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Institute of Medicine report calls for extensive overhaul of drug safety procedures at FDA, CDER


FDA's withdrawal of rofecoxib (Vioxx, Merck) in 2004 and other controversies have prompted numerous reports from legislators, the scientific community, and others calling for substantial changes in FDA's and its Center for Drug Evaluation and Research's (CDER's) roles as the nation's overseers of medication safety. The outcry for FDA reform reached another peak in late September when a committee convened by the Institute of Medicine (IOM) of the National Academies released its report, "The Future of Drug Safety," which recommended a "coherent and integrative approach" to transform the agency and a pharmaceutical industry that the committee says has had its credibility "compromised" in the eyes of the public.

Commissioned by FDA following the rofecoxib withdrawal, the authors of the report did not include employees from the pharmaceutical industry, in part to provide an objective view of the agency and to eliminate potential conflicts of interest. Following an extensive literature review, open meetings, and comments from industry leaders, FDA personnel, and nonprofit groups, the report formulated recommendations for major alterations in FDA's structure, procedures, and work climate, which were welcomed by many industry experts.

The editors of the New England Journal of Medicine (NEJM), in an editorial accompanying the publication of an article by members of the IOM committee in NEJM, said the time for FDA reform is now.


One of the primary suggestions in the IOM report addressed the instability of the FDA commissioner role. The agency has been without a fully approved commissioner since September 2005 and has been overseen by an "acting" commissioner for all but 18 months during the past 5½ years. The last fully approved FDA Commissioner, Lester Crawford, DVM, PhD, resigned in September 2005-only 2 months after his approval-and last month pleaded guilty to charges of fraud from the US Department of Justice, relating to allegations that he concealed his ownership of stock in companies that had products under FDA regulation from the US Department of Health and Human Services (HHS) during his tenure.

Meanwhile, the nomination of Dr Crawford's successor, acting FDA Commissioner Andrew von Eschenbach, MD, has stretched to more than a year. Although Dr von Eschenbach and the agency have resolved some medication issues during this time, most notably the highly politicized issue of over-the-counter availability of the Plan B emergency contraceptive, the agency's efforts have been hampered by the absence of a fully vested leader.

"A large, complex, science-based regulatory agency cannot perform optimally in the absence of stable, capable leadership and clear, consistent direction," the IOM report said. "An acting commissioner does not carry the same weight symbolically, and lacks the authority to articulate agency positions. Without stable leadership strongly and visibly committed to drug safety, all other efforts to improve the effectiveness of the agency or to position it effectively for the future will be seriously, if not fatally, compromised."

The study committee suggested that the Food, Drug and Cosmetics Act be amended with the requirement that FDA commissioners serve terms of 6 years once appointed by the President and approved by Congress and be removable "only for reasons of inefficiency, neglect of duty, or malfeasance in office."


In their NEJM article, 2 members of the IOM committee, Bruce Psaty, MD, PhD, and Sheila Burke, MPA, RN, described FDA as a "suboptimal work environment" plagued by inconsistent CDER review decisions, polarization between the offices in charge of pre-marketing drug reviews and post-marketing product surveillance, and a "disregard and disrespect for scientific disagreement" on the part of CDER managers in addition to the instability in FDA's key leadership position.

"Every organization has its share of dysfunctions, disgruntled staff members, and organizational disputes, but the committee came away from various encounters with CDER staff and management with a deep concern about CDER's organizational health," the IOM report elaborated. "There is evidence of a persistent problem with retention, turnover, and morale at CDER."

An external management advisory board appointed by the HHS secretary would specialize in the transformation of the agency's culture "by improving morale and retention of professional staff, strengthening transparency, restoring credibility, and creating a culture of safety based upon a lifecycle approach to risk-benefit." The FDA commissioner, the director of CDER, and the board also would collaborate on a plan for changing the agency's culture to better fulfill FDA's role in protecting public health.

"A variety of promising steps have been taken to improve interactions among offices, evaluate and improve internal processes, and even familiarize disciplines with one another," the committee stated. The establishment of the board would help to sustain those efforts, according to the committee.

The composition of FDA advisory committees also was a target for change. To eliminate the potential for conflicts of interest, FDA should require "a substantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee's decision," the report said.

Other structure-related recommendations included allowing the Office of Surveillance and Epidemiology (OSE) to assume a more formal role in drug regulation, including having at least 1 staff member take part in teams that review New Drug Applications; establishing the position of chief scientist, who would oversee FDA's intramural research facilities; building CDER's epidemiologic expertise through the hiring of more personnel; and using CDER's informatics to aid in assessing medications once they have entered the market.


HHS's Office of Inspector General (OIG) has scrutinized FDA's handling of postmarketing research, and an audit released in July 2006 questioned the agency's prioritization of gathering information for a medication once it was approved (Formulary. 2006;41:406–410). The IOM committee also stressed that FDA strategies pertaining to tracking and compiling postmarketing safety data must be rethought.

Current postmarketing surveillance relies chiefly on FDA's Adverse Event Reporting System (AERS), which accumulates data via both voluntary and mandatory reports submitted spontaneously from healthcare providers, consumers, and pharmaceutical manufacturers via MedWatch.

While committee members acknowledged that the AERS provides some benefit, they said FDA should continue its implementation of technological improvements, including data-mining and electronic data submission, to enhance the agency's ability to discern clear "safety signals" that may separate adverse drug events associated with a medication from "noise."

A renewed emphasis also should be placed on FDA's handling of postmarketing, or phase 4, studies that are often necessary after a medication has received a hastened approval, according to the committee.

"The current system, in which the binary decision regarding approval essentially signals the end of information gathering, imposes a huge responsibility on CDER to make the right decision about new drugs," stated IOM committee members Dr Psaty and Ms Burke in their NEJM article. "New postmarketing regulatory powers would provide the FDA with additional opportunities to act in a timely fashion."

The committee also supported review by FDA advisory committees of all new molecular entities (NMEs) before, or shortly after, their approval to provide additional support to CDER, and said more postmarketing regulatory authority should be granted to the agency, especially in the realm of distribution. Under this recommendation, FDA would wield additional power in restricting the distribution of medications by attaching conditions to a product's distribution-such as requiring changes in labeling, additional warnings, and moratoriums on direct-to-consumer advertising. Additional powers granted to FDA would also allow the agency to conditionally limit product distribution based on specific facilities, pharmacists or specially trained physicians, the performance of specified medical procedures, or the performance of specialized additional clinical trials or other studies.

In addition, CDER also should "regularly and systematically [analyze] all postmarket study results" and publicize the significance of their findings after weighing risk-benefit information, the committee said.


A major flaw identified by the IOM committee in the current incarnation of the Prescription Drug User Fee Act of 1992 (PDUFA), set to expire in October 2007, is that the act focuses chiefly on expediency while lacking any safety-related provisions, a necessary addition if the act is to be renewed by Congress.

"The goals on which FDA reports to Congress need to include actionable performance goals for drug safety activities in the premarket and postmarketing periods to ensure that important agency functions receive sufficient resources," the committee said.

Such provisions would need to be measurable, such as reports on the number of NMEs approved or postmarketing commitments outstanding, so that Congress would have the ability to track the agency's performance in safety-related matters, the committee said, but would not resolve the problematic area of FDA and CDER's reliance on PDUFA for funding.

CDER currently receives a majority of its funding from PDUFA, which leads to the public perception that the interests of industry precede those of public safety at the agency, according to IOM committee members Dr Psaty and Ms Burke in the NEJM article. However, additional funding from Congress for FDA's efforts would be required to diminish that reliance.


Whether Congress will mandate any or all of the IOM recommendations before the end of the year remains to be seen. The results of the midterm elections will have a major effect on when and what reforms are undertaken, with the logical first step in any case being congressional approval of acting FDA Commissioner Dr von Eschenbach as full commissioner, who pledges to enact the IOM recommendations if confirmed.

"While considerable work has been done over the past 2 years to improve our approach to drug safety, work still remains to be done," Dr von Eschenbach said. "I am committed to taking additional steps and will look to the initiatives recommended by the Institute of Medicine to ensure we continue to fulfill our mission."

Regardless of the expediency of action taken by Congress and the agency, IOM committee members Dr Pfalty and Ms Burke cautioned in the NEJM article that FDA should resist any temptation to simply pick and choose areas of reform and instead embrace a holistic plan.

"The committee sees its recommendations as an integrated package-not a menu of options," they said.

SOURCES Curfman GD, Morrissey S, Drazen JM. Blueprint for a stronger Food and Drug Administration. N Engl J Med. 2006;355:1821.

Committee on the Assessment of the US Drug Safety System, Baciu A, Stratton K, Burke SP, eds. The future of drug safety: promoting and protecting the health of the public. Washington, DC: National Academies Press, 2006. Available at: http:// http://www.iom.edu/cms/3793/26341/37329.aspx Accessed November 3, 2006.

Psaty BM, Burke SP. Protecting the health of the public-Institute of Medicine recommendations on drug safety. N Engl J Med. 2006:355;1753–1755.

Statement by Dr. Andrew von Eschenbach, acting commissioner of food and drugs, regarding the Institute of Medicine Future of Drug Safety report; Washington DC: US Food and Drug Administration: September 22, 2006. Available at: http:// http://www.fda.gov/bbs/topics/news/2006/new01461.html. Accessed October 11, 2006.

Statement by Mike Leavitt, secretary of Health and Human Services, on the Institute of Medicine report on the future of drug safety. September 22, 2006; Washington DC: United States Department of Health and Human Services; September 22, 2006. Available at: http:// http://www.hhs.gov/news/press/2006pres/20060922.html. Accessed November 3, 2006.

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