Observations from Past Approvals for Acute Bacterial Sinusitis

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Observations fromPast Approvals forAcute
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 gt 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 CriteriaClinical 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 gt 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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Efficacy DeterminationTiming 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

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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.