# Presentation: 067614

## Observations fromPast Approvals forAcute Bacterial Sinusitis

- Janice Pohlman, M.D.
- AIDAC Meeting, October 29, 2003

## 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?**

## 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**

## 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)**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Efficacy: Timing of Test of CureGuidance 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**

## 

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

**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**

## 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**

## 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**

## 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**

## Micro Trial: Sinus Puncture YieldsApproved 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**

## 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**

## 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 (22-87.5%) and are dependent upon pathogen definition, method of collection, and the population being reported on.**

## 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.**