‘Breakthrough’ Designation Can Be Misleading: Researchers
Three Harvard Medical School researchers say that four years of experience with the FDA breakthrough therapy designation program indicate that while it has accelerated approval of some important drugs, the term “breakthrough designation” itself can be misleading to patients and healthcare providers. They suggest that Congress or FDA consider modifying the program name to make it less misleading.
Writing in the New England Journal of Medicine, the researchers say that when drugs are designated as breakthroughs and expedited through the FDA approval process with the use of substantial resources, many patients and doctors will reasonably expect such drugs to offer major advances. “Yet on the basis of experience with the breakthrough designation so far,” they add, “it seems that new drugs can meet technical requirements for the designation, and then be approved, despite having only modest efficacy.”
From 2014 to 2016, the study shows, a total of 26 of the 108 new molecular agents and original biologic agents that were approved by FDA received the breakthrough designation. The writers say the program encourages the use of historical controls or other alternatives to traditional current control groups, as well as smaller trials that require less time to complete.
“One controversial feature of the breakthrough therapy designation is its name,” the report says. “Unlike other programs, which have titles that relate to the speed of development (fast track), speed of FDA review (priority review), or speed of overall approval (accelerated approval), the designation ‘breakthrough’ appears to signify an exceptional magnitude of therapeutic benefit. When drugs are designated as ‘breakthroughs’ by the government’s expert medicines agency and then described as ‘game-changers,’ ‘miracles,’ and ‘cures’ in the popular press, the public may reasonably expect them to provide a cure or to dramatically improve how patients feel, function, or survive…. Yet the designation does not in fact require drugs to be curative, or even dramatically better that existing alternatives. Indeed, designation requests can be made and designation assigned at around the time the IND application is submitted, long before the evidence to substantiate such claims is available or the traditional approval threshold has even been established.”
The article suggests that to better align expectations with product qualities while preserving program benefits, Congress could eliminate the potentially misleading term “breakthrough” along with the separate designation and incorporate the most salutary breakthrough features, such as shortened response timelines, into the fast-track program. And until Congress acts, it says, FDA could raise the low baseline of comparison by broadening the definition of “existing therapies” to include any product that is actually available to patients, such as off-label uses of existing products, accelerated approvals, and dietary supplements. “Although new drugs could still be approved without such a comparison,” the authors say, “the term ‘breakthrough’ implies superiority over the current standard of care, a comparison that may not occur under the current requirements.” The authors also call for close postmarket follow-up of breakthrough designated drugs in light of numerous studies showing a higher incidence of safety-related label changes and other risks associated with expedited premarket testing of new drugs.
In a response, three FDAers say that to gain designation as a breakthrough therapy, a candidate drug “must show potential for benefit above that of available therapies. Such therapies have usually been approved by FDA but can be an unapproved use of a drug or surgical intervention, provided there is compelling evidence of safety and effectiveness, including extensive evidence in published literature. FDA excludes from available therapies any drug that is approved through the accelerated approval process until confirmatory evidence regarding a clinical endpoint is obtained, a policy decision that errs on the side of facilitating the development of additional options until definitive evidence of clinical benefit is shown.”
The three note that not all drugs with breakthrough therapy designations ultimately deliver on their promise. “The standard criteria include preliminary clinical data showing substantial improvement over existing therapies, with respect to a relevant endpoint, rather than the ‘substantial evidence’ needed for approval,” they write. “One can argue that if the preliminary evidence for all drugs with the breakthrough therapy designation were to be confirmed in later-stage trials, the bar for the designation was set too high…. FDA needs the tools to identify and accelerate the approval of drugs that can substantially improve the lives of patients with serious or life-threatening diseases who have inadequate options. Fast-track and breakthrough therapy designations have done just that, while not without challenges, certainly without compromising the thoroughness of our review or the standards of evidence to support approval.”