GAO Report: FDA Needs to Enhance Its Oversight of Approved Drugs on the Basis of Surrogate Endpoints
The Government Accounting Office issued a report today citing weaknesses in FDA’s oversight of postmarketing studies for drugs approved on the basis of surrogate endpoints. The report lists several drugs to treat cancer and other life‐threatening diseases that were approved on the basis of surrogate endpoints and have remained on the market despite a lack of confirmatory clinical studies to prove their efficacy. The report indicates that no drug has been recalled by FDA due to failure to complete efficacy studies.
A surrogate endpoint is a biomarker (or biological measure of the effect of a drug) that is intended to substitute for a primary clinical endpoint, such as patient survival. Surrogate endpoints are used to enable clinical studies which would otherwise be difficult to conduct due to the small number of clinical events or where the primary endpoint is death. In such cases, the surrogate endpoint provides evidence acceptable to FDA to demonstrate a direct clinical benefit of the drug being tested. Examples of surrogate markers include CD4 count for death from HIV infection and elevated cholesterol levels for an increased risk of heart disease.
Commencing in 1992, FDA has allowed drug makers to obtain accelerated approval for novel drugs to treat cancer and other diseases using surrogate endpoints. Since then, FDA has yet to withdraw a drug from the market due to insufficient or unimpressive data. For example, in 2003, FDA approved Iressa® for treatment of lung cancer based on early results that it shrank tumors, even though later studies demonstrated that the drug failed to increase patient survival. Despite numerous reports of pneumonia (including fatalities), Iressa remains on the market for a selected patients. Another example includes ProAmatine® for treatment of low blood pressure, which remains on the market although
postmarketing studies to establish its clinical benefit have gone incomplete for 13 years.
The GAO report finds that FDA has taken a passive approach to enforcing confirmatory study requirements and has not developed specific timelines for sponsors to complete these studies. The GAO states that “The combination of its ineffective monitoring and lack of criteria outlining when a drug should be withdrawn from the market make it difficult for FDA to utilize its enforcement authority.” Due to the uniqueness of individual drugs, the FDA has disagreed with the GAO’s recommendation to clarify the conditions under which it will utilize its authority to expedite market withdrawal of a drug
approved on the basis of surrogate endpoints. While acknowledging that confirmatory studies have not been completed in a timely manner in certain cases, FDA officials stated that withdrawing a drug could mean eliminating the only available treatment for a certain condition.
FDA officials said that the success of the accelerated approval process was minimized by the GAO report. The accelerated approval process has expedited access to new treatments to millions of patients that would not have been possible under the agency’s traditional approval process. While FDA commented that it would consider exercising withdrawal authority in situations where a clear safety concern resulted from confirmatory clinical trial data, the agency underscored that the purpose of the regulations governing use of surrogate endpoints is to establish efficacy, not safety, of the tested drug.
According to the GAO, there is little likelihood that FDA will ever utilize its withdrawal authority in the absence of specific timelines for completion of confirmatory studies or parameters for use of its authority to withdraw such drugs from the market.
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