Development of Antibiotics forOtitis 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•1998 FDA Draft Guidance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 thedrug works and is safe for children withotitis media?
Otitis Media:Incidence & Epidemiology
•25,000,000 visits for otitis media yearly inthe 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 tympanicmembrane and middle ear”)
•tympanocentesis: required in both studies atbaseline. Second tap desirable to obtain data onMEF concentrations and promptness ofbacteriologic 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 theeffectiveness of any anti-infective drug.”
AOM in the 80s: What Happened
•no new formal guidance on otitis from FDA
•“internal discussions” on AOM centered onrequirement to perform tympanocentesis onevery child enrolled in a trial
–procedure is difficult to do
–too few are trained to do it
–it’s 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 Documenton AOM
•number of trials: two suggested
- “clinical only” study (no tympanocentesis at baseline) toestablish equivalence to an approved product
- one clinical/microbiologic study with tympanocentesis atbaseline
•case definition: should be rigid
•tympanocentesis: strongly encouraged in thosepatients judged to be therapeutic failures
•endpoints: clinical; clinical and microbiologic
•test of cure: not specifically addressed
1992 Points-to-Consider Documenton AOM (continued)
The open micro study should establishacceptable microbial and clinical outcomein at least 25 patients with H. influenzae, inat least 25 patients with S. pneumoniae, andin at least 15 patients with M. catarrhalis.
1992 IDSA/FDA Guidelines onAOM
•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 patientswho 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 ascritical measure of treatment efficacy; performtympanocentesis in all failures
•endpoints: primary efficacy endpoints are clinicalcure at TOC and pathogen eradication.
•test-of-cure: TOC visit 2-4 weeks after studyentry.
•Enhance efforts to enroll patients with penicillin-resistant organisms
1998 AOM Draft Guidance:Advisory Committee Recommendations
With regard to the microbiologic endpoint:
1998: “Tympanocentesis obtained at the on-therapyvisit should not be considered evidence ofdocumented eradication. Rather, a negativeculture result may represent antimicrobialsuppression.”
2001: “Tympanocentesis obtained on therapy shouldbe 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 24months of age
•Enroll patients with ruptured TM’s, historyof recurrent otitis, antibiotic prophylaxis
•Include patients with recent AOM who havefailed 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 secondaryendpoint
•Would encourage follow-up as secondary with tapsfor failures
2001 AC Recommendations(continued)
Most informative tap:
•Consensus was taps on therapy and at thetime of failure were needed
•Cure rates should be bacteria specific suchthat the cure rate exceeds the spontaneouscure rate by some arbitrary amount, say 10or 20%
2001 AC Recommendations (continued)
Clinical only and Micro studies:
•Why would we want to do clinical only studiesanymore for this indication? No meaningfulefficacy data
•With high spontaneous cure rate, what informationwill be gained from them?
•Don’t see how can do efficacy studies withoutknowing the organism
•Therefore, tighten up inclusion criteria for clinicalonly study
Clinical case definition for AOM
•Experience tells us, AOM can be a difficultcall
•Even when the inclusion criteria are tight,and case report forms document presence ofspecific objective criteria, there is a broadrange of culture-positive results forinvestigators, from “low to high”
Back to the Future
clinical case definition: How strict is strict?
trial design considerations: tympanocentesis forone 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?