The US Food and Drug Administration (FDA) fast-track approval process for drugs to treat serious and life-threatening conditions requires makers to conduct post-marketing studies on their products, but a new study has found that some such studies have still not been completed more than eight years after the drugs were approved for marketing.

The requirement is included in the agency’s expedited process, which bases approval on surrogate endpoints which are not yet proven substitutes for clinical endpoints. The FDA fast-tracked 90 applications for drugs based on surrogate endpoints between 1992 and November 20, 2008 but, by December 19 last year, just 64% of the required post-marketing studies had been “closed,” eg, either completed or deemed by the agency to be no longer necessary or feasible, a new study by the Government Accountability Office (GAO) has revealed.

The FDA also approved 69 applications based on surrogate endpoints for New Molecular Entitles (NMEs) through its traditional approval process from January 1998 to June 30, 2008. It considers surrogate endpoints in the traditional process to be valid substitutes for clinical evidence and does not therefore require post-marketing confirmatory studies, but it did ask for 175 post-marketing studies to obtain other information on many of these NMEs, However, by February 13 this year, only around a half of these studies had been closed, the GAO also found.

The FDA has authority to speed a drug’s removal from the market if the sponsor fails to complete a required confirmatory study “with due diligence” or if such a study fails to confirm the drug’s benefit. But, says the GAO, the agency has never exercised this authority, “even when such study requirements have gone unfulfilled for nearly 13 years,” nor has it ever specified the conditions which would prompt it to take such action.

“Weaknesses in FDA’s monitoring and enforcement process hamper its ability to effectively oversee postmarketing studies,” says the Office. “FDA has not routinely been reviewing sponsors’ annual submissions on the status of studies in a timely manner. It has little in the way of readily-accessible, comprehensive data to monitor studies’ progression and does not consider such oversight a priority,” it adds.

Responding to the GAO’s criticisms, the FDA says these issues are being dealt with, and that the new funding and tougher powers which Congress granted the agency in 2007 to force drugmakers to complete requested trials, including imposing fines on those who do not, have led to a complete overhaul of the agency’s tracking system. There is no need for the agency to develop the “clarifying guidance” which the GAO report recommends, it adds.

The GAO acknowledges that the FDA is implementing initiatives to improve its oversight but adds that it is too early to tell if these will be effective, and emphasises that the development of clarifying guidance would enhance its oversight.

The GAO investigation was requested in February 2008 by Republican Senator Charles Grassley, who said a review was warranted because of “the way things have turned out with drugs like” Schering-Plough/Merck & Co’s cholesterol-lowerer Vytorin (ezetimibe and simvastatin) and GlaxoSmithKline’s diabetes drug Avandia (rosiglitazone).

“It’s not clear if the FDA’s own policies are being enforced internally, whether the agency is supposed to require companies to perform follow-up studies. These policies are designed for patient safety,” said Sen Grassley.

Approvals based on surrogate endpoints can help get new drugs and treatment possibilities onto the market more quickly, Sen Grassley said this week, responding to the GAO’s findings. “Once those drugs are on the market, the FDA also needs to monitor the outcomes, and this GAO report indicates that the follow-up hasn’t been happening as it needs to be. The report should serve as an impetus for the FDA to improve the post-market surveillance of these drugs, giving patients and their doctors meaningful information and necessary safeguards," he said.