Red tape tightrope: regulating financial conflicts of interest in FDA advisory committees.

• Author: Davis, Colleen O.

1. INTRODUCTION

   In 2001, the Food and Drug Administration (FDA) approved the oral contraceptive Yasmin for use. (1) A similar contraceptive, Yaz, was approved in 2006. (2) Both drugs are manufactured by Bayer, a pharmaceutical company. As early as 2004, Bayer scientists reported that Yasmin carries a '"several-fold increase' in reporting rates for blood clots compared to three other oral contraceptives, and that Yasmin's rate of all serious adverse events was ' 10 fold higher' than that of other products." (3) Despite this, the FDA approved Yaz two years later, though it contained the same hormone that caused the blood clots in Yasmin. (4) A 2009 study found that this hormone, drospirenone, increased a user's risk of venous thromboembolism by a factor of 6.3. (5)

   Yaz and Yasmin have been linked to 100 deaths, and over 10,000 lawsuits have been filed against Bayer claiming that consumers have been harmed by taking the contraceptives. (6) In December 2011, the FDA reexamined Yaz and Yasmin. (7) A panel voted to include the risk of blood clots on labels, though it declined to require Bayer to indicate that the risk was any greater than that for other contraceptives, despite a study published in the British Medical Journal that indicated that the risk of blood clots were twice as high for users of Yaz and Yasmin than for other contraceptives. (8) The FDA panel voted 15-11 to allow the contraceptives to remain on the market, finding that their benefits to consumers outweighed their risks. (9) Scientists and consumer advocates soon observed, however, that four (possibly five) members of the FDA panel had financial ties to Bayer, and all four voted to keep the drugs on the market. (10) They each had disclosed these conflicts of interest to the FDA, and the FDA allowed them to vote on the panel anyway. (11) In February 2013, Bayer faced roughly 13,600 lawsuits in the United States regarding the contraceptives, excluding claims already settled. (12) Further, as of February 2013, Bayer had also "reached agreements, without admission of liability, to settle the claims of approximately 4,800 claimants in the U.S. for [about SI billion.]" (13) Yaz and Yasmin are still on the market, and Bayer profited $1.42 billion from them in 2012. (14)

   This incident is only the latest of several in recent years that have caused many to question the FDA's transparency and bias in its review and approval processes. Conflict of interest within FDA advisory committees has been discussed before, (15) but several new regulations have loosened FDA conflict of interest requirements, and recent events such as the Bayer incident raise questions as to whether the current regulations are effective. Further examination of these issues is in order. This Note explores the depths of financial conflicts of interest in these processes, how they are regulated, and how they should be regulated. Part II discusses current conflict of interest regulations imposed upon the FDA. Part III examines the arguments for loosening regulations. Part IV addresses the argument for tightening regulations, including a more in-depth discussion of the Yaz/Yasmin incident as well as other drug scandals that implicate the integrity of the FDA. Part V assesses the legitimacy of these arguments and makes a recommendation for avoiding conflicts of interest on advisory committees that jeopardize public safety.

2. BACKGROUND AND CURRENT FINANCIAL CONFLICT OF INTEREST LAW IMPOSED UPON THE FDA

   The FDA regulates approximately twenty-five cents per dollar spent in the United States. (16) In 2008, this figure included $466 billion in food sales, $60 billion in cosmetics, $18 billion in vitamin supplements, and $275 billion in drugs. (17) Drug expenditures alone reached $329 billion in 2011 and nearly $326 billion in 2012. (18)

   Given these figures, the ubiquity of drugs in America should come as no surprise. The Mayo Clinic estimates that 70% of Americans take at least one prescription drug, and that over half take at least two. (19) Between 11% and 20% of Americans take five or more prescription drugs in a given month. (20) The very wealthy and the very poor tend to take more prescription drugs and more frequently than the middle class. (21) The very poor, often the least educated, are the most likely to be taking four or more prescription drugs at a time. (22) Americans consume 80% of the world's pain medication. (23) Setting aside growing criticism that American healthcare professionals overmedicate their patients and focus on treatment-based care rather than prevention, (24) the FDA has a direct impact on drug safety. Its failures, whether through negligence, ignorance, or corruption, pose an immediate danger to the nearly three quarters of American citizens who use prescription drugs.

   1. The "Shared Pool" Dilemma

      The FDA approves drugs and devices through advisory committees of experts and representatives. The FDA uses fifty-one committees "to obtain independent expert advice on scientific, technical, and policy matters." (25) The experts include academicians and practitioners in all healthcare fields. (26) Committees also include industry representatives "[a]lmost without exception," (27) a consumer advocate, and sometimes a patient representative. (28) (Industry representatives are non-voting members and are not subject to conflict of interest regulations. (29)) The scientific experts on these committees are also in high demand, precisely for their expertise, as consultants or clinicians for regulated industry. (30) Nyssa Ackerley explains, "[a]cademic and institutional research also increasingly relies on industry sources for funding. This situation, whereby the same experts are in demand by both the federal government and regulated industry, has been described ... as the 'shared pool dilemma.'" (31) Excluding these experts from decision-making on FDA advisory committees leaves only a "pool of 'experts' less qualified than those disqualified, by virtue of the simple fact that [the more qualified experts] are so pre-eminent in their fields that industry seeks out their advice and services." (32)

      Katherine McComas states that this shared pool dilemma rests upon two assumptions: first, "that a finite number of qualified experts exists for any given topic," and second, "that the mere presence of a real or potential conflict of interest may result in a member acting in a biased manner." (33) The assertion that too few non-conflicted experts exist to fill panels may be somewhat supported by the fact that roughly 23% of the FDA's committee positions remain vacant. (34) The FDA also sometimes has trouble convening a non-conflicted panel, which is arguably as detrimental to patients as eradicating conflicts from the panels. (35)

      The shared pool dilemma, if it exists, leads to two possible outcomes, both of which carry frightening risks. First, the most qualified experts will sit on advisory committees, though some of them will necessarily have financial conflicts. On the other hand, if conflicted experts are excluded, the experts deciding the fate of a drug will be less qualified to make such an impactful decision than their conflicted counterparts. That is, those committee members with comparatively less expertise will be deciding the profits of an industry and the health of the patients potentially affected by the drug's approval or rejection. The merits of the shared pool dilemma, and therefore the necessity that the FDA choose between these two uncomfortable outcomes, is discussed in Part III.

      McComas examines the difficulty of finding both qualified and disinterested experts. (36) Though there may never be a way to prove a causal relationship between a committee member's conflict of interest and a biased vote, this should not relieve the FDA of its duty to minimize that possibility. This apparent difficulty has caused a multitude of conflict of interest regulation to clarify precisely who is eligible to sit on an advisory committee, (37) which conflicts can be disregarded, and which cannot. Yet, despite this, the conflict-related scandals persist, drugs get recalled, and people die. (38) The next Section discusses these laws and their success at filtering advisors with financial conflicts.

   2. Current Conflict of Interest Regulations Imposed Upon the FDA

      Financial conflicts of interest impact FDA review and approval processes in two major ways. First, investigators compensated by study sponsors may feel pressure to produce results satisfactory to the sponsor, which are often and increasingly pharmaceutical companies. (39) Thus, the studies presented to FDA advisory committees are often not objective, either because of investigators' selective inattention to certain outcomes, deliberate manipulation of data, or somewhere in between on the spectrum. (40) The second way conflicts of interest may affect the approval process occurs when investigators compensated by the study's sponsors are the same individuals sitting on an FDA panel that votes to allow a product to reach the market. (41) Though of course the same individuals may be implicated in either type of conflict, this Note focuses primarily on the second. The first implicates the integrity of individuals and drug companies; the second implicates the integrity of the FDA. The approval process is the final step before a potentially deadly (or life-saving, or completely inefficacious) drug reaches the market. This phase, more than any other phase in a drug's life cycle from its inception to public consumption, must be free of personal financial conflicts. (42)

      Applicants for FDA approval of a product relying on clinical studies must disclose financial arrangements between the sponsor and the investigator. (43) Members of an advisory committee must also disclose to the FDA financial ties to the applicant, (44) so ignorance of such a conflict is typically not at issue. Rather, the conflicts are disclosed, usually from both...