Food and Drug Administration Advisory Committees (1992)

The Food and Drug Administration (FDA), in mid-1992, had 41 standing technical advisory committees or panels that supported the work of its three centers responsible for the evaluation and regulation of human drugs, biologics, and medical devices. We refer in this report to these committees and their administrative support as the FDA's ''advisory committee system.''

In late 1991, the Institute of Medicine (IOM), in response to a request from the FDA, undertook a study of the agency's advisory committee system. This request was initiated by Commissioner David A. Kessler. He asked that the IOM examine the optimal use of FDA advisory committees in the evaluation of drugs, biologics, and medical devices and also consider such committees in relation to agency management and agency accountability. The Commissioner himself emphasized his desire to receive a report that provided operational guidance for the agency. In addition, he singled out as the most important issue the committee's examination of financial "conflict of interest" controls as they affected advisory committees.

The IOM convened a committee to conduct this 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, others have served in the past, and several were previously involved as FDA officials in the design of the current system.

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 between agency professionals and the scientific and medical communities. Although this report focuses on advisory

committees, the IOM committee recognizes and endorses the use of these other means of obtaining independent expert advice.

The FDA advisory committee system was established at the agency's initiative to provide it with technical assistance related to the development and evaluation of drugs, biologics, and medical devices, to lend credibility to its decisions and decision-making processes, and to provide a forum for public discussion of certain controversial issues. In general, the IOM committee believes that the existing system is fundamentally sound, has served the agency well, and does not need wholesale reorganization. It should be retained and strengthened. However, the IOM committee recommends a number of administrative and procedural changes that are designed to improve the performance and usefulness of the advisory committee system.

The IOM committee believes that the primary role of FDA technical 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 agency on general criteria for evaluation and on broad regulatory issues that are not related to a specific product. (A role specific to CBER, which the IOM committee recognizes, is the review of intramural research programs and personnel.) Several key terms and assumptions 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. As a practical matter, the issue of independence of advisory committees is usually raised with respect to their relation to the FDA.

The high stakes associated with FDA decisions mean that parties disappointed by its actions have strong incentives to charge that the independence of advisory committees is compromised by undue FDA influence. However, the issues of independence and undue influence may arise as a result of subtle facets of the process; for example, the recruitment of committee members; delays in distribution of advance materials; the content and tone of agenda questions; and even seating arrangements at committee meetings. The IOM committee makes recommendations on all these issues, which collectively point to greater safeguards of the independence of committees.

Second, "expert scientific advice" implies that members will be acknowledged experts in some area of science 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 approval 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, whether or not regulatory action on a specific product is under consideration.

It is important to acknowledge that there are significant practical limits on the FDA's use of advisory committees. The most important limit is the time committee members are able to commit to the activity. Another limitation is the necessity that the agency be selective in choosing questions for committees from an enormous amount of material and wide range of issues under review. Still another limit is the difficulty of exercising tight control over agenda time, with the consequence that committee discussion time is often severely truncated. Finally, the use of advisory committees is limited by the resources that the FDA has available to support them.

The ability of the FDA to attract and retain qualified individuals who possess "expertise in the subject matter with which the [advisory] committee is concerned" is critical to the successful operation of the advisory committee system. The "subject matter" of advisory committees pertains to (a) the evaluation of drugs, biologics, and medical devices regarding their safety and effectiveness, including indications and contraindications for use and related issues of labeling, and (b) to broader technical issues related to product evaluation, such as specific methodologies for assessing a particular class of therapeutic agents. Given the purposes of FDA advisory committees,

In this context, "diversity" goals of gender, race and ethnicity, and geography also guide the selection of committee members. The IOM committee believes that these goals are not incompatible with the criterion of scientific and technical competence but reflect legitimate policy objectives of a pluralistic society that are designed to ensure a range of viewpoints on what are seldom purely technical issues. However, meeting these diversity goals may necessitate special efforts by the FDA to identify women and minority group members who possess the necessary expertise.

Some constraints may limit the access of the Department of Health and Human Services (DHHS) to scientific and technical expertise as it seeks to meet its diversity goals. Current policy of the Department of Health and Human Services prevents an individual from serving concurrently on more than one Public Health Service advisory committee without a special departmental waiver. This policy limits the expertise that can be tapped for a particular committee and impedes meeting diversity objectives.

Although the Federal Advisory Committee Act (FACA) requires that advisory committee membership be "fairly balanced in ... the points of view represented and the functions to be performed," this criterion provides little operational guidance to agency heads in the nomination and selection of technical advisory committee members who advise on a wide and unpredictable range of issues. The IOM committee believes that "balance" for the FDA's technical advisory committees should be interpreted as a mix of relevant scientific disciplines and a diversity of scientific views. The IOM committee also believes, and court decisions now support, that it is

ultimately the Commissioner's responsibility to see that such balance is achieved.

The IOM committee considered the wisdom of recommending that 'balance" be interpreted as committee membership that included representatives (or advocates) of specific constituencies, irrespective of scientific competence. The committee rejected this premise on the grounds that the primary role of advisory committees is to provide the agency with the best scientific interpretations and advice and not to represent specific constituencies.^*

The FDA uses a number of procedures to generate nominees for advisory committees. The only agency-wide formal mechanism is the annual Federal Register announcement of advisory committee vacancies required by the FACA. Informal nomination-seeking practices vary across centers, within centers, and over time.

The IOM committee considers the responsibility of nominating qualified individuals for FDA advisory committees to be shared by medical and scientific societies, medical school deans and department chairs, consumer and patient organizations, and other interested parties.

The IOM committee regards the expression of consumer views on FDA technical advisory committees as both valuable and necessary. For medical device advisory panels, these views are provided by nonvoting consumer representatives, as required by statute. For all drug and two biologics advisory committees, they are supplied, not by nonvoting consumer representatives, but by consumer-nominated, technically qualified voting members.

The committee attaches great importance to the criterion of technical expertise for the nomination and selection of voting members of FDA advisory committees and opposes granting voting member status based on representation of specific constituencies. It considered and rejected the extension to drug and biologics advisory committees of the legally-required CDRH approach of nonvoting consumer and industry representatives but chose not to recommend modification of the law.

The IOM committee believes that the concept of "consumer"—both for consumer-nominated members and consumer representatives—should be expanded to include patients or patient-nominated individuals, whose viewpoints can be valuable in the product evaluation process. The FDA should actively solicit nominations from consumer and patient organizations for technically qualified individuals to serve as voting members on all of its advisory committees. The agency should continue to solicit nominations from the consortium of consumer organizations, but it should also reach out to other interested parties. In the judgment of the IOM committee, the practice of allowing any outside organization to screen (and thus to screen out) nominees for FDA advisory committees is unsound.

Until early 1991, the Secretary of Health and Human Services appointed members of FDA technical advisory committees. This sometimes resulted in

nominees who may not have been scientifically qualified or who were selected to bring a politically preferred view on scientific and regulatory matters before the FDA. Following enactment of the Food and Drug Administration Revitalization Act of 1990, the Commissioner has appointed technical advisory committee members, but he remains under an obligation to send nomination packages to the Office of the Secretary 10 days in advance of any appointment. The IOM committee believes that vesting power to appoint committee members in the Commissioner constitutes a substantial step forward in both expediting the appointment process and ensuring that such appointments are responsive to the specific scientific and technical needs of the agency.

The Commissioner, under his authority to appoint advisory committee members, should clearly indicate to all FDA staff that center directors, office and division directors, and executive secretaries share responsibility for recruiting qualified advisory committee members. Nominations should come to the Commissioner from the center directors.

The IOM committee believes that it is essential that members of FDA's advisory committee be impartial and objective and not compromised by financial conflicts of interest. It is also critical that they be free of demonstrated intellectual bias. These goals are both practical conditions for the effective performance of advisory committees and an expression of deeply held democratic values. To achieve these ends, the IOM committee has addressed the FDA's standards and procedures for controlling financial conflict of interest and intellectual bias.

At the outset of this study, Commissioner Kessler asked that the IOM committee provide the FDA with specific guidance on the handling of

potential financial conflicts of interest involving advisory committee members. Controversies over this issue were threatening the FDA's ability to use advisory committees. The study revealed that the "problem" identified by the Commissioner involved the interaction of new conflict of interest statutes and executive orders, the legal interpretation of what these laws required, their administrative implementation, and several highly visible committee meetings. Moreover, this interaction was occurring in a highly politicized environment and in a compressed period of time.

The financial conflict of interest laws that apply to full-time federal employees also apply to advisory committee members who are appointed, as those at the FDA are, as special government employees (SGEs). As applied to advisory committee members, these laws exist to ensure that their impartiality is not compromised by their personal financial interests, or those of their spouses and immediate families, or of their employers.

Advisory committee members are screened for potential conflict of interest at two different times. First, candidates for membership are evaluated at the time of nomination and, if appointed, file a statement disclosing their financial interests. This initial screen provides the basis for a set of so-called "exclusions," namely, specific companies, products, or issues that might come before a committee and that the individual may not consider.

Although this stage of review is important, by far the greater number, and more difficult, conflict of interest issues arise when a member's financial interests are found to intersect with particular meeting agenda items. For each committee meeting, the FDA reviews each committee member's interests and affiliations in relation to the agenda to determine whether a potential financial conflict or the appearance of such conflict exists. The discovery of a potential conflict disqualifies a member from participating in the particular discussion of a specific agenda item unless a waiver is granted. The law allows a waiver if (1) the member's interest is not substantial, (2) if it is too remote or inconsequential to affect his or her impartial judgment, or (3) if the member's participation is so important that it outweighs the potential conflict. Any waiver must be sought and approved before the individual member may participate in the committee's discussion of the specific matter in question.

Events in 1989 and 1991 raised questions about financial conflict of interest to a new prominence. In 1989, in the wake of several well-publicized instances of high-level government officials engaging in unlawful financial transactions for personal benefit, including the generic drug scandals that affected the FDA (although not with respect to any advisory committee), the executive branch took action. The President's Commission on Federal Ethics Law Reform recommended that standards of conduct be updated and that

the Office of Government Ethics (OGE) be given authority to issue uniform regulations for all executive branch agencies. Executive Order 12674, issued by President George Bush on April 12, 1989, revoked the decentralized regulatory scheme that had been established in 1965 and directed the OGE to develop "a single, comprehensive, and clear set of executive branch standards of conduct that shall be objective, reasonable, and enforceable" (56 FR 33778, July 23, 1991). The OGE, which had been part of the Office of Personnel Management, was established as a separate agency of the executive branch on October 1, 1989.

Congress, unwilling to cede leadership in this arena to the executive branch, enacted the Ethics Reform Act of 1989 (Public Law 101–194) on November 30, 1989. This act included a provision [Section 208(b)(3) discussed below] intended to facilitate the use of expert advisory committees by empowering agency heads to grant waivers from the law's basic prohibition when the need for an individual member outweighed any potential conflict.

Responsibility for implementing the executive order and the new statute fell primarily on the OGE and, within DHHS, on a new unit in the Office of the General Counsel. That unit, the Office of the Special Counsel for Ethics (OSCE), is responsible for DHHS-wide policies and procedures safeguarding the ethics of government employees and for coordinating departmental policy with OGE. Within the FDA, an existing unit, the Division of Ethics and Program Integrity (DEPI), retained responsibility for approving waiver requests from the centers on behalf of the Commissioner.

In 1991, several FDA advisory committees convened to review high-profile products that presented particularly controversial problems of potential conflict of interest. The topics on which the agency sought advice included the controversy over the review of THA as a drug for the treatment of Alzheimer's disease; the dispute over the possible propensity of ProZac to induce suicide in September 1991; the safety of silicone gel breast implants in November 1991 and again in February 1992; and a controversy over the use of photopheresis in the treatment of scleroderma. Although each of these committee meetings originated in unique circumstances, all drew unprecedented attention to FDA's procedures for controlling potential conflicts of interest, and they arrived at FDA's doorstep in the same period of time.

What did these cases reveal? First, the agency had been processing waivers under outdated standards that had not been updated to accord with the 1989 statute. Second, although waiver provisions are part of the federal criminal code, government lawyers were not involved in reviewing waivers. Consequently, the FDA's Chief Counsel, in the fall of 1991, assigned two lawyers to review waivers, and they began to question the agency's existing

procedures. Soon thereafter, OSCE became involved on behalf of the department and eventually replaced the agency's lawyers. Third, OSCE and the OGE introduced new and expansive waiver standards and procedures. Fourth, the units in the FDA still responsible for conflict of interest compliance continued to perform their roles without any high-level policy guidance. Fifth, both the agency's lawyers and those from OSCE, who felt compelled to change the rules to accord with the law and executive order, dealt with waiver issues on a case-by-case basis, and provided little general guidance to those administrators responsible for managing the advisory committee system. To make matters worse, all of these changes were occurring within a very short span of time.

Not surprisingly, the conflict of interest problem was far more visible inside FDA than outside. And within the agency no one fully grasped that nature of the changes that were taking place. However, to some it appeared as though conflict of interest restrictions might cause the advisory committee system to grind to a halt because new standards had not been operationally clarified and the process had been greatly complicated.

Any attempt to address the problem must deal with issues of law, of bureaucratic procedure, and of administration. The IOM committee considered reforms that would require new legislation and those that could be implemented within existing statutory authority.

The IOM committee considered several options that would require new legislation. The first would substitute for the present disqualification system one that required committee members to publicly disclose all of their interests and affiliations, and then relied on public scrutiny to assess the objectivity of their advice. The IOM committee found this approach unacceptable, as it would allow participation of members with significant, direct financial interests that should be disqualifying and would undermine the appearance of objectivity.

A second option would be a system that coupled full disclosure of all interests with a general rule barring participation by members with significant financial interests. Although this proposal may contain the core of a promising reform of the system for regulating conflict of interest, the IOM committee did not explore fully its ramifications. The committee's judgment and that of many we spoke to was that a major legislative overhaul of this magnitude was simply unlikely. Given FDA's expressed needs, our charge, and our timetable, the committee turned to solutions that were feasible within the existing statutory framework. However, this approach is clearly a candidate for further study.

What can be done under existing authority? Potentially, a good deal, as the following options suggest. Although the first option below could be implemented by FDA itself, the successful implementation of the other recommendations would require the active involvement of the Commissioner and his office, the supportive collaboration of the OSCE, and at least the tolerance of the OGE.

One theoretical option for FDA would be to avoid appointing advisory committee members as special government employees, thus circumventing the restrictions of the federal conflict of interest law. This solution has the notable disadvantage of attempting to define the problem away, which is hardly a way to instill confidence in the system. Moreover, new legislation would possibly be needed to allow payment of members and sharing of trade secret information.

Second, the FDA itself could exercise greater care in the initial appointment of advisory committee members. It could demand even more information than is currently required to enable it to identify in advance potential members whose financial interests would clearly disqualify them for some committee meetings. Yet because the interpretation of a prohibited interest is already extremely broad, and potential conflict cannot be identified before meeting agendas are set, serious pursuit of this problematic approach might disqualify valuable members and produce no gain in integrity. Moreover, the conflicts of interest that might arise over the duration of a committee membership are unpredictable at the time of appointment.

Third, the FDA, working with OSCE, could formulate and codify criteria for granting 208(b)(3) waivers. The IOM committee believes that this is essential. Codification would be a lengthy process, but some mutual understanding of the grounds for justifying a waiver is badly needed. A checklist of variables must be formulated that includes: the size of the interest; the character of the interest; the likelihood than an interest will be affected by agency action based on the committee's advice; and the actual importance of the member to the committee's deliberations. Regarding the latter point, membership alone should not be taken automatically as a decisive measure of a member's importance.

Of immediate importance is the need to clarify the criteria for dealing with potential conflicts arising from institutional or employer financial interests, research grants and contracts to committee members, and member involvement with competing products and technologies. Regarding institutional financial interests, most advisory committee members are university employees; most of their employers operate medical schools,

hospitals, and hospital pharmacies. OCSE, with the FDA, should develop clear criteria for dealing with waiver requests that arise because a committee member is affiliated with an institution, some of whose financial interests flow from such subordinate entities (e.g., revenues derived from prescribing drugs). In addition, most universities hold diversified endowment funds; it is often the case that some of these funds are invested in pharmaceutical, biotechnology, or medical device securities. OCSE, with the FDA, should clarify the criteria for dealing with these ''employer interests.''

Fourth, the agency has the authority to streamline its own internal policies and procedures for deciding when to seek waivers and how to prepare their justifications. The IOM committee believes that this action is also essential. Responsibility for preparing the initial waiver request should reside with the division. The decision to request a waiver should be made by the center director. The IOM committee sees no need for review by the DEPI or by FDA's Chief Counsel, as long as OSCE has a reviewing role. Central agency review of waiver requests should be by a high-level policy official in the Office of the Commissioner.

Fifth, the FDA should develop and adhere to strict schedules for processing waivers. It should present waiver requests to OSCE no later than three weeks in advance of a meeting.^* The Commissioner should seek agreement from the OSCE that it will review any proposed waiver within three days. The Commissioner may even wish to establish default rules that penalize centers for late submissions (e.g., the member is disqualified or the agenda item is postponed).

Sixth, the FDA must update the training programs of its officials with responsibility for implementing conflict of interest policies involving advisory committee members. These training programs should build around the substantive and procedural changes suggested above. Participation should be required of all FDA professional staff who deal with advisory committee members.

Seventh, the FDA must also initiate and maintain orientation programs for advisory committee members. Individual members should clearly understand the criminal laws that govern financial conflict of interest and the justifications for granting waivers. However, the IOM committee believes that guidance on conflict of interest should be linked to a broader orientation program (discussed below and at length in Chapter 8). This linkage is important because an exclusive focus on conflict of interest will necessarily emphasize the risk of criminal prosecution and the need for intensive inquiry into personal financial matters—an emphasis that would surely obscure the public service dimension of advisory committee membership.

Eighth, the FDA and OSCE, on behalf of DHHS, should seek the issuance by OGE of a government-wide general 208(b)(2) waiver regulations as soon as possible. This statutory authority has yet to be exercised but is intended to remove certain conflicts from a case-by-case determination. Institutional financial interests and holdings could be dealt with by such a rule.

Finally, the FDA, and DHHS, should seek the revision of Executive Order 12674 requiring case-by-case consultation with OGE on all waiver requests.

The foregoing discussion has dealt with financial conflict of interest as regulated by Section 208 of Title 18 of the U.S. Code. It has not addressed the issue of intellectual bias, which refers here to the potential effect, subtle or overt, of a scientist's prior research or public statements on his or her objectivity. Advisory committee members who bring strong opinions about specific matters to their assessment of data are not necessarily and automatically biased. A judgment of bias turns on their willingness to hold their personal views in abeyance while examining the pertinent data in a careful and impartial way.

Although the legal restrictions that might govern the treatment of intellectual bias on the part of advisory committee members may be quite uncertain, the matter should nevertheless be of concern to the FDA. One reason for such concern is that a committee whose advice is not impartial defeats the purpose of seeking independent expert advice. A second is that committee members who were not open to persuasion by evidence would erode public confidence in a mechanism that FDA has devised to generate such confidence.

The IOM committee holds the view that the FDA should be sensitive to the possibility than an advisory committee member might be so committed to a point of view on a potential matter, or so publicly identified with that view, that his or her objectivity cannot be assumed. Under such circumstances, which the committee has no evidence will occur often, the FDA should exclude that member from participating in the discussions of the matter. If the determination of bias rests on publicly stated positions, full exclusion may be warranted. However, if exclusion stems from the member's prior research, especially as a principal investigator, the FDA should not be deprived of that individual's expertise. This can be solved by

inviting the person to address the committee as a witness (or as a "guest"). A sensible approach might recognize just three roles for committee members in the case of intellectual bias: (a) full voting participation; (b) full exclusion from a meeting or an agenda item; or (c) appearance as "witness" or ''guest'' of the agency.

Issues of intellectual bias do not involve legal questions of financial conflict of interest. Therefore, remedies should be determined by the Commissioner, on advice of the relevant center director. Any legal ramifications should be dealt with by the agency's Chief Counsel. The entire issue, clearly, is one deserving further attention by the agency.

Few written policies exist to guide FDA advisory committee operations. Not surprisingly, substantial variation occurs in the actual use of committees both among and within centers. Some of this variation is justified by the heterogeneity of the subject matter, and the IOM committee wishes to avoid recommending rigid standardization in such cases. As a general proposition, however, substantial uniformity in policies and procedures for advisory committee operations is both desirable and feasible.

FDA advisory committee meetings are seldom scheduled more than a few months in advance, and specific agendas are usually a result of the decision to hold a meeting. These practices complicate advance scheduling by committee members of their participation in meetings and advance planning by sponsors of products being evaluated by the advisory committee.

The IOM committee believes that advance scheduling (and accompanying deadlines for such actions as sponsor submissions of data, agency review of an application, and advance distribution of materials to the committee) would allow more effective planning by busy advisory committee members for their participation in meetings and impose greater discipline on the product evaluation process. The committee is aware that such a proposal is not without its "costs"; some of these include the difficulties that would be faced by FDA in advance scheduling of agendas, the heavy demands made on reviewer time, and the potential for compromising the review of the data. Nevertheless, although the IOM committee has not examined in great detail the impact of this proposal on FDA reviewer time or its budgetary implications, it regards the benefits of advance scheduling of meetings and agenda items as outweighing most potential disadvantages.

The general criteria for determining advisory committee agendas vary from center to center and tend to derive from historical practice as much as explicit policy.

• The 1976 Medical Device Amendments required the Center for Devices and Radiological Health (CDRH) to bring all premarket approval applications (PMAs) to an advisory committee; the center now has some discretion on that issue under the Safe Medical Devices Act of 1990. Based

on its interpretation of what the law requires, CDRH asks advisory committees whether a given PMA should be approved; it does not go beyond this question.

• The Center for Biologics Evaluation and Research (CBER) brings specific product license applications (PLAs) and establishment license applications (ELAs) to its advisory committees, as well as general matters of biologics development. It formulates and asks questions of the committee in much the same way as does the Center for Drug Evaluation and Research. Unlike the other centers, however, CBER also asks its advisory committees to review its intramural research programs and evaluate intramural research personnel.

• The Center for Drug Evaluation and Development (CDER), in September 1991, clarified the range of issues that it might bring to an advisory committee: the approvability of specific drugs; general drug development; issues pertaining to marketed drugs; and the management of the new drug evaluation (NDE) program.¹ Advice on the approvability of specific drugs may be sought on clinical trial design; the data supporting safety, effectiveness, overall risk-benefit, and dosing and scheduling; appropriate surrogate endpoints; other needed studies; postmarketing surveillance; indications for specific populations; and shifts of prescription drugs to over-the-counter status. General advice may be sought on the development of guidelines for classes of drugs, clinical study design issues, and specific safety issues for particular drugs.

In addressing the management of the new drug evaluation program, the CDER document expands several important aspects of the advisory committee's tasks. Committees may be asked to review periodically (usually annually), first, the pending new drug applications (NDAs) and the major new indications of other drugs in the CDER pipeline; second, the "important products under development," that is, investigational new drugs (INDs); and third, the priorities and resource allocations of CDER's reviewing divisions for the management of INDs, NDAs, abbreviated NDA (ANDA) applications, and supplements to approved applications.

The IOM committee considered a number of aspects regarding setting committee agendas. For example, the notice of an FDA advisory committee meeting must be published in the Federal Register at least two weeks in advance of the meeting; this may require submission for publication by the center at least six weeks before a meeting. An announcement includes a general description of the agenda, for example, the specific NDA of a given sponsor, and the general topics of the meeting; however, this description varies in its specificity.

The general questions that the FDA must consider in evaluating drugs and biologics are whether, in the determination of safety, the risks of a compound are outweighed by its benefits and whether "substantial evidence" from well-controlled trials exists to support the claims of effectiveness. It would help the review process if advisory committee members were regularly reminded of these decision criteria as they review a sponsor's data.

Setting the detailed agenda of an advisory committee meeting and preparing specific questions for it are primarily the responsibility of FDA staff. They are not feasible tasks for committee members themselves to undertake. Yet, the exercise of this responsibility by FDA sometimes results in criticism regarding its apparent efforts to manipulate or influence committee deliberations.

An issue brought to the attention of the IOM committee was whether FDA questions to an advisory committee should be restricted to scientific and clinical matters or whether they should include the relevant regulatory questions. The IOM committee believes that the scientific and regulatory questions pertaining to an issue are interrelated and that any attempt to presume a distinction between them is artificial.

The FDA is sometimes charged with asking "loaded" or leading questions. The committee has made no determination whether this has occurred. It believes, however, that it is necessary to distinguish between the tone and objectivity of FDA questions and the fact that particular questions may at times indicate the problems that the agency perceives in an application. The committee is not troubled by the fact that precise questions often will reveal the agency's concerns about an application.

A major complaint of FDA advisory committee members that has been heard for many years is that the agency often fails to distribute materials sufficiently in advance of a meeting to permit their careful review by committee members. Some delays are attributed to limited personnel and administrative resources of the agency, to its natural tendency to complete reviews at the last minute, and to its long tolerance of such practices. Whatever the reasons, the effective and efficient use of advisory committees requires that members receive review materials a reasonable period of time before a meeting.

In the committee's view, the responsibility for fulfilling this recommendation rests not only with committee executive secretaries, but also with the directors and the application reviewers of the appropriate division. The committee also believes that scheduling committee meetings and agendas in advance should facilitate compliance with this recommendation.

The format of materials sent to advisory committee members varies according to how much of an application the FDA decides to send. The materials typically include the sponsor's data, the agency reviews, and the questions to be discussed at the meeting. Although advisory committee members have suggested that the FDA prepare such material in a format that would facilitate its review, the agency understandably resists such "packaging." This major deficiency could be easily remedied, however, by the preparation of concise (20–25 page), complete, and integrated summaries of the sponsor's application and the agency's review.

The CDRH assigns primary review responsibility for a particular PMA to one advisory committee member, mainly to obtain a clinical evaluation of the application. The IOM committee believes that this practice can also ensure a more thoughtful committee discussion and that it distributes the work load more evenly among committee members. In addition, the practice has great utility in those situations in which the match between committee expertise and a particular agenda item may be weak. (See the discussion on "custom tailoring" below.)

Five types of communication before an advisory committee meeting deserve attention: FDA communication to advisory committee members; communication among committee members; communication between sponsors and members; FDA communication to sponsors; and FDA communication to the public.

First, advance communication by FDA officials with advisory committee members before a meeting has generally been limited to one member at a time, based on an interpretation of the strictures of the Federal Advisory Committee Act (FACA). However, the Chief Counsel to the FDA indicated in a letter to the IOM committee that "such preliminary issues as agenda topics, materials, and questions" could be discussed simultaneously with some or even all members of a committee.

Second, FDA guidance, based also on an interpretation of the FACA, to advisory committee members has generally been that communication among individual members before a meeting is precluded. Again, the FDA Chief Counsel has written that "preliminary discussions" among committee members do not violate the law.

Third, as a matter of FDA policy, sponsors are discouraged from communicating with advisory committee members before a meeting. The

agency informs sponsors and committee members of this stricture. This policy is designed, in general, to protect the independence of the committee from lobbying by sponsors.

Fourth, the FDA takes the view that it is not obligated to share with sponsors, or the general public, its communications to advisory committee members before a meeting. The IOM committee, however, believes that it is appropriate for the FDA to provide sponsors with copies of all information that it sends to advisory committees. This practice would facilitate the preparation by the sponsor of its response to agency questions.

Fifth, as a general practice, the FDA releases to the public the questions that it has prepared for the advisory committee on the morning of a meeting. The IOM committee agrees with this practice and does not recommend earlier release to the public.

A recent report by Kutak, Rock & Campbell, which dealt with FDA's handling of financially sensitive information, basically concurred that FDA release of the questions to the public on the morning of a committee meeting was sound practice.² The FDA has before it the Kutak Rock & Campbell report and this IOM report on advisory committees; it must address the implications of where the two intersect and make any appropriate policy determinations.

The successful conduct of an advisory committee meeting involves the conscientious efforts of the committee chair, the members, FDA officials, and the sponsors. To improve the deliberations of advisory committees and the quality of their advice to the FDA, this section recommends a number of steps to be taken regarding the interactions among these parties.

One of the keys to an effective advisory committee meeting is the allocation and control of agenda time. Typically, the initial assignment of

time to agenda items is done by FDA professionals, sometimes in consultation with committee chairs. Once time is allocated, of course, it is important that committee meetings adhere to the established schedule. For this to occur, it is necessary that the chair exercise control over agenda time.

The protection of opportunities for committee discussion is perhaps the primary reason for the chair to exercise strict adherence to the agenda schedule. Discussion time often gets squeezed because it is the last scheduled item on an agenda, sponsor and agency presentations frequently go longer than scheduled, and some committee members may leave to return home.

FDA advisory committee meetings often receive television coverage, which can be intrusive in committee deliberations. FDA regulations governing television or "electronic recording equipment" (21 CFR 10.200–206) vest authority in the advisory committee chair to control such coverage as necessary.

Voting by CDER and CBER advisory committees occurs at the discretion of the committee chair or according to the tradition of the reviewing division. Depending on the committee, no votes may be taken, votes may be taken only on scientific questions, or votes may be taken only on regulatory questions. All CDRH committees vote on the regulatory question only, i.e., the approvability of a device.

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.

Seating arrangements at advisory committee meetings should facilitate committee discussions rather than the convenience of the audience. As a general rule, the IOM committee believes that the division director should not sit next to the committee chair. Nor should other FDA personnel sit among the committee members.

The FDA has rechartered, or soon will recharter, all of its advisory committees. This will permit agency officials who are organizing a given meeting to draw voting members from any other FDA advisory panel or committee, or from a pool of consultants, on an as-needed basis. Although this "custom tailoring" authority is welcome in principle, it has not yet been used with any frequency, and it poses several challenges to the agency.

In general, the IOM committee believes that the continuity of the standing advisory committee should be maintained and that custom tailoring should be used sparingly to augment a committee's expertise relative to a specific agenda item. On the one hand, the IOM committee recognizes that it may be necessary to add voting members in some cases in which the scientific or clinical scope of a committee may not be adequate for considering a particular class of drugs, biologics, or devices. On the other hand, the frequent use of this flexible authority by the FDA may make it vulnerable to charges of "stacking the deck" with committee members likely to favor its views.

Some FDA centers or divisions provide little or no follow-up to advisory committee members regarding the results of their deliberations. Failure to do so is a source of complaints. A systematic effort to provide follow-up would convey a strong positive message to advisory committee members that the agency attaches great value to their service.

Several prior reports on FDA that deal with advisory committees call for varying degrees of centralization of committee management functions. These reports also highlight the need to address issues of organization and management.

FDA's technical advisory committees are chartered by the Commissioner of Food and Drugs for the purpose of advising him on the safety and effectiveness of drugs, biologics, and medical devices. In addition, committee members are appointed by him and requests for waivers of conflict of interest are granted by him. Legally, advisory committees report to the Commissioner.

In actual operation, however, the current FDA advisory committee system is highly decentralized and substantial variations exists both across and within centers. These variations have arisen as a result of historical,

organizational, and idiosyncratic influences that are not always rooted in genuine scientific or functional differences among committees. The IOM committee believes that unjustified variation in the use of advisory committees should be minimized in the interest of strengthening their role as independent advisors to the FDA.

This highly decentralized system lacks any agency-wide administrative policy and management guidance. It thus appears vulnerable to controversies that might be avoided or more effectively managed, given a greater agency-wide management capability.

The directors of the three centers should have explicit responsibilities for managing the advisory committee system. Center directors should implement agency-wide policy for advisory committees; monitor the recruitment of members for technical expertise, source of nomination, and identification of qualified women and minority candidates; personally approve any "custom tailoring" of committees to avert charges that FDA staff are seeking to influence the outcome by the selection of members known to favor a particular view; help design an orientation and training program for committee members; examine issues that arise in a particular committee that may cut across several committees; and support innovation in the use of advisory committees.

Office and division directors of the product review units should also have explicit responsibilities for managing the advisory committee system. They should be actively involved in recruiting advisory committee members, preparing committee agendas, and developing specific questions.

Executive secretaries should report to a central unit within each center. Their responsibilities are primarily to provide administrative support to committee operations. Executive secretaries should also report to the appropriate division director to assist that individual in the program-related work of the committees. The IOM committee recognizes that CDRH executive secretaries differ from those in CDER and CBER in that they are also engaged in the technical review of applications; thus, some comments may not apply to them.

In general, the IOM committee believes that a clarification of the roles of all FDA officials responsible for the advisory committee system is long overdue. The objective of this role clarification should be to ensure that advisory committees provide the independent expert advice that the agency requests and needs.

The authority to set the daily rate of compensation for FDA advisory committees resides with the Commissioner of Food and Drugs. He is subject to four constraints—two legal, one budgetary, and one administrative. The statutory limit on compensation for all federal government advisory committee members is the daily rate for a Senior Executive Service IV position, currently $429.50 per day. Regulations of the General Services Administration further limit the daily rate to that of a GS-15 in the General Schedule, currently $320 per day, unless the agency head personally determines that a higher rate "is justified and necessary." The budgetary limit is the obvious requirement that an agency head must have funds to cover the costs of whatever rate is adopted.

Although agency heads have authority to set rates for the members of the committees that advise them, FDA's status as a Public Health Service agency also limits the exercise of that authority. As a practical matter, no single PHS agency can pay advisory committee members at rates much higher than those of the other agencies. Currently, the Centers for Disease Control pays committee members $188 per day, while the National Institutes of Health and the FDA pays $150 per day.

FDA advisory committee members are paid only for those days on which they attend a meeting. The agency is barred by regulation from paying them for homework for normal meeting preparation, even though a member may spend five days or more in preparation. However, CDRH does compensate individual advisory committee members for homework if they conduct an

"agency-directed assignment" that results in a tangible end product, usually a report, that is not the end product of the advisory committee. Typically, this involves using members as primary reviewers of applications. Neither CDER nor CBER compensates committee members for homework in this way.

FDA regulations also permit payment to advisory committee members at the daily rate for travel time that involves 50 percent of an additional day beyond the meeting time and that results in the loss of some regular compensation. However, no use is made of this authority.

The IOM committee believes that all Public Health Service advisory committee members are underpaid, including those who advise the FDA. This is true both with respect to the maximum daily rate allowed by law and GSA regulations and with respect to the opportunity cost to members of foregone consulting fees from drug or device firms of $1,000 a day or more. Moreover, younger members in academic medicine often confront the perception that service on an FDA committee carries less academic reward than that of an NIH study section.

The IOM committee believes that public service should be adequately compensated, although obviously not at the rates of the private sector. It is concerned that the current meager rate of compensation may dissuade some individuals from serving as FDA advisory committee members and may diminish the incentive to others to prepare adequately for meetings. In general, the IOM committee is concerned that these rates do not accurately reflect the value that FDA and the general public attach to the important work performed by advisory committee members.

The IOM committee notes that legislation enacted in October 1992 authorizes the FDA to charge user fees for product evaluation. Under this new authority, it may be appropriate for the FDA to review the compensation of advisory committee members in relation to their contribution to product evaluation.

A recurring complaint from advisory committee members has been the absence of an adequate orientation and training program. Although the centers and most divisions have made a number of efforts, no systematic agency-wide or center-wide orientation program has been organized. The IOM committee believes that the need for such a program is clear; program content and organization are addressed in the body of the report.

This report recommends many concrete steps for improving the use of advisory committees by the FDA in the evaluation of drugs, biologics, and medical devices. Throughout the report are general expressions of concern about agency management and accountability, which may not be captured fully by its specific recommendations. Thus, the IOM committee deems it necessary to summarize the latter in relation to these larger considerations.

In the judgment of the IOM committee, it is important to differentiate between the management of the advisory committee system and the management of the product evaluation process as affected by the advisory committee system. Regarding advisory committee system management, the IOM committee's most important recommendation is that a high-level position be established in the Office of the Commissioner to provide administrative policy and management guidance to the advisory committee system. Although the precise location of such an office is properly determined by the Commissioner, an appropriate place may be the Office of the Deputy Commissioner for Operations, to which the directors of the three relevant centers now report.

Advisory committees, the IOM committee believes, have become a permanent fixture in the FDA's evaluation of products, and their effective use should be a responsibility of FDA officials at all levels. Improvements in management would flow from clarifying the roles and responsibilities of all officials involved in the advisory committee system—from the Commissioner through the center, office, and division directors, down to the executive secretaries. Such clarification should include changing the job descriptions of these officials as necessary. The IOM committee acknowledges the important role of FDA office and division directors in the work of advisory committees; it does not recommend circumventing these officials by proposing to locate operational responsibility for committees elsewhere, but urges clarification of their responsibilities for the effective performance of the system.

An orientation program for advisory committee members, which could also be used in training responsible FDA officials, would improve the performance of the entire system. Other management-related recommendations pertain to the recruitment of qualified members and establishment of a pool of potential members; greater involvement by the Office of the Commissioner in conflict of interest issues (both in developing internal FDA policies and procedures and in negotiating with the DHHS Office of the Special Counsel for Ethics and the Office of Government Ethics); and more attention to preparation for and conduct and follow-up of advisory committee meetings.

Various recommendations of the IOM committee address improvement of the product evaluation process and the role of advisory committees in that process. In particular, we believe that advance scheduling of committee meetings and agendas, with attendant deadlines for the sponsor and the agency, would bring greater discipline to the product evaluation process and make more effective use of advisory committees.

The IOM committee recognizes that its recommendations for improved management of the advisory committee system will require additional resources. Therefore, the report provides an estimate of the incremental costs of the IOM committee's recommendations. The IOM committee regards the recommended review of advisory committee member compensation as an important management issue that deserves attention by the Commissioner and the Secretary of Health and Human Services. The compensation of committee members should be reviewed in relation to the newly-adopted user fee system for product evaluation.

The FDA as an entity, and not just its component parts, should be accountable for the effective performance of its advisory committee system. The IOM committee's recommendations lead to ways of increasing agency-wide accountability. Here, as in the recommendations above on improving management, the committee emphasizes the importance of designating a high-level official in the Office of the Commissioner who should be responsible for administrative policy and management guidance for the advisory committee system.

It is also important as a component of accountability to recognize that advisory committees are advisory to the FDA, and that the authority for decisions rests with the agency. It would be unnecessary to reiterate this basic distinction were it not that some agency critics regard advisory committees as independent adjudicatory bodies that should hear sponsors' views, on the one hand, and agency views, on the other, and decide in favor of one party or the other. Acknowledging this basic authority-advisory distinction should facilitate advisory committees becoming even more effective and influential than they are at present, which the IOM committee endorses.

Consequently, the IOM committee's recommendations emphasize practical ways (especially in Chapter 7) to ensure the intellectual independence of advisory committees. The rationale for this emphasis is to increase the likelihood that advisory committees will render that impartial, expert advice that the agency and the public should expect.

In the conduct of this study, the IOM committee has discovered the multifaceted complexity of the FDA advisory committee system. It has benefited from many thoughtful letters, memoranda, and communications on aspects of this complexity. As a result, the committee believes that its report could serve to increase agency accountability for the advisory committee system.