Study 2: Approval evidence for supplemental indications
The second study concluded that the FDA increasingly approves supplemental indications with less than level I evidence (randomized, controlled trials with placebo or active comparator (BMJ. 2015;351:h4679. doi: 10.1136/bmj.h4679).
Of an examined 295 such approvals since 2005, the largest portion was for oncology (27%). Other indications were infectious disease (15%); cardiovascular disease and prevention (12%); psychiatry (12%); musculoskeletal and rheumatology (10%); neurology (8%); gastroenterology (6%); and other (1%). Orphan drug status accounted for 20% of the approvals.
Only 30% of modified indications were supported by efficacy trials with active comparators. Level I evidence supported half of modified use approvals and 11% of approvals expanding the patient population. Almost all of the expansion approvals were into pediatric populations, and the vast majority (94%) of evidence for those was extrapolated from adult clinical trials.
Uncontrolled trials supported 34% of expanded population approvals, and nine (14%) of these supplemental approvals had no trials with clinical endpoints.
Findings were similar with other approval pathways. Among new indications, 32% had clinical endpoints, as did 30% of modified indications. Only 22% of expanded population indications rested on clinical endpoint data.
“Clinical outcomes were most often used in trials supporting supplemental indication approvals of neurologic (48%) and infectious disease drugs (45%); by contrast, 70% of oncology supplemental indications were supported exclusively by trials using surrogate outcomes.”
Uncontrolled trials supported one-third of expanded population supplements; 14% of these had no clinical trial evidence. Similarly, one-third of orphan drug indications were supported by uncontrolled or historical cohort studies. Significantly fewer orphan than nonorphan approvals were supported by clinical trials (18% vs. 35%).
Again, the situation is likely to accelerate. The Best Pharmaceuticals for Children Act provides up to 6 months of additional market exclusivity for a new approval, “which can be extremely lucrative for the sponsor,” the authors noted. The 21st Century Cures Act will also play into the situation, they said.
“The high degree of heterogeneity of supporting evidence for supplemental indications, in the setting of legislation promoting drug approvals based on decreasing evidentiary standards, underscores the need for a robust system of postapproval drug monitoring for efficacy and safety, timely confirmatory studies, and reexamination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Both studies were supported in part by the Greenwall Faculty Scholars Program in bioethics and the Harvard program in therapeutic science. Dr. Kesselheim and his coinvestigators had no financial disclosures.
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*Correction, 9/24/2015: An earlier version of this article misstated the review's findings.