Is the AOM Indication Making a Come-Back?

We will get to the new Hoberman study[1] in a moment, but first a bit of background. AOM, AECS and AECB were labeled indications for antibiotics in the 80s and 90s but were summarily thrown out from the indication catalogue shortly after the 1998 FDA Guidelines were published. The arguments for dismissal were many but can be condensed to these 2 issues: (1) many if not most patients with these conditions have a non-bacterial illness, and (2) the use of NI trials was not proper, as HESDE was never proven convincingly, at least not by FDA standards.

In the absence of new Guidances to show us how to conduct a ‘proper’ otitis / sinusitis / bronchitis trial, sponsors have stayed away from these indications. They had experienced too much regulatory uncertainty of late with anti-infectives, did not think that superiority trials were feasible or had a reasonable chance of success. Big Pharma had bigger fish to fry; therefore, they left the therapeutic area of anti-infectives without much regret and never looked back.

The hope that one day we would have a diagnostic tool to differentiate viral from bacterial etiology is still just that …a hope. Nevertheless, studies in recent years have punched a few holes into the FDA argument that these admittedly self-limiting diseases are trivial, all viral, and not influenced by antibiotics. They have shown that – even if mortality is zero and complication rates are low – there is a benefit for select patient groups in these indications along the “feel / function” axis. Also there is a societal benefit in lost-days of work and use of health-care services that can also be established.

In other words, the science is slowly catching up and refuting the FDA arguments.

The recently published Hoberman trial was a well-designed trial in infants and toddlers (age 6-23 months) comparing a 10-day treatment course of amoxiclav with a 5-day course. The trial was double-blind and placebo-controlled, the endpoint as robust as it gets: otoscopic improvement and complete symptomatic relief. Results consistently showed better efficacy for the 10-day treatment. The difference was highly significant statistically but importantly also showed meaningful symptomatic improvement.

So, this is a landmark study of clinically relevance for managing AOM. It selected children not based on culture evidence of bacterial infection but on clinical entry criteria as clinicians would do in daily practice.

Time to Treatment Failure. From Tähtinen [2]
It is also a trial that demonstrated that treatment duration matters.

There are only few trials in the published literature that try to correlate efficacy with treatment duration, and they are in tonsillitis and in cystitis, which we will discuss in a future blog.

Note that the study did not have a ‘pure’ placebo control arm; in that case the treatment effect would have been even predictably more dramatic. However, a prior study by Tähtinen, also double-blind and placebo-controlled, had such a placebo control arm and showed a very robust benefit with amoxiclav [2]. Btw, the funding for both studies came from NIH and the Foundation for Paediatric Research, not Big Pharma.

Will these studies give sponsors enough confidence to test respiratory antibiotics as part of their PREA pediatric commitments? Will this study trigger a new FDA Guidance for ABOM allowing a NI design? Will the Agency wait for more evidence?

The evidence is accumulating, albeit slowly.

When the science moves on, FDA is likely to act eventually, but we never know exactly when the threshold will be reached for action. We also don’t know FDA’s HESDE requirements. However, we could argue that the Hoberman / Tähtinen studies beat the quality of the 2 Snodgrass trials that FDA found sufficient as anchors for the ABSSSI indication. We believe it is now time to amend prior rules which prohibited NI trials in AOM. It is sad though, if even the FDA had bigger fish to fry.

Perhaps we should design and do Hoberman-like studies in tonsillitis, AECS and AECB before throwing the baby out with the bath water!

AOM       acute otitis media
ABSSSI   acute skin/skin structure infection
AECS      acute exacerbation of chronic sinusitis (aka ABECS)
AECB      acute exacerbation of chronic bronchitis (aka ABECS)
PREA     pediatric research equity act
HESDE  historical evidence of significant drug effect

[1]  A Hoberman. Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children. NEJM 2016;375:2446
[2]  P Tähtinen. A placebo-controlled trial of antimicrobial treatment for acute otitis media. NEJM 2011;364:116

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