Breakthrough Designation: Pivotal Trials Lack Randomization, Double-Blinding and Control Groups

Regulatory NewsRegulatory News | 17 July 2018 |  By 

A review of all therapeutics receiving a breakthrough designation and approved from 2012 to 2017 found a lack of randomization, double-blinding and control groups in pivotal trials supporting approval, a research letter published Tuesday in JAMA found.
The research letter, written by Jeremy Puthumana, Joshua Wallach and Joseph Ross of Yale University, also revealed the use of surrogate endpoints in such pivotal trials and smaller trials too. However, of the 46 therapies approved with the designation, 25 (54%) were considered first-in-class.
So is the US Food and Drug Administration (FDA) doing too little to stop these novel therapies from coming to market without enough evidence?
Ross explained to Focus: “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. 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.”
But there is a level of uncertainty in terms of risk with such expedited approvals, and particularly when the trials are small.
Ross added: “When approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval: 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.”
The use of post-market studies is also important to ensure the treatments are made available safely, Ross noted.


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