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Study Considerations: Acute Bacterial Otitis Media

Study Considerations: Acute Bacterial Otitis Media. Recurrent / Treatment Failure Rosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products. Study Considerations: Revisiting the Guidance. Targeted Populations: AOM. Current Draft Guidance

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Study Considerations: Acute Bacterial Otitis Media

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  1. Study Considerations:AcuteBacterial Otitis Media Recurrent / Treatment Failure Rosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products

  2. Study Considerations: Revisiting the Guidance

  3. Targeted Populations: AOM • Current Draft Guidance • Proposal for change • Discussion of definitions • Types of Trials • Items for Discussion

  4. 1998 Draft Guidance / 1992 Points-to-Consider • One indication: AOM • Exclusion Criteria includes • systemic anti-infective drug product in the previous 7 days prior to enrollment (clinical-only study) • systemic anti-infective drug product in the previous 3 days prior to enrollment (clinical/microbiological study) • patient receiving antimicrobial prophylaxis for recurrent otitis media • penicillins/aminopenicillins, cephalosporins, macrolides approved with all-comers with above exclusions

  5. Proposal for change Recent AIDAC Advice • Dr. Leggett (11/2001) “...there was a thing about not being able to use antibiotics within the last 7 days of the last month. I think that would be another way to actually enrich the resistant population because isn’t that who we have the trouble with, the more severe illness and the more resistant pathogens?” • Dr. Wald (11/2001) “....I think that groups of children that we should be studying are children with severe disease..”

  6. Proposal for change Challenge of antibiotic resistance Underlying factor: PRSP (diagram not to scale) All AOM Severe Recently Treated PRSP

  7. Proposal for change

  8. Developed w/ PRSP in mind Some enrichment stategies used to maximize patients with bacterial AOM esp. PRSP Label: Augmentin ES-600® “..is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media .........characterized by the following risk factors: antibiotic exposure for AOM within the preceding 3 months, AND either of the following: age < 2 years, daycare attendance” This “recurrent or persistent” sub-population not pre-defined and inserted post development to differentiate 14:1 from 7:1 formulation Lesson Learned: this population needs to be pre-defined. Proposal for changeDrug Development, “High-Dose”Augmentin

  9. Proposal for changeDrug Development, Fluoroquinolones for Peds • 1989: Specific Underlying Dz, older child Cystic Fibrosis, Cancer, >6 years • 1993: Expand diseases and age CF, Cancer, Sickle Cell, CompUTI, COMsupprativa,etc. Unanimous: not for investigation in routine indications • 1997: Continue development for severe indications Treat “the sicker sub-populations” of generally well children with gram-positive resistant organisms

  10. Proposal for changeDrug Development, Fluoroquinolones for Peds • Dr. McCracken’s Statement (1997 AIDAC Meeting) “…the fluoroquinolones could then be evaluated in hospitalized pediatric patients with community or hospital-acquired pneumonia and possible middle ear or sinus infections caused by resistant pathogens, PRSP, i.e. in recurrent or persistent OM…” • 2002 and beyond: At least one fluoroquinolone undergoing development for AOM for the specific sub-population of “Recurrent/ Non-responsive OM” Arguedas A et al. Gatifloxacin Treatment of Recurrent/Non-Responsive Acute Otitis Media. 41st ICAAC 2001: Abstract G-1534

  11. Proposal for change: SummaryWhat we have heard and learned • Enrich the population for Acute Bacterial Otitis Media, especially PRSP AOM • Study “recurrent and/or persistent” disease • Do not exclude recent antibiotic use • Drug DP for PRSP: Not for routine use • safety issues • Other drugs available for routine OM • Save the new drug, curb more drug resistance • The Need for Pre-defined Populations

  12. Proposal for Change: An Answer

  13. Proposal for Change: An Answer Two indications would represent two distinct populations with RESISTANCE factor overlap (diagram not to scale) AOM R/TF AOM PRSP

  14. Precise Definitions Define the elements of the additional indication Reach a consensus about the definitions Clarify terms to avoid confusion

  15. Definitions: RecurrentIs this what we heard? > 3 episodes of AOM over the last 6 months OR > 4 episodes of AOM over the past year • generally accepted and used definition • children with underlying factors • young children with anatomical immaturity • clinically: thought of as a distinct population • microbiologically: subset with  PRSP?

  16. Definitions: Treatment FailureIs this what we heard? During therapy: No improvement observed in signs and symptoms of AOM after at least 48 hours of antibiotic management OR Post therapy: Presentation with signs and symptoms of acute otitis media within 7 days of completing a course of antibiotics for acute otitis media • Microbiologically: subset with  PRSP • Inclusive of accepted definition of Persistent AOM (3rd day) AND exclusive of the time point (beyond 1 week after EOT, hard to differentiate re-infection vs. new-infection)

  17. Descriptive names for “sub-populations” not clearly defined “difficult-to-treat OM” “otitis-prone children” “hard-to-treat OM” children “at-risk” Inclusion Criteria included in recent protocols to study “stepped-up” therapy for these “sub-populations” < 24 months daycare attendance 3 or more siblings Definitions: need for precision

  18. Definitions: Enrichment overall • Use these listings as enrichment strategies for bacterial OM for both indications R/ TF AOM AOM PRSP

  19. Definitions: Enrichment overall • Use these listings as enrichment strategies for bacterial OM for both indications Younger than 2 yrs Daycare attendance R/ TF AOM AOM PRSP

  20. Targeted Populations <=>Relevant Indications <=>Drug Development Programs<=> Types of Trials

  21. Types of Trials: Recurrent/Treatment Failure AOM

  22. Acute Bacterial Otitis Media Study Considerations: SummaryOverviewand Items for Discussion

  23. Items for Discussion: Proposed Additional Indication of R/TF AOM • Definition for “Recurrent” AOM • Definition for “Treatment Failure” AOM • Do these two groups fit the population to pre-define for “not-for-routine” drug development programs w/ PRSP emphasis? • Is it reasonable to have these two groups be placed together in the new indication? • Are the types of trials for this indication appropriate? Any other types of studies?

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