Do Breakthrough Therapies Need More Rigorous Evaluation?

A new study published in JAMA reviewed the premarket development and review times of drugs approved between 2012 and 2017 that were granted Breakthrough Therapy designation and found that the crucial studies that supported these approvals lacked key features, including randomization, double-blinding, and control groups.

A common perception among physicians concerning the Breakthrough Therapy designation is that the drugs are supported by stronger evidence than is required by the statute. When researchers surveyed internists and specialists from endocrinology, hematology, and infectious diseases back in 2016, they found “substantial deficits” in physician understanding of FDA approvals. Overall, they did find greater awareness among specialists than internists.¹

For their current study,² the authors assembled a list of new drugs and biologics that were FDA approved between January 2012 and December 2017 and were listed on the Drugs@FDA database. Further, for those drugs that were granted Breakthrough Therapy designation, details on the FDA-determined regulatory and therapeutic characteristics along with postmarketing requirements were gathered. The authors also reviewed pivotal trials that supported the approval of these drugs and documented:

• Randomization
• Blinding
• Comparator group
• Primary endpoint
• Number of patients

To hone in on the timeline of these drugs, they also identified 3 regulatory dates using public FDA documents and patent extension notices: investigational new drug (IND) activation (when human testing can begin), new drug application (NDA) submission, and FDA approval.

Of the 46 drugs receiving Breakthrough designation during the study period, a majority were anticancer agents (n = 25; 54.3%), followed by infectious disease drugs (n = 8; 17.4%)—half the drugs approved were also first-in-class. While all 46 drugs received a Priority Review—which is a process that allows expedited review of high-impact drugs—30 were designated as orphan products and 24 qualified for Fast Track review.

The median number identified for pivotal trials used for the indicated approval was 1 (interquartile range [IQR], 1-2), and the median number of enrolled patients for the indication approval was 222 (IQR, 124-796). Only about 60% of approvals were made based on randomized trials, 45.7% were double-blinded, and 54.3% used an active placebo control group. Only 21.7% of trials used a clinical primary endpoint; a majority of the trials (about 80%) used surrogate endpoints.

Further, the authors found that pivotal trials that supported the breakthrough approvals and led to an Accelerated Drug Approval were less likely to be randomized, compared with those without an Accelerated Approval (16.7% versus 85.7%, respectively; P <.001). They were also less likely to be double-blinded or include a control group.

Overall, the median time from IND activation to FDA approval was 4.9 years (IQR, 2.7-7.6), which included 4.1 months (IQR, 2.0-7.0) between IND activation and FDA submission, and 6.9 months (IQR, 5.1-8.0), between the NDA submission and FDA approval. A postmarketing safety/efficacy requirement was documented for 100% of the Accelerated Approvals, compared with 64.3% that did not receive an Accelerated Approval.

FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies, the authors conclude.

References

1. Kesselheim AS, Woloshin S, Eddings W, Franklin JM, Ross KM, Schwartz LM. Physicians’ knowledge about FDA approval standards and perceptions of the “Breakthrough Therapy” designation. JAMA. 2016;315(14):1516-1518. doi: 10.1001/jama.2015.16984.
2. Puthumana J, Wallach JD, Ross JS. Clinical trial evidence supporting FDA approval of drugs granted breakthrough therapy designation. JAMA. 2018;320(3):301-303. doi:10.1001/jama.2018.7619.