Antibiotics - Recent Developments

Thanks to John Rex for notifying me about the two developments I will discuss here.

The first is an upcoming (March 1) FDA Workshop entitled, “Current State and Further Development of Animal Models of Serious Infections Caused by Acinetobacter baumannii and Pseudomonas aeruginosa.”  The FDA recognizes that clinical trials for pathogen-specific antibiotics will be difficult when the number of infections targeted by the product is expected to be small. They also recognize the value of animal models in predicting both antibiotic dosing and efficacy in humans. As summarized by the FDA, the purpose of this workshop is to discuss “the additional scientific work needed to evaluate current animal models of infection and evaluate potential animal models that may predict response in humans could advance the development of antibacterial drugs targeting a single species.” No briefing materials are posted for the workshop, so I can’t provide specifics as to FDA thinking here.  During the last FDA workshop on pathogen-specific antibiotics, we discussed the potential to use the animal efficacy rule that the FDA has established for special pathogens like antrax and plague where clinical trials for efficacy are not feasible at all.  This is Rex et. al.’s (requires subscription – sorry) Tier D pathway for antibiotic approval. I thought that the consensus at the workshop was that such an approach was not necessary since some clinical data relevant to efficacy could be obtained even if the data were limited.

On the other hand, as I noted, Paul Ambrose kept pointing out that if inferential trials for these products were not possible, animal models and PK/PD could provide a strong rationale for approval. It looks like the FDA may be trying to put investors’ money in Paul’s mouth (or something like that).  It looks to me, trying to read between these lines, like the FDA wants to try and put a more standard definition around the kind of animal models, perhaps even specifying strains of bacteria to be studied and methods to be used, such that uniform datasets can be evaluated when looking at different products. I would anticipate that some clinical data will also be required for approval.

It seems clear that this will be an important workshop for those interested in pathogen-specific antibiotics and especially for those with expertise in animal models and PK/PD. Will we see further guidance on this from FDA this year?

 

A separate development that might be of interest to antibiotic developers comes from Europe and EMA.  I mentioned in my previous discussion of pathogen-specific antibiotics that Europe had more tools available with which to approve products where robust clinical trial data are not readily available. One of these is conditional market approval (CMA).  The FDA has a similar pathway for approval – but it relies specifically on the availability of biomarkers – something we do not have for antibiotics (with the exception of TB). The EMA just completed an analysis of products approved under their conditional approval pathway since 2006. According to EMA, “medicines that were granted a CMA target seriously debilitating or life-threatening conditions such as HIV infection, breast cancer, severe epilepsy in infants or multi-drug resistant tuberculosis. 14 were orphan medicines.”  But a CMA is valid only for one year at which time the conditional approval must be renewed or new data must be presented to allow for full approval.  In 90% of cases, sponsors complied with the requirements of EMA in seeking full market approval and in 70% of cases, sponsors were able to comply with pre-discussed timelines for achieving full approval. Obtaining the data required for full approval took an average of four years.  But this means that for those four years, important new medicines were available for the patients that needed them during which time companies were able to successfully gather data to further support marketing approval (See Figure below). Although the FDA is still faster than EMA for full approvals in general, one must envy the Europeans for their more broadly applicable conditional approval pathway.