What happens when the FDA decides on new policies during the course of a clinical trial? Last week, Replidyne and Forest Laboratories reported that the FDA issued a non-approvable letter for Faropenem, an antibiotic. The FDA wanted further clinical studies for all the indications sought by the sponsors and stated that superiority would need to be demonstrated, as opposed to traditional non-inferiority standard. In other words, the FDA was asking that the sponsors demonstrate that the new compound was better than the standard of treatment rather than equivalent. Safety issues were apparently not raised.
As noted in the Replidyne press release – "[h]istorically the FDA has not required superiority design studies such as placebo-controlled studies for the approval of antibiotics…" – and why would you? Wouldn’t it be unethical to take people with infections and give them a placebo? Remember Tuskegee? When you know people are infected, you treat them.
Did this signal a change in policy on the part of the agency? Did the change in policy occur mid-way between the time that the sponsors outlined to the FDA their clinical trial plans and the time when the FDA was going to make its decision? If so, who, if anyone, is setting policy?
Earlier this year, Senator Charles Grassley (R-Iowa), using overly dramatic antics not seen since a 1930s film, raised question over the emergence of some adverse events associated with another antibiotic, Ketek which was approved with non-inferiority trials. He demanded to know how safety questions regarding the drug were handled.
As a result, question also fell on whether or not non-inferiority should be the standard for antibiotics. In the wake of the Ketek issue, the FDA indicated it would re-evaluate the use of non-inferiority trials for antibiotics.
Usually that kind of policy change involves at least an advisory committee meeting to discuss the matter. But if a company submits its clinical trial design to the FDA and meets its endpoints with sound data, is it fair to subject the company to a last minute change in policy?
Reportedly, many companies are getting out of the business of making antibiotics because the hurdles are becoming too great or the economics unattractive. Is another hurdle a finicky FDA that crosses signals to sponsors? All of this occurs at a time when new antibiotics are much needed as older ones face the development of resistance. Is public health being well served, or is this a public health response to a political problem?
By the way, Happy Halloween.