Two wrongs may not make a right, but when it came to Pulmonary-Allergy Drugs Advisory Committee member Les Hendeles' views on the approvability of InterMune's idiopathic pulmonary fibrosis therapy pirfenidone, two "no's" made a "yes."
Hendeles, whose day job is professor of pharmacy and pediatrics at the University of Florida Health Science Center, first voted "no" to the question of whether InterMune's pivotal trials showed "substantial evidence" of efficacy in IPF, as measured by changes in forced vital capacity.
Hendeles was one of five committee members to vote "no" on that question; there were seven "yes" votes. Hendeles noted FDA's definition of "substantial evidence" and his view that the dataset--one study showing improvement in FVC, one failing to show a change, and no unequivocal indication of an overall survival benefit--didn't make the cut.
Then he voted "no" on whether InterMune had provided sufficient evidence of safety; there he was one of three "no's," vs. seven "yes" votes. Hendeles described pirfenidone as a "theophylline-like drug" and explained his vote by asking, "have you ever heard of Vioxx?"
Then he voted "yes" on approvability. That made him one of two committee members who ended up taking the formal position that InterMune failed to demonstrate "substantial evidence" of efficacy but that the drug should be approved.
His explanation of the apparent contradiction (as we note in "The Pink Sheet DAILY") was simple. Based on the indication of a mortality benefit and the complete lack of effective alternatives, he "would be on the first Delta flight to Japan," where pirfenidone is approved already, if faced with a diagnosis of IPF.
That, in a nutshell, explains the committee vote (and what is likely to be FDA's final action on the appication) perfectly.
Bear in mind that Hendeles is not some naif from academia with no idea how the regulatory process works. He has been involved in FDA advisory committees for three decades and has weighed in on many different aspects of the regulation of pulmonary drugs in that time. He knows the regulatory process pretty well.
The fact is that InterMune's dataset doesn't meet the letter of FDA's definition of substantial evidence. That's not just our opinion: FDA's own statistician says just that in her written summary provided for the committee.
But FDA is prepared to approve this application anyway, because the concept of substantial evidence is and always has been more flexible than that.
Plenty of sponsors have learned that the bar is often higher than the definition makes it sound. But this is an important case of where and when it can be lower.
IPF is a disease that all parties agree is horrific, involving a steady decline in lung function towards a certain and unpleasant death, with absolutely no treatement options that seem to do anything to help. It also has a relatively small (approximately 100,000 patients in the US) and reasonably well-defined patient population.
And these days FDA has the tools to approve drugs like this with more confidence. InterMune is proposing a Risk Evaluation & Mitigation Strategy to highlight the need for liver monitoring and limit the risk of phototoxicity. The company also plans to sell the drug via a centralized distribution system, though it is not proposing that as part of the REMS per se. (That seems like an increasingly common strategy, by the way--read more here.)
Committee members urged a registry, as well as deeper dives into potential markers of response. All that seems very easy for InterMune to do--and for FDA to accept as a reassurance that it will ultimately gather sufficient data to prove (or disprove) a mortality benefit from therapy.
Hendeles put it perfectly: Who wouldn't take pirfenidone, given its success in improving lung function scores in one trial, and consistent albeit not statistical signficiant sign of an increase in survival?
That may not be "substantial evidence" by the letter of the definition. But these days and for this type of therapy, it is probably sufficient.
Hendeles, whose day job is professor of pharmacy and pediatrics at the University of Florida Health Science Center, first voted "no" to the question of whether InterMune's pivotal trials showed "substantial evidence" of efficacy in IPF, as measured by changes in forced vital capacity.
Hendeles was one of five committee members to vote "no" on that question; there were seven "yes" votes. Hendeles noted FDA's definition of "substantial evidence" and his view that the dataset--one study showing improvement in FVC, one failing to show a change, and no unequivocal indication of an overall survival benefit--didn't make the cut.
Then he voted "no" on whether InterMune had provided sufficient evidence of safety; there he was one of three "no's," vs. seven "yes" votes. Hendeles described pirfenidone as a "theophylline-like drug" and explained his vote by asking, "have you ever heard of Vioxx?"
Then he voted "yes" on approvability. That made him one of two committee members who ended up taking the formal position that InterMune failed to demonstrate "substantial evidence" of efficacy but that the drug should be approved.
His explanation of the apparent contradiction (as we note in "The Pink Sheet DAILY") was simple. Based on the indication of a mortality benefit and the complete lack of effective alternatives, he "would be on the first Delta flight to Japan," where pirfenidone is approved already, if faced with a diagnosis of IPF.
That, in a nutshell, explains the committee vote (and what is likely to be FDA's final action on the appication) perfectly.
Bear in mind that Hendeles is not some naif from academia with no idea how the regulatory process works. He has been involved in FDA advisory committees for three decades and has weighed in on many different aspects of the regulation of pulmonary drugs in that time. He knows the regulatory process pretty well.
The fact is that InterMune's dataset doesn't meet the letter of FDA's definition of substantial evidence. That's not just our opinion: FDA's own statistician says just that in her written summary provided for the committee.
But FDA is prepared to approve this application anyway, because the concept of substantial evidence is and always has been more flexible than that.
Plenty of sponsors have learned that the bar is often higher than the definition makes it sound. But this is an important case of where and when it can be lower.
IPF is a disease that all parties agree is horrific, involving a steady decline in lung function towards a certain and unpleasant death, with absolutely no treatement options that seem to do anything to help. It also has a relatively small (approximately 100,000 patients in the US) and reasonably well-defined patient population.
And these days FDA has the tools to approve drugs like this with more confidence. InterMune is proposing a Risk Evaluation & Mitigation Strategy to highlight the need for liver monitoring and limit the risk of phototoxicity. The company also plans to sell the drug via a centralized distribution system, though it is not proposing that as part of the REMS per se. (That seems like an increasingly common strategy, by the way--read more here.)
Committee members urged a registry, as well as deeper dives into potential markers of response. All that seems very easy for InterMune to do--and for FDA to accept as a reassurance that it will ultimately gather sufficient data to prove (or disprove) a mortality benefit from therapy.
Hendeles put it perfectly: Who wouldn't take pirfenidone, given its success in improving lung function scores in one trial, and consistent albeit not statistical signficiant sign of an increase in survival?
That may not be "substantial evidence" by the letter of the definition. But these days and for this type of therapy, it is probably sufficient.
image from flickr user RubyJi used under a creative commons license
1 comment:
Hey lol, seeing this I remember the mathematics we studied in our school days. We sometimes face some trouble in taking decisions, but can over come them.
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