1. SDA/CTFA Topical Antimicrobial Coalition Presentation to FDA Nonprescription Drugs Advisory Committee March 23, 2005

2. 2 AGENDA The Value of Surrogate Endpoint Testing, G. Fischler Statistical Issues in Study Design, J. Bowman Questions

3. The Value of Surrogate Endpoint Testing for Topical Antimicrobial Products George Fischler The Dial Corporation

4. March 23, 2005 4 Overview Clinical trials Standardized test methodology Surrogate endpoints

5. March 23, 2005 5 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

6. March 23, 2005 6 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.”

7. March 23, 2005 7 Clinical Trial Issues for Prophylactic Indications Size Ethics Immunological host status Mode of transmission Intended beneficiary – Test subject vs. population Compliance

8. March 23, 2005 8 Key Point Standardized, defined and peer reviewed test methodologies ensure reliability, reproducibility and comparability of test results

9. March 23, 2005 9 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.”

10. March 23, 2005 10 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

11. March 23, 2005 11 Fischler G.E., et al. 2002. The Effect of Modification to the ASTM E1174 Healthcare Personnel Handwash Method on the Evaluation of Antimicrobial Effectiveness 30 subjects per product

12. March 23, 2005 12 Sickbert-Bennett E. E., et al. 2004. The Effects of Test Variables on the Efficacy of Hand Hygiene Agents

13. March 23, 2005 13 Surrogate endpoint testing provides meaningful and appropriate tools to determine the threshold efficacy criteria for topical antimicrobial products Key Point

14. March 23, 2005 14 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

15. Healthcare Personnel Handwash

16. March 23, 2005 16 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 log 10 following the initial application of 5 mL of product and 1.9 log 10 reduction after ten subsequent applications of 60 seconds duration each time.

17. March 23, 2005 17 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

18. March 23, 2005 18 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

19. March 23, 2005 19 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

20. March 23, 2005 20 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

21. Surgical Hand Scrub

22. March 23, 2005 22 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

23. March 23, 2005 23 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

24. Pre-operative Skin Preparation

25. March 23, 2005 25 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 log 10 ) proposed in the TFM immediately after treatment

26. March 23, 2005 26 The efficacy criteria should be appropriately set to reflect the performance of currently recognized effective products Conclusion

27. March 23, 2005 27 AGENDA The Value of Surrogate Endpoint Testing, G. Fischler Statistical Issues in Study Design, J. Bowman Questions

28. Statistical Issues in Study Design Jim Bowman Hill Top Research, Inc.

29. March 23, 2005 29 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

30. March 23, 2005 30 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)

31. March 23, 2005 31 Statistical Criteria vs Point Estimate – Objective: mean value > ‘x’ log reduction With 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.

32. March 23, 2005 32 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

33. March 23, 2005 33 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

34. March 23, 2005 34 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.

35. Summary

36. March 23, 2005 36 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