# Presentation: 280836

## Draft Guidance for Industry Developing Antimicrobial Drugs for TreatmentAcute Otitis Media

**Brad Leissa, MD**
**ODE IV **
***leissab@cder.fda.gov***

- July, 1998

_**Round 2**_

##    For the clinical-only AOM study, in the interest of increasing diagnostic specificity at entry, should the guidance recommend minimal baseline clinical findings and/or tests for evaluability?
e.g., tympanometry or electroacoustic reflectrometry (where age appropriate)?

*e.g., *tympanometry or electroacoustic reflectrometry (where age appropriate)?

**Question 1**

**Bacterial  vs.  Viral   vs.  Other?**

- July 1998

## AIDAC Response (#1)

- Optimize specificity and minimize inter-investigator variability
-  Standardize otoscopy (biphasic)
- “Tympanometry and electroacoustic reflectometry are practical...and should be required. “
- “Need a bulging TM on study entry.”

- July 1998

## Change to Guidance?

*Strongly recommend* at study entry:
- Presence of bulging TM. (_*esp*_. clinical-only)
- Biphasic pneumatic otoscopy consistent with MEE. 
- Tympanometry or electroacoustic reflectometry consistent with MEE. 

- ** ****In the absence of a bulging TM**

- July 1998

## Question 2

**Is 1-2 weeks post-therapy sufficient time to assess a drug’s efficacy in the treatment of AOM?**

-    What is the appropriate timing for the AOM test-of-cure visit? (independent of the PK/PD of the drug)

- July 1998

## AIDAC Response (#2)

- “TOC visit at 1-3 weeks post-therapy may be most reasonable.”
- “The 3-5 day on-therapy visit is very important.”

- July 1998

## Change to Guidance?

-   Recommend TOC visit occur 2-4 weeks _*after entry*_ into study.

- July 1998

## Question 3

-     In light of the 1992 DAIDP Points-to-Consider document, for the clinical/microbiological study, is the evaluation of **25**  *S. pneumoniae* sufficient (*depending on the drug*) in light of increasing concerns about resistance _**or**_ should greater *S. pneumoniae* experience be sought in designing clinical trials?

- July 1998

## AIDAC Response (#3)

- “Pneumococcus is our biggest problem.”
- “Need at least 100 *S. pneumoniae*.”

- July 1998

## Change to Guidance?

-     “*S. pneumoniae* resistance has become an increasing concern for the global medical community.  *S. pneumoniae* is the major pathogen in acute otitis media.  Because of this concern, *25 patients with S. pneumoniae* may be insufficient to garner approval for this pathogen in acute otitis media.  Greater certainty in the investigational drug’s purported efficacy against this pathogen may be desirable.”

- July 1998

## Question 4

-    Depending on the drug (e.g., ß-lactam), should AOM clinical studies be conducted in geographic areas where  *S. pneumoniae *resistance and/or            ß-lactamase resistance are _**known**_ “problems”?

- July 1998

## AIDAC Response (#4)

- “Geographic location is becoming less of an issue as resistance increases everywhere. However, because of this problem, need more tympanocenteses to address efficacy in resistant pathogens.”
- “Need patients enrolled from across the U.S. including areas of high-risk resistance.”

- July 1998

## Change to Guidance?

- No change to revised guidance.
- The issue of recruiting study centers by geographic area -- where increased drug resistance prevalence may exist -- is not currently addressed in the document.

- July 1998

##   The IDSA/FDA Guidelines suggest:
  “Patients should be followed up clinically and by otoscopy biweekly until MEE has completely resolved... The time to resolution of MEE should be recorded.”

-   “**Patients should be followed up clinically and by otoscopy biweekly until MEE has completely resolved... The time to resolution of MEE should be recorded****.**”

**Question 5**

- July 1998

##    The issue:  Should AOM  clinical trials (for drug approval) be designed to assess the time to MEE resolution?

**Question 5 (contd.)**

**This implies ... ** A drug’s efficacy claim
- for the treatment of AOM should be
- _linked_ to MEE resolution. **(?)**

- July 1998

## AIDAC Response (#5)

-    In sum, it is something of interest, something to be studied, but relative to an evaluability criterion, where you have patients required to follow-up for monitoring resolution of ear effusion, that is not what we are looking for.

- July 1998

## Change to Guidance?

-   Time to resolution of middle ear effusions is recommended as a _*secondary*_ efficacy analysis.

- July 1998

## Is the Clinical-only Study Germane to Demonstrating Effectiveness in AOM ?

- “I can probably think of 10 people, given enough time, who can do tympanocenteses. I would have to walk in the manufacturer’s shoes to know whether this [requiring tympanocenteses for all patients] is feasible.”
- “Tympanocentesis can be a very painful procedure and requires adequate anesthesia. If adequate anesthesia is not given, then it is unethical to perform.”

- July 1998

## Change to Guidance?

- No change to revised guidance.
- The clinical-only study is retained.

- July 1998

## Would Placebo-Controlled Studies be Valuable in Establishing Effectiveness for AOM?

-    “If you select patients correctly, you will more likely have children whose AOM is due to bacterial infections and therefore are more likely to see bacterial complications, and therefore a placebo-controlled trial would be unethical.”

- July 1998

## Placebo-Controlled Studies? (contd.)

-    [If a placebo-controlled study design was utilized] “you would have to exclude the very, very ill from the clinical-only trial. Namely, those with more pain, including a bulging & weeping TM.”

- July 1998

## Change to Guidance?

- No change to revised guidance.
- Active-controlled trials are still recommended.

- July 1998

## Letter from CDC(Drug Resistant Streptococcus pneumoniae Therapeutic Working Group)

-     “Since clinical-only studies would need to be prohibitively large to detect a difference if one truly existed between two drugs and their respective pathogen-directed efficacies, the committee believes a smaller bacteriologically-driven study would be more effective, especially since bacteriologic failure is correlated with clinical failure.”

- July 1998

## Letter from CDC (contd.)

-    Recommend repeat tympanocenteses 3-5 days after initiation of therapy (in “a small number of” patients who were culture positive at baseline _or_ only those deemed failures) as an important measure of treatment efficacy*.*

- July 1998

## Change to Guidance?

-    The during therapy failure rate (study days 3-5) is recommended as a secondary efficacy analysis.

- July 1998

## Letter from Industry

-    “We do not agree with the requirement for tympanometry for the clinical diagnosis of otitis media. The procedure is technically difficult to perform in very young children, and the results are difficult to interpret accurately.”

***In clinical-only study, ******primarily study children >6 months old***

- July 1998

## Letter from Industry (contd.)

-    “The document suggests that ‘recurrent otitis media’ may be pursued as a separate indication from AOM. Is this correct?”

***YES...****but please talk to us first*

- July 1998

## Letter from Industry (contd.)

-    “We suggest that the late post-therapy visit for AOM be deleted, as there is no need for clinical evaluations after the test-of-cure visit.”

***Optional visit***

- July 1998

## Additional Changes to Guidance...

- Include at study entry _***acute***_ (<48 hours) tympanic membrane perforations (swab of exudate) in the microbiologically-evaluable population (in general, limited to *S. pneumoniae*, *H. influenzae*, and *M. catarrhalis*).

- July 1998

## Analysis Plan added

- Two study populations of interest:
- Per protocol
- Clinical-only study
- Clinical/Microbiological study
- ITT
- All patients randomized who meet the inclusion/exclusion criteria

***Both analyses should show consistent results***

- July 1998

## Analysis Plan (contd.)Primary efficacy

- Clinical cure rate at the test-of-cure visit (TOC).
- Pathogen eradication rate (_ignoring_ susceptibility to study drugs) at TOC. (clinical/micro study)

- July 1998

## Analysis Plan (contd.)Secondary efficacy

- Clinical failure rate at the 3-5 day on-therapy visit.
- Pathogen eradication rate at TOC where the baseline pathogen is _susceptible_ to study drug. (clinical/micro study)
- Time to resolution of symptoms

- July 1998

## Analysis Plan (contd.)Secondary efficacy (contd.)

- Persistence of middle ear effusions at TOC.
- Clinical response by age group
- (2 yo vs. >2 yo)
- Clinical response for patients excluded from the ITT analysis

- July 1998

## AOM Guidance Summary

- Desire increased diagnostic specificity and objective evidence for ***bacterial**** *AOM in the clinical-only trial.
- Active-controlled studies are still recommended.
- Clinical-only study is retained.

- July 1998

## Summary (contd.)

- For the clinical-only study, primarily study children >6 months old
- TOC visit 2-4 weeks after study entry.
- Late post-therapy visit is optional.

- July 1998

## Summary (contd.)

- Everyone (AIDAC, consultants, CDC) is concerned about adequate *S. pneumoniae* drug coverage for AOM.
- >25 isolates should be studied to characterize a drug’s _in-vivo_ activity against the major AOM pathogen.

- July 1998

## Summary (contd.)

- Conducting studies in specific geographic regions (relating to areas where drug resistance is thought to be more prevalent) is not addressed.
- Time to resolution of middle ear effusions is recommended as a _*secondary*_ efficacy analysis

- July 1998

## Summary (contd.)

- Compare on-therapy failure rates (study days 3-5) -- _*secondary*_ efficacy analysis.
- Include _acute_ perforated TMs for microbiology.

- July 1998

## AOM Guidance

***Additional Comments and/or Recommendations?***

- July 1998