Monday, May 2, 2011

Antibiotics at FDA vs. EU - Compare and Contrast

European Medicines AgencyImage via Wikipedia

I just ran across something so striking, I had to share it with you.  The European Medicines Agency (EMA) just released a report on their Workshop on Antibacterials held in February. Clearly, the EMA is considering issuing guidances specific to anti-infective indications similar to the way FDA has issued such specific guidances.  Hopefully, that is where the similarity with FDA will end.  The agenda for the workshop covered non-inferiority trial designs for skin and skin structure infections and hospital acquired pneumonia.  They also discussed the issue of placebo-controlled vs. active comparator controlled non-inferiority trials for mild infections including acute otitis media in light of recent data.  Superiority trials for agents active against resistant pathogens were discussed.

For hospital-acquired pneumonia, Pr. Chastre essentially made the case for the FDA approach using all cause 28-day mortality as the appropriate endpoint for these trials. But a very reasoned discussion by Dr. Fromtling responded by noting that all cause mortality was not relevant to clinical practice nor is it a sensitive endpoint.  He also notes that the 10% NI margin applied to the microbiologically documented population makes such trials essentially infeasible.  He takes issue with the FDA proscription against any prior antibiotics that would make the study population irrelevant to clinical practice and is an infeasible design criterion in any case.  He makes a number of positive suggestions as to trial designs that would be both relevant and feasible.

Paul Ambrose presented an approach to justifying NI margins using PK/PD data and a Bayesian based pharmacometric method. He presented the application of such data to the tigecycline trial where M1 could be determined with great precision in a modern setting.  Clearly, there are important implications of the use of these methods for modern trial data analysis as well as the statistical design of such trials.  The opportunity for reducing patient numbers could be an attractive feature of such an approach.

John Rex made the case that for skin infections, the analysis at test of cure already takes into account any response or lack thereof at early time points.  Dr. Brad Spellberg has previously noted the clinical irrelevance of the proposed FDA early endpoints.  Dr. Rex also notes that a large treatment effect easily justifies margins of 15% or greater rather than the 10% suggested by FDA.

On the topic of superiority vs. NI studies of otitis, the discussion centered on data recently published on well-designed placebo controlled trials in the US and EU.  It is clear that otitis is an important entry indication into pediatric therapy.  But since the proscription against non-inferiority trials, industry has not studied this indication at all.  Further, the recent trials showing a clear advantage of therapy over placebo in young children with well-documented acute otitis media remove equipoise from consideration for this population.  It is no longer ethical to carry out such trials.  So, either we will develop new antibiotics for this indication in pediatrics or we will not – but a justification for NI trials now exists and one for placebo-controlled trials does not.

 There was a very well considered discussion of superiority trials for agents active against resistant pathogens.  It seemed clear that some way of bridging across multiple indications (where PK is at least somewhat similar) would be required to make such an approach viable.  Mark Goldberger noted that some clinical data combined with strong clinical and pre-clinical PK/PD and microbiological data could be used to support at least a conditional approval. This would depend on having approval for at least one standard anti-infective indication in a serious infection. It is likely that such approaches to new therapies for MDR pathogens will have to be evaluated on a case-by-case basis.

Overall, the tone and tenor of the discussion as portrayed in the report was considered and rational.  No one seemed to be screaming that clinical signs are biomarkers and therefore invalid as parts of endpoints in clinical trials. The EMA seems to appreciate antibiotics and they take seriously their responsibility to make sure that we have a pipeline of these valuable therapeutic agents – especially during a time when new resistance mechanisms or old mechanisms in new virulent strains seem to be popping up at every turn. The EU understands the importance of feasible trial designs in maintaining such a pipeline. This report stands in stark contrast to the Anti-infectives Drug Advisory Committee meetings of the FDA. I leave it to you to compare and contrast.

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