Antibiotic Development - EU vs. US.

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The European Medicines Agency has now released its new guidance on the development of antibacterial drugs.  This document demonstrates how advanced they are in their thinking compared to the US FDA.  I will highlight a few key points that differentiate their approach from that of the FDA below.

The EMA notes that a number of patient types will not have elevated temperatures or white blood cell counts at the time of enrollment.  They therefore do not require these as inclusion criteria. 

In Europe, it is clear that clinical outcome at test of cure is the preferred primary endpoint for studies of antibacterial agents.  This is completely in line with the desires of most physicians and in complete disagreement with the FDA. The EMA would treat the test of cure in the all treated and the clinically evaluable populations as co-primary – again in distinction to the FDA.

The EMA does not specify the non-inferiority margin to be used.  They indicate that one must have reason to believe that the treatment effect of the comparator drug would be superior to placebo and that the non-inferiority margin would conserve at least some of that effect.  But no specific margins are specified and it seems like the determination of the margin for any given study of any given indication could be discussed on a case-by-case basis. 

In this regard, Europe suggests that the historical database of so-called placebo-controlled trials is inadequate for the justification of treatment effect in modern trials.  They therefore encourage the use of pharmacometric analysis of modern trials for this purpose. The FDA is about to makes its first exploration of the value of pharmacometrics (hopefully) this year.  

Europe also provides a discussion of alternative trial designs in their guidance document that clearly shows they are thinking about difficult clinical development issues that could impede our ability to bring new therapeutic options to the sickest patients with the greatest medical need.  This is an area the FDA is just beginning to consider.  The EMA devotes an entire section of their guidance to this.  They discuss the study of rare infections such as endocarditis and meningitis.  They discuss adaptive designs implying they would be willing to discuss a Bayesian approach.  In this case the EMA clearly wants to be part of a detailed and careful discussion before agreeing – but at least they are open to the discussion. Although they clearly state that a randomized active control trial is always preferable, they clearly recognize that in some circumstances, an active control may not be feasible and a historical control might be necessary.  Again, such an approach would require considerable discussion with the EMA.

The EMA clearly states their preferences, but recognizes that it must be open to innovative approaches if we are ever to deliver the kind of targeted therapy we want to those patients with the greatest medical need. This openness, this willingness to discuss new approaches provides a breath of fresh air when compared to similar discussions at FDA who do not even seem to be sure where to start.  I suggest they start by looking at the EMA guidance and actually embarking on a serious harmonization process with the EMA.

When comparing guidance documents for antibacterial drugs, there is no comparison. For those of you with antibacterial products in development where you are struggling with innovative design options – go to Europe. At least you will get an open and considered hearing.