No Evidence that FDA Breakthrough-Designated Anticancer Drugs Provide Improvements in Efficacy, Safety or Novelty

Comparison with non–breakthrough-designated drugs reveals only faster times to approval

An analysis of anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2012 and December 2017 revealed that breakthrough-designated anticancer drugs were associated with faster times to approval. However, there was no evidence that these drugs provide improvements in safety or novelty, nor there was a statistically significant advantage in efficacy when compared with non–breakthrough-designated anticancer drugs. The findings are published in the Journal of Clinical Oncology

The FDA breakthrough therapy programme was established in 2012 to expedite the development and review of new medicines. A new medicine must be intended to treat a serious or life-threatening disease in order to qualify and, on the basis of preliminary clinical evidence, have the potential to offer substantial improvement over existing treatment options.

To evaluate the times to approval, efficacy, and safety of breakthrough-designated versus non–breakthrough-designated anticancer drugs, a group of researchers studied 58 new anticancer drugs approved by the FDA between 2012 and 2017. Regulatory and therapeutic characteristics, such as time to FDA approval, pivotal trial efficacy endpoint, novelty of mechanism of action were compared between breakthrough-designated and non–breakthrough-designated anticancer drugs.

The authors used random-effects meta-regression to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumours, serious adverse events, and deaths not attributed to disease progression.

Among 58 studies drugs, 25 (43%) received breakthrough therapy designation.

The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non–breakthrough-designated drugs (difference, 1.9 years; p = 0.01).

There were no statistically significant differences between breakthrough-designated and non–breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; p = 0.11), hazard ratios for PFS (0.43 v 0.51; p = 0.28), or RRs for solid tumours (37% v 39%; p = 0.74).

Breakthrough therapy–designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; p = 1.00).

Rates of deaths (6% v 4%; p = 0.99) and serious adverse events (38% v 36%; p = 0.93) were also similar in breakthrough-designated and non–breakthrough-designated drugs.

The authors admitted that their study has some limitations. Follow-up on the products in the analysis is limited. The authors studied the evidence available to patients and clinicians at the time of approval; however, risk-benefit profiles may change as confirmatory studies are completed and other evidence is collected. There are inherent challenges in assessing drugs on the basis of limited information, and greater attention to the lack of surrogate measures that are well correlated with survival or other patient-important outcomes is needed. The study team did not consider alternative measures of clinical benefit that have been proposed, such as restricted mean survival time and milestone outcomes; these measures may be relevant in some cases, e.g. in the interpretation of recent immunotherapy trials, but there is no consensus on their use. As is the case with all observational studies, causal inferences cannot be made, and additional unobserved predictors may explain the association between breakthrough status and faster times to approval.

The authors concluded that although some therapies demonstrated clinically meaningful benefits, to date there is little evidence that FDA breakthrough-designated anticancer medicines offer substantially improved efficacy or safety or are more likely to act via a novel mechanism of action as compared with non–breakthrough-designated drugs. Continued follow-up, rigorous confirmatory studies, and more robust and transparent criteria for breakthrough designation are needed.

The study was supported by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science and the Engelberg Foundation (A.S.K.). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the article for publication.


Hwang TJ, Franklin JM, Chen CT, et al. Efficacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines. JCO, Published online 24 April. doi: 10.1200/JCO.2017.77.1592.