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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, November 7, 2001

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Outcomes in Trials of

Antibacterial Drugs for AOM

Clinical: Symptomatic improvement, or

symptomatic & otoscopic improvement, etc.

Bacteriologic: eradication of bacteria Bacteriologic/Clinical: Clinical improvement

plus eradication of bacteria in clinical

failures

During Therapy

End of Therapy

After Therapy

Choice of Outcome

Timing of Outcome

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Timing of Clinical Outcomes in Trials of

Antibiotic Therapy for Acute Otitis Media

Antibiotic Therapy Post Antibiotic Therapy

48-72 Hrs

Day 4-6

End of Therapy

Day 10-12 Day 28-30

Test of Cure

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Effect of Antibiotic Treatment

on Earache in Severe AOM

1 2 3 4 5

Mean

Pain

Score

1.0 PlaceboPenicillin

Mygind et al

Clin Otolaryngol

1981;6:5

Day

*

*

* p < 0.01

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Treatment of Severe AOM

% initial treatment failure

Placebo &Myringotomy

Amoxicillin &Myringotomy

N=34 N=96 N=156

23.5% ** 11.5% 9.6% **

** P< 0.01 Kaleida, et al. Pediatric s, 1991

Amoxicillin

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Amoxicillin vs Placebo

for Non-severe AOM

Kaleida et. al. Pediatrics 1991;87:466

AmoxN=522

PlaceboN=527

P-Value

Initial Rx Failure 3.9% 7.7% 0.009

Effusion 2 wks 46.9% 62.5%

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Bacteriology of Clinical Recurrences of AOM

1 Month After Completion of Treatment

0%

20%

40%

60%

80%

100%

Days 1-7 Days 8-14 Days 15-21 Days 22-28

Bacteriologic Relapses New Infections

from Leibowitz et al ICCAC Abstract #1968, Sept 2000

Relapses vs New Infections determined forStreptococcus pneumon iaeby

PFGE and serotyping, and forHaemoph i lus inf luenzaeby beta-lactamase

production

N=39 N=34 N=21 N=9

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Clinical Recurrences of Acute

Otitis Media After Therapy

Not reduced by prior antibiotic therapy

(Kaleida et al, etc)

Common in patients with eradication of

the initial pathogen (Leibowitz, Carlin,

DelBaccaro)

New infections more common than

relapses (Leibowitz, Carlin, DelBaccaro)

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Correlation of Bacteriologic and Clinical

Outcomes in Acute Otitis Media after 3-6

days of Antibiotic Therapy

ClinicalSuccess

93%

Clinical

Failure

7%

ClinicalSuccess

62%

Clinical

Failure

38%

Bacteria Eradicated

from the Middle Ear

Bacteria Persist

in the Middle Ear

P = 0.001

Carlin et al. Pediatr 1991; 118:178

N=253 N=40

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Early eradication of pathogens from middle ear fluid

during antibiotic treatment of acute otitis media is

associated with improved clinical outcome

Bacteriologic Failures

Culture (+) n = 57

Dagan et al, PIDJ 17; 776-82, 1998.

Cure

36 (63%)

Failure

21 (37%)Cure

64 (97%)

Failure

2 (3%)

N = 123

Bacteriologic Success

Culture (-) n = 66

Clinical status

from day 4-6

to day 10

Culture result

on day 4-5

Note: 91% of the clinical failures were culture (+) on day 4-5

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Clinical Success Rates in Acute

Otitis Media

* P=0.001, ** P=0.013Marchant CD et. al. J Pediatr 1992;120:72

Bacteriologic Success 236/253 (93.2%)

Bacteriologic Failure 25/40 (62.5%)

Non-Bacterial AOM 124/155 (80.0%)

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The Pollyanna PhenomenonMeasuring the Efficacy of Anti-bacterial Drugs in

Acute Otitis Media

20

30

40

50

60

70

8090

100

E

fficacy%

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

Bacteriologic

Efficacy

Clinical

Efficacy

Poor drugs look better

than they really are

Excellent drugs appears

worse than they really are

Placebo

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The Pollyanna PhenomenonMeasuring the Efficacy of Anti-bacterial Drugs in

Acute Otitis Media

20

30

40

50

60

70

8090

100

E

fficacy%

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

Bacteriologic

Efficacy

Clinical

Efficacy

Poor drugs look better

than they really are

Excellent drugs appear

worse than they really are

Placebo

Clinical Efficacy

in Bacterial AOM

Drugs appear, and are equal

Sample Sizes Required to Detect Differences Between Antibacterial

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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 80

Bacteriologic efficacy of drug A when compared with

drug B with 90% bacteriologic efficacy

Numberofpatien

tsrequired

Bacteriologic

diagnosis and

outcome

Bacteriologicdiagnosis/clinical

outcome

Clinical diagnosis

and 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 Pediatr ics1992;120: 72-77.

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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

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Standard Bacteriologic

Efficacy

Good Drug 90%

Fair Drug 70%

Poor Drug 50%

Tap Water 30%

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Sample Sizes Required to Detect Differences Between an

Antibacterial Drug with 90% Bacteriologic Efficacy and Drugs with

Fair Efficacy (70%), Poor Efficacy (50%), or Tap water (30%) in

Clinical Trials of Acute Otitis Media

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Tap Water

(30%)

Poor Drug

(50%)

Fair Drug

(70%)

Numberofpatientsrequired Bacteriologic

diagnosis andoutcome

SymptomaticResponse

BacterialDiagnosis and

Clinical Outcome

Marchant et al J Pediatr ics1992;120: 72-77

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Sample Size Calculations for

Clinical Outcomes

Standard BacteriologicEfficacy

Kaleidaet al % Effusion-free

*

Good Drug 90% Amoxicillin 53.1%

Fair Drug 70% 47.9%

Poor Drug 50% 42.7%

Tap Water 30% Placebo 37.5%

* White = Actual Data Yellow = Extrapolated Data

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No Efficacy (30%) Poor Efficacy (50%), Poor Efficacy (70%), or in


0

200

400

600

800

1000

1200

1400

1600

1800

2000

Tap Water

(30%)

Poor Drug

(50%)

Fair Drug

(70%)

Numberofpatients

required

Bacteriologicdiagnosis andoutcome

Symptomatic Failure

in Severe AOM **

Middle Ear Effusionat 14 Days in Non-severe OM

Symptomatic Failure

in Non-Severe AOM

Bacteriologic Outcomes from Marchant et al J Pediatr ics1992;120: 72-77

Clinical Outcomes based on Kaleida et al Pediatrics 1991;87:466

** compared with

myringotomy

not placebo

B t i l i S t ti d T t f C ** O t

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Bacteriologic, Symptomatic and Test of Cure ** Outcomes

in Trials of Antibacterial Therapy in Acute Otitis Media

20

30

40

50

60

70

80

90

100

Efficacy(%)

Recurrence rate5% 10% 15% 20% 25% 30%

Bacteriologic Outcome

Symptomatic Outcome During Therapy

** Test of Cure = symptomatic failures during therapy + clinical recurrences after therapy

Based on data from: Marchant CD et al 1992;120:72 & Kaleida et al Pediatrics 1991;87:466

Drugs appear worse than they really are

Drugs appear better than they really are

Placebo

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Fair Efficacy (70%), Poor Efficacy (50%), or Tap water (30%) in


0

200

400

600

800

1000

1200

1400

1600

1800

2000

Tap Water

(30%)

Poor Drug

(50%)

Fair Drug

(70%)

Numberofpatientsrequired

Bacteriologicdiagnosis andoutcomeSymptomaticResponse

Test of cure with 10%recurrence rate

Test of cure with 20%recurrence rate

Test of cure with30% recurrence rate

Bacteriologic and Symptomatic Outcomes from Marchant et al J Pediatr ics1992;120: 72-77

Test of cure assumes no effect of antibiotics on recurrence rates as demonstrated by Kaleida et alPediatrics 1991;87:466

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Timing of Outcomes in Trials Correlating

Clinical and Bacterriologic Endpoints in

Acute Otitis Media

Antibiotic Therapy Post Antibiotic Therapy

Day 4-6 End of Therapy

Day 10-12

Dagan et al

Carlin/

Marchant

et al

Carlin et al J Pediatr 1991;118:178

Marchant et al J Pediatr 1992;120:72Dagan et al Pediatr Infect Dis J 1998;17:776

B t i l AOM B t i l i B t i l i /Cli i l

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Bacterial AOM: Bacteriologic, Bacteriologic/Clinical

and Clinical Outcomes

(Double Tap, Tap and Tap of Clinical Failures, and Single Tap

with Clinical End of Therapy and Test of Cure Outcomes)

20

30

40

50

60

70

80

90

100

Effic

acy

%

Bacteriologic

Efficacy

Bacteriologic

Outcome if Clinical

Failure Day 4-10

End of Therapy

Clinical

Outcome

Excellent drugs

appear worse than

they really are

Poor drugs

look better than

they really are

PlaceboBased on Dagan et al. Pediatr Infect Dis J 1998;17:776.

Drugs appear,and are equal

Test of Cure

Clinical

Outcome

S l Si R i d t D t t Diff B t

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No Efficacy (30%) Poor Efficacy (50%), Fair Efficacy (70%), in

Clinical Trials of Bacterial AOM (Tympanocentesis Trials)

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Tap Water

(30%)

Poor Drug

(50%)

Fair Drug

(70%)

Numberofpatients

required

BacteriologicOutcome - "DoubleTap"

BacteriologicOutcome in ClinicalFailures - " Tap &Tap of Failures"

Clinical Failure inBacterial AOM -Initial Tap Only

Test of Cure inBacterial AOM -Initial Tap Only -Recurrence Rate15%

Based on Dagan et al Pediatr Infect Dis 1998;17:776

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Clinical Impact of Drug Efficacy

StandardBacteriologic

Efficacy

Number of children withpersistent symptoms on day

3-6 who otherwise would beasymptomatic 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

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Clinical Trial Sizes to Distinguish Between Drugs

with 90% and 30% Bacteriologic Efficacy

The Tap Water Standard

OutcomeReference usedfor calculations

# SubjectsAnalyzed

# SubjectsRecruited

Bacteriologic Double Tap Howie 1972Marchant 1992

30 40

Bacteriologic in Clinical FailuresTap & Tap of Failures

Dagan1998

52 70

Clinical at End of Therapy Dagan1998

146 195

Symptomatic Response 3-6 Days Carlin1991

234 312

Test of Cure Outcome with 15%Clinical Recurrence Rate

Dagan1998

248 331

Study Designs: Initial Bacteriologic Diagnosis:

* Assumes bacteria are isolated from 75% of AOM cases

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The Tap Water Standard

OutcomeReferences Used for

Calculations# Subjects Recruited &

Analyzed

Initial Treatment Failure in

Severe AOM (vs Myringotomy)

Kaleida 1991

Marchant 1992

356

Clinical Resolution 7-14 Days(Meta-analysis)

Rosenfeld 510

Middle Ear Effusion at End ofTherapy

Kaleida 1991Marchant 1992

526

Clinical Outcome at 3-5 Days Marchant 1992 542

Test of Cure Outcome with a20% Clinical Recurrence Rate

Marchant 1992Kaleida 1991

854

Initial Treatment Failure inNon-Severe AOM Kaleida 1991Marchant 1992 1914

Trial Designs - No Tympanocentesis:

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The Poor Drug Standard


# SubjectsAnalyzed

# SubjectsRecruited


62 83


Dagan1998

210 280

Clinical at End of Therapy Dagan1998

278 371


466 622


Dagan1998

528 704



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The Poor Drug Standard



Analyzed



Kaleida 1991

Marchant 1992

716


Rosenfeld 1082


Middle Ear Effusion at End ofTherapy Kaleida 1991Marchant 1992 1196



1888



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The Fair Drug Standard


# SubjectsAnalyzed

# SubjectsRecruited


196 262


Dagan1998

696 928

Clinical at End of Therapy Dagan1998 882 1176


1606 2142


Dagan1998

1952 2604



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The Fair Drug Standard



Analyzed



Kaleida 1991

Marchant 1992

2250


Rosenfeld 3986


Middle Ear Effusion at End ofTherapy Kaleida 1991Marchant 1992 4806



7368



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Conclusions

1. Most trials using bacteriologic

diagnosis and clinical outcome have

been too small to distinguish between

a good drug and tap water and all have

been too small to distinguish between

a good drug and a fair drug

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Conclusions2. Most trials using clinical diagnosis and

a clinical outcome have been too small

to distinguish between a good drug

and tap water

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Conclusions

3. Data do not support the use of the

Test of Cure outcome as ascientifically valid outcome in clinical

trials of antibacterial drugs for AOM

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Recommendations

1. Clinical trial data in support of licensureof antibiotics for AOM should, at a

minimum, exceed the tap water

standard.

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Recommendations

2. The FDA should convene a panel of

experts to examine the design ofantibiotic trials for AOM using scientific

data and principles, and revise the

current Guidance for Industryaccordingly.

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Recommendations

3. If double tympanocentesis studies are to

be conducted, research into the

effectiveness of various methods ofsystemic and topical analgesia/

anesthesia for tympanocentesis should

be performed (industry should considersponsorship of such studies).

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Recommendations

4. Improved methods for trials with

clinical outcomes (e.g. more sensitive

outcomes, enriched populations, etc.)should be investigated in rigorous

studies. However, large numbers of

subjects may still be required to

demonstrate efficacy in clinical studies

despite such refinements.

Documents

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