On the credibility of the FDA’s breakthrough therapy designation

It could be seen, perhaps, as a testament to the scientific endeavour powering the pharmaceutical industry that the FDA found it necessary to develop the latest implement in its ‘toolbox’ for expediting access to new medicines. Rapid medical advances and a growing number of applications for new drugs meant that regulatory capacity rather than technological know-how was becoming the rate-limiting step in delivering innovative treatments to patients. To help overcome this, the FDA established its breakthrough therapy programme in 2012, adding to several existing expedited pathways, including fast-track and accelerated approval.


Breakthrough therapy designation was to be granted to medications ‘to treat serious or life-threatening conditions [and] that preliminary evidence suggested might provide a substantial improvement over existing options’.


It is no surprise that manufacturers jumped at the chance to secure breakthrough therapy designation for their investigational products. While the FDA would remain silent on the matter until approval, a company was free to publicise the fact that its new agent was considered a breakthrough from the moment this was granted: marketing gold. But more importantly it meant there was an opportunity to shorten approval time, perhaps by as much as 2 years.


What is surprising, however, is the success rate that industry achieved.

When it initiated the programme, the FDA expected only around two agents a year to gain breakthrough status. As it turned out, the number was five times that: 26 between 2014 and 2016.


An obvious question is what this represents: a trove of innovation, or a system that doesn’t work that well?

Two recent articles have suggested an unwelcome answer.

In assessing the first 4 years of the breakthrough programme, Darrow et al. highlight a gulf between what the ‘man on the Clapham omnibus’ might expect of a drug described as a ‘breakthrough’, and what it takes for a new drug to qualify under the technicalities of the system. The bar is too low, they argue, largely because the category of ‘existing options’ excludes treatments that could potentially be prescribed off-label, as well as agents approved under the accelerated approval pathway for which confirmatory evidence had not yet become available.


Meanwhile, Hwang et al. evaluated the 58 cancer drugs approved by the FDA between 2012 and 2017, comparing those with the breakthrough designation (43%) and those without it. This analysis demonstrated there was no association between the breakthrough designation and greater efficacy and found no evidence that breakthrough-designated drugs provide improved safety or are more likely to have a novel mode of action compared with those that lack the designation.


So now what?

If its credibility is beginning to be questioned, the good news is that the breakthrough programme is here to stay.


The FDA’s response to Darrow et al. reiterates the importance of prioritising the approval of drugs that might address unmet patient needs and argues that the very fact that not all drugs for which preliminary evidence suggests great promise go on to realise that potential is a sign that the system is working well.


The debate will no doubt continue, but for now this route to speedier approval will remain open for agents with sufficiently compelling preliminary data.


From the marketing perspective, however, where perception holds sway, the breakthrough designation could already have become a devalued currency. Dialogue from The Incredibles comes to mind:




  1. Darrow JJ et al. N Engl J Med 2018;378:1444-53
  2. Hwang TJ et al. J Clin Oncol 2018; doi: 10.1200/JCO.2017.77.1592. [Epub ahead of print]
  3. N Engl J Med 2018;378:1457-58

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