Observations from Past Approvals for Acute Bacterial Sinusitis

1. Observations fromPast Approvals forAcute Bacterial Sinusitis Janice Pohlman, M.D. AIDAC Meeting, October 29, 2003

2. Outline • Regulatory Guidance to Industry • 1992 Points to Consider, 1998 Guidance Document • Retrospective review of drug approvals (10) for Acute Bacterial Sinusitis (ABS) since 1990 • What are we seeing? • What have we learned since the Guidance Documents were released?

3. Industry Guidance (ABS) 1 • First study (clinical only) • Statistically adequate and well-controlled multicenter comparative trial • Rigorous case definitions with specific clinical or radiographic (CT, ultrasonic) entry criteria • Rigorous clinical and radiographic endpoints as primary effectiveness parameters • Sinus puncture not necessary, but encouraged in therapeutic failures

4. Industry Guidance (ABS) 2 • Second study (micro) • Sinus puncture at entry utilized in diagnostic criteria • Establishment of successful microbiologic, clinical, and radiographic outcomes in at least 100 patients • Post-therapy sinus puncture strongly encouraged in therapeutic failures • Outcomes on all patients should be reported (even those without pathogens at entry)

5. Caveats • Guidance Documents serve as “guidance” to industry • Submissions for ABS indication are generally part of an NDA package • Retrospective review of the work of others • data may not have been submitted • parameters of interest may not have been assessed as part of the review

6. ABS Inclusion Criteria Guidance Document • Patients should have a clinical diagnosis of ABS based on history, physical exam, and radiographs • diagnosis of acute sinusitis: signs and symptoms lasting for > 7 days • signs and symptoms should include: facial pain or pressure, purulent nasal discharge, nasal congestion, and cough • radiographic documentation should include CT, sinus X-rays, or ultrasound and include comments about opacity, air-fluid levels, or mucosal thickening

7. ABS Inclusion Criteria“Clinical Only” Trials (1) • Signs and symptoms should include: facial pain or pressure, purulent nasal discharge, nasal congestion, and cough • Use of major signs and symptoms (sinus pain and purulent nasal discharge) in the definition: • Both sinus pain and purulent discharge: 6/10 NDAs • One or both sinus pain and/or purulent discharge: 1/10 NDAs • Sinus pain and purulent nasal discharge contained in multiple symptom list: 2/10 NDAs • Purulent nasal discharge not required: 1/10 NDAs

8. ABS Inclusion Criteria “Clinical Only” Trials (2) • Diagnosis of acute sinusitis: signs and symptoms lasting for > 7 days • No reported minimum duration in 8/10 NDAs • One NDA required 7 days minimum • One NDA required 10 days minimum

9. ABS Inclusion Criteria “Clinical Only” Trials (3) • Radiographic documentation should include CT, sinus X-rays, or ultrasound and include comments about opacity, air-fluid levels, or mucosal thickening • Use of X-rays in all • Use of opacity and air-fluid levels in all • Use of mucosal thickening in all, but extent varies among NDAs: • 4-6 mm: 6/10 approvals • extent not reported: 4/10 approvals

10. Efficacy: ClinicalOutcome Definition • Guidance Document Definitions: • clinical cure:resolution of signs and symptoms at test-of-cure visit and at least no worsening in radiographic appearance • clinical failure: persistence of one or more signs and symptoms of sinusitis or patients receive additional (or new) antibiotics

11. Efficacy: Clinical Outcome Definition“Clinical Only” Trials • clinical cure:resolution of signs and symptoms at test-of-cure visit • 8/10 NDAs define clinical cure as SUCCESS • success incorporates categories of: • cure - resolution of all signs and symptoms • improvement - all signs and symptoms at least improved (or partial resolution) compared to baseline • at least no worsening in radiographic appearance • 5/10 NDAs explicitly use TOC radiograph in Sponsor outcome definition

12. Efficacy: Timing of Test of CureGuidance Document • End-of-Therapy Visit: • evaluation of patients near completion of therapy to optimize patient care (generally 48-72 hours post) • this visit should not be considered a test-of-cure • Post-Therapy (Test-of-Cure, TOC) Visit: • visit should occur approximately 1 to 2 weeks after completion of therapy • treatment durations for ABS generally range from 10-14 days, therefore the TOC visit approximates timing of the 3 week natural history resolution of ABS symptoms • results of clinical evaluation, including status of presenting signs and symptoms should be documented

13. Efficacy Determination:Timing of Test of CureApproved NDAs • Sponsors used the EOT visit for TOC determination in 5/10 NDAs and the post-therapy visit in 5/10 NDAs • MOs used the EOT visit for TOC determination in 2/10 NDAs and the post-therapy visit in 7/10 NDAs

14. Micro Trial: Pathogen DefinitionGuidance Document • Microbiologic diagnosis based on isolation of a bacterial pathogen from baseline maxillary sinus puncture • Documentation should include: Gram stain (with WBC and bacterial morphotype semiquantitation and quantitative bacterial cultures with susceptibility testing) • Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrahalis are considered pathogens regardless of colony count • Staphylococcus aureus is considered pathogen when isolated in pure culture with counts  104 CFU/mL

15. Micro Trial: Pathogen DefinitionApproved NDAs (1) • Major respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) • 6/10 NDAs considered these organisms pathogens regardless of colony count • 3/10 NDAs had no reported definition of pathogen • one NDA required quantity of  103 cfu/mL

16. Micro Trial: Pathogen DefinitionApproved NDAs (2) • Staphylococcus aureus (SA) • 8/10 NDAs consider SA as pathogen • only 3 of these applied Gram stain or quantitative measures to assess as pathogen • information was available for MO to apply Gram stain or quantitative requirements to SA pathogen definition in 2/5 NDAs without Sponsor defined parameters

17. Micro Trial: Sinus Puncture YieldsApproved NDAs • Sinus puncture cultures were positive in 22-87.5% of patients enrolled in the micro clinical trials • The rate of positivity was influenced (and analysis complicated) by pathogen definition: • NDAs with pathogen definition were positive in 36-55% of patients • NDAs with no recorded pathogen definition (any organism a potential pathogen) were positive in 66-72% of patients • 2/10 NDA puncture positivity rates (22% and 42%) were likely underestimated by presentation as micro evaluable positive rates

18. Micro Trial: Bacteriologic EfficacyApproved NDAs • Majority of bacteriologic outcome determinations extrapolated from clinical response in 9/10 NDAs • Single NDA with relatively complete post-treatment follow-up sinus puncture • Sinus puncture rarely done in cases of clinical failure • 4/10 NDAs did have sinus punctures repeated in the setting of clinical failure in limited number of patients

19. Summary: Lessons Learnedfrom Past Approvals for ABS (1) • The micro trial utilizes microbiologic data, in addition to the clinical information in the diagnosis of ABS. • Although the clinical only and micro studies are not directly linked, the inclusion criteria for both are often similar. • The rates of sinus puncture positivity varied widely (22-87.5%) and are dependent upon pathogen definition, method of collection, and the population being reported on.

20. Summary: Lessons Learnedfrom Past Approvals for ABS (2) • Although X-rays are recommended at the end of therapy to document clinical cure, they are seldom used as basis for determining efficacy.