1 Observations from Past Approvals for Acute 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: Clinical Outcome 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 Cure Guidance Document End-of-Therapy Visit: –evaluation of patients near completion of therapy to optimize patient care (generally 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 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 –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 Efficacy Determination: Timing of Test of Cure Approved NDAs

14 Micro Trial: Pathogen Definition Guidance 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  10 4 CFU/mL

15 Micro Trial: Pathogen Definition Approved 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  10 3 cfu/mL

16 Micro Trial: Pathogen Definition Approved 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 Yields Approved NDAs Sinus puncture cultures were positive in % 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 % of patients NDAs with no recorded pathogen definition (any organism a potential pathogen) were positive in % 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 Efficacy Approved 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 Learned from 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 ( %) and are dependent upon pathogen definition, method of collection, and the population being reported on.

20 Summary: Lessons Learned from 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.