Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation

The US Food and Drug Administration (FDA) Safety and Innovation Act of 2012 created the Breakthrough Therapy designation to expedite development and review of drugs and biologics intended to treat serious or life-threatening conditions for which preliminary clinical evidence may demonstrate substantial improvement over existing therapies, allowing the FDA to provide “intensive guidance on efficient drug development” and “rolling review.”¹ Although physicians and patients often perceive that breakthrough approvals are based on rigorous clinical evidence,^2,3 no systematic evaluation of the evidence supporting breakthrough approvals has occurred. We reviewed all new FDA approvals granted Breakthrough Therapy designation, characterizing the pivotal clinical trials that serve as the basis of FDA approval,⁴ and premarket development and review times.

We identified all new drugs and biologics first approved by the FDA from January 2012 through December 2017 using the Drugs@FDA database. For each therapeutic indication granted Breakthrough Therapy designation, we abstracted FDA-determined regulatory and therapeutic characteristics, as well as postmarketing requirements.⁵ Drugs granted Breakthrough Therapy designation may also qualify for other expedited review programs, including Accelerated Approval, Priority Review, and Fast Track. We then identified all pivotal trials supporting approval and determined use of randomization, blinding, comparator group, primary end point, and number of patients using methods described previously.⁴ Next, we 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.

We used Stata (StataCorp), version 13.0, to conduct Wilcoxon, Kruskal-Wallis, and Fisher exact tests as appropriate. Statistical tests were 2-sided and used a Bonferroni-corrected P value of .01 to account for multiple comparisons for differences by 5 prespecified regulatory and therapeutic characteristics.

From 2012 through 2017, the FDA approved 46 therapeutics with Breakthrough Therapy designation on the basis of 89 pivotal trials. The most common therapeutic areas were cancer (n = 25; 54.3%) and infectious disease (n = 8; 17.4%) and 54.3% (n = 25) were considered first-in-class. Therapeutics were also commonly designated as orphan products (n = 30; 65.2%) and qualified for Fast Track review (n = 24; 52.2%) and Accelerated Approval (n = 18; 39.1%); all were granted Priority Review (n = 46; 100%) (Table 1).

The median number of pivotal trials per indication approval was 1 (interquartile range [IQR], 1-2), and the median number of patients enrolled among all pivotal trials supporting an indication approval was 222 (IQR, 124-796). Among these approvals, 27 were made on the basis of pivotal trials using randomization (58.7%), 21 using double-blind allocation (45.7%), 25 using an active or placebo comparator group (54.3%), and 10 using a clinical primary end point (21.7%). Pivotal trials that were used to support breakthrough approvals with Accelerated Approval status were less likely than trials without Accelerated Approval to be randomized (3 trials with Accelerated Approval [16.7%] vs 24 trials without Accelerated Approval [85.7%], P < .001), double-blinded (1 trial with Accelerated Approval [5.6%] vs 20 trials without Accelerated Approval [71.4%], P < .001), and include a control group (3 trials with Accelerated Approval [16.7%] vs 32 trials without Accelerated Approval [96.4%], P < .001) (Table 2).

The median time from IND activation to FDA approval was 4.9 years (IQR, 2.7-7.6), including 4.1 years (IQR, 2.0-7.0) from IND activation to FDA submission and 6.9 months (IQR, 5.1-8.0) from NDA submission to FDA approval. All 18 approvals (100%) with Accelerated Approval had at least 1 clinical safety or efficacy-focused postmarketing requirement, as did 18 approvals (64.3%) without Accelerated Approval.

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. Furthermore, more than half were based on a single pivotal trial. On average, premarket development times were approximately 5 years, consistent with prior investigations,⁶ and FDA regulatory review and approval required less than 7 months on average.

This study was limited to new drugs granted Breakthrough Therapy designation and receiving FDA approval. Prior research suggests that use of randomization, double-blinding, control groups, and clinical outcomes is more common among pivotal trials supporting FDA approval of non–Breakthrough Therapy designated drugs, even among those undergoing Accelerated Approval.⁴ Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals.^2,3 FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.

Accepted for Publication: May 15, 2018.

Corresponding Author: Joseph S. Ross, MD, MHS, Section of General Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520 (joseph.ross@yale.edu).

Author Contributions: Mr Puthumana and Dr Ross had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Puthumana, Ross.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Puthumana.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Puthumana.

Supervision: Ross.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Wallach reported receiving grant funding from Laura and John Arnold Foundation. Dr Ross reported receiving grant funding from Laura and John Arnold Foundation, Johnson & Johnson, Medtronic, the US Food and Drug Administration, Blue Cross Blue Shield Association, Centers for Medicare & Medicaid Services, Agency for Healthcare Research and Quality, and from the National Heart, Lung, and Blood Institute of the National Institutes of Health. No other disclosures were reported.