agency's regulatory responsibilities is so vast and its involvement in leading-edge scientific and technical matters so deep that the agency cannot maintain contact with the frontiers of science and medicine without such expert advice. Hence, it is critical that the FDA avail itself of all means of obtaining such advice of which technical advisory committees are one.

When the FDA began using external sources of technical advice, following the 1962 drug amendments to the Food, Drug, and Cosmetic Act, it did so to compensate for the limited technical capabilities of its professional staff. Today, however, the situation is much changed, and for the most part the agency has a highly trained, scientifically qualified professional staff. In this context, the FDA obtains external advice, whether from advisory committees, workshops, or consultants, to complement the capability of its professional staff.

The FDA initiated an advisory committee system in the early 1970s to provide technical assistance related to the development and evaluation of drugs, biologics, and medical devices. The system was also designed to lend credibility to the agency's decisions and its decision-making processes. In addition, it was a means by which the FDA could provide a forum for public discussion of certain controversial issues.

In general, the IOM committee believes that the existing FDA advisory committee system is fundamentally sound, has served the agency well, and does not need wholesale reorganization. It should be retained and strength-

ened. However, later in this report, the committee recommends a number of administrative and procedural changes that are designed to improve the performance and usefulness of the system.

The IOM committee believes that the primary role of FDA advisory committees is and should be to provide independent expert scientific advice to the agency in its evaluation of specific drugs, biologics, or medical devices at any stage of consideration by the agency. A related role is to advise the FDA on general criteria for evaluation and on broad regulatory issues that are not related to a specific product.

Several key terms warrant further comment. First, independence refers to freedom from influence by the sponsor of the product under consideration, by any other entities or persons that could gain or lose as a result of the outcome of the process, and by the FDA itself. However, the focus of concern about committee independence has changed over time. For example, in 1976, the Fountain Committee (see Chapter 4) believed that committees might be too independent of FDA professional staff and subject to the influence of drug sponsors. By 1990, the concern was the opposite: it was claimed by some that advisory committees were subject to excessive influence by the FDA's reviewing divisions.

The high stakes associated with FDA decisions mean that parties disappointed by the agency's action have strong incentives to charge that the independence of advisory committees is compromised by undue FDA influence. Yet, the issues of independence and undue influence are quite elusive and pertain to many facets of the process—for example, the recruitment of committee members, delays in advance distribution of materials, the content and tone of agenda questions, and seating arrangements. The IOM committee makes recommendations on all of these issues, the direction of which points to greater safeguards of the independence of committees.

Second, expert scientific advice implies that members of advisory committees will be acknowledged experts in some technical or scientific field that is relevant to the purview of the specific advisory committee.

Third, advisory committees advise the FDA and do not themselves have authority to make decisions that obligate the agency or any private party to a course of action.

Fourth, advisory committees respond to specific questions that have been identified by the professional staff of the agency. These questions may deal with study design or methodology, adequacy of data, and assessment and interpretation of risks and effectiveness.

Finally, although advisory committees have a prominent role in the product licensing stage, they are sometimes used earlier in the product development cycle and sometimes invited to consider postmarketing issues.

The IOM committee believes that it is proper for the FDA to use committees at any stage of review when scientific advice is needed.

It is important to acknowledge that there are significant practical limits on the FDA's use of advisory committees. The most important general limit is the amount of time that committee members are able to commit to the activity (measured in meetings per year, days per meeting, days of preparation per meeting, and travel time). The amount of resources that the FDA has available to support advisory committees also limits their use. In Appendix A, we estimate the additional resources that the FDA will require to implement the recommendations of this report. The IOM committee recognizes that resources for advisory committees must be considered in the context of overall FDA budget priorities and that there is widespread concern about the adequacy of the agency's budget to meet its growing statutory responsibilities.

There are also specific limits on what any given advisory committee meeting can accomplish. One such limit is the necessity for the agency to be selective in choosing questions for committees from an enormous amount of material under review. Another is the difficulty faced by an advisory committee chair in attempting to control agenda time at meetings, with the consequence that committee discussion time is often severely truncated.

FDA advisory committees operate within the legal framework of the Federal Advisory Committee Act (FACA). The post-World War II era, and especially the 1960s, saw the evolution of widespread use of advisory committees by many federal government agencies. In 1972, Congress enacted the FACA to regulate this development. Although not written primarily for technical advisory committees, the FACA was passed and became effective just as the FDA was beginning to make extensive use of such committees. It provides the statutory framework for all federal advisory committees, including those of the FDA.^* Because references to the FACA are made throughout this report, we describe it briefly at this point.

The FACA incorporates three conflicting themes. One concern of Congress was to introduce uniform procedural standards for federal advisory committees.1 The other congressional objectives were to promote an open, transparent process and to reduce the number of advisory committees. These

themes reflected a concern in the U.S. Senate that industry-oriented advisory committees, acting in closed meetings, had assumed too large a role in agency decision making.

The major requirements of the FACA are as follows. To form an advisory committee, an agency head must:

• determine that it is necessary and in the public interest,

• consult with the General Services Administration (GSA),

• file a GSA-approved charter, and

• announce its formation in the Federal Register.

Committees must be rechartered every two years using the same procedures.

The FACA requires a formal nomination process for advisory committee members, including a Federal Register solicitation; that committee membership be "fairly balanced" and that meetings be announced in the Federal Register 15 days in advance and be open and provide for public participation.^* The original FACA openness requirement was reinforced in 1977 by the Government in the Sunshine Act, which requires that deliberations of government collegial bodies, including advisory committees, occur in open session.

The FACA also requires that a federal official oversee all advisory committee meetings, including calling a meeting, approving the agenda, being present at all times, and adjourning the meeting if necessary. Detailed records—minutes and a transcript—of advisory committee meetings must be kept. Unless exempted under the Freedom of Information Act, these records are available to the public.

The IOM committee that conducted this study drew on several sources of information and used a variety of methods in its analysis.

• The committee met on four occasions, in December 1991 and in February, May, and August 1992. These meetings were two days long, except for the final meeting, which was a one-day executive session.

• Three IOM committee members had been personally responsible for designing and managing the FDA advisory committee system in prior

capacities as FDA officials. They thus provided the committee with an invaluable historical perspective and a keen sense of agency dynamics.

• Five members of the IOM committee had served or were serving on FDA advisory committees in the areas of drugs, biologics, and medical devices and thus brought direct experience to bear on the IOM committee's deliberations.

• The IOM committee and its staff interacted with senior FDA professionals throughout the study. This included the participation of the latter in the first three meetings of the IOM committee; three half-day meetings with leaders of the CDER, CBER, and CDRH (mentioned below); and individual meetings of the IOM committee chair with the directors of the CDER, CBER, and CDRH, as well as with the Deputy Commissioner for Operations and the Senior Advisor to the Commissioner. In addition, project staff had several large meetings on FDA premises with senior FDA staff in January, April, and June 1992, as well as many smaller meetings.

• The IOM committee also organized three work groups to conduct its activities. One work group consisted mainly of the academic clinical members of the committee, and these individuals personally interviewed nearly 50 current or former FDA advisory committee members.

• Another committee work group dealt mainly with FDA officials. It held three half-day meetings in February, respectively, with the leaders of the CDER, the CBER, and the CDRH.

• The Industry Liaison Panel, convened by the IOM committee, was established to obtain the views of the pharmaceutical, biotechnology, and medical device industries on FDA advisory committees. It drew its members from the prescription drug, over-the-counter drug, biotechnology, and medical device industries. Its report, a useful input to the IOM committee, was widely circulated to the FDA, consumer organizations, and other interested parties and, in turn, elicited very useful commentary.

• The third work group, on industry and consumers, held a half-day meeting with the Industry Liaison Panel to discuss the latter's report.

• The IOM project staff contacted consumer organizations, including all members of the FDA Consumer Consortium, and solicited their views on advisory committees. They also conducted interviews later with several consumer organization representatives.

• The IOM committee sent a letter to a number of food and drug attorneys who had experience with the agency or with clients who dealt with the agency, soliciting their views on FDA advisory committees. The committee received several useful responses.

• The IOM project staff interviewed the executive secretaries of all FDA advisory committees across the three centers (CDER, CBER, and

CDRH). They also interviewed the CDER office and division directors responsible for advisory committees.

• Numerous meetings or telephone conference calls were held between members of the IOM committee and its staff and representatives of the FDA, the Department of Health and Human Services, and others. These included the Division of Ethics and Program Integrity, the Office of Consumer Affairs, senior FDA staff, the Chief Counsel of the FDA, the DHHS Special Counsel for Ethics, and the Office of Government Ethics.

• IOM project staff, at the direction of the committee, requested information from FDA staff on numerous occasions. These requests were typically fulfilled with dispatch and efficiency.

• IOM project staff compiled an extensive collection of documents pertaining to FDA advisory committees, on which the committee drew in preparing its report.

• The study also drew on information from a concurrent FDA survey of the members of drug advisory committees by the Office of Planning and Evaluation.

• The study commissioned papers on the following topics: the use of advisory committees in drug, biologics, and device approval in the United Kingdom, France, Germany, the Netherlands, and the European Community; a history of the Anti-Viral Drugs Advisory Committee; the federal conflict of interest statutes; the Federal Advisory Committee Act; and the prospects for and problems with early involvement of advisory committees in the product evaluation process. These papers are not printed in this report; nevertheless, they all provided useful input to the work of the committee.

In January 1992, at a meeting that followed the IOM committee's first meeting, FDA senior staff advised the IOM staff of the necessity to conduct interviews with key FDA personnel. Although the amount of raw data on FDA advisory committees was enormous (e.g., lists of members, agendas, meeting transcripts, and other such materials), very little had been analyzed or digested, much less shaped into a manageable form.

Even so, the committee and its staff were unprepared for the extent of variation in practice regarding advisory committees that exists among and within centers. As one committee member put it, "On no occasion when two or more centers were present in the same meeting was there a single answer to any question." Although the report refers frequently to this phenomenon, no attempt has been made to document the extent of variation among the centers in their use and management of advisory committees. To have done so would have required an enormous data collection effort, with quite uncertain benefits. The IOM committee instead has addressed itself to the need for an increased measure of consistency and standardization across and

within centers in instances in which no programmatic or functional reason for variation could be identified.

This report is organized into three parts, which are divided into eight chapters. Part I, Overview, includes the summary of the report and this chapter. The summary includes all of the study's recommendations. Part II, Background, constitutes an historical account of the evolution of the FDA advisory committee system (Chapter 2), a description of the current system (Chapter 3), and, in Chapter 4, a consideration of the recurring issues that pertain to the advisory committee system.

Part III, The FDA Advisory Committee System, addresses the matters on which operational guidance was requested. Chapter 5 deals with committee membership issues of recruitment, nomination, and appointment and briefly with potential financial conflict of interest. However, Chapter 6 is devoted to the subjects of financial conflict of interest and intellectual bias as these issues affect the operation of advisory committees. Chapter 7 deals with a number of operational issues related to advisory committees. Chapter 8, in turn, considers matters involving the organization and management of the advisory committee system.

It is often the case in discussions of the FDA, especially in the area of drug evaluation and regulation, that reference is made to European countries that provide for faster introduction of new drugs to the market. For example, the practices of the Committee on Safety and Medicines (CSM), an advisory body serving the Department of Health and Social Services' Medicines Control Agency in the United Kingdom, are often held up as an alternative approach to that of the FDA.

The IOM committee, in support of this study, commissioned a very thoughtful paper on the use of advisory committees in drug and device approval in the United Kingdom, the Netherlands, Germany, France, and the European Community.^* In all countries save the Netherlands, an official government agency makes the decision about approving drugs, biologics, and, in some cases, medical devices for introduction to the market. The

Netherlands has a commission of part-time, nongovernment experts, and this body makes the official decisions to approve new drugs.

Although there are potentially interesting lessons to be learned from cross-national comparisons, it is impossible to disentangle the issue of the use of advisory committees from the larger political, economic, and institutional questions of product evaluation and regulation. The IOM committee decided that the pursuit of cross-national comparisons in the use of advisory committees, however intriguing, would take it too far afield from its charge to provide the FDA with operational guidance on its use of technical advisory committees.

For its purposes, the IOM committee has adopted operational rather than formal scientific or legal definitions of the three groups of products whose regulation and review are the subject of this report. Our report considers "drugs" to be those products that are reviewed and regulated by FDA's Center for Drug Evaluation and Research and, correspondingly, "biologics" those regulated by the Center for Biologics Evaluation and Research and "devices" those regulated by its Center for Devices and Radiological Health. These operational definitions obviously match the administrative responsibilities of the FDA.

There do not appear to be well-established scientific definitions of these three product groups. There are, however, official regulatory definitions in statute or agency regulations. The FDA's structure parallels the dichotomy that the law draws between drugs and devices, but the distinction between drugs and biologics chiefly reflects historical factors and, in turn, administrative convenience. Although biologics are formally regulated mainly under the so-called Biologics Act of 1902, now Section 351 of the Public Health Service Act, they also fit the definition of "drug" in the 1938 Federal Food, Drug, and Cosmetic Act, and are also subject to some controls based on the later law.

The situation is further complicated, from a technical legal perspective, because some medical products may integrate as components both drugs (or biologics) and devices, making them potentially subject to the separate legal requirements applicable to each category. These dual-class or combination products have sometimes provoked jurisdictional conflicts among the three centers within the FDA. However, the agency, acting under requirements of the Safe Medical Devices Act of 1990, has in the past year adopted new regulations for dealing with combination products and product jurisdiction issues and has negotiated three inter-center agreements in support of these regulations.

Drugs are defined in Section 201(g)(1) of the Federal Food, Drug, and Cosmetic (FDC) Act, as amended, mainly by the criterion that they are "articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them [which are] intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals." This definition is broad enough to encompass biologics for regulatory purposes; the statute also specifies that this definition "does not include devices or their components, parts, or accessories."

Biologics are defined under Section 351 of the Public Health Service Act as "any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of diseases or injuries of man." The meaning of these terms is elaborated in (21 CFR 600.3(h).

Devices are defined in Section 201(h) of the FDC Act 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 recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, 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, intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal 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 any of its principal intended purposes." This definition also includes "devices intended for use in the diagnosis of conditions other than disease, such as pregnancy, and in vitro diagnostic products, including those previously regulated as drugs."