Design of Clinical Trials of Antibiotic Therapy for Acute Otitis Media

Colin D. Marchant, M.D.

Boston University School of Medicine

and

Tufts University School of Medicine

FDA Anti-Infective Drugs Advisory Committee Meeting, July 11, 2002

Clinical FailureClinical Failure Clinical SuccessClinical Success

Culture-positiveCulture-positiveon day 3-7on day 3-7

21/57 21/57 (37%)(37%)

15/40 15/40 (38%)(38%)

Culture-negativeCulture-negativeon day 3-7on day 3-7

2/66 2/66 (3%)(3%)

P < 0.001P < 0.001

17/253 17/253 (7%)(7%)

P < 0.001P < 0.001Carlin et alCarlin et alJ Pediatr J Pediatr

118:178-83, 1991118:178-83, 1991

Dagan et alDagan et alPediatr Infect Dis Pediatr Infect Dis J 17:776-82, 1998 J 17:776-82, 1998

Correlation Between Clinical and Correlation Between Clinical and Bacteriological Outcome in Acute Otitis MediaBacteriological Outcome in Acute Otitis Media

The Pollyanna PhenomenonMeasuring the Efficacy of Anti-bacterial Drugs in Acute Otitis

Media

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60

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90

100

Eff

icac

y %

Marchant CD, et al J Pediatr 1992;120:72

BacteriologicEfficacy

ClinicalEfficacy

Poor drugs look betterthan they really are

Excellent drugs appear worse than they really are

Placebo

Clinical Efficacyin Bacterial AOM

Drugs appear, and are equal

Sample Sizes Required to Detect Differences Between Antibacterial Drugs for Acute Otitis Media (AOM): Comparison of Bacteriologic Versus Clinical

Outcomes in a Trial of 2 Drugs With Varying Bacteriologic Efficacy (Half the patients would be in each arm of a study)

0

2000

4000

6000

8000

10000

12000

14000

16000

30 40 50 60 70 80Bacteriologic efficacy of drug A when compared with

drug B with 90% bacteriologic efficacy

Num

ber o

f pat

ient

s re

quire

d

Bacteriologicdiagnosis andoutcome

Bacteriologicdiagnosis/clinicaloutcome

Clinical diagnosisand outcome

Measuring the comparative efficacy of antibacterial agents for acute otitis media: The “Pollyanna Phenomenon.” Colin D. Marchant, Susan A. Carlin, Candice E. Johnson, and Paul A. Shurin. J Pediatrics 1992;120: 72-77.

Clinical Impact of Drug Efficacy

StandardBacteriologic

Efficacy

Number of children withpersistent symptoms on day3-6 who otherwise would be

asymptomatic for eachmillion prescriptions

Perfect Drug 100% 0

Good Drug 90% 20,000

Fair Drug 70% 60,000

Poor Drug 50% 100,000

Tap Water 30% 140,000

Based on Marchant et al J. Pediatr 1992;120:72

Clinical Impact of Drug Efficacy

Standard

Bacteriologic Efficacy

Number of children with persistent symptoms on day 3-6 who otherwise would be

asymptomatic for each million prescriptions

Perfect Drug 100% 0

Good Drug 90% 20,000

Fair Drug 70% 60,000

Poor Drug 50% 100,000

Tap Water 30% 140,000

Based on Marchant et al J. Pediatr 1992;120:72

Design Issues

1. Sample size

2. Outcome measures

3. Patient selection – low/high risk

4. Diagnostic criteria at entry

All are important, but in relative order of importance:

Otitis Media specific:

General:

randomized, double-blind, compliance, etc.

Four Trial Designs

1. “Double Tap”

2. “Tap at Entry and Tap of Clinical Failures”

3. “Tap at Entry with Clinical Outcome”

4. Clinical Criteria for Entry and Outcome

Parameters Used in Sample Size Calculations

• Significance level = 0.05

• Power = 0.90

• Inverse sine method

• All sample sizes are for a 2-limbed trial with half of subjects in each limb

Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs

Good Drug (90%) vs. Placebo (30%) Design # Recruited # Taps # Analyzed

Double “Tap” 40 70 30

“Tap” & “Tap” of Failures

70 80 52

Initial “Tap” &

Clinical Outcome195 195 146

Clinical Outcome 542 0 542

Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et alPediatr Infect Dis J 1998;17:776.Pediatr Infect Dis J 1998;17:776.

Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs

Good Drug (90%) vs. Poor Drug (50%)

# Recruited # Taps # Analyzed

Double Tap 83 145 62

Tap & Tap of Failures

280 304 210

Initial Tap &

Clinical371 371 278

Clinical 1136 0 1136

Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et alPediatr Infect Dis J 1998;17:776.Pediatr Infect Dis J 1998;17:776.

Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs

Good Drug (90%) vs. Fair Drug (70%)

# Recruited # Taps # Analyzed

Double Tap 262 458 196

Tap & Tap of Failures

928 966 696

Initial Tap &

Clinical1176 1176 882

Clinical 4146 0 4146

Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et alPediatr Infect Dis J 1998;17:776.Pediatr Infect Dis J 1998;17:776.

Sample Size for Measuring Efficacy of Antibiotics in Acute Otitis Media

1. Depends on the outcome selected2. Depends on population studied3. Minimum standard: Large enough to demonstrate

that a new antibiotic is better than no antibiotic – otherwise efficacy has not been measured

4. Adequate standard: Should exclude a 20% difference in bacteriologic efficacy between antibiotics – ensure that no more than 40,000 children per million children treated will remain symptomatic because of unmeasured inferiority

Recommended Guidance for IndustrySample Size

1. Response rates (eradication, clinical, etc) should be based on data from clinical trials, not assumption or expert opinion

2. Trial size must be large enough to demonstrate that a drug is a least better than a placebo.

3. The difference between two drugs should be a clinically important one, such as persistent symptoms at a rate of 40,000 per million prescriptions, i.e. a 20% difference in bacteriologic efficacy

4. Should also consider the power of sub-group analyses, e.g. organism specific response rates

Outcomes for Measuring the Efficacy of Antibiotic Therapy

in Acute Otitis Media

1. Directly meaningful, or validated against meaningful outcomes

2. Objective or at least reproducible3. Sensitive (are affected by antibiotic therapy)4. Timely – measured at a time point when

antibiotic therapy has an effect5. Supported by evidence (not assumption)

Outcomes in Clinical Trials of Antibiotic Therapy in Acute

Otitis Media

1. “Double Tap”

2. “Tap and Tap of

Clinical Failures”

3. “Tap at entry and

Clinical Outcome”

4. Clinical OutcomeSample Size Decreases

Information increases Eradication by MIC Pathogen eradication rates, Correlations with PK/PD, etc.

Recommended Guidance for IndustryTrial Design - Tympanocentesis

1. “Double tap” studies are preferred - have been validated, provide more information, and require the smallest sample size, and the fewest number of taps (among studies with taps)

2. “Tap and Tap of Clinical Failures” is an alternative that if large enough will provide useful information

3. If clinical outcomes other than symptomatic response are to be used as outcomes, they should be validated

Recommended Guidance for IndustryPopulation Selection/Enrichment

1. Trials should include “enriched’ populations: The young, treatment failure, prior antibiotic therapy, day care, etc are the most challenging cases and clinicians need to know whether antibiotics are efficacious in these patients. These patients should be included, not excluded from clinical trials

Recommended Guidance for IndustryDiagnostic Criteria

1. Symptoms: should have at least one of: earache, irritability, fever

2. Otoscopic exam: should have at least one opaque, bulging eardrum with reduced mobility

3. A trial site should isolate pathogens from at least 70% of cases at entry

Ethical Issues

• Is it ethical to license, market and prescribe drugs without knowing that they are efficacious (pass the tap water standard)?

• Is it ethical to perform drug trials in humans that will not yield scientifically valid data?

• Is it ethical to perform tympanocentesis?

• Is it ethical to perform double tympanocentesis studies?

Do the benefits outweigh the risks?

1. Tympanocentesis is briefly painful but not permanently harmful

2. The benefits of the knowledge gained outweigh the risks

3. Still, there is a need for research into the effectiveness of various methods of systemic and topical analgesia/anesthesia for tympanocentesis should be performed (industry should sponsor such studies).