Legislation Expands FDA Oversight, IT Systems

Legislation to reauthorize the Prescription Drug User Fee Act (PDUFA IV) includes a host of provisions designed to enhance FDA policies for ensuring the safe use of medications. These initiatives should provide more timely information on emerging concerns about certain medicines, but also could drive up the cost of new drug development and delay access to new treatments.

Jill Wechsler

The new measure will implement an FDA–industry user fee agreement issued last January (2007), as well as a similar user fee plan for medical devices. Because these fees have to be renewed by September 30, 2007, the legislation provides a vehicle for Congress also to renew incentives for manufacturers to study pediatric uses of drugs and devices, while further strengthening drug safety policies. The bill gives FDA authority to require postapproval clinical trials and to revise product labels within a set time frame. There is more funding to expand the agency's information systems for tracking adverse events and for detecting emerging safety problems. And manufacturers of more risky medications will have to spell out a range of pharmacovigilance activities to inform patients and prescribers of possible dangers and to ensure appropriate product use.

More fees for services

In adopting PDUFA IV, Congress will boost the annual fees paid by pharmaceutical and biotech companies to adjust for inflation and the increased cost of overseeing the drug development and review process in an efficient and timely fashion. FDA and industry initially agreed on a new user fee program that would collect nearly $400 million a year in 2008, with steady increases over the program's five-year period. An additional fee program bolsters FDA review of drug TV advertising.

However, the legislators are boosting drug user fees even more to broaden the range of activities that fall under postmarket safety review. The increased payments will support additional staffers in FDA's Office of Surveillance and Epidemiology (OSE) in the Center for Drug Evaluation and Research (CDER) and enhance the safety office's role in evaluating postapproval risk information and labeling changes. An important change in the PDUFA program, moreover, permits the use of fee revenues to support drug safety oversight and assessment throughout a product's life cycle—and not just during the first two or three years after product approval, as currently allowed.

Although some parties feel that FDA already is overly dependent on user fees, the agency will need all the added fee revenues the legislators provide because FDA's appropriated funding is barely keeping up with inflation.

Managing risks

An important drug safety measure in the legislation gives FDA added authority to require a Risk Evaluation and Mitigation Strategy (REMS) from sponsors when such an approach is needed to manage particularly risky products. Initially, the legislators wanted to require a REMS for all new drugs, but agreed with manufacturers that such a broad mandate could waste time and resources if applied equally to well-understood, low-risk products.

For those drugs that raise increased safety concerns, manufacturers may submit a REMS plan in a new or supplemental application, or FDA may require this process based on new safety signals or information that raises concerns about the safety of a drug already on the market. A REMS would evaluate the need to:

• conduct additional postapproval studies and clinical trials to assess a specific safety signal.

• require labeling changes to disclose new safety concerns.

• prepare and distribute a Medication Guide or patient package insert.

• develop a communication plan for disseminating additional health care information to health care professionals.

• seek FDA prereview of advertising and marketing materials to ensure that ads describe serious risks appropriately and fairly.

• limit drug prescribing and distribution. FDA may determine that certain treatments should be prescribed only by health professionals that have special training or expertise and only for certain patients. Distribution similarly may be limited to select wholesalers and pharmacists. Such limited access programs also may require additional laboratory testing, patient monitoring and/or patient enrollment in a registry.

More disclosure

In addition to establishing a REMS for certain products, the legislation will give FDA authority to implement new oversight and disclosure policies for all drugs. A key provision requires sponsors to submit more information about ongoing clinical trials to the ClinicalTrials.gov Web site and mandates disclosure of the results of these studies, as discussed in ACT's View from Washington last month. The bill also seeks to enhance drug safety by requiring:

Speedy labeling changes. Congress strengthens FDA authority to require manufacturers to make certain labeling changes to reflect new safety information. Under current policy, discussions between sponsors and FDA about the need to revise a product label may take months, or even years. The legislation sets time frames for negotiating such changes, including the need for black box warnings and additional information on contra-indications, precautions or adverse reactions. The label-revision system provides a process for sponsors to challenge a requested labeling change and for resolving such disputes. But if FDA insists on a certain change, it will have more teeth to compel manufacturer compliance.

Timely completion of postapproval studies. FDA currently may request additional clinical trials and analysis following approval of a new drug, but the agency lacks authority to levy fines and other penalties on companies that fail to complete these studies as expected. Sponsors claim that many studies that seem reasonable when a new product is approved for market later appear inappropriate, and many projects have trouble enrolling patients in trials after a drug becomes widely available. The new policy calls for discussion of postapproval study options earlier in the approval process to ensure that agreements are realistic and address important issues. FDA also can request more postapproval studies after a drug is on the market. Manufacturers will have to propose a timetable for completing studies, report periodically on their progress, and explain why they cannot meet set goals if problems arise—and should not be subject to hefty fines.

Curbing conflicts of interest. The legislation reflects Congressional concerns that too many members of FDA advisory committees have financial links to industry. Although policymakers recognize that these panels can benefit from input from well-known experts despite their conflicts, the bill aims to make advisory committees more objective on safety issues by limiting the number of waivers used to permit such testimony. Congress also wants FDA to more actively solicit scientists and medical experts without financial ties to pharmaceutical companies to improve the advisory process.

Expanding information

A prime initiative for reducing drug safety problems is to modernize FDA's electronic information system. User fees have supported improvements in the agency's IT infrastructure for new drug review and oversight; now PDUFA IV will provide additional resources to establish an all-electronic regulatory submission and review environment over the next five years. The envisioned system will allow manufacturers to send in applications electronically with automated cross-links to previously submitted data, and FDA reviewers will be able to retrieve all relevant submissions and utilize tools for searching and analyzing data. The goal is a system that can handle two-way transmission of regulatory correspondence and other information.

A modern IT system also would improve FDA's current adverse event reporting system (AERS) for collecting and analyzing adverse event reports from manufacturers, health professionals, and patients. Congress also supports FDA efforts to build a more robust active surveillance system instead of relying on spontaneous adverse event reports to identify emerging safety problems.

Additional resources will permit FDA to contract with government health programs and private health plans to access population-based epidemiological data on millions of patients that can better inform postmarketing drug surveillance. Expanded collaboration with government and academic organizations and with the Centers for Education and Research on Therapeutics (CERTS) will enable FDA to learn more about how a drug works in real-world postmarket circumstances, including the extent and outcomes of off-label drug uses. The legislation notes that procedures should be put in place to protect the privacy of any individually identifiable health information in FDA drug use surveillance systems.

To be able to use these new resources effectively, PDUFA funds also will support an expansion in FDA staff epidemiologists, safety evaluators, and programmers trained to utilize such IT resources. New research in this area should provide a better understanding of the role of epidemiologic analysis and use of databases in evaluating drug safety.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com