Development of Antibiotics for

Otitis Media:
Past, Present, and Future

Janice Soreth, M.D.

Director
Division of Anti-Infective Drug Products
 Outline of the Past and Present
1977 Guidance
1992 Points-to-Consider Document
1992 IDSA/FDA Guidelines
1998 FDA Draft Guidance
 Back to the Future?
tympanocentesis for all?
single v. multiple?
clinical-only studies?
placebo-controlled trials?
trial versus trials
Bottom line: What do we need, to know the
drug works and is safe for children with
otitis media?
 Otitis Media:
Incidence & Epidemiology
25,000,000 visits for otitis media yearly in
the U.S.
accounts for 1 out of 3 pediatric office visits
by 1 year of age:
62% > 1 episode AOM; 17 % > 3
by 3 years of age:
80% > 1 episode AOM; 46 % > 3
categories: occasional AOM to otitis prone
 1977 FDA Guidance on AOM
number of trials: not addressed
case definition: clinical evidence of AOM
(evidence of inflammation of tympanic
membrane and middle ear)
tympanocentesis: required in both studies at
baseline. Second tap desirable to obtain data on
MEF concentrations and promptness of
bacteriologic cure.
endpoints: both clinical and microbiologic
test of cure: not addressed; 4 weeks of follow-up
 1977 FDA Guidance on AOM
(continued)

In the absence of culture of middle ear fluid,

no specific claim can be made regarding the
effectiveness of any anti-infective drug.
AOM in the 80s: What Happened
no new formal guidance on otitis from FDA
internal discussions on AOM centered on
requirement to perform tympanocentesis on
every child enrolled in a trial
procedure is difficult to do
too few are trained to do it
its hampering enrollment in trials
it costs too much
Is there a better way to design AOM trials,
and know whether a drug works or not?
 1992 Points-to-Consider Document
on AOM
number of trials: two suggested
- clinical only study (no tympanocentesis at baseline) to
establish equivalence to an approved product
- one clinical/microbiologic study with tympanocentesis at
baseline
case definition: should be rigid
tympanocentesis: strongly encouraged in those
patients judged to be therapeutic failures
endpoints: clinical; clinical and microbiologic
test of cure: not specifically addressed
1992 Points-to-Consider Document
on AOM (continued)

The open micro study should establish

acceptable microbial and clinical outcome
in at least 25 patients with H. influenzae, in
at least 25 patients with S. pneumoniae, and
in at least 15 patients with M. catarrhalis.
 1992 IDSA/FDA Guidelines on
AOM
number of trials: two suggested
- a micro study (100 patients)
- a comparative clinical trial (tap optional); double-blind
case definition: clinical criteria listed
tympanocentesis: tap required in those patients
who are not clinical successes (failure, relapse,
recurrence)
endpoints: clinical; clinical and microbiologic
test-of-cure: 1-2 weeks after completion of therapy
 1997 & 1998 FDA Draft Guidance on AOM

number of trials: two suggested

- a micro study, non-comparative; increase numbers
- a comparative clinical trial
case definition: tighten, tighten, tighten
tympanocentesis: repeat tap at study day 3-5 as
critical measure of treatment efficacy; perform
tympanocentesis in all failures
endpoints: primary efficacy endpoints are clinical
cure at TOC and pathogen eradication.
 1998 AOM Draft Guidance:
Advisory Committee Recommendations

With regard to the microbiologic endpoint:

1998: Tympanocentesis obtained at the on-therapy
visit should not be considered evidence of
documented eradication. Rather, a negative
culture result may represent antimicrobial
suppression.

2001: Tympanocentesis obtained on therapy should

be the primary microbiologic endpoint.
 1998 AOM Draft Guidance:
Advisory Committee Recommendations 1998
(continued)

Enroll more patients < 2 years of age.

Gain much more experience with penicillin-
resistant organisms.
 1998 AOM Draft Guidance:
Advisory Committee Recommendations

Increase the number of patients under 24

months of age
Enroll patients with ruptured TMs, history
of recurrent otitis, antibiotic prophylaxis
Include patients with recent AOM who have
failed a course of antibiotics
 2001 AC Recommendations
Timing of assessment of clinical outcome:

primary endpoint should be end of therapy visit ;

late follow-up visit is an important secondary
endpoint
Would encourage follow-up as secondary with taps
for failures
 2001 AC Recommendations
(continued)
Most informative tap:
Consensus was taps on therapy and at the
time of failure were needed
Cure rates should be bacteria specific such
that the cure rate exceeds the spontaneous
cure rate by some arbitrary amount, say 10
or 20%
 2001 AC Recommendations (continued)
Clinical only and Micro studies:
Why would we want to do clinical only studies
anymore for this indication? No meaningful
efficacy data
With high spontaneous cure rate, what information
will be gained from them?
Dont see how can do efficacy studies without
knowing the organism
Therefore, tighten up inclusion criteria for clinical
only study
Clinical case definition for AOM
Experience tells us, AOM can be a difficult
call
Even when the inclusion criteria are tight,
and case report forms document presence of
specific objective criteria, there is a broad
range of culture-positive results for
investigators, from low to high
 Back to the Future
clinical case definition: How strict is strict?
trial design considerations: tympanocentesis for
one and all?
baseline/on-therapy/at time of failure
endpoints and timing of assessments:
clinical-only studies
micro-based studies
non-inferiority v. superiority designs
placebo-controlled trials
spectrum of disease:
severity, chronicity
distinct patient populations
 Back to the Future
Question of the day:

What do we need to know,

what constitutes substantial evidence,
that a novel antimicrobial drug works and
is safe for children with otitis media?