SDA/CTFA Topical Antimicrobial Coalition

Presentation to FDA Nonprescription Drugs Advisory CommitteeMarch 23, 2005

March 23, 2005 2

AGENDA

The Value of Surrogate Endpoint Testing, G. Fischler

Statistical Issues in Study Design, J. Bowman

Questions

The Value of Surrogate Endpoint Testing for Topical Antimicrobial

Products

George Fischler

The Dial Corporation

March 23, 2005 4

Overview

Clinical trials Standardized test methodology Surrogate endpoints

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Definitive randomized and controlled clinical trials, typically used to assess therapeutic benefit are not practical in measuring the prophylactic benefits of topical antimicrobial products

Key Point

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Larson, E. 1995. APIC Guideline for Handwashing and Hand Antisepsis in Health Care Settings.

“Although a definitive, double blind, clinical trial of the effects of handwashing with an antiseptic product on nosocomial infection rates may be infeasible, it appears that, at least in certain high risk situations, such antimicrobial products are beneficial.”

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Clinical Trial Issues for Prophylactic Indications

Size Ethics Immunological host status Mode of transmission Intended beneficiary

– Test subject vs. population

Compliance

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Key Point

Standardized, defined and peer reviewed test methodologies ensure reliability, reproducibility and comparability of test results

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FDA, 1978 TFM

“..the reduction of the normal flora, both transient and resident, has been sufficiently supported to be considered a benefit. The only determination that remains therefore, is how much of a reduction in microbial flora will be required to permit claims for the various product classes.”

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Fischler G.E., et al. 2002. The Effect of Modification to the ASTM E1174 Healthcare Personnel Handwash Method on the Evaluation of Antimicrobial Effectiveness

Three methods– Current ASTM– Pre 1994 ASTM (NDA)– 1994 TFM

Comparison of methods– Inoculum application– Neutralization– Timing of baseline enumeration

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Fischler G.E., et al. 2002. The Effect of Modification to the ASTM E1174 Healthcare Personnel Handwash Method on the Evaluation of Antimicrobial Effectiveness

Test MethodInoculum Addition

Timing of Baseline

Measurement

Baselinelog10 /hand Neutralization

1st Washlog10

Reduction

Final Washlog10

Reduction

CHG in Recovery

Fluid

Current ASTM 3x1.5 ml After inoculum 9.2172 Immediate 2.4225 3.4453 48 ppm

Former ASTM 4.5 ml After inoculum 9.2087 Delayed 2.4622 3.7937 22 ppm

1994 TFM 5 mlAfter inoculum + "cleansing"

wash6.4942 Delayed -0.0073 1.1092 43 ppm

4% CHG Handwash (5 ml product, 15 second wash and 30 second rinse)

Comparison of ASTM E1174 Method and Proposed TFM Method

30 subjects per product

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Sickbert-Bennett E. E., et al. 2004. The Effects of Test Variables on the Efficacy of Hand Hygiene Agents

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Surrogate endpoint testing provides meaningful and appropriate tools to determine the threshold efficacy criteria for topical antimicrobial products

Key Point

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The published literature represents a body of scientific evidence supporting that the proposed microbial reductions reflect clinical benefit, and importantly represent current infection control practice

Key Point

Healthcare Personnel Handwash

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Zafar A.B. et al. 1995. Use of 0.3% Triclosan to Eradicate an Outbreak of MRSA in a Neonatal Nursery

The single additional infection control measure of changing the handwash and bathing product to Bactistat (0.3% triclosan handwash) was associated with the immediate termination of the acute phase of the MRSA outbreak.

Surrogate handwash (ASTM E1174) results (from 1995 Huntington company literature) indicate 1.7 log10 following the initial application of 5 mL of product and 1.9 log10 reduction after ten subsequent applications of 60 seconds duration each time.

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Webster J., et al. 1994. Elimination of Methicillin-resistant Staphylococcus aureus from a Neonatal Intensive Care Unit after Hand Washing with Triclosan

Following introduction of a 1% triclosan handwash, new cases of MRSA colonization were monitored for one year

No changes were made to procedures or protocols

A gradual elimination of MRSA in the ward was noted during the 12 month period

Compared with the previous 12 month period, fewer antibiotics were prescribed, and fewer (P< 0.05) nosocomial infections recorded

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Hilburn J., et al. 2003. Use of Alcohol Hand Sanitizer as an Infection Control Strategy in an Acute Care Facility

Data were collected in one unit of a 500-bed facility over a 16 month period during the introduction of an alcohol (60% ethanol) hand gel

Primary infection types were urinary tract and surgical site infections

Infection types and rates demonstrated a 36% reduction in infection rates for the 10 month period during which the hand sanitizer was in use compared with the previous 6 month period

The study concludes that use of an alcohol gel hand sanitizer is an effective tool in an infection control program

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Fendler E.J., et al. 2002. The Impact of Alcohol Hand Sanitizer Use on Infection Rates in an Extended Care Facility

Data on infection rate and type were collected in a 275 bed extended care facility over a 34 month period, during which an alcohol (60% ethanol) hand gel was used in two units of the facility

Primary infection types were urinary tract, respiratory, and wound infections.

A 30% reduction in infection rate was found in the units where the hand sanitizer was used compared to the other units over the 34 months

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Doebbeling B.N., et al. 1992. Comparative Efficacy of Alternative Hand-washing Agents in Reducing Nosocomial Infections in Intensive Care Units

During an 8 month period a prospective crossover design trial involving 1894 patients in three ICUs was conducted.

A comparison of 60% alcohol (isopropanol), with or without non-medicated soap, and a chlorhexidine gluconate product was made

152 nosocomial infections were seen when chlorhexidine was used, as compared to 202 infections for the soap/alcohol combination

This difference was directional but not significant

Surgical Hand Scrub

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Bryce E.A., et al. 2001. An In-use Evaluation of an Alcohol-based Pre-surgical Hand Disinfectant

A prospective trial of a 70% alcohol (isopropanol) pre-surgical hand treatment compared to 4% chlorhexidine gluconate and 7.5% povidone iodine treatments

Evaluated both short (< 2 hours) and longer surgical procedures

Found no statistical difference in microbial hand counts following the use of any of the treatments for cases less than 2 hours

Matched pair analysis of longer surgical cases also found no difference in treatment

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Parienti J.J., et al. 2002. Hand-rubbing With an Aqueous Alcoholic Solution vs. Traditional Surgical Hand-scrubbing and 30-day Surgical Site Infection Rates

Compared the effectiveness of an alcoholic hand rub solution to either a chlorhexidine or povidone iodine hand scrub at reducing surgical site infections in a randomized trial

Statistically, no difference was found in infection rates between the two procedures in infection rate

Pre-operative Skin Preparation

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Aly R. et al. 1998. Clinical Efficacy of a Chlorous Acid Preoperative Skin Antiseptic

Under clinical conditions a comparison of a standard 4% chlorhexidine gluconate skin prep was compared to a new preparation on both abdominal and inguinal skin sites

An examination of baseline flora at both sites was undertaken, and only subjects whose skin flora met certain criteria were included

The active control product (4% CHG) reduced resident flora by less than the required amount (3 log10) proposed in the TFM immediately after treatment

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The efficacy criteria should be appropriately set to reflect the performance of currently recognized effective products

Conclusion

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AGENDA

The Value of Surrogate Endpoint Testing, G. Fischler

Statistical Issues in Study Design, J. Bowman

Questions

Statistical Issues in Study Design

Jim Bowman

Hill Top Research, Inc.

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Statistical Issues

Log Reduction Criteria– Historically based on point estimates (mean)– No requirement of sample size

Variability needs to be considered– There are several ways to take variability

into account

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Examples from Other OTC Monographs

Sunscreen Monograph– Mean value is calculated and the standard error

is used to calculate the label SPF value

Antiperspirant Monograph– Mean value must be statistically significantly

greater than a certain level (i.e. 20% sweat reduction)

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Statistical Criteria vs Point Estimate

– Objective: mean value > ‘x’ log reductionWith point estimates manufacturers have

historically conducted studies with sample sizes they deemed appropriate and submitted data to the FDA

With statistical criteria being utilized (i.e., statistically greater than a specific number), appropriate sample sizes are a function of the variability of the data.

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Statistical Criteria vs Point Estimate

We have conducted data reviews and statistical simulations using data at hand looking into the variability

Data review consisted of data from 13 studies conducted with an active material, simulations were conducted to better understand the variability

If statistical criteria are to be utilized, then lower criteria will be necessary to achieve the same level of efficacy based on our data review

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Statistical Criteria vs Point Estimate

OTC Antiperspirant monograph requires statistically significantly greater than 20% reduction.

This requires point estimates of sweat reduction to be >25%-30% reduction in order to achieve the level of benefit mandated

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Next Steps

Historically, the FDA and Industry have relied on point estimates.

However, if statistical significance is required, then lower log reduction criteria are necessary to achieve the same level of efficacy based on our data review.

We would like to work with the FDA on setting these criteria for specific indications at specific time points.

Summary

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Clinical trials are not appropriate for assessing prophylactic benefit

Standardized methodologies ensure reproducibility Surrogate endpoints are appropriate Literature supports that the proposed microbial

reductions reflect clinical benefit Efficacy criteria should reflect the performance of

recognized effective products

Key Point Summary