When Should Unmet Need Trump Inadequate Data?
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
The Esbriet review exemplifies FDA’s eternal struggle between requiring adequate evidence of efficacy and giving patients with deadly diseases a chance at treatment.
FDA has proven time and again that it will extend considerable regulatory flexibility to drugs for serious unmet medical needs and orphan diseases, but it decided to issue a “complete response” letter for InterMune Inc.’s Esbriet (pirfenidone) for idiopathic pulmonary fibrosis in 2010 – and IPF patients had to wait four more years for approval of the first drugs to treat the rare and fatal lung condition.
Review documents show that FDA struggled with the decision, and that it had an unexpected ally in choosing to wait for better evidence of efficacy: patient advocates.
“We must always be vigilant that we do not allow desperation to be substituted for evidence of efficacy,” ODE II Director Rosebraugh said.
While FDA is free to contradict the conclusions of its advisory committees, it rarely does so. So the May 4, 2010 “complete response” letter for Esbriet was something of a surprise, because the Pulmonary-Allergy Drugs Advisory Committee had supported approval.
The advisory committee was “likely trying to respond to an unmet need,” review team leader Banu Karimi-Shah said, pointing out that two advisory committee members voted that there was not sufficient efficacy data to support approval but voted for approval anyway. The March 9, 2010 Pulmonary-Allergy Drugs Advisory Committee voted 9-3 in favor of approval, although the panel was split 7-5 that there was substantial evidence of efficacy (Also see "Pirfenidone Panel Highlights Difficulty Of Selecting Primary Endpoint In IPF" - Pink Sheet, 15 Mar, 2010.).
“Although IPF is an orphan disease, the requirements to establish effectiveness are not different, with the exception that the overall database may be smaller,” Karimi-Shah stated.
After the committee meeting, “we received correspondence from both academic physicians and patient advocacy groups, questioning whether efficacy had been met,” Office of Drug Evaluation II Director Curtis Rosebraugh said in his Oct. 15, 2014 summary review. “In my experience, it is an unusual occurrence that patients with a desperate illness would write advocating the need for more proof of drug effect.”
FDA’s recent patient-focused drug development meeting on IPF reinforces the perception that the advocacy community is more willing to give FDA breathing room to make approval decisions than is often the case when the first therapy for a deadly disease is under review. The IPF patient meeting, held only a few weeks before the approvals of Esbriet and Boehringer Ingelheim GMBH’s Ofev (nintedanib), was notable for how rarely the two drugs were mentioned. Patient testimony focused on the desire for therapies to improve IPF symptoms and increase quality of life (Also see "Pulmonary Fibrosis Patients Talk Quality Of Life More Than Potential New Treatments" - Pink Sheet, 6 Oct, 2014.).
Before making a decision, however, the Esbriet review team took the issue of pirfenidone’s approvability to Center for Drug Evaluation and Research top management with a regulatory briefing, a type of meeting sometimes called an “internal advisory committee” that allows the review division to get high-level input on difficult decisions.
The April 16, 2010 regulatory briefing produced “a general consensus that efficacy standards had not been met,” Rosebraugh said.
The ODE II director characterized the original Esbriet NDA data as “a surrogate primary endpoint which yielded inconsistent results in two trials and limited evidence of clinical benefit.” Based on “the totality of the data and expert input,” Karimi-Shah said, FDA issued the May 4, 2010 “complete response” letter requiring another clinical efficacy trial.
“Patients and physicians are desperate for a non-surgical therapy that may have clinical benefits,” Rosebraugh said in a May 4 memo explaining the decision. “We at the Agency also feel this desperation, however we must always be vigilant that we do not allow desperation to be substituted for evidence of efficacy.”
“Approving a drug that does not have the purported effect could have devastating consequences for patients,” Rosebraugh said. “Giving patients an ineffective drug puts them at risk for adverse effects (e.g. liver failure) without any benefit. As well, recognizing an ineffective drug therapy as effective could dampen urgency in developing therapies and delay further research efforts. There are also costs to society associated with providing a medical therapy such that we need to be sure that limited resources are used wisely.”
Rosebraugh’s declaration of the importance of evidence even in the face of overwhelming need stands in contrast to increasing public pressure to tilt the playing field for therapies for serious illnesses.
That that will only increase with the 21st Century Cures Act that is taking shape on Capitol Hill. A recent discussion draft contains provisions that could have led to a first-cycle pirfenidone approval, like an expansion of the “breakthrough therapy” program to allow for approval based on a different data package than the traditional two randomized controlled clinical trials (Also see "New Rx Approval Standards, Faster Pathways Offered In Cures Legislation" - Pink Sheet, 2 Feb, 2015.).