FDA Amendments Act Raises Confidence and Questions

One of the main questions raised by the recently enacted FDA Amendments Act of 2007 (FDAAA) is whether all the many new requirements for assessing drug safety and investigating risks will make manufacturers hesitate to develop any test therapy that exhibits adverse events or formulation problems. Conversely, it may turn out that all the new rules raise public confidence in the US Food and Drug Administration's ability to detect and deal with safety issues, and that will make it easier to bring innovative therapies to market.

One thing is for sure: it will be some time before pharmaceutical companies can obtain a clear answer. What is clear right now is that manufacturers will be paying much higher user fees in the FDA fiscal year that began Oct. 1, 2007. Congress managed to approve FDAAA before PDUFA IV expired on Sept. 30, 2007. And the last-minute rush forced the legislators to compromise on many issues, which could have long-term ramifications for agency operations and manufacturer research decisions.

Curbs on drug advertising, stronger label warnings, limited distribution programs, and broad research disclosure requirements may all combine to limit prescribing. This "makes marginal drugs even more risky" for industry research and development programs, observes attorney John Kamp, who heads the Coalition for Healthcare Communications. He predicts that safety or efficacy questions about a product in Phase II may make a company hesitate to go forward.

Conversely, all the new regulatory tools now available to FDA could boost the agency's confidence about its ability to tackle safety issues that crop up after a drug comes to market. Such enhanced authority could make the agency less likely to delay a new approval.

Jill Wechsler

Giving and taking

Overall, manufacturers applauded the government's enactment of FDAAA. In addition to continuing user-fee support for drug approvals, the bill retained incentives for industry to conduct additional pediatric studies, curbed the scope of new penalties for fraud and noncompliance, and kept the door open for direct-to-consumer (DTC) advertising of new drugs. At the same time, FDA gained more authority to control drug marketing and labeling, require postapproval studies, establish active surveillance systems, and make clinical trial operations and results more transparent.

Implementation will be an arduous, time-consuming task. The legislation contains at least 200 specific provisions, noted FDA commissioner Andrew von Eschenbach in discussing next steps for the agency. Delays in finalizing the bill and late additions to the revised user-fee program also put off the calculation of actual user fees for the fiscal year that began Oct. 1, 2007.

The job of sorting out many of the new requirements now falls to FDA Deputy Commissioner and Chief Medical Officer Janet Woodcock. She recently took over as the acting director of the Center for Drug Evaluation and Research (CDER) following the departure of Steven Galson to become the Department of Health and Human Services's acting surgeon general. Woodcock implemented the initial user-fee program during her 10 years as CDER director and has been the driving force behind FDA's Critical Path Initiative and campaign to modernize good manufacturing practices.

In Washington This Month

Unfortunately, FDA is likely to receive few added resources for its efforts to improve the drug-development process. The new Reagan–Udall Foundation established by FDAAA is supposed to award grants to scientists within and outside the agency who are engaged in projects related to the Critical Path Initiative. But FDA is authorized to spend only $1.3 million on the program, and that funding must come from its own tight budget. In addition, little new money is available to spur the development of antibiotics. FDAAA authorizes Congress to provide additional funds to accomplish the complex bill's many goals, but FDA is unlikely to actually get all the money.

Some last-minute changes to the Act may also create serious legal problems for pharmaceutical companies. The final bill contains murky language about whether FDA regulations pre-empt states' drug-labeling laws. This thorny issue has pitted federal regulators against states eager to establish more stringent disclosure policies for medical products. The vagueness of the FDAAA provision is expected to lead to a major legal battle on this topic, which may well end up before the Supreme Court.

Balancing the rules

The main elements in the FDA legislation for enhancing medical-product safety have been known for several months (see "Enhancing Drug Safety," in the September 2007 issue of Pharmaceutical Technology). However, many important decisions were made only at the end of the debate. There had been uncertainty about which activities would be part of the new Risk Evaluation and Mitigation Strategy (REMS) program, and which new requirements would apply to all drugs.

For example, the final bill enhances FDA's authority to require labeling changes, additional postmarket studies, and advertising curbs for all drugs—not just for products that warrant a REMS. Conversely, the legislation stops short of requiring a REMS for all new drugs, as originally proposed, and leaves it up to FDA to decide whether a drug seeking market approval warrants added REMS components to ensure that the benefits of a medical product will outweigh its risks (see sidebar, "Weighing REMS and other remedies").

Weighing REMS and other remedies

Similarly, the legislation authorizes FDA to require pharmaceutical companies to seek agency prereview of planned TV ads. And it requires all drug TV and radio commercials to include a "major statement" of a drug's side effects and contraindications. This policy is much more agreeable to manufacturers than an alternative proposal to ban consumer advertising of drugs during the first year on the market. The Institute of Medicine panel that examined FDA drug-safety oversight backed a moratorium on new drug advertising, as did many members of Congress. But the likelihood that even a limited advertising ban would violate first amendment rights to free speech persuaded the lawmakers to adopt the prereview option instead.

Giving FDA authority to require postapproval studies, labeling changes, and risk disclosure in DTC advertising for all drugs reduces the need for the agency to impose the REMS policy broadly, explains attorney Scott Lassman of WilmerHale. Instead, FDA gains more authority to obtain additional drug-safety information and to inform the public of emerging safety issues. Moreover, manufacturers that fail to make requested labeling changes or to conduct timely postmarketing studies would be in violation of the law and subject to civil monetary penalties. Pharmaceutical companies also could be penalized for failing to implement an approved REMS, failing to register clinical trials appropriately, and for airing false and misleading drug advertising. These policies aim to boost public confidence in FDA's ability to obtain needed information about drug risks and to enforce appropriate drug marketing and distribution practices.

Consulting safety staffers

An important strategy for policymakers anxious to ensure appropriate drug use is to raise the profile of FDA's postmarket assessment activities. Some members of Congress believe that FDA has been slow to respond to emerging drug-safety concerns because agency staffers responsible for postmarket safety evaluation have been ignored and marginalized by the offices that evaluate and approve new drugs for market. Earlier this year, there was a push on Capitol Hill to establish a separate drug safety office at FDA to give postapproval risk-assessment activities more clout. But both industry and agency officials opposed the idea as likely to disrupt a balanced approach for weighing drug risks and benefits.

Instead, FDAAA specifies in numerous places that important decisions related to drug safety such as the need for postapproval studies or for a REMS should be evaluated by both new drug reviewers (i.e., the Office of New Drugs, OND) and postapproval safety experts (i.e., the Office of Surveillance and Epidemiology, OSE). FDAAA calls on FDA to enhance communication between pre and postmarket review staff and to report to Congress in two years about how well it is addressing the safety issues that OSE identifies.

At the same time, FDA will expand OSE operations with the help of additional user-fee revenues earmarked for postmarket surveillance. Under the PDUFA IV agreement, user-fee revenues may support the safety monitoring of any drug on the market—not just newly approved drugs. OSE also gains $30 million from fee revenues to contract with data banks and health plans for access to information on drug adverse events. The agency envisions a "transformation of the drug-safety program" by tapping into population-based epidemiological and observational data banks to carry out targeted postmarketing surveillance, to look at class effects of drugs, and to better detect safety signals. The final bill also boosts user fees by an additional $225 million over five years, starting with $25 million more for fiscal year 2008. This funding will support the extra work involved in designing and overseeing the REMS program, monitoring labeling changes, and establishing the enhanced clinical-trials registry and results database.

Closing the gap

By providing more resources for postmarket oversight, FDAAA may help elevate the status of OSE and epidemiologists. But it remains to be seen how much the physicians and clinicians that review new drug applications pay attention to the safety assessors.

The still-wide gulf between the two operations was apparent at the joint meeting in July 2007 of FDA advisory committees for Endocrinologic and Metabolic Drugs and for Drug Safety and Risk Management. The purpose was to evaluate concerns raised by several postmarketing studies about the increased risk of heart attacks for patients taking GlaxoSmithKline's (GSK) diabetes treatment "Avandia" (rosiglitazone).

At this high-visibility session, OND staffers disagreed with their counterparts at OSE about removing Avandia from the market. The safety experts claimed that serious risk evidence for Avandia warranted a re-evaluation of the drug's health benefits. OSE officials indicated that it would be better to pull a potentially safe drug from the market than to permit patient access to an unsafe one, especially if alternative treatments are available. The advisory panels agreed that Avandia has serious adverse event problems, but, in the end, voted to keep the drug on the market with added label warnings reflecting increased cardiovascular concerns, as recommended by OND staffers and GSK. However, the contradictory messages from these FDA experts added to the perception that the agency does not have a solid grasp on how to handle difficult drug-safety decisions.

The opinions expressed by OSE staffers also raise concerns among manufacturers that such views will encourage an even more risk-averse approach at FDA in approving new drugs for market. Many drug manufacturers agree with Novartis CEO Dan Vasella that FDA has become overly cautious in assessing new medicines in the wake of all the highly publicized safety controversies.

For example, the European Medicines Agency recently approved Novartis's diabetes drug "Galvus" (vildagliptin), while FDA has requested additional clinical trials for the drug that will take several years to complete. The agency also has indicated that it is unlikely to approve any new COX-2 inhibitors after denying applications for Merck's "Arcoxia" (etoricoxib) and more recently for Novartis's "Prexige" (lumiracoxib). In addition to delaying approvals, FDA is investigating any signal of unexpected adverse events and making some of this information public.

FDA has begun to publish an online drug-safety newsletter that highlights hot issues and adverse events for newly approved products. The agency also issues MedWatch reports about safety issues almost daily.

While FDAAA is lengthy and complex, it won't be the last word from Congress on protecting the public from dangerous medicines. The legislators are likely to renew efforts next year to establish a legal pathway for follow-on biologics. Such a measure would provide a legislative vehicle for perhaps a full moratorium on TV commercials for prescription drugs and stiffer penalties for violating new disclosure and registration requirements.

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