FDA Responds to Institute of Medicine Drug Safety Recommendations—In Part

The withdrawal of rofecoxib in September 2004 and the reports of health risks associated with several other drugs¹ have raised questions about the integrity of the US drug safety system. In response, and at the request of the Center for Drug Evaluation and Research of the Food and Drug Administration (FDA), the Institute of Medicine (IOM) issued a comprehensive review and set of recommendations for reforms.² The FDA has taken the unusual step of providing a detailed, public response.³ The FDA's new initiatives and its responsiveness to the IOM report represent incremental progress that offers insights into FDA's culture and perhaps glimpses at the future of drug safety.

The FDA is an underfunded agency charged with regulating products that collectively constitute nearly 25% of the US gross domestic product.⁴ A century ago, the agency started as a bureau with authority to remove adulterated and misbranded drugs from the market after they had caused injury, and it has evolved into a complex bureaucracy that now regulates the development and testing of new drugs prior to approval for marketing. The power of the FDA to manage the risks of drugs after approval, however, is largely limited to threats of bad publicity in the form of “Dear Doctor” letters or other public announcements, or the rarely used power to enjoin further sales.

The FDA's ability to use these postapproval powers is further hampered by its reliance on a postmarketing surveillance system that could hardly be weaker.⁵ The mainstay is the Adverse Event Reporting System (AERS), which collects information on suspected cases and offers only the weakest type of evidence about their association with drug use. Postmarketing commitments, the phase 4 studies agreed to by sponsors, are another major source of drug safety information; however, the completion rate for these studies has declined from 62% in 1970-1984 to 24% in 1998-2003.⁶ Despite the need for high-quality postmarketing studies, the number of pending commitments has remained fairly constant over the past 3 years at about 800,^{7 - 9} and the FDA lacks a systematic approach to monitoring them.¹⁰

To improve the system, the IOM Committee on the Assessment of the US Drug Safety System recommended an ongoing systematic effort to monitor safety during the entire market life of a drug. This life cycle approach includes identifying safety signals, designing studies to confirm them, evaluating benefits as well as risks, using risk-benefit assessments to integrate study results, and communicating key findings to patients and physicians. The IOM recommendations were designed as an integrated package to achieve this ongoing life cycle approach to drug evaluation.²

A former FDA commissioner identified the proposed 6-year term for future commissioners as the only “new” recommendation from the IOM (recommendation 3.1 [Table]).² The other IOM recommendations were the same as or substantially similar to recommendations made in many previous reports.^{11 - 12} The FDA's failure to implement so many previous recommendations may not bode well for the prognosis of implementing the IOM recommendations.

Within the limitations imposed by current funds and staff, the FDA offered a detailed response to the IOM recommendations (Table).³ Responses consistent with the IOM recommendations include, for instance, the plans for reviewing the AERS (recommendation 4.1); increasing access to study data from large automated health care databases (4.2); evaluating risk minimization plans (4.4); developing and systematically improving risk-benefit analyses (4.5); creating a new advisory committee on communication with patients and consumers (6.1); and developing risk communication plans (6.2). Some responses appear to have been constrained by a lack of resources (7.1). For example, the IOM committee recommended building internal epidemiologic and informatics capacity to improve postmarketing studies (4.6), but the FDA response focuses on access to data rather than increasing staff and improving its expertise.

In other cases, the FDA responses appear to reflect the culture, vision, and values of the status quo at the agency.³ For instance, the IOM recommended that the secretary of Health and Human Services appoint an external management advisory board to help transform the center's culture (3.2 and 3.3). The management consultants mentioned in the FDA response do not appear to be the comprehensive approach to changing the agency's culture recommended by the IOM.

More importantly, while recommending that additional funds for the FDA come from general appropriations rather than PDUFA (Prescription Drug User Fee Act) fees (7.1), the IOM committee recognized that PDUFA might continue and, therefore, urged the creation of safety-related performance goals as well as time-to-approval goals (4.3) to redress the imbalance between preapproval reviews and postapproval safety activities. The FDA, however, called for no specific safety-related performance goals.

In addition, the agency's lack of transparency in the review process has adversely affected both FDA culture and public perception. To enhance transparency, the IOM made a number of recommendations (4.8, 4.10, and 4.12), including the public release of the FDA's risk-benefit analysis after the completion of postmarketing studies (4.13). The FDA plans to release this information only on a case-by-case basis. Transparency is important not only to maintain the confidence of the public, but also to provide valuable information to medical professionals about the uncertainties associated with drugs on the market. Although the FDA makes many binary decisions, such as whether to approve a drug or to request a label change, physicians and patients deserve to hear the full range of evidence, opinions, and uncertainties that may underlie regulatory decisions. The FDA best serves the health of the public by delivering data and information in all their complexity and, at the same time, offering its best, expert overall assessment of the evidence.

To address transparency on advisory committees, the IOM committee recommended that a substantial majority of members be free of significant financial conflicts (recommendation 4.10). A new draft guidance,¹³ anticipated in the response,³ proposes to make the requirements for a waiver more stringent and to allow individuals with financial conflicts of interest to participate, with the limitation that they may not vote on committee actions. But the proposal places no limit on the number of individuals who, despite financial conflicts, may serve on these committees.

Perhaps most importantly, the IOM identified the imbalance in authority between the Office of New Drugs and the Office of Surveillance and Epidemiology (formerly the Office of Drug Safety) as a major weakness in the drug safety system. In an effort to facilitate a collaborative and constructive team approach, the IOM recommended joint authority for the Office of New Drugs and Office of Surveillance and Epidemiology in the postapproval setting (3.4). The FDA response, which included several pilot projects, made no commitment to joint authority for the Office of Surveillance and Epidemiology. The FDA also provided tepid responses to a number of other recommendations (4.3, 4.8, 4.9, 4.12, and 5.4), which together constitute an effort to move the agency beyond drug approval and passive surveillance and toward a more proactive and public health–oriented approach to ensuring the safety of the US drug supply.

While the FDA responses represent incremental progress, they also suggest that the agency failed to embrace fully the values of transparency, independent review, and equality between the preapproval and postapproval activities of the agency.

When, as in the current system, drug approval largely marks the end of drug evaluation and signals the transition to drug marketing,⁵ the central tension is between the 2 extremes of maximizing rapid introduction of drugs into the market and maximizing opportunities to ensure the safety of the drug supply. Under PDUFA, the balance tilted toward rapid introduction of new drugs. In several surveys, about 18% of FDA medical officers reported that they “felt pressure to approve . . . a drug despite reservations about its safety, efficacy or quality.”^{11 ,14} Scientific disagreements within the agency during the preapproval evaluation, as occurred with Ketek,¹⁵ may well be excellent predictors of drugs that eventually have postmarketing safety problems—a hypothesis that could be evaluated empirically as part of an effort to advance regulatory science. Suppression of healthy scientific disagreement has perhaps cultivated skepticism about the FDA's integrity, and attempts to enforce consensus may, in light of legitimate scientific disagreement, simply cultivate serial whistleblowers.

In this setting, enhanced risk-benefit assessments may be particularly helpful. The FDA response to this IOM recommendation (4.5) was fairly comprehensive, but surprisingly late for an agency that has made determinations, for many years, about which drugs are “safe and effective for the intended use.” In addition to their usefulness in counseling patients, risk-benefit analyses are also especially useful for identifying missing information and, thus, important for isolating the scientific questions that merit further study. At several stages, risk-benefit assessments are thus an integral part of the life cycle approach to drug evaluation.

Some sponsors selectively publish favorable findings,¹⁶ sometimes with ghost authors,¹⁷ and some fail to publish unfavorable findings, sometimes by omitting data from published studies^{18 - 19} and sometimes by failing to publish the study at all.^{20 - 21} This selective approach to publication distorts the publicly available evidence base and undermines any efforts at genuine risk-benefit analyses. The IOM recommendations about registering clinical trials and eventually making the results public are important for public health (4.11).

Traditionally, the pharmaceutical industry has the primary responsibility for evaluating the efficacy and safety of drugs. On occasion, sponsors have made study design choices that selectively favor their products. In active-treatment comparison trials, for instance, some sponsors have chosen inadequate doses or inferior comparison treatments that are likely to make their products appear superior.^{22 - 23} While such studies may be useful for marketing, often they do not address important public health questions. The IOM committee envisioned a public-private partnership that would help define the key public health questions that merit investment in large, long-term trials (4.3). This partnership would not only identify studies of greatest interest but also recommend the best design features through an independent unbiased process.

Under PDUFA, the United States has increasingly become the country of first launch, the public testing ground for new medicines, but no corresponding effort has been made to strengthen postmarketing risk surveillance, risk assessment, risk management, and risk communication. Indeed, during the first 10 years of its regime, PDUFA prohibited the use of user fees for improvements in drug safety. According to David Kessler, head of the FDA from 1990 to 1997, “PDUFA should have had funding on the safety side from the beginning, but the industry refused to accept that. . . . We wanted it. The industry said no.”²⁴ Indeed, PDUFA has created at least the appearance that the FDA has industry rather than the public as its primary client. This impression is reinforced by the negotiations that take place between the FDA and industry to develop PDUFA renewal plans that are only later open for public comment.²⁵

The life cycle approach recommended by the IOM, if it is implemented, will permit both rapid drug approvals and ongoing efforts to ensure the safety of the US drug supply. The current round of PDUFA negotiations and the FDA reform bills pending in the US House and Senate offer a fresh opportunity to harmonize these important twin goals. The IOM committee specifically rejected the notion that these goals are trapped in a zero-sum game in which speed is traded against safety. Rather, by enhancing the opportunities for effective postapproval risk monitoring and management, the FDA can more confidently and more quickly release new drugs to the market despite the uncertainties normally associated with the preapproval process. An increase in transparency and regulatory authority after approval allows for bolder action before approval, and in the end, the public is the winner.