6
Ensuring Committee Integrity

This chapter deals with two important issues: How should the FDA protect the deliberations of its advisory committees against potential financial conflicts of interest on the part of individual committee members? And what steps should the agency take to guard against possible intellectual bias of committee members. The committee dealt with the first of these issues extensively, giving it more attention than any other single subject. It was specifically asked to do so by the FDA Commissioner Kessler, because this perplexing issue was affecting the agency's ability to use advisory committees in the evaluation of new products.

We use ''intellectual bias'' to refer to a different concern, namely, the possibility that a committee member may be so convinced about the right answer to a question of science or medicine—or so clearly identified with a particular view—that he or she may not be (or appear to be) able to approach a matter before the committee with an open mind. This concern is sometimes discussed under the label "conflict of interest," but the committee has treated it separately precisely because the federal law contains an elaborate set of restrictions addressed solely to the matter of financial conflict.

Concern about intellectual bias, which is addressed in the final section of this chapter, proves to be equally perplexing and may assume comparable importance at the FDA. But it came into clear focus only near the end of our study, and thus has received less thorough discussion and assessment. The topic is a candidate for further attention in connection with the work of the FDA advisory committees, just as it is now receiving extensive scrutiny and debate among policymakers and academic scientists who confront it in other contexts.

Potential financial conflict of interest and intellectual bias are obviously critical matters for the Food and Drug Administration and for the public. For the FDA's advisory committees to serve their purposes, their judgments must be—and must be seen to be—the product of the members' independent



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Food and Drug Administration Advisory Committees 6 Ensuring Committee Integrity This chapter deals with two important issues: How should the FDA protect the deliberations of its advisory committees against potential financial conflicts of interest on the part of individual committee members? And what steps should the agency take to guard against possible intellectual bias of committee members. The committee dealt with the first of these issues extensively, giving it more attention than any other single subject. It was specifically asked to do so by the FDA Commissioner Kessler, because this perplexing issue was affecting the agency's ability to use advisory committees in the evaluation of new products. We use ''intellectual bias'' to refer to a different concern, namely, the possibility that a committee member may be so convinced about the right answer to a question of science or medicine—or so clearly identified with a particular view—that he or she may not be (or appear to be) able to approach a matter before the committee with an open mind. This concern is sometimes discussed under the label "conflict of interest," but the committee has treated it separately precisely because the federal law contains an elaborate set of restrictions addressed solely to the matter of financial conflict. Concern about intellectual bias, which is addressed in the final section of this chapter, proves to be equally perplexing and may assume comparable importance at the FDA. But it came into clear focus only near the end of our study, and thus has received less thorough discussion and assessment. The topic is a candidate for further attention in connection with the work of the FDA advisory committees, just as it is now receiving extensive scrutiny and debate among policymakers and academic scientists who confront it in other contexts. Potential financial conflict of interest and intellectual bias are obviously critical matters for the Food and Drug Administration and for the public. For the FDA's advisory committees to serve their purposes, their judgments must be—and must be seen to be—the product of the members' independent

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Food and Drug Administration Advisory Committees assessment of the scientific evidence presented to them. At the same time, the criteria by which candidates for committee appointment are screened and the participation of appointed members is regulated must be both realistic and fair. These criteria must protect the agency's processes from real risks of inappropriate influence and yet not disqualify or embarrass all scientists and clinicians who have had any connection to the drug, biologics, or device industries. The chapter deals first with financial conflict of interest, indicating the origins of the IOM committee's concern for this issue, reviewing the statutory framework that governs the area, examining the system by which the FDA administers the conflict-of-interest laws, analyzing the rapid changes in that system, including a number of controversial cases and some encouraging prospects for improvement, and concluding with a number of recommendations. The chapter addresses the issue of intellectual bias in a concluding section. FINANCIAL CONFLICT OF INTEREST The reality facing the FDA is that over the past decade, perhaps longer, sponsors of drugs, biologics, and devices have turned increasingly to academic researchers to help develop and test new products. This pattern is particularly obvious in the biotechnology industry. Consequently, many of the same experts whose advice the FDA wishes to obtain have affiliations with regulated firms, some with many such firms. The recognized expertise of such individuals makes them attractive to both government and industry. In addition, the agency has sought advisory committee advice on a growing range of scientific and regulatory issues, and it is under pressure to increase the agenda items considered by its committees. One result of these coincident developments has been to generate potential financial conflicts of interest for one or more committee members in connection with every committee meeting. The tensions that result from this set of relationships cannot be eliminated but must not be ignored. The goals of any system for mediating these tensions must be to protect the integrity of the FDA's decisions and at the same time to allow the agency access to essential expertise. The IOM Committee is concerned that the current system for managing potential financial conflicts of interest, as now administered, may be jeopardizing the latter goal without significantly advancing the first. When Commissioner Kessler met with the IOM Committee on December 6, 1991, he emphasized his desire for guidance in "solving" the FDA's current problems with conflict of interest and its advisory committees.

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Food and Drug Administration Advisory Committees The Commissioner stressed that, "If [the committee] does nothing else but solve our conflict of interest problem, then we will have been well served." However, neither the Commissioner then nor the FDA senior staff later provided the Committee with a detailed picture of this "conflict-of-interest problem." The full dimensions of the problem were not then appreciated, we believe, because they were undergoing significant change even as the study began. It took the better part of this study for the Committee and its staff to gain an understanding, which may still be incomplete, of the "problem." The IOM committee entertained the hypothesis that numerous members of the FDA advisory committees were participating in decisions in which they had significant personal financial interests—with or without permission to do so. We did not find evidence that this was the case. The IOM committee also considered the possibility that the "problem" was basically one of perception—a widely held belief that some advisory committee members, even if not in violation of the law, were compromised by their relationships with industry. Although it is not easy to measure public perceptions on such a matter, and we have not attempted to do so, the committee believes this is not a trivial concern. The range of relationships that the current law, as interpreted, treats as presumptively disqualifying financial interests has become so broad that virtually no advisory committee member is untouched. Thus the FDA confronts the need to consider granting conflict-of-interest waivers for one or more members at almost every meeting, creating or bolstering an impression that the system is seriously compromised. In the committee's judgment, however, the core of the problem, or at least the portion on which thoughtful recommendations might make an immediate contribution, is internal to the FDA and the department. The problem resides in the system for identifying potential financial conflicts, for the agency's determining whether to seek a waiver (which is specifically provided for in the governing law) that would permit the participation of a specific member in advisory committee deliberations, and for evaluating that request for a waiver in a particular case. A sometimes bewildering number of organizational entities are involved in administering conflict-of-interest laws. They are identified in Table 6-1 on the following page.

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Food and Drug Administration Advisory Committees Table 6-1 The FDA Conflict-of-Interest Players Food and Drug Administration CDER, CBER, and CDRH and their respective committee management staffs Division of Ethics and Program Integrity (DEPI) Committee Management Office Office of the Chief Counsel, FDA Department of Health and Human Services Office of the Special Counsel for Ethics (OSCE), in the Office of the General Counsel Other Federal Agencies Office of Government Ethics (OGE) General Services Administration (GSA) Department of Justice Office of Personnel Management (OPM) Office of Management and Budget (OMB) THE STATUTORY FRAMEWORK A familiarity with the current federal conflict-of-interest law as it applies to the FDA advisory committee members is necessary to understand the "problem" that Dr. Kessler asked us to evaluate. The key statutory provision is 18 U.S.C. §208, which is part of the U.S. Criminal Code, and it applies to all federal government employees. Members of the FDA's technical advisory committees are covered because they are appointed as "special government employees" (SGEs) who serve the government on a part-time or intermittent basis.* Appointment as an SGE allows an advisory committee member to be paid and compensated for expenses; it also facilitates disclosure to committee members of confidential or proprietary information, which is often the bulk of the material in a drug, biologic, or device application. Section 208 (summarized in Table 6-2) has two main parts. Subsection (a) prohibits (i.e., makes criminal) a government employee from participating "personally and substantially" in any "particular matter" in which, to his/her knowledge, "he, his spouse, minor child, general partner, organization *   As defined in the FDA Staff Manual Guide 3118.6, April 18, 1986, this category includes "anyone who is retained, designated, appointed or employed to perform services with or without compensation for a period not to exceed 130 days during any period of 365 days whether on a fulltime or intermittent basis."

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Food and Drug Administration Advisory Committees in which he is serving as officer, director, trustee, general partner, or employee, or any person or organization with whom he is negotiating or has any arrangement concerning prospective employment, has a financial interest."* The law does not distinguish among types of financial interests, nor between large and small or significant and insignificant interests. By common consensus it goes well beyond such things as monetary payments or marketable securities. This broad reach of subsection (a) is qualified by subsection (b), which allows for three exceptions (or waivers) to this general prohibition. Subsection (b)(1) allows the official responsible for appointing an employee to grant an exception to participate in a matter in which the employee's interest "is not so substantial as to be deemed likely to affect the integrity of the services which the Government may expect." Subsection (b)(2) authorizes the promulgation of regulations that categorically except certain types of interests. As the law was amended in 1989, this authority can be exercised only by the Office of Government Ethics (OGE). Finally, subsection (b)(3), which was added to the law the same year, exclusively for advisory committee members, allows the official responsible for appointing a committee member to grant an exception if he/she concludes that the agency's need for the member's service in the particular matter outweighs any risk that this impartiality will be compromised. Each of these three waiver authorities is examined in greater detail below. *   Section 208(a) reads: "Except as permitted by subsection (b) hereof, whoever, being an officer or employee of the executive branch of the United States Government, ... including a special Government employee, participates personally and substantially ... through decision, approval, disapproval, recommendation, the rendering of advice, investigation, or otherwise, in a judicial or other proceeding, application, request for a ruling or other determination, contract, claim, controversy, charge, accusation, arrest, or other particular matter in which, to his knowledge, he, his spouse, minor child, general partner, organization in which he is serving as officer, director, trustee, general partner or employee, or any person or organization with whom he is negotiating or has any arrangement concerning prospective employment, has a financial interest—shall be subject to the penalties set forth in section 216 of this title."

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Food and Drug Administration Advisory Committees Table 6-2 Federal Conflict of Interest Law Affecting Advisory Committee Members (18 USC § 208) Section of Statute Bases for Determination of Financial Conflict 208(a), from 1978 Ethics in Government Act Prohibits any federal officer or employee from participating personally and substantially in a particular matter in which, to his/her knowledge the employee, his/her spouse, minor child, or general partner, an organization in which he/she is serving as an officer, director, trustee, general partner, or employee, or a person or organization with which he/she is negotiating for or has an arrangement concerning prospective employment has a financial interest. Types of Waivers Test for Granting Waiver Current Status 208(b)(1), from 1978 Ethics in Government Act If the FDA Commissioner determines that "the employee's interest is not so substantial as to be deemed likely to affect the integrity of the services which the Government may expect." Now used by FDA for consultants; formerly used for advisory committee members 208(b)(2), amended by 1989 Ethics Reform Act If the FDA Commissioner, on the basis of the OGE government-wide rule, determines that an employee's interest "is too remote or too inconsequential to affect the integrity of the services." OGE rule not yet proposed; agencies with such a rule the 1989 Ethics Reform Act may continue to use it until the OGE issues its rule; the FDA lacks such a rule 208(b)(3) added in 1989 Ethics Reform If the FDA Commissioner determines for an advisory committee member that "the need for individual services outweighs the potential for a conflict of interest created by the financial interest involved." Now used by the FDA for all committee members; requires that the OSCE and the OGE occur.

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Food and Drug Administration Advisory Committees Subsection 208(b)(1) Subsection (b)(1) permits the government official responsible for appointing the employee to issue an advance written determination, a (b)(1) waiver, finding that "the employee's interest is not so substantial as to be deemed likely to affect the integrity of the services which the Government may expect." Although this language appears to require an assessment of the magnitude or character of the employee's interest, the section allows consideration of other factors, according to the OGF. These include the magnitude of the employee's other holdings (e.g., as a way of asking "how much would it really matter if his/her stock in Company X doubled in value?"), the likelihood that the interest could be materially affected by a decision made or advised on by the employee, and the type of interest involved). The presence of subsection (b)(1) in the law arguably supports the conclusion that section 208(a) covers any financial interest, no matter how small. Under a 1990 Executive Order, an agency that contemplates granting a (b)(1) exception must first "consult" with the OGE if it is practical to do so. This does not necessarily mean that the OGE must approve the agency's decision. Any (b)(1) exception granted without consultation with, or even in defiance of advice from, the OGE will nonetheless be valid. However, under DHHS policy, any exception granted under (b)(1) does require approval by the Office of the HHS Special Counsel for Ethics. In other words, the Commissioner is not authorized to approve a waiver without OSCE approval. Subsection 208(b)(2) Subsection (b)(2) of section 208 authorizes the issuance of regulations that categorically exempt certain classes of financial interests as being "too remote or too inconsequential to affect the integrity of the service of the" employee. Before the 1989 amendment of (b)(2), individual agencies had authority to grant such categorical waivers; if they did so, those regulations remain in effect today. After the legislation, however, the power to issue such regulations was lodged exclusively in the OGE, and agencies without these rules are now precluded from issuing them. Since the FDA had no (b)(2) regulations before the 1989 amendments, and because the OGE has not yet issued such regulations, the FDA has no basis to grant (b)(2) waivers. The language of subsection (b)(2) allows class exemptions based on either of two criteria. The interest may be "too inconsequential," i.e., too small, which implies an absolute criterion independent of the likelihood that

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Food and Drug Administration Advisory Committees an interest might be affected or, even if affected, might threaten an employee's integrity. Alternatively, the interest may be "too remote," which seems to speak to the likelihood that the value of the interest would not be affected by the advice given or by any decision based on that advice. Pursuing the latter prong, subsection (b)(2) might allow the OGE to issue a regulation exempting endowment holdings of educational institutions from the class of employer financial interests that would otherwise disqualify an advisory committee member. The OGE says it is developing regulations to implement (b)(2). As described to the IOM committee, the regulations will speak to both the magnitude and type of interests and to the functions performed. They may initially cover only ownership interests in business enterprises, e.g., shares of stock and perhaps other equity interest such as partnerships. Thus far the OGE has not developed, and may not even have considered, criteria for evaluating the remoteness of other types of interests, such as research grants. However, the DHHS Special Counsel for Ethics is engaged in discussions with counsel for other science-oriented agencies to explore criteria for waiving research grant "conflicts." Any criteria ultimately developed by this group will, of course, still need the OGE approval and then promulgation as regulations. Quite obviously, adoption of any (b)(2) regulations is many months, and probably years, away. The process requires consultation, before any proposal is published in the Federal Register, between the OGE and the Office of Personnel Management, the Department of Justice, and the Office of Management and Budget. After publishing the proposal as a Notice of Proposed Rule-Making (NPRM), the OGE must allow for public comment, respond to this comment by changes in the proposal or justification of the proposed action, and proceed once again through the executive branch review process (OPM, Justice, OMB) to develop the final rule. Subsection 208(b)(3) Subsection (b)(3), the most significant of the waiver authorities, and of most immediate concern to the FDA and the IOM committee, applies specifically and exclusively to members of advisory committees. Under this provision, the appointing official is allowed to grant a waiver for a committee member, who would otherwise be disqualified from discussing a particular matter, i.e., a specific agenda item, to participate in deliberations on that matter without violating the law. "The exercise of this authority calls for a judgment in writing "that the need for the individual's services outweighs the potential for a conflict of interest created by the financial

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Food and Drug Administration Advisory Committees interest involved." This exemption was added to the law in 1989 to facilitate the participation of members of expert advisory committees. For an the FDA advisory committee, subsection (b)(3) requires a judgment by the FDA Commissioner that the value of a committee member's participation outweighs the risk of conflict of interest posed by his or her financial interest. It provides the framework within which virtually all "waivers" for the FDA advisory committee members are processed. Subsection (b)(3) clearly calls for a context-specific judgment, one that takes into account not only the interest involved but the contribution that the member can make to the committee's deliberations on the matter before it. Thus, the law presumably allows an assessment of the member's expertise, familiarity with the issues, and uniqueness on the committee in light of the issues to be addressed. And exercise of the authority would seem to call for a personal judgment by the FDA Commissioner—or by the official to whom he delegated his authority. The Commissioner's authority to grant waivers under (b)(3) is in addition to the authority to grant waivers under (b)(1) and, if the OGE regulations are ever promulgated, under (b)(2). Thus, if an the FDA advisory committee member qualified for a (b)(1) waiver or a categorical (b)(2) waiver, there would be no need to consider his/her eligibility to participate under (b)(3). On the other hand, this also means that a member who could not qualify for a waiver under (b)(1) or (b)(2), e.g., because his or her interest is too large or too likely to be affected, may still be eligible for a (b)(3) waiver based on his or her importance to the committee's deliberations. The FDA Commissioner's authority to grant waivers under subsections (b)(1) and (b)(3) is, under DHHS policies, subject to review by the Office of the Special Counsel for Ethics (OSCE); his authority under the Executive Order requires consultation with the OGE. Thus, the impact of this legal regime on the FDA advisory committee members, and on the advisory committee system, will be a function of three factors: (1) the types of interests held to fall under the prohibition of section 208(a); (2) the kind and number of relationships that advisory committee members (and their family members and employers ) have with manufacturers of the FDA-regulated products; and (3) the specific issues on which the FDA seeks committee advice. Importantly, for this study, each of these factors has been undergoing change. It is important to emphasize that 18 U.S.C. §208 is a criminal statute whose violation carries criminal penalties and whose enforcement involves criminal investigation procedures. Accordingly, it is entirely appropriate for the FDA and the DHHS to take seriously their obligations to protect both the agency's decisional process and the members of advisory committees from committing violations.

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Food and Drug Administration Advisory Committees The granting of a waiver must be understood in this context. What is being waived by the agency is not an individual's conflict (or potential conflict); a waiver is an acknowledgement of a conflict. Instead, what is being waived is the criminal liability of the advisory committee member that would attach to participation with a prohibited interest. Seen in this light, the system has an obvious justification. Some committee members who have complained about the intrusiveness of the agency's questions or delays in approval of their appointments or their participation, may not have fully appreciated the importance of the exercise in protecting them as well as the agency. FDA'S ADMINISTRATION OF CONFLICT-OF-INTEREST RESTRICTIONS Federal conflict-of-interest laws impinge on the FDA advisory committee operations at two stages, each of which has multiple steps. The first stage is when an individual scientist or clinician is being considered for initial appointment and involves screening prospective committee members for potential conflicts of interest. It is this point at which most of the information about and individual's personal, family, and employer or institutional financial interests is sought and provided. The identification of potential conflicts of interest, however, does not result in rejection of many candidates at this stage simply because the specific issues on which their advice will be sought are not generally known. The conflict-of-interest laws do not forbid the FDA to appoint as advisory committee members individuals who have financial relationships with the FDA-regulated firms. They do forbid the participation of a committee member in a "particular matter" in which he or she has a financial interest. Thus, a judgment of whether the law applies can only be made by considering, in the case of advisory committee members, the specific agenda items on which their advice will be sought. Each committee agenda item, therefore, presents an occasion for evaluating a member's potential conflict-of-interest. Consequently, agency and departmental administration of conflict-of-interest laws focuses on the second stage, when meeting agendas are known and the "particular matters" to come before the committee have been identified. This stage involves identifying potential conflicts and determining when to seek waivers, preparation of waivers, and processing waivers.

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Food and Drug Administration Advisory Committees Screening Potential Committee Members The recruitment, nomination, and appointment of the FDA advisory committee members has been described in Chapter 5. This section focuses on the stage at which the FDA seeks to identify a prospective member's potential financial interests and thereby equip itself to monitor compliance with section 208. Once a nominee for committee membership has been tentatively approved at the center level, a member of the FDA staff, usually the committee executive secretary or a member of the advisory committee management staff, contacts the individual by telephone to determine his or her availability and to identify any factors that might preclude appointment or diminish the individual's effectiveness. In all three centers, this initial conversation also includes ''prescreening'' questions that solicit information about the nominee's financial interests and relationships. The purpose is to discover future potential conflicts of interest. At the time of this study, the prescreening forms being used were several years old and did not elicit information about spousal or employer financial interests. Although the FDA has no formal threshold, an advisory committee nominee at this initial stage may be judged to have so many attachments to the drug, biologics, or device industries that the appointment should not be made. The rationale is that numerous potential conflicts will limit the individual's ability to participate in committee discussions. Occasionally a potential member is ruled out because his or her attachments to industry are simply too great to pass an "appearances" test, even though they might not require frequent disqualifications. Any decision not to pursue recruitment of a prospective committee member because of excessive potential conflicts is taken with the concurrence of the division or office director. Following this preliminary screening of a prospective committee member, he/she is sent an "appointment package" that solicits more specific professional and financial information. Although the appointment packages sent by the three centers differ in small details, they are roughly equivalent. Of particular interest is Form 2637—the Confidential Statement of Employment and Financial Interests. Form 2637 seeks information about financial holdings or business arrangements with any firm, regardless of whether it is known to be regulated by the FDA, as well as employment by and/or consultantships with FDA-regulated firms. (Current instructions for completing the form do not clearly specify that the SGE should include the financial interests of his or her spouse, minor children, partner, and any organization in which he/she serves as officer, director, trustee, general partner or employee, and of any person or organization with whom he/she is negotiating or has any arrangement for prospective employment.) The

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Food and Drug Administration Advisory Committees Remedies Because no clear set of legal restrictions is operative here, the agency has a wider range of remedies from which to choose than it has under section 208. If the determination of bias rests on publicly stated positions, exclusion is probably warranted. There may be other cases in which this may also be appropriate, e.g., when a member is an inventor of the technology under review (even if he or she has no financial interest in its approval). And denial of participation surely would reduce the risk of recrimination and embarrassment. There may, however, be instances in which exclusion of a member for possible bias would deprive the committee members who do participate of information helpful in their independent evaluation. If exclusion stems from the member's prior research, especially as a principal investigator, the FDA should not have to forego that individual's expertise. This can be solved by inviting the person to address the committee as a witness (or as a "guest"). In such an instance, it would be desirable to situate the individual so that he or she does not appear to occupy his usual role as a voting member of the committee. On the other hand, there is some disadvantage to creating too large a set of roles at committee meetings to accommodate various perceived levels of partiality. A sensible rule of thumb 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. Short of complete exclusion, the success of any more limited remedy will depend on full public disclosure of the facts that give rise to the concern that the objectivity of an erstwhile committee member may be, or may be thought to be, in doubt. It may be possible to say that "Dr. Jones has agreed to recuse himself from the discussion of Product Y because of concerns that, based on prior work in the field, his objectivity may be challenged. He therefore will not participate in the committee's formulation of advice, nor will he vote. He has been asked by the FDA to be available as a witness to answer questions from voting committee members." Screening The development by the FDA of a system to screen for potential intellectual bias will require considerable thought. A member's prior research will probably be revealed in the screening for financial conflict of interest. All relevant publications presumably will be included in a potential member's curriculum vitae. However, it may be necessary for the agency to

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Food and Drug Administration Advisory Committees inquire specifically about public positions, especially any taken before regulatory agencies or judicial proceedings. This brief discussion barely penetrates the surface of a complex and very sensitive issue. It is sensitive, in part, because committee members whose objectivity might be challenged on other than financial grounds are often likely to resent the suggestion that they cannot be trusted. This is particularly true if the suggestion comes from the agency, which has appealed to their spirit of public service. Perhaps the heightened attention given to the subject within the scientific community will generate greater sensitivity on the part of individual committee members. One further observation is in order. We consider the matter of intellectual bias to be a problem for the FDA to address and resolve. It is not covered by the federal conflict-of-interest laws and its possible occurrence is therefore not properly addressed through the formal waiver process. It obviously has legal ramifications to the extent that agency decisions might be subject to attack because of the participation of a committee member who lacked, or was accused of lacking, the requisite objectivity. But these are ramifications that the FDA's Chief Counsel is very capable of assessing and providing guidance on to the agency. The IOM committee recommends that the FDA develop criteria and procedures for identifying potential intellectual bias of advisory committee members and protecting the objectivity and impartiality of advisory committees. The committee recommends that the agency routinely request information about research interests and publicly stated positions on scientific issues from advisory committee members. It recognizes that the agency must rely to a large extent on committee members themselves to provide such information. When the agency concludes that a committee member has demonstrated a lack of objectivity on a matter, the member should be excluded from participation in the committee deliberations concerning that issue. If information reveals only the possibility of bias, the agency should determine whether to permit the member to participate. A member who is excluded from participation in committee deliberations might nevertheless be invited to offer views as a guest or witness called by the committee. Individual cases should be ruled on by the Commissioner, after consultation with the appropriate center director.

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Food and Drug Administration Advisory Committees NOTES 1.   Berg, Richard K., Conflict-of-Interest Requirements for Federal Advisory Committees, Report to the Administrative Conference of the United States (Washington, D.C., May 1989). 2.   Barinaga, M. Confusion on the Cutting Edge. Science 257:616–619, 1992. 3.   Marshall, E. When Does Intellectual Passion Become Conflict of Interest? Science 257:620–621, 1992. 4.   Marshall, E. NSF Deals with Conflicts Every Day. Science 257:624, 1992. 5.   Marshall, E. Intellectual Conflicts—Boon or Bust? Science 257:624, 1992.

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Food and Drug Administration Advisory Committees APPENDIX A Suggested Approach to the Codification of Section 208(b)(3) Waiver Criteria Supplemental Statement of Richard A. Merrill The IOM committee recommends, appropriately in my view, that the FDA and the DHHS Office of the Special Counsel for Ethics (OSCE) "immediately begin the process of codifying the criteria for granting 208(b)(3) waivers, especially with respect to employer interests, research grants and contracts, and competing products and technologies." This statutory provision, specifically enacted for members of federal advisory committee, holds that an agency head may waive the potential financial conflicts of an advisory committee member if he determines that "the need for the individual's services outweighs the potential for a conflict of interest created by the financial interest involved." It is this authority on which the FDA now exclusively relies in deciding whether to allow members with potential financial conflicts to participate in committee deliberations on a particular matter. The IOM committee report itself does not offer concrete guidance on how this might be done. This apparent deficiency of the report becomes understandable when one grasps the difficulty of the exercise and recalls that the committee's schedule allowed for only four face-to-face meetings. Framing a discussion of which kinds of potential conflicts should be considered serious and which not, and of how to assess the importance of a single member to a committee's deliberations is a complex undertaking. Reaching judgments on these issues requires extended discussion and debate. There was scarcely time to attempt the first of these challenges, and no opportunity at all for the full committee to engage in the extended discussion needed to reach agreement on the second. What follows is one member's attempt to outline the analysis he would follow in attempting to carry out the IOM committee's recommendation. It does not necessarily reflect, either in its approach or in the normative judgments implied, the views of any other committee member. It is offered to provoke further analysis within the FDA and OSCE rather than to prescribe a solution to the problem that they jointly confront. The problem of codifying the criteria for approving waivers under 208(b)(3) is complicated by two main facts. First, the range of matters on which the FDA seeks advice from its advisory committees, when coupled

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Food and Drug Administration Advisory Committees with the prominence and diverse activities of the members of these committees, generates a substantial number of presumptive "exclusions" that dictate nonparticipation or require consideration of waivers. An FDA committee meeting seldom occurs today without one or more members facing exclusion from one or more items on the agenda. In short, the agency faces a large "caseload" of potential waivers. Second, the caseload is large in major part because the conflict-of-interest law, section 208(a), sweeps extremely broadly, embracing as potentially disqualifying of an individual committee member not only small personal (and family) financial interests but interests or relationships of the member's employer. As most committee members work for universities or other research and health-care providing institutions, most have, through their employers, traceable if indirect ties to multiple research grants, clinical research arrangements, and a vast array of paid-for health care services. As the law is now interpreted, any of these interconnections can give rise to a potential conflict—and thus require either exclusion or a waiver—for an advisory committee member. Relatively few such interconnections, in my judgment, ought realistically to be viewed as jeopardizing the impartiality of a committee member's advice. And this, as I understand it, is the central concern of the conflict-of-interest laws, i.e., a concern to prevent governmental decision making, or in this context advice obtaining, from being compromised by the self-interest of the advice giver. The implication of this judgment is that a large, but indeterminate, percentage of the presumptive exclusions revealed by the FDA's system of comparing committee member interests (including employer interests) with committee agendas are plausible, if not compelling, candidates for the exercise of the Commissioner's waiver authority. The goal sought by the IOM committee's recommendation is the development of general criteria or guidelines that facilitate decision making about the appropriateness of waivers in individual cases. We believe that it should be possible to identify and articulate categories of interests that ordinarily ought not be considered disqualifying, i.e., should be considered waiverable. It also may be possible to identify other categories that ordinarily should be considered disqualifying. And it may even be possible to enunciate criteria for deciding whether a committee member should be allowed to participate even with a significant potential conflict in a particular matter because of his or her importance to the committee's deliberations. The recent history of the development, review, and approval of (b)(3) waiver requests for members of the FDA advisory committees, recounted in the IOM committee report, illustrates the consequences of the failure to develop general criteria for approving such requests. For some months now, each new waiver request appears to have been treated as a novel case,

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Food and Drug Administration Advisory Committees requiring extended negotiations over the appropriateness and terms of granting a waiver and the content and format of the document explaining the agency's decision. Such a case-by-case approach virtually assures that the process will prove both burdensome and deeply frustrating. The IOM committee found signs that officials in the FDA and OSCE recognize the need to regularize the waiver review process and reach agreement on the treatment of certain categories of potential conflicts. The committee's recommendation is essentially that this effort be extended and given priority. The product we visualize would be a series of written guidelines, or even a grid, for decision making. For example, one ''guideline'' now under consideration by the FDA and OSCE would say something like: "The fact that a committee member's institutional employer operates a hospital or clinic that dispenses and charges for the FDA-regulated products, including products of the manufacturer whose application is to be reviewed, will not ordinarily be deemed disqualifying. Accordingly, a waiver to allow him or her to participate in committee deliberations is appropriate." Without necessarily endorsing this illustration, the IOM committee's hope is that other classes of interests that under the law would be presumptively disqualifying can be generically categorized as waiverable or as not waiverable. There are many obstacles to the achievement of this goal. Some are empirical. It requires comprehensive knowledge that may not be easily assembled about the types and magnitudes of interests that the FDA committee members report that now trigger exclusions. We were given many examples, but no information that would allow a judgment about which potential conflicts were representative or how often any one occurred. Another set of obstacles is institutional. Since many decisions about whether a type or size of interest should be viewed as disqualifying are, ultimately, matters of judgment, it is to be expected that individuals will disagree about the proper disposition of paradigm cases. The present arrangements arguably require the concurrence, or at least the acquiescence, of three offices—the FDA Commissioner, the OSCE, and the Office of Government Ethics—before any waiver can be approved. Achieving agreement at this level on any set of generic guidelines is likely to be a long-term task. This Appendix addresses a third set of obstacles to the achievement of what the IOM committee has termed "codification." For lack of a better word, I will label these "analytical." In order to decide whether a particular kind of interest should disqualify a committee member, or, since the statute treats most interests as disqualifying, whether a waiver is appropriate for a given committee member, one needs to have some understanding of the underlying goals of the conflict-of-interest law. I suggest that the primary

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Food and Drug Administration Advisory Committees goal should be to prevent the participation of committee members whose advice might, because of self-interest, be distorted. One could add to this formulation, as the present law does, a qualification: If a member's value to the committee's deliberations is great enough, even some risk of distortion may be accepted. This formulation of the statutory goal is not quite congruent with the language of 208 (b)(3), which arguably calls for an individualized judgment about a member's value to committee deliberations in every case. However, because the determination of a member's value appears to be a more complex inquiry, I believe it would be more fruitful to concentrate first on the dimension that requires consideration of a waiver in the first place—the presumptively disqualifying financial interest—and see if it is not possible to categorize and then rank such interests in terms of their potential to undermine impartial advice-giving. I also believe that this is not only possible but compatible with the statute. It seems to me quite plausible to argue, for instance, that for some sorts of interests—though perhaps not many—the threat to impartiality is so negligible that the fact of selection for committee membership should be taken as sufficient evidence of a member's value to the committee's deliberations. The willingness of the FDA and OSCE to consider agreeing that employer health care delivery activities, e.g., university hospitals, should never (or rarely) be viewed as disqualifying—i.e., should be automatically waiverable—is evidence that this legal interpretation is not preposterous. I should add that even if it proves difficult to reach agreement on many other automatically waiverable classes of financial interests, the exercise of categorization and ranking should help improve relations between the agency and the OSCE. One frequent complaint that we heard from the FDA officials was that they never knew what the rules were. This can be translated as "we never know what sorts of interests would really raise eyebrows at OSCE." The waiver review process would be greatly improved if it were possible for the OSCE to say, and the FDA officials to know (even if they do not agree), what sorts of interests will be most difficult to grant waivers for. On the other hand, OSCE staff members might develop a greater understanding for the agency's position if the FDA officials were able to articulate the factors that they consider important in assessing a committee member's value to committee deliberations. The attitude that committee membership—another live body eligible to vote—is all that is necessary to convince center personnel that an individual member, despite a significant potential conflict, is absolutely crucial to deliberations cannot inspire confidence that the FDA is exercising the sort of discriminating judgment that the law seems to contemplate.

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Food and Drug Administration Advisory Committees The effort suggested could have value beyond assisting the FDA and the OSCE in preparing and reviewing proposed (b)(3) waivers. The part of the task discussed in this Appendix—classification of disqualifying financial interests in terms of their likely effect on committee member impartiality—would be directly relevant to the Office of Government Ethics' consideration of possible (b)(2) waiver regulations. The reader will recall that section 208(b)(2) allows the OGE—and only the OGE—to promulgate regulations categorically exempting certain types of magnitudes of financial interest as "too remote or too inconsequential' to affect a government employee's honest performance of his or her functions. This sort of waiver does not require an assessment of the employee's, e.g., the committee member's, importance to committee deliberations. Thus the effort to identify types of financial interest whose potential influence is so improbable that mere membership can be considered outweighing is a logical prelude to the exercise that the OGE must eventually undertake to implement (b)(2). The OGE should welcome the FDA/OSCE effort, even if it does not agree with every part of their classification. The FDA/OSCE analysis should advance thinking in this most difficult area and provide examples of (b)(2)-waiverable interests that are common among medical and scientific researchers but perhaps not frequently encountered among other federal personnel. What can be said, if anything, about the sorts of interests that ought to be considered as jeopardizing a committee member's impartiality? Although the following discussion reflects personal judgments, it may offer the beginning of a framework for thinking about that question. For me, certain generalizations seem plausible, though not incontestable. The magnitude of a financial interest surely is likely to make a difference; we would worry more about a committee member's objectivity, in assessing a company's product, if he or she owned shares of stock in the company than if he or she owned one share. The law may not see a difference here, but most people do. And the law would appear to allow this difference to be accorded weight in a decision whether to grant a waiver. Differences of magnitude—at least in ownership interests or direct payments—are relatively easy to discern and deal with. At least they are easy to array on a chart or grid. It may not be easy to agree on what threat to impartiality is presented by interests of different sizes. And searching for agreement at several different levels may not be worthwhile. Perhaps it should be enough to reach agreement on "de minimis" levels that would, if not exceeded, ordinarily allow a waiver. (We are not speaking about establishing a de minimus standard for applying the presumptive disqualification of 208(a), but rather are seeking one measure of the presumptively disqualifying interest that define its eligibility for waiver. In short, we are not

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Food and Drug Administration Advisory Committees quarreling here with the prevailing interpretation of 208(a), which holds that even a single share of stock or a $100 speaking honorarium is a prohibited interest, although in another context many of us surely would do so.) Matters get more complicated when one tries to categorize financial interests by type. But the exercise is not futile. It is possible to frame generalizations about what kinds of interests are more worrisome than others. The central question that seems likely to help clarify thinking about which interests really threaten impartiality is "whose interest is it?" This question can be examined with reference to employer interests and personal interests. The statute forbids a committee member's participation in any matter in which he or she, a family member, or an employer holds any financial interest. I suggest that personal (including family) interests are more likely to threaten an individual's objectivity than the financial interests of his or her employer. To be sure, one can think of examples of both sorts that would defy this generalization, and perhaps—on close examination—those examples would swallow the principle. Even so, as one starting place for analysis, it is likely to prove helpful to make the personal-employer dichotomy one of the dimensions of a grid of financial interests, all of which under the current law are deemed presumptively disqualifying. We have been provided examples of three types of employers' interests that are believed to trigger section 208(a): (1) sales by the employer, or by a subordinate unit of the employer, of the FDA-regulated products made by companies that have new product applications pending before the FDA; (2) research or other grants from such companies; and (3) gifts from such companies to support institutional programs, e.g., an endowed chair. No doubt there are other many others, among which it ought to be possible to draw distinctions based on the likelihood that a committee member might modify his or her advice in order to protect an employer's relationship with a company. It would not be imprudent, in my view, for the FDA to take the position that interests falling in the first category ought always to be waiverable absent clear evidence that the employer receives a substantial amount of its income from such sales or that the committee member him-or herself benefitted personally from decisions affecting the usage or sale of the company's product. A similar judgment might be supportable for research grants other than those made to a committee member personally. My goal here, however, is not to offer conclusions about which kinds of employer interests ought to be considered routine, possible, or unlikely candidates for waiver, but simply to suggest an approach to thinking about this question. The approach involves, first, the categorization of the various types of employer interests the FDA committee members have displayed and, second, thoughtful assessment of the likelihood that interests within a

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Food and Drug Administration Advisory Committees particular category will undermine an individual committee member's impartiality. The same sort of exercise is appropriate in assessing the personal interests of committee members. To simplify the task, it might well be prudent to conflate member interests and family interests, i.e., to assume that a spouse's or minor child's financial interest is as likely (or unlikely) to affect a member's impartiality as his or her own. It would be a crude generalization, to be sure, but crude generalizations will be necessary to develop a framework that can guide—and, which is the ultimate goal, simplify and thus expedite—review of individual waiver requests. Within the category of personal interests, individual research grants are apparently a common source of presumptive disqualification. The dollar value of a grant probably ought to be a consideration in assessing the likelihood that it may affect a committee member's impartiality. But equally important, it seems to me, is the extent to which a grant contributes to a researcher's personal income, as distinct from institutional income. I would be inclined, as well, to differentiate between research grants provided in the past and grants that currently support a member's research. The influence, if any, of the former must be in the member's hope for future research support from the same source, and I do not find it implausible that an individual's judgment is less likely to be influenced by a hope that support might someday be renewed than by the fear that current support may be terminated. I would, at least tentatively, draw a similar distinction between other sorts of company payments to a committee member. A concluded consulting arrangement that once paid a $2,500 yearly honorarium strikes me as less worrisome that an on-going relationship that provides rewards, even of smaller magnitude, in future years. Indeed, it may be appropriate to draw a broader distinction between interests that a member already owns, and whose value will not significantly change, and interests whose enjoyment, or whose value, may depend on the success of the company that is the source of the interest. A consulting fee paid in the past may be the source of hope for future beneficial relationships, but its value will not be diminished if the company never provides support again. By contrast, the value of stock owned by a committee member in a company whose products he or she is asked to evaluate is clearly affected by the future success of the firm, and very possibly by the profitability of the new product. The range of personal financial interests that one can assemble from examples provided by the FDA is large, and their variety may appear to defy any systematic effort at description, much less a categorical assessment of their likely affect on impartiality. But one cannot know this without making

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Food and Drug Administration Advisory Committees the effort. And there is a value to the intellectual exercise even if a formal decision making grid or set of decisional guidelines remains incomplete. It will force those involved to articulate and explain their judgments about the appropriateness of granting waivers in specific cases. It may also yield—and this would be no small achievement—a common vocabulary for describing and analyzing individual cases. And, if engaged in jointly by officials from both the FDA and the OSCE, it may help to reveal common ground and to clarify differences. The discussion thus far has focused on only the first element of the statutory formula for granting (b)(3) waivers—the potential of different types and magnitudes of financial interests to undermine a committee member's impartiality. Section 208(b)(3) also requires consideration of a member's importance to committee deliberations. The suggestion made here is that some interests can be classified as so unlikely to threaten impartiality that selection for committee membership can be taken as sufficient evidence of importance to offset the remote risk. But there may be few such interests, and they are likely to be an employer's rather than personal or family interests. Thus, in evaluating many waivers attention must be given to a member's importance to committee deliberations. I believe that this second element should also be susceptible to categorical analysis, i.e., it should be possible to formulate guidelines for evaluating individual cases. And the committee's recommends that this should be done. There is one additional point to be made. Many readers may ask how the exercise sketched in the foregoing paragraphs fits with the statutory regime for regulating financial conflict of interest. The answer has already been suggested but warrants reiteration. Section 208(a) of the conflict-of-interest statute sweeps very broadly and, I acknowledge, as construed makes the sorts of distinctions discussed above irrelevant to a determination of whether an interest presumptively disqualifies a committee member from participating in advice on a particular matter. But section 208(b)(3) calls for an assessment, by the Commissioner of Food and Drugs, of the likelihood that a disqualifying interest will in fact affect the member's objectivity, as when as of his/her importance to the committee's deliberations. Such an assessment logically invites, and surely permits, consideration of the sorts of distinctions I have suggested.