From the Journals

About half of FDA expedited approvals lack double-blind trials


Key clinical point: Many expedited drug approvals lack gold-standard evidence.

Major finding: Just 45.7% of drugs granted Breakthrough Therapy approval by the Food and Drug Administration went through a double-blind, randomized study.

Study details: The review comprised 46 drugs granted Breakthrough status from 2012 to 2017.

Disclosures: Mr. Puthumana reported having no financial disclosures.

Source: Puthumana J et al. JAMA. 2018;320[3]:301-3.

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For some approvals, the benefits are worth the risks

Expedited drug approvals raise concerns that important questions about safety and effectiveness might be insufficiently answered before an agent makes it to pharmacy shelves, Austin B. Frakt, PhD, wrote in an accompanying editorial.

Several key facts suggest that the Food and Drug Administration’s expedited review programs may invite greater risks than benefits, he wrote.

Most new drugs are approved with relatively little data about long-term outcomes.

More than two-thirds of approvals are based on studies lasting less than 6 months.

The FDA approves novel therapeutic agents more quickly than do similar regulatory bodies in Europe and Canada, with a median time of 6 months for cancer drug approval.

Expedited reviews have increased in the last 2 decades. The increase is driven by drugs that are not first in their class, implying that they aren’t addressing unmet needs.

“The idea that doing something more quickly means it is not done as well has considerable face validity,” Dr. Frakt wrote. Nevertheless, at least one study suggests that expedited FDA approvals do confer substantial gains in quality of life. “[The study suggests] that the FDA’s expedited drug review programs include drugs that provide greater benefits than those undergoing conventional review. Indeed, to the extent the expedited programs handle drugs for conditions for which there is unmet medical need, relatively larger QALY [quality-adjusted life-year] gains are to be expected.”

However, drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings. But in some cases, at least, the trade-off seems worth it.

“Because expedited review programs are intended for drugs that treat serious conditions and address unmet medical needs, accepting greater risk may be reasonable and more consistent with patients’ preferences,” he said. “However, because many of these drugs also come with high price tags, financed with public funds through Medicare, Medicaid, and other programs, the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.”

Dr. Frakt is director of the Partnered Evidence-based Policy Resource Center at the Boston Veterans Affairs Healthcare System. His remarks are adapted from an accompanying editorial (JAMA. 2018;320[3]:225-6).



About half of the drugs approved under the Food and Drug Administrations’s Breakthrough Therapy designation have lacked the gold-standard evidence of a double-blind, randomized, placebo-controlled trial, according to a new JAMA report.

“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” wrote Jeremy Puthumana and his coauthors. “Furthermore, more than half were based on a single, pivotal trial.”

The average premarket development time was about 5 years, but regulatory review of these agents took less than 7 months on average, the report found.

Mr. Puthumana, of Yale University, New Haven, Conn., and his coauthors, reviewed all 46 of the drugs and biologics approved by the FDA from 2012 to 2017 under the designation. The Breakthrough Therapy designation allows for the rapid review of drugs and biologics for serious or life-threatening conditions where there is preliminary evidence demonstrating a substantial improvement over existing therapies. The researchers identified all pivotal trials supporting approval, looking at randomization, blinding, comparator group, primary endpoint, and patient numbers.

Of these drugs, most (25) were oncologic agents. Other indications were infectious disease (8), genetic or metabolic disorders (5), and other unspecified purposes (8). The median number of patients enrolled among all pivotal trials supporting an indication approval was 222.

Most of the approvals (27) were based on randomized trials, 21 (45.7%) were based on double-blind randomization, 25 (54.3%) employed an active or placebo comparator group, and 10 (21.7%) used a clinical primary endpoint.

Compared with drugs without accelerated approval, drugs with accelerated approval status were less likely to be examined in randomized or double-blinded trials(24 vs. 3 and 20 vs. 1, respectively), and were less likely to include a control group (32 vs. 3).

However, all drugs with Accelerated Approval status underwent at least one clinical safety or efficacy-focused postmarketing requirement, as did 64.3% of those without that status.

“Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals,” the authors wrote. “FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.”

Mr. Puthumana reported having no financial disclosures.

SOURCE: Puthumana J et al. JAMA. 2018;320(3):301-3.

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