No shortage of recommendations for PDUFA IV as Congress and professional organizations weigh in on drug safety

Key Points

The need to reauthorize the Prescription Drug User Fee Act (PDUFA) before it expires September 30, 2007, has set the stage for congressional action on broader legislation to improve the handling of drug safety issues. Bills under consideration aim to expand FDA oversight by establishing new requirements for postmarket risk assessment, for posting active clinical trials and resulting study data, and for completing postmarket studies.

Legislation recently reintroduced by Sen Edward Kennedy (D–Mass) and Sen Michael Enzi (R–Wyo) would require drug manufacturers to develop a risk evaluation and mitigation strategy (REMS) for each new drug introduced to the market. The REMS would include information about labeling, adverse event reports, and planned post-approval studies; higher-risk products could also necessitate medication guides, advertising restrictions, and special distribution programs.

Members of Congress plan to include such safety initiatives in a PDUFA reauthorization bill. A hearing by the Senate Committee on Health, Education, Labor and Pensions (HELP) took place in February to discuss PDUFA IV. The committee, headed by Sen Kennedy and Sen Enzi, plans to move forward with FDA user fee legislation by summer. The final PDUFA IV bill, if approved, would continue to allow user fees for medical devices and would allow the continuation of a program that offers incentives for pharmaceutical companies to study pediatric uses of medications. The bill will likely also include measures to permit broader foreign import of drugs and to reduce obstacles to generic drug development, including generic versions of biotech therapies. Limiting the number of proposals in PDUFA IV could prove challenging to legislators.

Although some consumer organizations have voiced opposition to user fees as a threat to FDA's independence, many patient advocates and health professionals consider the fees necessary to avoid delays in bringing new treatments to market. Advocates of the fees suggest that Congress has been unwilling to approve adequate funding to maintain an efficient drug review program. Reliance on user fees is "unlikely to change in the foreseeable future," commented Brian Meyer, MBA, director of the government affairs division of the American Society of Health-System Pharmacists (ASHP), at a FDA public meeting in February on the PDUFA IV plan.

The proposed user fee program would provide nearly $400 million in annual fees next year to support FDA review and oversight of new drugs and biologics. This includes an additional $30 million a year to improve FDA review and assessment of postmarket safety issues. The plan is to extend postmarket safety assessment beyond the first 2 or 3 years a drug is on the market, as specified under the current program, to cover the full life cycle of marketed drugs. The increased funds would support 82 additional staff members for FDA drug safety review programs, adverse event analysis, and oversight of drug safety issues. Key initiatives include improvement of the agency's adverse event reporting system and greater FDA access to broader health system databases that can provide additional epidemiological information related to patient drug use.

A main theme of PDUFA IV is better coordination of pre- and post-approval analysis and risk communication. FDA has proposed greater collaboration between new drug review and postmarket surveillance offices to ensure the input of safety analysts on application review and postmarket safety oversight.

Some physicians and pharmacists are concerned, however, that the proposed safety legislation would establish an unmanageable number of restricted drug distribution systems (RDDSs). ASHP would like FDA to issue clearer guidance for RDDS development and to assess how well these programs achieve their stated goals, Mr Meyer said. ASHP has recommended greater FDA guidance on epidemiology best practices to aid drug safety evaluation. The organization also has recommended more FDA access to population-based data to better detect drug safety signals.

Some healthcare providers support an FDA pilot program to improve the assessment of proposed drug product names. In an effort to help reduce medication errors due to look-alike and sound-alike proprietary names, FDA plans to develop guidelines for name evaluation, good naming practices, and proper name evaluation, and the agency plans to review propriety names earlier in the drug development process.

FEES FOR DTC ASSESSMENTS

A new initiative in the PDUFA IV plan would establish a separate user fee program to support FDA evaluation of direct-to-consumer (DTC) television commercials before they are broadcast. Pharmaceutical companies have agreed to pay $6.3 million to increase staffing of FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) and other marketing review offices in order to obtain more timely reviews of planned drug ads.

Some health professionals and members of Congress support mandatory early ad assessment as a way to reduce the number of misleading ads that could influence customers. ASHP prefers to delay all DTC promotion until postmarket data are collected, while the Academy of Managed Care Pharmacy (AMCP) wants required reviews of all forms of DTC advertising, not just television ads.

EXPEDITING RESEARCH AND DEVELOPMENT

Another goal of the user fee program is to encourage drug manufacturers to assess important efficacy and safety issues earlier in the drug development process to help avoid marketing delays. FDA plans to improve the quality of NDAs by providing more advice and guidance to researchers and sponsors during the clinical research process. A series of new guidances on specific clinical trial design issues have been created to clarify FDA's stance on topics such as testing clinical hepatotoxicity and on non-inferiority and adaptive clinical trial designs. Over the next 3 years, FDA plans to publish guidances on appropriate analysis of clinical trials with multiple end points, on approaches for enriched trial designs, and on use of imaging standards as end points in clinical trials.

A portion of user fee revenues is slated to underwrite FDA staff participation in important regulatory pathway initiatives. These include collaborations to improve predictive toxicology tests, to qualify new biomarkers, to examine ways to deal with missing clinical trial data, and to improve risk:benefit assessment models.

The PDUFA IV plan would add $4 million per year to FDA's budget to establish a completely automated application submission and review system with 2-way communication capability and improved tracking. In the last 5 years, user fee revenues have helped FDA develop standards for electronic submission of market applications and consolidate the agency's information technology (IT) infrastructure.

Under PDUFA IV, FDA would develop a 5-year IT plan that describes the next steps for FDA and pharmaceutical companies to achieve an all-electronic submission and review environment that ultimately will supersede paper submissions. FDA plans to publish a draft IT plan by the end of this year and to hold quarterly meetings to discuss IT developments and agency progress in establishing new-generation common systems.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.