# Presentation: 465794

## Acute Bacterial Otitis MediaSummary and Charge to the Committee

- Renata Albrecht, M.D.
- Division of Special Pathogen and Immunologic Drug Products
- ODEIV, CDER

## Acute Bacterial Otitis Media

- Bacterial pathogens responsible for morbidity (some self limited disease)
- Drugs evaluated to treat bacterial pathogens
- Product Labeling includes bacterial pathogens
- (Viral OM - self limited illness)

## Acute Bacterial Otitis Media

- DIAGNOSIS (AT BASELINE)
- Clinical signs and symptoms
- “Strict case definition”
- Tympanocentesis
- Identify causative bacterial pathogen
- Both !

## Acute Bacterial Otitis Media

- ENDPOINTS & TIMING (RELATIVE TO BASELINE)
- Clinical
- on therapy (time to resolution?  *Dr. Dagan*)
- end of therapy ( 2 -7 day after last dose ?)
- Microbiological
- on therapy
- extrapolate from clinical (no repeat tympano)
- tympanocentesis (day 3-5)
- end of therapy (extrapolate from clinical?)
- BOTH !

## Acute Bacterial Otitis Media

- POPULATIONS
- AOM
- (e.g. pens, cephs, macrolides)
- Recurrent AOM
- Treatment failure (persistent, nonresponsive) AOM
- (e.g fluoroquinolones, high dose betalactams)
- Do these enable enrichment for PRSP?

## Clinical Trial Designs

- CONTROLLED CLINICAL TRIALS
- Active controlled
- Placebo controlled

## Clinical Trial Design, Diagnosis, & Endpoints

- ACTIVE Control (noninferiority)*
- All patients have a clinical evaluation at baseline & endpoint
- only - no tympanocentesis = “clinical only”
- and baseline tympanocentesis = “single tap”
- add baseline & on therapy tympanocentesis = “double tap”
- *vs.  Superiority (would also reduce sample size)

## Clinical Trial Design, Diagnosis, & Endpoints

- PLACEBO Control (superiority)
- All patients would have a clinical evaluation at baseline & endpoint
- only - no tympanocentesis = “clinical only”
- and baseline tympanocentesis = “single tap”
- add baseline & on therapy tympanocentesis = “double tap”
- 3-arm

## Constraints: Rules & Regulations21 CFR 314.126

- Adequate and well-controlled studies!
- placebo, dose ranging, no treatment, active, or historical control
- In patients with the disease!
- “The method of selection of subjects provides adequate assurance that they have the disease or condition being studied ... “
- (compare/contrast to patients with “clinical syndrome”)

## Drug development in otitis media

- Practical issues
- What are barriers to performing tympanocentesis in clinical trials?
- Are placebo-controlled trials practical in the U.S. at this point in time?
- How acceptable are these procedures to patients and parents?
- Can we perform trials more efficiently while still obtaining useful data?

## Questions

- 1.	**Should a comparative trial incorporating tympanocentesis be required for demonstrating the effectiveness of drugs for AOM?**
- 	In your response, address the following:
- The role of each of the types of studies discussed: clinical-only studies, single tympanocentesis trials, double tympanocentesis trials, placebo-controlled trials
- The utility of a strict case definition versus use of tympanocentesis at baseline for diagnosis of AOM
- The relative value of comparative versus non-comparative data in trials that include tympanocentesis.

## Question 1

- 1a)   Is tympanocentesis the best way to establish the diagnosis of acute *bacterial* otitis media?
- 1b)   Is a controlled study incorporating tympanocentesis the best study design to establish that an antimicrobial agent (antibacterial) is safe and effective in treating acute *bacterial *otitis media?

## Question 1

- 1c)    Is it reasonable to consider placebo-controlled studies in evaluating drugs for AOM?
- If yes, can this be considered in all patients with AOM, or should this be restricted to a subset (and which subset)?
- Role of tympanocentesis?

## Questions

- 2.	**Does the committee agree with the definitions of recurrent AOM and AOM treatment failure, used to identify a separate population of patients for study?**
- In your response, address the following:
- The use of these definitions to identify patients more likely to have penicillin-resistant *Streptococcus pneumoniae*
- The likelihood of differences in treatment response in this population vs. general AOM
- (is this a means to suggest that agents developed for this separate population should not be used in all AOM)

## Questions

**Question 2 Definitions**
**Recurrent Acute Otitis Media**
- 3 episodes of AOM over the last 6 months
- 4 episodes of AOM over the past year
**Treatment Failure**
- During Therapy: No improvement observed in signs and symptoms of AOM after at least 48 hours of antimicrobial management, or
- Post Therapy: Presentation with signs and symptoms of AOM within 7 days of completing a course of therapy for acute otitis media

## Question 2

- Is the subpopulation of patients defined as having recurrent OM/treatment failure OM reasonable for drugs intended for drug-resistant pathogens (conversely, not intended an initial therapy in AOM)?

## 3. Do double tympanocentesis trials have a role in demonstrating effectiveness of drugs 
		a) for general AOM? 
		b) for recurrent/treatment failure AOM?
In your response, address the following:
The timing of clinical and microbiologic assessments 
The relative importance of clinical vs. microbiological assessment, including the value of an on-therapy tympanocentesis in a child who is clinically improving
The ability of the on-therapy tympanocentesis results to predict clinical outcome
Sufficient study sites (including sites within the U.S.) to perform double tympanocentesis

**	****	****a) for general AOM? **
**	****	****b) for recurrent/treatment failure AOM?**
- In your response, address the following:
- The timing of clinical and microbiologic assessments
- The relative importance of clinical vs. microbiological assessment, including the value of an on-therapy tympanocentesis in a child who is clinically improving
- The ability of the on-therapy tympanocentesis results to predict clinical outcome
- Sufficient study sites (including sites within the U.S.) to perform double tympanocentesis

- Questions

## Question 3

- When should clinical studies with double tympanocentesis (baseline and on-treatment) be requested?
- In all AOM studies
- in studies of recurrent OM/ nonresponsive OM

## Other Issues for Discussion

- Alternative methods of clinical outcome assessment (e.g., time to resolution of AOM symptoms/signs)
- Activity against the major pathogens in AOM is expected: How should existing data (e.g., PK/PD, in vitro susceptibilities) that suggest decreased activity of a drug for an AOM pathogen be taken into account in the clinical trial design?
- Age distribution of patients within placebo-controlled and active-controlled studies
- Other factors (e.g., day care attendance, prior antibiotics as exclusion criteria, seasonality)

## Issues raised

- Diagnosis (of acute *bacterial* otitis media)
- Tympanocentesis (establish presence of pathogen)
- baseline
- on therapy
- Clinical trials design
- active control
- placebo control
- (no control)
- Endpoints