Practice Economics

More expanded drug indications approved on less rigorous evidence

Publish date: September 23, 2015

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FDA regulations skirt agency’s ‘safe and effective’ vow to the public

The FDA provides too many expanded drug indications with too little supporting research.

Independent examinations of the agency’s records, including the two studies by Dr. Aaron S. Kesselheim and colleagues, are finding that up to 90% of these approvals provide few or no advantages for patients. The FDA’s flexible criteria and low threshold for approval do not reward more research for breakthroughs but instead reward more research for minor variations that can clear this low threshold.

Patients and doctors have clamored for expedited approval pathways that allow clinical access to new drugs sooner – a process that also generates revenue for drug companies to fund more breakthrough research. But faster approval means taking less time to prove these drugs safe and effective for their new indications. And in an age when prescription drugs are the fourth-leading cause of death in the United States and the third-leading cause in Europe, according to some reports, this doesn’t seem to be a wise move.

Expedited trials – and approvals based on nonclinical data – are incapable of providing patients or doctors with valid information on what new clinical benefits a drug provides.

Patients and doctors must trust the FDA to live up to its claims of providing drugs that work not only for their approved indications, but help more than they harm. But its expedited approval processes only require, in most cases, that the drugs provide “nonzero” levels of effectiveness.

The United States and other countries need an alternative paradigm – one in which research focuses on better medicines for patients rather than for profits, where clinical trials with low risk of bias look for real benefits and faithfully report harms.

Dr. Donald W. Light, an osteopathic physician at Rowan University, Cherry Hill, N.J., and Dr. Joel Lexchin of the School of Health Policy and Management at York University in Toronto made these comments in an accompanying editorial (BMJ 2015;351:h4897). They had no disclosures.


 

FROM BMJ

References

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.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

*Correction, 9/24/2015: An earlier version of this article misstated the review's findings.

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