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October 12, 2011

Clinical Trials of Orphan Drugs for Cancer—Reply

Author Affiliations

Author Affiliations: Division of Pharmacoepidemiology and Pharmacoeconomics, Harvard Medical School, Boston, Massachusetts (akesselheim@partners.org).

JAMA. 2011;306(14):1545-1546. doi:10.1001/jama.2011.1464

In Reply: Although more therapeutic options for patients with orphan diseases are needed, the precarious position of such patients does not justify subjecting them to treatments that have been inadequately studied and may therefore be ineffective or dangerous. The Food and Drug Administration's flexibility regarding clinical trial designs for orphan cancer drugs has meant that these drugs can be approved on a more expedited time frame, and this approach may have some advantages, for example, in life-threatening circumstances or where no other therapeutic options exist. But our study found that such flexibility can also lead to a worrisome lowering of trial design standards, including a higher rate of acceptance of unblinded or single-group studies and the use of surrogate end points to assess efficacy. For nonorphan drugs, trials with these characteristics are usually conducted during phase 1 and phase 2 testing, and then the drugs are subjected to at least 1 phase 3 comparative and randomized study prior to approval. A substantial number of new products are abandoned after such phase 3 studies demonstrate problematic adverse effects or lack of efficacy.1 We found that this important step in evaluation was omitted for the vast majority of orphan cancer drugs.