The FDA has not been afraid to use its new authority to smooth the approval path of new drugs by designating them “breakthrough therapies”, with 20 such rulings so far. But the regulator has not been clear about which candidates qualify for this new category or how drug developers benefit.
Engaging in a diplomatic mission, top FDA officials parachuted in to the Asco cancer meeting to talk up breakthrough designation at a time when there is grumbling in the industry about the agency moving the goalposts on agreed-upon trial designs (What is a special protocol assessment worth, anyway?, May 14, 2013). And though the new powers intend to speed desperately needed new drugs on their way to market, it is not at all clear that the FDA will have the human resources to accomplish both the speedier approvals and standard reviews at the same time.
Break on through
The breakthrough designation was created in the Food and Drug Administration Safety and Innovation Act, the fifth reauthorisation of the prescription drug user fees that fund much of the regulator’s drug review (PDUFA V nears final act, May 31, 2012). Breakthrough therapies are intended to be of even greater importance than priority review, fast-track, accelerated approval and orphan drugs, although interpretation was left to agency staff. Likewise, the law directs the FDA to work more closely with drug sponsors in developing and executing a clinical plan, but left the mechanics to the regulator’s interpretation.
In spite of the 20 designations, agency leadership has so far done little to explain the decisions, nor how clinical programmes will be expedited. Appearances by Richard Pazdur, director of the office of oncology drug products, and Commissioner Margaret Hamburg helped shed some light.
Speaking to oncologists at the meeting, Dr Pazdur said he has interpreted the law as meaning that drugs must have shown signs of early efficacy in order to qualify. Specifically, the data must indicate that the drugs are “transformative therapies that are really going to offer patients an option where no other therapy existed, or are dramatic improvements that looks like they’re going to transform patients’ lives – both the quality and the quantity of their lives.”
Unlike orphan designations, more than one drug in a class targeting a specific disease can earn the breakthrough moniker, which will allow for the possibility of clinical failure, he said. Thus its advantage only extends through approval and will not offer commercial protection as the orphan designation does.
The first compound to be awarded the breakthrough therapy title was Vertex Pharmaceuticals’ Kalydeco and VX-809, in January. As of May 23, Dr Pazdur said eight of the 20 awarded had been oncology or haematology drugs, and of the first 51 requests, 26 had been in oncology or haematology. Of those applications that have not been successful, 14 were denied and three withdrawn. In oncology and haematology 10 have been denied and one withdrawn.
A breakthrough designation earns a more “iterative” clinical development programme, with frequent – as often as monthly – consultations with regulators on the trial progress “to ensure that the package that is submitted will be able to be expedited in review”, Dr Pazdur said.
Many breakthrough products may be able to earn approval on single-arm studies, and when strong efficacy signals emerge in pivotal trials the agency is prepared to downsize or end trials early, he said. “Patients in randomised studies that are randomised to the control arm will be minimised if there is preliminary evidence from the study that the drug that is being investigated really represents a breakthrough in the disease.”
Should the transformative potential of a candidate not be borne out with continued study, the agency has the power to rescind the designation.
Dr Padzur also told industry representatives that one of the reasons the agency had turned down drugs so far was insufficient data – while there is no minimum threshold for trial size, patient samples in the single digits are probably too small to qualify. Subsequent applications can be submitted following an initial rejection.
Twenty breakthrough candidates are now demanding ever more resources, and Dr Padzur acknowledges that even though drug review is largely supported by user fee revenue, under government budgetary constraints such as pay freezes and travel cuts the staff may be stretched.
“Working smarter” is the answer coming from the agency for now, something that does not necessarily inspire confidence in Leerink Swann analyst Howard Liang. He wrote: “As [breakthrough] designations become more common (20 granted to date), a question in our mind is whether lack of [designation] becomes a disadvantage if FDA resources become constrained.”
Guidance is due out soon that hopefully will clear up many of the questions that the FDA's leadership attempted to answer at Asco. How well the agency manages its newly competing priorities will be closely watched.