FDA Approval Process Under Scrutiny

Clinical trials may take longer and become larger as proposals emerge to strengthen regulatory policies.

Members of Congress, patient advocates, and some industry experts say it is time to re-evaluate Food and Drug Administration approval and postapproval operations. Safety concerns about prescription drugs continue to mount, along with charges that new drugs are coming to market without adequate testing and that postmarket surveillance has suffered. Some legislators want to give FDA authority to require postapproval studies and labeling revisions. FDA officials maintain that recently proposed internal initiatives can fix most of its problems.

The Senate Health, Education, Labor, and Pensions (HELP) Committee held hearings last month to discuss FDA's drug approval process. Panel chairman Mike Enzi (R-WY) and lead Democrat Edward Kennedy (D-MA) plan to develop bipartisan legislation addressing drug safety issues and FDA procedures, but appear willing to take their time to weigh all options.

Kennedy complained that it took five years for the public to learn that Vioxx may double the risk of heart attack or stroke, and suggested that user fees have allowed FDA to review new drugs much more quickly, while oversight of post-approval drug safety has lagged. But Kennedy also agreed with Enzi that "overreacting could be as dangerous as doing nothing," and that it is critical to "find the right approach."

More studies
FDA officials are trying to fend off proposals that would radically change the drug approval system, partly for fear that more onerous study requirements would not really improve the process. FDA acting deputy director Janet Woodcock pointed out that sponsors now are conducting more clinical studies than 10 or 15 years ago. Vioxx and Celebrex had more people in trials than any other anti-inflammatory drug, and sponsors still did not learn about serious side effects until much later.

The clamor over drug safety has widened the debate over just how long and how large clinical trials need to be to document safety and efficacy. Bruce Psaty of the University of Washington told the Senate committee that the pre-approval evaluation of COX-2 inhibitors was inadequate, and that medicines that will be used by millions of Americans for long periods of time should be studied in large, long-term clinical trials.

Woodcock acknowledged that drugs designed to treat a visible symptom such as pain usually are not studied very long in the pre-approval stage, compared to trials for drugs to treat asymptomatic conditions such as high cholesterol. It is hard to tell how long a study needs to be, Woodcock commented, adding that there would be no drugs to treat asymptomatic conditions at all if study requirements are too burdensome.

One proposal for improving the current approval process is to grant "conditional" or "staged" approvals followed by extensive postapproval study requirements. Ray Woosley of the University of Arizona described a plan that would allow limited approval of a new drug for a carefully defined patient population following comprehensive Phase II testing. This first study phase would involve about four years of trials based on more complete characterization of dose-response relationships and targeted drug interaction studies. The product's label would be expanded following several years of additional larger trials and intensive safety assessment. Woosley points out that this approach would make needed drugs available faster while also strengthening postapproval oversight and safety examination.

Sponsors generally oppose conditional or limited approval designations for fear that lingering safety concerns would stymie marketing efforts and raise legal liability concerns. And FDA officials do not seem highly enthusiastic about leaving a product's approval status uncertain.

Fight for independence
In addition to revising pre-approval requirements, reformers want to overhaul FDA oversight of postmarket safety surveillance. The main proposal is to establish an office to oversee drug safety issues that is separate from FDA's new drug review operation.

Some FDA critics want the drug safety operation totally independent of the agency, similar to organizations that review transportation accidents. But most are willing to keep the new entity within FDA, just separate from the Office of New Drugs in the Center for Drug Evaluation and Research (CDER). Legislation developed by Sens. Chris Dodd (D-CT) and Charles Grassley (R-IA), chairman of the Senate Finance Committee would do just that.

FDA officials oppose creating a separate drug safety agency, and most experts seem to agree. Woodcock explained that it is important for the people who evaluate a drug in the first place to play a role in monitoring the product over its full life cycle. She described drug review and oversight as a continuum between pre- and postmarket monitoring, a process that requires input from experts familiar with the drug and its whole class. Most new drugs are approved for narrow indications with the expectation that further clinical trials, including studies on children, will lead to broader labeling.

She also rejected suggestions that reviewers who approve a drug would be conflicted about later efforts to remove it. FDA uses a team approach for application reviews, and if serious safety issues arise more people become involved and the review process opens up. A separate drug safety office would suffer from a lack of familiarity with the drug's benefits, in addition to its risks.

FDA has proposed several initiatives to address fears that drug safety problems fail to gain a full hearing at the agency. A new drug safety oversight board composed of experts from FDA offices and from other federal agencies is being formed to provide an objective perspective on the safety of marketed drugs. A new grievance process will provide a forum for dissenting FDA scientists to air their concerns.

Another FDA plan involves posting the latest drug safety information on the new Drug Watch Web site. FDA acknowledges that it took an unusually long time to reach agreement on needed labeling changes for Merck's Vioxx after cardiovascular adverse events emerged, but believe that the new site will prevent delays between when FDA learns about a safety problem and when that information reaches prescribers and patients.

Critics contend that the safety board and Web site are just window dressing and will lack real teeth in addressing serious safety problems. They are examining a number of additional proposals to give FDA more power:

* Strengthen FDA authority to require labeling changes on approved drugs. While FDA usually reaches agreement quickly with sponsors on needed warnings and other labeling changes, the Vioxx case shows that such negotiations can take months.

Sandra Kweder, deputy director of CDER's Office of New Drugs, acknowledged at the first Senate hearing that the ability to require changes in labeling would be "very helpful" to the agency. Kennedy expressed the growing sentiment that "negotiations with a drug-maker should never delay accurate information for patients and doctors."

* Mandate completion of post-approval studies. FDA now can require sponsors to conduct additional studies only for drugs approved under its accelerated approval process. Otherwise, the agency may ask a sponsor to conduct certain Phase IV studies as a condition of market approval, but it lacks authority to impose penalties if such commitments are not fulfilled. Kweder said it would be helpful for FDA to be able to require a clinical trial to address safety issues that emerge after a drug is on the market.

An FDA analysis of industry performance of Phase IV study commitments in 2004 shows that sponsors completed about 15% of about 1700 planned postapproval studies each year. Most are pending, about 50 studies fall into the "delayed" category, and a little more than 200 were submitted to the agency.

? Boost FDA authority to remove problematic drugs from the market. Most drug withdrawals are voluntary, but often result from FDA urging. FDA has legal authority to pull a drug off the market if it can show that the product poses an "imminent risk," but that is usually difficult to do. Critics contend that withdrawal discussions can take a long time and want to give FDA authority to levy fines or impose other penalties on manufacturers who fail to comply quickly to postapproval safety concerns.

? Expand information on clinical trials. Congress wants to strengthen and expand clinical trial registries to better inform the public about investigative drugs under study. There also is a push for public disclosure of clinical trial results, including those that end up producing unfavorable data. Pharmaceutical companies say they are posting more research data voluntarily, but most observers believe that a specific mandate is needed to gain full access to important safety information.

? Boost FDA resources. Many observers feel that FDA's budget is too lop-sided, with most resources devoted to new drug approval and too little to post-approval monitoring. The administration's budget plan for 2006 proposes to expand funding for drug safety surveillance, but that amount still would be far below levels needed to conduct more proactive safety analysis and epidemiological studies.

The official FDA policy is that Congress should hold off on legislative change until the agency's internal reforms have a chance to address these problems. FDA is finalizing three draft guidances on managing the risks in medical products, which were issued almost two years ago. One guidance addresses the scope of clinical assessment of safety issues in the premarket study phase; another describes when special risk management plans are needed for certain drugs.

FDA also is working with the Institute of Medicine on a review of the drug approval process. The project should begin in six months and be completed within two years. Meanwhile, more legislative proposals are likely to surface, and more inquiries will be held. FDA officials believe that innovative research methods and cutting-edge analytical approaches could greatly enhance the safety of new medical treatments, provided that poorly designed legislation does not discourage risk-taking in the drug development process.