David's New Book

Friday, October 5, 2012

FDA - About Face on Otitis!

As recently as 2010, the FDA stated in their guidance on the design of non-inferiority trials for antibacterial drugs that such designs were not appropriate for acute otitis media, acute bacterial exacerbations of chronic obstructive pulmonary disease and for acute bacterial sinusitis.  They insisted on superiority design trials for approval for these infections.

Then, two placebo-controlled trials were published in the New England Journal (see my earlier blog on this for links to the articles).  One was conducted in Europe and took 3 years to enroll.  The other was performed in the US and was enrolled in about 5 years.   In both trials, very strict clinical criteria were used to define otitis media in children.  This differentiated these trials from many previously published placebo controlled trials where the definitions for diagnosis were not strict and where the treatment effect for antibiotics was, at best, controversial.  In both trials, there was about a 35% treatment effect with the failures occurring in the placebo group starting about day three and continuing through day 8 of study.  In the placebo groups there were perforations of the eardrum, mastoiditis and even pneumonia.

Both the EMA and the FDA held workshops where this issue was addressed.  In both, there was more or less a consensus that equipoise, at least for these carefully defined cases, had been lost and that non-inferiority trials could be undertaken.  Issues that remain unresolved are what the non-inferiority margin would need to be and how many trials would be required to achieve approval.

But in their latest guidance document, the FDA now allows the performance of non-inferiority trials to evaluate new antibacterial drugs in the treatment of acute otitis media in children.  This represents a complete about face carried out based on compelling data.  EMA came to exactly the same conclusion and they too propose allowing non-inferiority trials for the study of new drugs in the treatment of well-documented acute otitis media.

For some pharmaceutical companies, this may seem irrelevant. They see little medical need in this area and they have already adapted to a world where clinical trials in this area were infeasible.  But hold the phone!  Stop the presses!  Acute otitis media is a KEY entry indication into the pediatric world.  And while the few intravenous antibiotics in the pipeline that target resistant pathogens  are inappropriate for this indication, there are few pipeline compounds that could provide needed new alternatives to the therapy of otitis media in children.  Examples that spring to mind include solithromycin from Cempra and BC-3781 from Nabriva. Both of these compounds offer the advantage of overcoming common resistance mechanisms in bacterial pathogens that cause otitis media and allowing physicians options other than the fluoroquinolones that are not approved for use in children.  (Of course there may be others and forgive me if I have omitted your particular favorite). 

So my hat is off to FDA and to EMA for (finally) recognizing the reality that antibiotics work in this infection and for putting this recognition into their guidance.  Of course, what is not specified in either guidance is the specifics of carrying out such a study.  From my own point of view, given the large treatment effect, a 10% NI margin on clinical outcome (based on symptoms plus a careful evaluation of the eardrum) in patients will well documented disease should be more than reasonable. As always, we await further developments . . .