Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Breakthrough drugs often approved with no randomized trials

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

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

Major finding: 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.

Read the article.


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


WHEN benefits OUTWEIGH 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However, drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings.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).