Enhancing Drug Safety

As expected, legislation to reauthorize the Prescription Drug User Fee Act (PDUFA IV) has been expanded with a host of provisions designed to shape drug development and ensure the safe use of medications. With PDUFA IV, Congress will provide the US Food and Drug Administration with more tools and legal authority to monitor and mitigate drug risks and also will impose new requirements on manufacturers for assessing, preventing, and correcting safety problems.

Jill Wechsler

This broad bill implements an FDA–industry user-fee agreement issued in January 2007, as well as a similar user-fee plan for medical devices. Because the fees have to be finalized by Sept. 30, 2007, the legislation also provides a vehicle for Congress to retain incentives that were set to expire. The incentives encourage manufacturers to study pediatric uses of drugs and devices. In the drug-safety area, the bill gives FDA authority to require postapproval clinical trials and to revise product labels within a set timeframe. Manufacturers will have to disclose more information about study results and ongoing clinical trials and list various pharmacovigilance activities to ensure the appropriate use of risky medications. The legislation provides more funding for FDA oversight of postmarket drug use and for expanding the agency's information systems that track adverse events and detect emerging safety problems.

Raising fees for services

The final legislation boosts the user fees paid by pharmaceutical companies even more than the amount negotiated by industry and FDA last year. The PDUFA IV agreement raised fees to nearly $400 million for 2008 to adjust for inflation and the increased cost of overseeing the drug-development and review process in an efficient and timely fashion. Furthermore, an additional fee program seeks to bolster FDA review of drug advertising on television. 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 its appropriated funding is barely keeping up with inflation (see sidebar, "Push for more appropriations").

Push for more appropriations

An important change in the PDUFA program permits the use of fee revenues to support drug-safety oversight and assessment throughout a product's life cycle—not just during the first two or three years after product approval, as currently allowed. The increased payments will support additional staffers in FDA's Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research, and enhance the safety office's role in evaluating postapproval risk information and labeling changes.

One specific PDUFA project is to improve FDA's system for assessing proposed product names, an initiative that aims to reduce medication errors from look-alike and sound-alike names. The program calls for sponsors to submit proposed proprietary names during Phase III testing or earlier so that FDA will have time to meet a 180-day review timeframe without delaying application approval. Added resources will enable FDA to issue guidance documents about how manufacturers should select and evaluate product names and propose such names to the agency. In the future, FDA plans to shift responsibility for testing proposed proprietary names to manufacturers, a process that will be tested in a pilot program.

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Managing risks

A central provision of this broader FDA reform legislation gives FDA added authority to require a Risk Evaluation and Mitigation Strategy (REMS) from companies when the regulators decide that a formal approach is needed to manage prescribing. The legislators initially wanted to require a REMS for all new drugs, but they agreed with manufacturers that such a broad mandate could waste time and resources if applied to well-understood, low-risk products. The REMS process creates "a complicated and bureaucratic safety and oversight system that may not be workable in practice," advised Caroline Loew, senior vice-president at the Pharmaceutical Research and Manufacturers of America, in testimony before the House Energy and Commerce Committee in June.

For those drugs that raise increased safety concerns, manufacturers may submit a REMS plan in a new or supplemental application, or FDA may require such a process based on new safety signals or other 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 healthcare information to healthcare professionals

• Seek FDA prereview of advertising and marketing materials to ensure that ads describe 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 could be limited to select wholesalers and pharmacists. Such limited-access programs also may require additional laboratory testing, patient monitoring, and patient enrollment in a registry.

Increasing disclosure

In addition to establishing a REMS for certain products, the legislation enhances FDA authority to implement new oversight and disclosure policies for all drugs. Some of these policies are described below.

Speedy labeling changes. Congress strengthens FDA authority to require manufacturers to make certain labeling changes that 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 timeframes for negotiating such changes, including the need for black-box warnings and additional information about warnings, contraindications, precautions, or adverse reactions. The negotiating process also includes provisions 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 power 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. Long timeframes for completing postapproval studies have frequently been a source of controversy. 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. But FDA staffers and patient advocates believe that manufacturers often put postapproval studies on the back burner.

The new policy calls for postapproval study options to be discussed 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 timetables for completing studies, report periodically on their progress, and explain why they cannot meet set goals if problems arise.

More information about active clinical trials. To better inform patients of opportunities to participate in clinical trials, sponsors will have to submit more information about ongoing clinical trials to the clinicaltrials.gov website. The legislation extends the registration requirement to all regulated drugs and beefs up registration listings to include a long list of specific trial information, including whether there is an expanded access program for a not-yet-approved treatment. Congress emphasizes that the registration system should make it easy for patients to search for trials based on disease or condition, trial location, and other factors, and that listings should be updated frequently.

Mandatory disclosure of research results. A key goal of the new policy is to link clinical-trial registration to results information. Many pharmaceutical companies already do that voluntarily, but the legislators want a more comprehensive approach. Although the details remain sketchy, policymakers expect that results listings will include published studies and all FDA information about the drug (except proprietary trade secrets) such as the approved product label, review package, and related safety information.

A thorny issue is whether sponsors can comply with registration and results-disclosure policies without drawing charges of illegal promotion. Manufacturers fear that posting information about the indication and study design of a test product could be seen as promoting unapproved uses. Similarly, requiring sponsors to provide summaries of a study in lay language could be regarded as making false claims. Pharmaceutical companies believe that such summaries are of limited value and that clinical-trial results should be written primarily for a medical and scientific audience.

Reduction of 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 experts' input, despite their conflicts, the legislation seeks to limit 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 and ensure that outside advice about safety issues is objective.

Improving IT

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 information technology (IT) infrastructure for new-drug review and oversight. Now PDUFA IV will provide additional funds to establish an all-electronic regulatory-submission-and-review environment during the next five years. The envisioned system will allow manufacturers to send applications electronically with automated crosslinks to previously submitted data, and FDA reviewers will be able to retrieve all relevant submissions and use tools to search and analyze data. The goal is a system that can handle the two-way transmission of regulatory correspondence and other information.

A modern IT system also would improve FDA's current system for receiving and analyzing adverse-event reports from manufacturers, health professionals, and patients. Moreover, Congress supports FDA efforts to build a more robust active-surveillance system to identify emerging safety problems instead of relying on spontaneous adverse-event reports. Additional resources will permit FDA to contract with government health programs and private health plans to access population-based epidemiological data about millions of patients, which can greatly expand postmarketing drug surveillance. More collaboration with government, academic organizations, and with the Centers for Education and Research on Therapeutics, 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, though, that such programs should include procedures to protect the privacy of individuals.

PDUFA funds also will support an increase in FDA staff epidemiologists, safety evaluators, and programmers to better use internal and external IT resources. New research will provide a better understanding of the role of epidemiologic analysis and the use of databases in evaluating drug safety.

Scrutinizing drug ads

A new addition to PDUFA is a user-fee program to enhance FDA's review of direct-to-consumer (DTC) broadcast drug advertising. Companies that sponsor TV commercials for prescription drugs have agreed to pay $6.3 million in 2008 to increase the staff of FDA's Division of Drug Marketing, Advertising, and Communications, and other review offices. FDA's goal for the next five years is to provide advisory reviews of TV commercials in 45 days and to rereview previously submitted ads in 30 days.

Some members of Congress sought to ban consumer advertising of new drugs for months or years after a new product comes to market, noting that even a more efficient and comprehensive review of DTC ads would remain voluntary. Instead, legislators agreed to authorize stiffer fines and penalties for companies that fail to ensure accuracy and balance in drug advertising. All parties will be watching closely to see if misleading commercials contribute to drug-safety concerns.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com.

Additional resources

The Coalition for a Stronger FDA

The FDA Alliance

House Energy and Commerce Committee

HR 2900: Food and Drug Administration Amendments Act of 2007 (Engrossed as Agreed to or Passed by House)

PDUFA IV

S.1082: Food and Drug Administration Revitalization Act (Engrossed as Agreed to or Passed by Senate)

Senate Health Committee