Europe Leads the Way!

The European Medicines Agency (EMA) has just released their long-awaited addendum to the antibacterial guidance they released late last year.  It is an amazing document compared to the guidance documents released in the last few years by the FDA in the US.  Clearly, this was the work of a very thoughtful group of smart individuals who kept trial feasibility high on the priority list of considerations.  They also worked hard to avoid the FDA trap of justifying non-inferiority margins at the expense of real-world considerations like trial numbers and endpoints.

In general, the EMA addendum uses clinical response at test of cure as their endpoint.  No fuss, no bother.  Their suggested non-inferiority margins for various indications are as follows:

Complicated UTI – 10%

Community-acquired Pneumonia – 10%

Complicated Skin and Skin Structure Infection – 5-10%

Complicated Intra-abdominal Infection – 12.5%

Hospital-Acquired Pneumonia and/or Ventilator Associated Pneumonia – 12.5%

In my view – these trial designs are all quite feasible in terms of patient numbers with two possible exceptions – anything less than a 10% margin (the 5-10% for skin infection) is probably not realistic and 12.5% for HAP/VAP is, in today’s world, is also probably not feasible.  There is even a feasible pathway forward for an oral only antibiotic for community-acquired pneumonia - an option that does not exist at the FDA (at least for now).

The EMA allows for up to 24 hours of prior antibiotic therapy within the 72 hours prior to enrollment.  They recommend that only a single dose be allowed for UTI and CAP patients – but that is still quite a feasible approach and stands in stark contrast to the FDA.   The EMA also suggest that sponsors perform an “exploratory” analysis of patients who received and did not receive antibiotics.  This suggests to me that this will not be a review issue at least for now – but it behooves sponsors to confirm this during their discussions with the EMA.

In another amazing coup – the EMA recognizes the efficacy of antibiotics for Acute Otitis Media in children similar to those studied in two placebo controlled trials as published in the New England Journal last year (see my blog on this).   This means trials (non-inferiority design) for antibiotics can once again be carried out in children with AOM – a situation that was going to be impossible under the requirement for a superiority design.  This is a critical move on the part of EMA because it opens an entry indication for treatment of pediatric infections that has been unavailable since 2003 or so.

Finally, in another startling development presaged by their general antibacterial guidance, the EMA opens the door for various superiority or open enrollment designs for the approval of drugs that target pathogens rarely causing infection where the medical need is high.  This will include antibiotics active against specific pathogens where resistance is a major problem and antibiotics tackling key resistance mechanisms that may still be rare today.  In their addendum, the EMA clearly recognizes the difficulties in carrying out such trials and the inherent risks in approving such therapies, even with a limited label, based on small numbers of treated patients.  But they also recognize the public health risk of the lack of antibiotics to address these highly resistant pathogens and are paving a pathway forward for sponsors to develop these needed products. The EMA notes (as does the FDA actually) that it is up to sponsors to come forward with specific proposals – but this addendum clearly shows that the EMA is open for business and, more importantly, for protecting the health and safety of patients around the world.  The FDA has to reboot their entire approach to achieve what the EMA has already done – and we’re not there yet!

So – the antibiotic waters in Europe are warm!  Come on in!!

Next week – the Innovative Medicines Initiative explained.