Date post: | 24-Dec-2015 |
Category: |
Documents |
Upload: | naomi-matthews |
View: | 213 times |
Download: | 0 times |
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
20
30
40
50
60
70
80
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).