The U.S. Food & Drug Administration (FDA) has come under significant attack in recent months from a wide variety of sources. Several factors—a quick succession of prominent medical device recalls; adverse safety findings with respect to several pharmaceuticals, most notably Vioxx; and political imbroglios at the agency—have contributed to a growing level of skepticism as to whether the FDA is effectively accomplishing its mission of regulating the safety and efficacy of drugs and medical devices marketed in the U.S.

In the midst of this storm, the agency published a new set of "Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products." The new requirements include a preamble which enunciates the agency’s position with respect to the preemptive effects of its labeling regulations on potential tort liabilities for manufacturers, 71 Fed. Reg. 3922-39976 (January 24, 2006). On the one hand, the positions expressed in the preamble and in certain amicus briefs filed by the FDA in tort cases are generally felt to be friendly to industry interests. On the other hand, anecdotal reports from industry suggest that the new drug application process has slowed and become more difficult in recent months, purportedly as the FDA’s response to ongoing criticism. (See, e.g., "New Sense of Caution at FDA" by Andrew Pollock, New York Times, September 29, 2006.)

Manufacturers who have suffered under the rigors of FDA scrutiny may be tempted to take satisfaction in the public derision directed at the agency. They shouldn’t. To function effectively, the system requires the respect of the general public as well as a healthy level of mutual respect between the regulator and industry. If the current environment does not improve, industry can expect significant adverse effects: a lessening of the agency’s willingness to advocate the preamble’s preemption positions as well as increasing delays in the handling of applications for approval of new drugs and medical devices.

Two major reports in 2006 advanced particularly pointed criticisms of the FDA: a report from the U.S. Government Accountability Office (GAO) and a report from the Institute of Medicine (IOM). The GAO Report focuses principally on a structural analysis of the FDA’s operations, while the IOM Report examines the agency’s relationships with the industries it regulates, and the scope and implementation of its regulatory authority.

The GAO Report

In its recent report to Congress, the GAO focused on the FDA’s ability to monitor postmarket drug safety issues. The GAO Report provides an outline of relevant FDA organizational structures and offices and those offices’ procedures for postmarket drug safety decision making. The report discusses why the GAO deems the FDA’s present organizational structure and procedures to be ineffective in handling postmarket drug safety issues, and it analyzes recent measures taken by the FDA in an attempt to approve its methods for postmarket decision making and implementation. Finally, the GAO Report makes recommendations that it believes will improve the FDA’s ability to make and enforce postmarket drug safety decisions.

The GAO Report discusses the roles of two distinct FDA offices actively engaged in postmarket drug safety monitoring activities. The first is the Office of New Drugs (OND). The second is the Office of Drug Safety (ODS). After the Prescription Drug User Fee Act of 1992 (PDUFA) was passed, pharmaceutical manufacturers —referred to as "sponsors" in the report —began to pay fees to the FDA. These fees were used to hire additional drug application reviewers and implement other changes that resulted in a more expeditious drug application review process. In view of this more efficient process made possible by PDUFA, Congress reauthorized the Act in 2002 and incorporated as a new goal that the FDA monitor postmarket drug safety in an effort to protect the public from unforeseen adverse effects. OND and ODS, which are part of the FDA’s Center for Drug Evaluation and Research (CDER), have been jointly responsible and actively engaged in carrying out the FDA’s postmarket monitoring responsibilities.

OND is responsible for approving drugs and monitoring safety issues throughout the lifecycle of approved drug products. It has the authority to address postmarket drug safety issues when they arise and to impose policies and procedures to mitigate safety concerns. OND staff is made up of physicians, pharmacologists, toxicologists, and microbiologists whose focus is to provide physicians and patients with the drugs needed to treat a variety of diseases and conditions. OND devotes approximately 50% of its time to drug safety issues. In contrast, ODS’s sole focus is on postmarket drug safety. Its staff consists of pharmacists and epidemiologists who are responsible for reviewing and analyzing adverse event reports. The ODS works closely with the OND, yet has no authority of its own.

The GAO Report faults the FDA’s lack of unambiguous critical standards and the agency’s poor internal communications for the difficulties which OND and ODS have had in determining when postmarket drug concerns require FDA intervention and what methods of intervention should be employed. Additionally, the GAO Report cites problems that it believes are the result of the FDA’s lack of authority and inability to require drug sponsors to monitor and report postmarket adverse events. This lack of authority, coupled with an ineffective means of data collection, only further acts to increase response delays resulting from communication difficulties that exist between OND and ODS. As a result, the FDA’s reliance on drug sponsors to conduct studies voluntarily and to provide the agency with data and trial results creates difficulties in the FDA’s tracking and monitoring of drug safety issues, which forces it to rely upon incomplete or untimely information or results in its own risk-benefit analyses of postmarket products. Moreover, although ODS and its staff are primarily epidemiologists focused on postmarket drug safety issues and how drugs are actually being used in the general population, the GAO Report implies that ODS’s lack of specific goals and independent authority result in additional delays in the FDA’s handling of drug safety issues and concerns.

Furthermore, although the FDA has recently created the Drug Safety Oversight Board (DSB) and implemented new policies and process teams to improve how the agency responds to postmarket drug safety issues, the GAO Report strongly suggests that the FDA’s newest measures are simply not enough. The report recommends that the FDA, through the DSB, create a clear and unambiguous dispute resolution process to facilitate decision-making and future communications between OND and ODS. Additionally, the GAO maintains that increased funding is necessary to allow the FDA to expand its capabilities to monitor and develop sources for collection of postmarket drug safety data. According to the report, although the FDA has begun to work with the Centers for Medicare and Medicaid Services in an effort to obtain additional drug data, this method could prove to be risky and unreliable for the FDA, when compared to its having the ability to conduct active surveillance and independent clinical research to ensure that postmarket drugs are safe.

The report concludes that the Commissioner of the FDA should take the following four actions:
1) establish a mechanism for systematically tracking ODS recommendations and subsequent safety actions;
2) with input from the DSB and the Process Improvement Teams, revise and implement the draft policy on major postmarket drug safety decisions;
3) improve CDER’s dispute resolution process by revising the pilot program to increase its independence; and
4) clarify ODS’s role on FDA’s scientific advisory committee meetings involving postmarket drug safety issues.

The IOM Report

Another recent report published by the IOM, discusses the present role of the FDA in ensuring drug safety and suggests how the FDA could increase its capabilities. The report presents five recommendations that the IOM believes would greatly improve the efficacy of the FDA and its abilities to monitor and ensure drug safety.

Organizational Culture

First, the report discusses the "organizational culture" of the CDER. According to the IOM, the instabilities and high turnover rates render the agency incapable of operating efficiently and implementing clear, consistent policies and procedures. The agency’s leadership is described as being polarized and politicized, which reduces its efficiency and ability to coordinate its efforts. Additionally, the IOM alleges that the high turnover rate is indicative of low morale, which results not only from office politics and the agency’s polarization, but also from poor organization and handling of scientific disagreements and differences of opinion.

The IOM Report recommends the creation of an external Management Advisory Board comprised of individuals experienced in changing and leading large-complex organizations. It further suggests clear and unambiguous assignments of goals and roles for ODS and for the Office of Surveillance and Epidemiology (OSE). Additionally, to treat the imbalance of authority that exists between the OND and OSE, the IOM Report recommends changes that would result in the OND and OSE having joint authority in postmarket regulatory actions.

Science & Expertise

Second, the IOM Report points to the FDA’s Adverse Event Reporting System (AERS) as "outdated and inefficient," although there are adequate technologies available that would increase the FDA’s capability to monitor and track adverse events when they occur. Similarly, the report criticizes the FDA’s abilities to test drug safety hypotheses and make continuing risk-benefit assessments throughout the lifecycle of a drug. The IOM suggests that the FDA revamp its technology and its methods for assessing both drug safety and drug efficacy, so as to improve its risk-benefits analysis. Additionally, the IOM suggests the implementation of Risk Minimization Action Plans, to ensure that drug safety continues beyond the approval of a product. Moreover, the IOM Report suggests that the FDA restructure its organization by creating additional leadership positions for experts and scientists. Similarly, the report recommends that by increasing the number of epidemiologists and other such experts it employs, the FDA would increase its credibility and be better prepared to monitor complex-scientific drug safety issues.

Regulatory Authorities

Third, the report concludes that the FDA is lacking in regulatory authority. The IOM views the FDA’s role as too much of an advisory or collaborative role. It strongly recommends that Congress require postmarket trials and monitoring programs. It also suggests restricted distribution of drugs to facilities, pharmacists, or physicians with special training and expertise. Additionally, the IOM Report recommends that the FDA’s authority be increased to allow the FDA to enforce harsh penalties and sanctions against drug sponsors that fail to comply with drug safety monitoring standards. Finally, the report recommends that drug sponsors be required to accumulate and submit data relating to their products and label new products or new combinations of drugs with a special symbol, such as the black triangle used in the United Kingdom.

Communication

Fourth, the IOM Report finds that the public would benefit from having more information as to how drugs are studied. It states that patients would be better prepared to make health care decisions if they were more aware of how the FDA functions. Additionally, the IOM concludes in its report that sources of information presently employed by the public result in consumers receiving incomplete or inaccurate pictures of the risks or benefits of drugs. It recommends that the FDA increase its monitoring and establish stricter controls governing advertising directed at the public and prescribing physicians.

Financial Resources

Finally, the IOM Report points to ending the FDA’s reliance upon sponsor paid fees mandated under PDUFA as a crucial step necessary to assure the agency’s ability to implement needed systemic and technological changes. The report implores Congress to approve increased funding and resources for the agency, so that it can conduct independent research and hire more effective leadership and expert personnel.

Conclusion

The findings and recommendations of the GAO Report and the IOM Report are the subject of much debate. The broader debate over the appropriate relationship between a government agency and the industries it regulates will likely always be with us, especially with industries that are as important to the health and welfare of the country as the pharmaceutical and medical device industries.

It is important for representatives of those industries to understand the criticisms of the FDA that have been advanced, so they can serve as effective partners to the regulators in making the system work. Anticipating the pressures faced by the regulators in the current environment, industry should be more careful than ever to relate well and appropriately to FDA personnel and to provide the necessary scientific information to support their applications.