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 . . .
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