In the US, the Food and Drug Administration determines whether a new drug is sufficiently safe and effective to be made available to doctors for use by patients. To do this, it must find a balance between requiring sufficient high quality clinical evidence from premarket evaluation and allowing promising new drugs to enter the marketplace quickly with continued evaluation after approval. The FDA maintains a “usual requirement” of “more than one” well controlled clinical trial that independently proves a drug’s efficacy. However, it also describes several situations in which fewer trials or studies with non-clinical outcomes, such as surrogate markers of disease, might suffice for premarket evaluation. Thus, FDA approval is binary, but the clinical trial evidence that forms the basis of the FDA’s decision varies widely.
Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review, The BMJ, doi.org/10.1136/bmj.j1680, 03 May 2017.
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To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.
Drugs@FDA database and PubMed.
All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both.
Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.
The quantity and quality of postapproval clinical evidence varied substantially for novel drugs approved by the FDA on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both. Fewer than 10% of approved indications had one or more published randomized controlled, double blind study showing superior efficacy based on clinical outcomes that examined the same indication for which the drug was first approved by the FDA after a median of 5.5 years after approval. These findings should inform both clinical decision making and regulatory policy regarding requirements before and after approval of novel drugs.