of orphan drugs in cases where trials evaluating long-term clinical outcomes is not feasible and in cases where premarketing trials can be completed with fewer patients and with less cost. Mortality and other clinical outcomes can be rare and hard to measure, particularly in trials with a limited population of patients. However, because of their small numbers and shortened time frames, trials that assess surrogate end points may provide a limited view into a drug’s safety. Drugs approved on the basis of surrogate end points must be followed up with Phase IV verification studies, although the GAO has pointed out that for a substantial number of drugs approved on the basis of surrogate end points, including midodrine (ProAmantine), approved as an orphan drug in 1996,38 the required Phase IV studies have not been completed even after years of experience.39

From a safety standpoint, new orphan drugs were generally studied in fewer than 1,000 participant prior to approval, and nearly a third of those patients were young and healthy volunteers in Phase I trials. Therefore, the safety record for these products, as with all new drugs, is incomplete at the time of FDA approval. Monitoring the postapproval use of orphan drugs to evaluate potential safety concerns is important, especially for drugs approved despite serious methodological concerns expressed by FDA medical officer reviews. In the past, there have been cases where methodological concerns raised at the FDA level have not been translated adequately onto the label or in communications about an approved drug.40


Harris G. F.D.A. backtracks and returns drug to market. NY Times. 3 Sept 2010, at A11.


General Accounting Office. FDA needs to enhance its oversight of drugs approved on the basis of surrogate endpoints (GAO-09-866). 23 Sept 2009. Available at: http://www.gao.gov/new.items/d09866.pdf.


Schwartz LM, Woloshin S. Lost in transmission—FDA drug information that never reaches clinicians. N Engl J Med 2009;361(18):1717-1720.

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