InterMune’s roller coaster ride with the idiopathic pulmonary fibrosis therapy pirfenidone took a steep dive back down when FDA issued a “complete response” letter asking for another clinical trial on May 4.
That decision, in one sense, is hardly surprising: FDA already made public the conclusion of its statistical reviewer that the NDA for pirfenidone didn’t meet the definition of “substantial evidence” for efficacy. Slam dunk non-approval.
Except that conclusion was presented to an FDA advisory committee in March for its consideration—with the remarkable outcome that many committee members seemed to agree that the data wasn’t sufficient to meet the “substantial evidence” standard, yet they voted for approval anyway.
It sure looked like a case where FDA was ready to be very flexible in the interest of making a potentially useful drug available for a horrific and untreated disease. One committee member actual voted “no” on the whether there was sufficient proof of efficacy, “no” on whether there was sufficient evidence of safety—and then “yes” on approvability. (Or, as we put it at the time, “No+No=Yes.”)
Apparently “substantial evidence” isn’t as flexible as all that. According to InterMune, FDA says it needs another trial to demonstrate sufficient evidence of efficacy. It may have to be a survival trial, or perhaps a trial with forced vital capacity as an endpoint.
InterMune says it won’t know for sure what will be required to support approval until after it meets with FDA to discuss the complete response letter. Still, the pivotal trial included in the NDA took three years from start to finish; replicating it means a prolonged delay.
So much for a “flexible” standard for substantial evidence, huh?
Maybe not. There is one wildcard in all this: pirfenidone is approved in Japan and marketed there by Shionogi. FDA wanted to review the Japanese trial data, but InterMune provided only summaries; the company didn’t think it would be worthwhile investing the time and resources to make individual case-level data available to the agency.
Our impression of the advisory committee was (and is) that the agency wanted the committee to, in effect, give them permission to approve pirfenidone based on something much less robust than you would expect for, say, a COPD therapy. FDA got that permission.
Still, it isn’t hard to understand why FDA would at least want that data before taking a chance on approving this application.
It may be that the “substantial evidence” standard still turns out to be more flexible than it appears to be—but with the caveat that, no matter how “substantial” it is, FDA expects to see all the data.
That decision, in one sense, is hardly surprising: FDA already made public the conclusion of its statistical reviewer that the NDA for pirfenidone didn’t meet the definition of “substantial evidence” for efficacy. Slam dunk non-approval.
Except that conclusion was presented to an FDA advisory committee in March for its consideration—with the remarkable outcome that many committee members seemed to agree that the data wasn’t sufficient to meet the “substantial evidence” standard, yet they voted for approval anyway.
It sure looked like a case where FDA was ready to be very flexible in the interest of making a potentially useful drug available for a horrific and untreated disease. One committee member actual voted “no” on the whether there was sufficient proof of efficacy, “no” on whether there was sufficient evidence of safety—and then “yes” on approvability. (Or, as we put it at the time, “No+No=Yes.”)
Apparently “substantial evidence” isn’t as flexible as all that. According to InterMune, FDA says it needs another trial to demonstrate sufficient evidence of efficacy. It may have to be a survival trial, or perhaps a trial with forced vital capacity as an endpoint.
InterMune says it won’t know for sure what will be required to support approval until after it meets with FDA to discuss the complete response letter. Still, the pivotal trial included in the NDA took three years from start to finish; replicating it means a prolonged delay.
So much for a “flexible” standard for substantial evidence, huh?
Maybe not. There is one wildcard in all this: pirfenidone is approved in Japan and marketed there by Shionogi. FDA wanted to review the Japanese trial data, but InterMune provided only summaries; the company didn’t think it would be worthwhile investing the time and resources to make individual case-level data available to the agency.
Our impression of the advisory committee was (and is) that the agency wanted the committee to, in effect, give them permission to approve pirfenidone based on something much less robust than you would expect for, say, a COPD therapy. FDA got that permission.
Still, it isn’t hard to understand why FDA would at least want that data before taking a chance on approving this application.
It may be that the “substantial evidence” standard still turns out to be more flexible than it appears to be—but with the caveat that, no matter how “substantial” it is, FDA expects to see all the data.
image from flickr user RubyJi used under a creative commons license
3 comments:
intermune can return at 40-50$?!
the FDA stated very clearly about the agency’s position in selecting primary endpoint, which is “Measure Mortality; mortality should support primary end point” (Ref 2 – slide 5 of part 4).
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When Intermune meets the FDA, there is 50% chance that the FDA would like to run a third trial in which FVC is primary end point with mortality as the second end point, and mortality should support primary end point. This is not a confirmation study, as both Capacity trials did not show benefits in mortality. That’s the best Intermune can reasonable get. However, it would be an additional 3-4 years and success rates would be less than 30%. The other possibility is that FDA would like to run a new clinical trial with survival as primary endpoint. This would mean additional 5-6 years and success rate would be below 10%. If that’s the case, Intermune most likely would abandon Pirfenidone project.
What is the chance of EU approval? There are a few other companies conducting phase III trial for IPF. Among them, Gilead Science (GILD) is evaluating effectiveness of Ambrisentan (endothelin receptor antagonist) in treating IPF; Actelion just finished its phase III BUILD-3 study with Bosentan in IPF (failed to meet primary endpoint). Both Gilead and Actelion are using progression-free survival as primary end point. These are very respectful companies. If FVC is a valid primary end point for IPF, they would use it because it is shorter and cheaper. I think the chance of approval for Pirfenidone in EU is also very slim.
What other issues are ahead of Intermune?
As many investors lose money, the company is exposed to potential lawsuits. Intermune executives have given investors the impression that FDA approved FVC as the primary end point. As of May 9, 2010, the archived news release in 2007 is still on the ITMN web site stating “FVC as the primary endpoint of CAPACITY is supported by the FDA and the EMEA” (Ref 3). In fact, we know from FDA memo that FDA was actually not supporting it (Ref 1, 2). Do not be surprised if the SEC starts to investigate this issue.
Intermune still has a HCV protease inhibitor (ITMN-191/RG7227) in phase II trial. However, Vertex and Merck’s HCV protease inhibitor programs are at least 18 months ahead of Intermune; and the efficacy verses risk profile of RG7227 is probably no better than the others. Most investors still believe that ITMN’s problem is similar like DNDN was in 2007. The reality is that ITMN is not DNDN. As the light further shed inside, the price will continually decline in the next few months.
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