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Observations fromPast Approvals for

Acute Bacterial Sinusitis

Janice Pohlman, M.D.

AIDAC Meeting, October 29, 2003

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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?

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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– 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

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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

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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

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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

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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

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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

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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.

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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.