Thursday, August 4, 2011

Sign the Pledge!

Having watched the debate over the debt limit along with the struggles of Republican candidates, I have come to the conclusion that some of them have the right (no pun intended) idea. We need antibiotics developers to sign a pledge.  They must pledge to just say “no” to quote the words of Nancy Reagan.   They must also pledge to explain this response to the FDA in frank, simple and straightforward terms. 

What am I talking about?   As it stands, the FDA has made it infeasible to develop antibiotics for approval in the US for essentially all respiratory tract indications.  Mild infections such as otitis, bronchitis and sinusitis now require placebo controlled trials for approval.  The conduct of such trials in moderate to severe bacterial exacerbations of COPD would be considered unethical by most investigators.  The FDA also has so far ignored data published last year showing a very important antibiotic effect in otitis media whereby any equipoise that might have previously existed no longer does. They also require an infeasible design both for community-acquired and for hospital acquired pneumonia.  Thus, all key respiratory infection indications have been wiped off the map of the US antibiotics market. 

The problem is that I don’t think that the FDA yet understands that these designs are both unnecessary and infeasible.  They continue to suffer the delusion that one can actually carry out such trials. This delusion is apparently reinforced by two factors.  (1) The FDA continues to receive a number of INDs for new antibiotics.  This makes them think that there is no problem in the introduction of new antibiotics to market in spite of the dearth of approvals in the last decade. (2) When companies do come to them at the end of phase II, I believe from a few contacts at such meetings that the FDA is not being told in clear terms that the trial designs required are infeasible and that sponsors will not engage in carrying out such trials. I don’t even know if FDA understands their role in the recent Novartis-Paratek debacle for example.

Sponsors, especially large pharmaceutical companies, don’t want to alientate “the agency” since they work in many therapeutic areas.  Regulatory departments of these large companies are usually extremely conservative and, understandably, don’t like to challenge regulatory agencies.  But for antibiotics, especially at FDA, there is no other way.

My recommendation is shock therapy.  This must be administered by the pharmaceutical industry since the FDA is not listening to words.  Sponsors, at the time of discussions around both phase II designs and at the end of phase II meetings where phase III trial designs are discussed, must be clear and forthright with the agency stating what their limits are in terms of trial designs and what, for them, is commercially feasible and what is not. Even though the FDA does not care about the business aspect of pharmaceuticals, I think they do care about the public health implications of having no new antibiotics approved in key indications.  They also care (I think) about the imminent prospect for off label use where physicians recognize the value of therapy in an indication that the FDA could not approve (doripenem and hospital-acquired pneumonia leaps to mind).

So I ask all sponsors to sign the pledge!  Be frank (politely) and forthcoming with the agency about your limits in trial designs both during discussions around phase II (where the agency is less concerned) and around phase III. The only way for shock therapy to succeed, unfortunately, is if sponsors start walking away in large numbers from the US marketplace while clearly explaining their position to the FDA. 

I already hear the hoof beats – but does the FDA hear the departing stampede yet? 

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