The FDA Can Change Its Requirements After Completion of a Trial and then Require New Trials for Approval

Another really interesting development at the FDA is the policy that they can change their minds about previous agreements. In the old days, maybe even up to 7 years ago or so, if you had a discussion with the FDA on your trial design and they agreed with it in writing, they would not reject your data because they had come out with new policy requiring a different design. This is important. A company will pay about $30 million for a single Phase III antibiotic trial. To get approval, you need to run two such trials for each indication (skin infection, pneumonia, etc.). These trials usually take about 2 years to run and at least another 6-12 months for data analysis and submission of the dossier to regulatory agencies. Most companies plan on spending about $70 million on trials and other requirements to get approval for a single indication. Before putting that much money in play, companies like some reassurance that the trial design they are using will, if the study reaches its endpoints, lead to approval by the FDA. There is a process in place at the FDA (Special Protocoal Assessment or SPA) where sponsors can submit specific trial protocols and get written comments back from the FDA. This, in the past, was extremely valuable to all parties. The withdrawal of approval of Ketek for sinusitis and bronchitis because they did not run placebo controlled trials that they didn't know they needed to run is one example of how the exchange between industry and the FDA has become dysfunctional. In 2005, Advanced Life Sciences started Ph. III trials of their antibiotic, cethromycin, which they had licensed from Abbot a number of years earlier. It is similar to Ketek, but thought to have a better safety profile. They agreed a trial design with the agency and completed their trials in 2007. An NDA (New Drug Application for approval to market) was submitted to the FDA and accepted by them in 2008. In 2009, the FDA informed Advanced Life Sciences that the trial data submitted did not prove that their drug was efficacious because the design and therefore results did not conform to guidelines promulgated by the agency in 2009. Advanced Life Sciences is now in the throes of trying to complete such a trial. Their drug will now be delayed by years if it ever does get approved.

An even more abysmal example of this occurred just after Thanksgiving, 2009 when the FDA notified Theravance that the data from two phase III trials in hospital-acquired pneumonia would have to be analyzed based on a primary endpoint of all cause mortality and not the previously agreed primary endpoint of clinical outcome. Theravance had designed these two trials to look at clinical improvement in the actual pneumonia being treated as a primary endpoint and examined all cause mortality as a secondary endpoint as agreed with the FDA at the outset of the studies. If Theravance is unable to provide enough data to satisfy the FDA statistically that they succeeded in improving the new primary outcome of all cause mortality, they will have to run at least one more study in this indication. I would estimate that trials in hospital-acquired pneumonia probably run around $50 million each because of the complexity of the patients and the severity of the illness involved. So Theravance and its partner Astellas have probably already sunk $100 million into these trials and they may have to sink yet another $50 million to get to the new goalposts - and this will only be after at least another 2-3 years of study.

Another company, Replidyne, went belly-up following a similar change of opinion in midstream by the FDA. If companies cannot have some assurance that the large investment required up front for clinical trials of antibiotics won't be thrown down the toilet from the get-go because the FDA can change the goalposts at any time, why should they take the risk at all? This is especially true now when the goalposts seem to move every month!

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