Misconceptions Exist About Clinical Evidence for Breakthrough Therapies, Examination Suggests

Joseph S. Ross, MD, MHS

Both patients and physicians appear to have misconceptions regarding the strength of evidence that support treatments with the US Food and Drug Administration’s (FDA) Breakthrough Therapy designation, according to a new examination.

Conducted by Joseph S. Ross, MD, MHS; Jeremy Puthumana, MS; and Joshua D. Wallach, PhD, MS, the analysis revealed that therapies granted this designation often reach the point of regulatory approval with trial data that lacks randomization and controls, and often consists of small numbers of enrolled patients.

“When approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval,” Ross, an associate professor of medicine, as well as public health, at Yale School of Medicine, told MD Mag. “Uncertainty over whether the effect observed in the single small trial will be observed in a larger population or replicated in another trial; uncertainty over whether the effect observed over the short-term will persist over the longer-term, or whether new risks—or even benefits—might be observed over the long-term; and uncertainty over whether the effect observed on the outcomes used in these shorter trials—usually surrogate markers of disease, like a laboratory test—will be confirmed by eventual demonstration of benefit and safety based on clinical outcomes like improved mortality or improved symptoms.”

Data revealed that since its inception in 2012, 46 therapies have been granted a Breakthrough Therapy designation by the FDA, with the majority approved in 2015 (n = 10; 21.7%) and 2017 (n = 17; 37%), and a large portion of them (n = 25; 54.3%) marked as first-in-class approvals. The majority, 54.3% (n = 25), of the treatments were therapies for cancer, with infectious disease (n = 8; 17.4%) having the next highest amount. In total, 60.9% (n = 28) of the approvals were drugs, with the remaining 39.1% being biologic agents.

Many of these therapies were also granted additional designations by the FDA. All told, 30 (65.2%) therapies were also granted Orphan Drug status, 24 (52.2%) were given Fast Track designation, and notably, all 46 (100%) were granted Priority Review. It was also common for these therapies to be given Accelerated Approval (n = 18; 39.1%).

The average number of trials per indication for Breakthrough Therapies was 1 (interquartile range [IQR], 1-2), and the median number of patients enrolled in all trials supporting an indication was 222 (IQR, 124-796). In total, 58.7% (n = 27) of the trials utilized randomization, 54.3% (n = 25) used a placebo or comparator control, 45.7% (n = 21) used double-blind distribution, and 21.7% (n = 10) had a clinical primary end point.

Data revealed that breakthrough approvals were less likely to be supported by randomized pivotal trials if they were also granted Accelerated Approval status (n = 3; 16.7%) than if they were not (n = 24; 85.7%; P <.001). Likewise, of the supporting trials with Accelerated Approval status, 1 was double-blinded (5.6%) and 3 featured control groups (16.7%), while 20 (71.4%) and 32 (96.4%) of those that were not given the accelerated designation were double-blind and controlled, respectively (P for both <.001).

“To me, if we are going to be making this trade-off to allow novel drugs come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous post-market trials are conducted within a reasonable period of time,” Ross explained, “resolving some of this uncertainty and making sure that the drugs are associated with the benefit/safety profile that we expect based on the initial clinical studies, allowing clinicians and patients to make fully informed decisions about whether to use these novel treatments.”

Notably, all 18 (100%) therapies with Accelerated Approval had at ≥1 clinical safety- or efficacy-focused post-marketing obligation, as did 18 approvals (64.3%) of the therapies without the accelerated designation.

Post-market analysis has become a bolstered area of funding since the market removal of rofecoxib (Vioxx) after unforeseen and substantial cardiovascular event risks were experienced in tens of millions of patients in the United States. Meanwhile, the overall process of approval has sped up, with the mean time for non-expedited New Drug Applications (NDA) and Biologics License Applications (BLA) dropping from just under 2 years in 1993 to only 10 months in 2016, according to an essay in the New England Journal of Medicine.

Ross et. al.’s analysis revealed that therapies granted the Breakthrough Therapy label were approved an average of 4.9 years (IQR, 2.7-7.6) from the time of Investigational New Drug (IND) application acceptance. The mean time from IND activation to FDA submission was 4.1 years (IQR, 2.0-7.0), and the average time from NDA submission to approval was 6.9 months (IQR, 5.1-8.0).

Previous research by Hwang et. al. has shown similar data, finding that therapies that do not go through 1 of the 4 possible expedited reviews offered by the FDA have an average clinical review time (from IND to approval) of 8 years. Meanwhile, those in ≥1 expedited program spent an average of 1 fewer year in development. Those granted Breakthrough Therapy designation averaged 3 fewer years in development—a rate 32% faster than therapies granted Fast Track status.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Ross told MD Mag. “To do so, our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs. My expectation is that this is what the public and clinicians (and Congress!) wants—more novel therapies coming to market as quickly as is reasonably possible, while still assuring drug safety and efficacy.”

The research letter, “Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation,” was published in JAMA.