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Highlights

Before approving a drug, the Food and Drug Administration (FDA) assesses a drug's effectiveness. This assessment may be based on evidence showing that a drug has a positive impact on a surrogate endpoint--a laboratory measure, such as blood pressure--instead of more direct clinical evidence, like preventing strokes. After approval, FDA often requires or requests a drug sponsor to further study the drug. Concerns have been raised about FDA's reliance on surrogate endpoints and its oversight of postmarketing studies. This report provides information on (1) all drug applications approved based on surrogate endpoints in FDA's accelerated approval process, (2) a subset of applications for potentially innovative drugs approved based on surrogate endpoints under FDA's traditional process, and (3) FDA's oversight of postmarketing studies. GAO identified drugs approved based on surrogate endpoints, obtained the status of related postmarketing studies, and reviewed FDA's oversight of a sample of 35 studies it required under its accelerated approval process, selected to include studies which were at varying levels of completion.

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Recommendations

Recommendations for Executive Action

Agency Affected Recommendation Status
Food and Drug Administration 1. To clarify FDA's enforcement authority under the accelerated approval process, the Commissioner of FDA should clarify the conditions under which the agency would utilize its authority to expedite the withdrawal of drugs approved based on surrogate endpoints under the accelerated approval process if sponsors either fail to complete required confirmatory studies with due diligence, or if studies are completed, but fail to demonstrate the clinical effectiveness of the drugs.
Closed - Not Implemented
FDA disagreed with this recommendation. While it stated it was committed to closely overseeing required postmarketing trials for drugs approved under accelerated approval, it indicated that this is a complex matter involving case-by-case assessments. As a result, FDA said that it would be difficult, if not impossible, to provide further clarification as to when it might utilize its authority to expedite withdrawal of drug approved on the basis of surrogate endpoints. FDA has reiterated this position in its annual updates on the status of this recommendation up to and including 2012, stating it has no plans to develop the clarifying guidance that we have recommended. It is important to note that, at the time our report was issued in 2009, FDA had never taken the step of removing a drug approved on the basis of a surrogate endpoint through the accelerated approval process when either the confirmatory studies were not completed or were completed but failed to demonstrate the drug's clinical effectiveness. However, since our report was issued, FDA has taken steps to remove four such drugs from the market, including Proamatine, Iressa, Mylotarg, and (for certain uses) Avastin. FDA stated it will not issue the guidance we recommend and requested that we close this recommendation as not implemented. While FDA took steps consistent with our recommendation by taking unsafe and/or ineffective products off the market, the agency remains continues to strongly disagree with the need for guidance on this topic.

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