Dr. Nambiar states that, “ The non-inferiority margin should be prespecified, based on historical evidence of treatment effect for the active comparator and be reliable and reproducible.” Drs. Spellberg (especially) and Kuti note that the endpoints found in today’s guidance documents are anything but that. In discussing the guidance for skin infection trials, Brad notes, “Given that sulfonamides were clearly greatly less effective than modern antibiotics and yet had a >95% success rate with this end point, how can this end point possibly distinguish less effective drugs from more effective drugs? This end point has no assay sensitivity according to the very data used to justify the end point. It is ironic that the statistical concern that non-inferiority studies could lead to approval of inferior therapies has led to selection of a new end point for future studies which, according to the very historical data used to justify it, can’t distinguish inferior from superior therapy. Finally, recent experience suggests that the cessation of lesion spread end point has much lower success rates (e.g., 70%) in modern studies than in the Snodgrass and Anderson data. This is another example of lack of constancy.”
Dr. Nambiar also notes that the trials should be feasible. While that is the case for trials in skin infections (even though that guidance document might have lots of other problems), it is certainly not so for any respiratory infections. The FDA has stated this before – that trial designs required by guidance must be feasible. So where are the feasible designs? Dr. Nambiar’s response when challenged on this point by the interviewer was to say that trials must be scientifically rigorous. Good – who could disagree with that? But if you can’t actually conduct the trial – what’s the point?
In discussing endpoints, luckily, Dr. Nambiar recognizes that a physicians assessment is valuable, even beyond specific data on how a patient feels, functions or survives. In conclusion, Dr. Nambiar discusses the fact that the new, scientifically rigorous approach by the FDA, along with guidance being provided by the Foundation for NIH, is important in thisw time of difficult challenges for antimicrobial chemotherapy. But both Drs. Spellberg and Kuti question the scientific rigor of the FDA’s approach as exemplified in recent Draft Guidance documents on several fronts. It seems that from the clinicians’ point of view, the FDA has developed a “pseudoscience” (my interpretation) around non-inferiority. In my own view, this restrictive view of non-inferiority design is impeding development of new antibiotics and is chasing companies out of the field.
Of interest, the Rib-X interview was very focused on the data gathering they are doing to be able to do in order to argue their case before the FDA. They also addressed issues of running global trials when the FDA and EMA do not agree on endpoints. There were no questions for R-b-X inviting them to challenge the FDA on trial feasibility. I suspect that Rib-X, like most companies, did not want to get into that discussion – certainly not publicly. But as I suggested in my last blog – I hope they will get into that discussion vocally when they do meet with the FDA privately.
The bottom line for me from these very interesting interviews is that infectious diseases clinicians and the FDA live on different planets or in different dimensions – I’m not sure which. Scientific rigor for the FDA is not at all that for the clinicians. Feasibility of trial design is another point of clear disagreement. So here we are – back where we started in 2006-8. How will we find a way forward?
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