Prescription for a cure: does the FDA's draft guidance adequately manage advisory committee members' conflicts of interest?

• Author: Kellogg, Ian J.

INTRODUCTION

On November 16, 1999, the Gastrointestinal Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended prompt approval of the drug Lotronex, used to treat women with irritable bowel syndrome. (1) Among the participants on the advisory committee was a paid consultant of the drug manufacturer, Glaxo, who had participated in the investigation of the drug for the company. (2) At the meeting, he acknowledged concerns about evidence that the drug caused some people to develop ischemic colitis, (3) but rather than delay approval of the drug he suggested "monitor[ing] it very carefully," with the expectation that complications would not prove too injurious. (4) The committee ultimately recommended approving the drug without further testing, and the FDA followed the committee's advice and formally approved Lotronex in February 2000. (5) Just nine months later, Glaxo withdrew the drug from the U.S. market after forty-nine patients taking Lotronex developed ischemic colitis and five died. (6) These and other similar events led to criticism of the FDA's handling of conflicts of interest from many fronts. (7)

On Friday, March 23, 2007, the FDA sought public comment on new guidelines for determining conflicts of interest and eligibility for participation in FDA Advisory Committee meetings. (8) Part I.A of this Note gives a brief history of the factual and legal background that led the FDA to propose the new guidelines, focusing on the FDA's own rationale a recognized inconsistency and lack of determinable standards under which waivers were granted in the past. The new guidelines, the salient features of which are summarized in Part I.B, purport to set forth "a more stringent approach for considering eligibility for participation...." (9) Their official purposes are "to [1] simplify and streamline the process by which FDA considers meeting participation, [2] increase the transparency, clarity, and consistency of the process, and [3] enhance public trust in this important function." (10) Part II.A assesses the guidelines' effectiveness and potential impact and concludes that disqualifying conflicted committee members as the rule, and granting non-voting waivers as the rare exception, (11) make great strides in effectuating the guidelines' purposes. In spite of these steps toward conflict-free advice, Part II.B discusses a number of lingering concerns about undue influence from committee members with financial conflicts under the terms of the Draft Guidelines: namely, that their language leaves sufficient loopholes that their purposes can be avoided. While this Note focuses on the FDA, the principles and suggestions about ways to eliminate or minimize potential conflicts are applicable to any agency that employs advisory committees to assist in product-specific analysis. (12)

1. THE FDA's 2007 DRAFT GUIDELINES

   1. Background

      The FDA is required to approve new drugs prior to sale. (13) The agency was created by the Food, Drug, and Cosmetic Act, which was passed following the deaths of over one hundred children caused by a widely marketed "elixir" for "strep" infections made by dissolving the curative sulfanilamide in diethylene glycol, a poisonous chemical used as antifreeze. (14) The current iteration of the Act requires a demonstration of "safety" and "efficacy," necessitating a long, complex, and expensive approval process. (15)

      The FDA is one of eleven health agencies that comprise the Department of Health and Human Services (DHHS), the cabinet-level department concerned with public health issues. (16) The FDA is tasked with evaluating applications submitted by pharmaceutical companies and determining, based on a review of scientific evidence pertaining to safety and efficacy, whether their drugs can be sold in the United States and under what terms. (17) This review process is handled in the first instance by an FDA sub-entity, the Center for Drug Evaluation and Research (CDER). (18) Often, the CDER will seek a recommendation from a federal advisory committee. Advisory committees range in size from three to fifteen persons and include members of the public, industry representatives, and scientific experts in the specific field in which the new drug is introduced. (19) While not binding on the FDA, (20) those recommendations are widely followed. (21)

      The scientific experts retained by the CDER to serve on federal advisory committees and to make recommendations on whether to approve or deny a new drug are often "Special Government Employees" (SGEs), part-time government employees, who are regularly employed elsewhere. (22) These experts are often pharmaceutical researchers employed by research institutions, including universities and pharmaceutical companies, with significant (and highly specialized) expertise in the relevant area. (23) The product-specific determinations made by these advisory committee members can have significant financial impacts on both the sponsoring (developing) company and its competitors. Depending on their personal, familial, or university affiliations, even the FDA recognizes that individual committee members might have serious conflicts of interest in some cases and that these conflicts can lead members to vote with their pocketbooks, or at least the appearance of such. (24) This Note focuses on potential financial conflicts of interest among SGEs on Federal Advisory Committees making recommendations to the FDA about whether to approve drugs for sale in the United States.

      The conflicts of interest of SGEs serving in advisory capacities to federal agencies exist at the intersection of four bodies of law: (1) the Federal Advisory Committee Act (FACA); (25) (2) federal conflict of interest laws and the regulations promulgated thereunder by the Office of Government Ethics (OGE); (3) the organic statutes creating (some) federal agencies and supplemental regulations promulgated thereunder; as well as, in some situations, (4) ethical specifications in the statutes or regulations under which a particular committee was convened. (26) In spite of this tangle of laws and regulations, many conflicts have slipped through the cracks. The FDA describes its own process for reviewing potential conflicts of interest as "complex and ... poorly understood." (27)

      The FDA adopted new conflict and waiver guidelines in 2000, (28) but the criteria were complicated and discretionary, leading to complaints of inconsistency. (29) Both before and after the 2000 guidelines were adopted, there continued to be demands for change in the way that the FDA handled conflicts of interest. (30) Various studies found both that committee members continued to be conflicted and that their conflicts were routinely waived. For example, USA Today reported in 2000 that fifty-four percent of supposedly independent experts "have a direct financial interest in the drug or topic they are asked to evaluate." (31) Even at meetings where the fates of specific drugs were discussed, USA Today found that thirty-three percent of advisory committee members had conflicts. (32) More recently, a Public Citizen study concluded that "at least 1 conflict was declared for at least 1 advisory committee member or voting consultant ... [at] 81% [of] product meetings...." (33) In the highly publicized re call of Vioxx, a private study commissioned by the New York Times found that twenty-seven of the thirty-two advisory committee members who debated the risks posed by COX-2 inhibitors had industry ties, including ten with recent ties to COX-2 manufacturers. (34) According to USA Today, "the FDA ha[d] waived the restriction [on financial conflicts for experts] more than 800 times" between 1998 and September of 2000. (35) Public Citizen agreed that conflicts of interest "rarely result in recusal of advisory committee members." (36)

      These examples are emblematic of the widespread criticism that the FDA has faced from the public, the press, and Congress. (37) As one trade publication put it, the Draft Guidelines "come in response to proposed legislation in Congress that aims to prevent experts that either have financial interests in or receive funding from specific pharma[ceutical] companies from voting on the approval of these companies['] drugs or on competing products.... The new rules should be seen largely as a pre-emptive attempt by the FDA[] ... to prevent political intervention in the agency's approval process." (38) The FDA stated that it remains "committed to strictly adhering to the laws and regulations governing the process for selecting advisory committee members" and that it seeks to "simplify and streamline[]" that process through the proposal and adoption of the new guidelines. (39) The guidelines--whether proposed to preempt Congressional action, curb public criticism, or otherwise--represent an attempt to synthesize applicable laws and regulations and to present a comprehensive, comprehensible, and unified approach to conflict of interest review by the FDA.

   2. "Determining Conflict of Interest and Eligibility for Participation in FDA Advisory Committees"

      1. Purpose and Summary

         Since before the adoption of the new guidelines, the FDA has purported to recognize the importance of conflict-free advice from its advisory committee members. The FDA says that "it is critical that the advice be free from conflict of interest and potential bias. If the advice FDA receives is biased or is seen as biased, it is of little value to the Agency." (40) The Draft Guidelines is an attempt to (at least appear publicly to) create policies to implement that goal.

         According to the FDA, the guidelines "implement a more stringent policy for considering eligibility for participation than would be permitted under the current legal framework." (41) This new policy has four basic tenets: (1) individuals with financial conflicts above $50,000 are generally prohibited; (2) individuals with conflicts of $50,000 or less may participate only...