1. 1 Nonprescription Drugs AC Meeting March 23, 2005 Testing of Healthcare Antiseptic Drug Products Michelle M. Jackson, Ph.D. Microbiologist Division of Over-The-Counter Drug Products

2. 2 Nonprescription Drugs AC Meeting March 23, 2005 Objectives Discuss proposed monograph requirements - simulation testing procedures - surrogate endpoints Discuss Industry Coalition’s (SDA / CTFA*) position * The Soap and Detergent Association and The Cosmetic, Toiletry, and Fragrance Association Industry Coalition (“Industry Coalition”)

3. 3 Nonprescription Drugs AC Meeting March 23, 2005 What Makes a Good Clinical Simulation Test Method Simulates as close as possible actual use conditions Design characteristics: –test product: final formulation –vehicle control arm (negative control): determine reduction due to mechanical action of handwashing only –active control arm (positive / internal control): used as an internal reference to validate the study Measures desired product performance Reproducible IndicationsCurrent TFM Healthcare Personnel Handwash Test product Active control Surgical Hand Scrub Test product Active control Vehicle Patient Preoperative Skin Preparation Test product Active Control

4. 4 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Label Indication: Handwash to help reduce bacteria that potentially can cause disease. Testing Process: Predicts the reduction of organisms that may be achieved by washing hands after handling contaminated objects. Measures reduction of transient organisms after single or multiple uses. Bacterial Reduction (log 10 ) 2-log CFU / 1st Wash 3-log CFU / 10th Wash TFM Endpoints:

5. 5 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Methodology Inclusion Criteria –18-69 years of age –Good health –No clinical evidence of skin disorders Exclusion Criteria –Diagnosed with a medical condition –Sensitivity to antimicrobial products –Pregnant or nursing Washout period (7 days) –Non-antimicrobial kits

6. 6 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Methodology Outline of test procedures: –Practice: Wash with bland soap –Baseline: Contaminate hands & sample –Wash 1: Contaminate hands; perform wash & sample –Wash 2: Contaminate hands & perform wash –Wash 9: Contaminate hands & perform wash –Wash 10*: Contaminate hands; perform wash & sample –Decontaminate: Sanitize hands with 70% alcohol * Cumulative Effect: progressive decrease in the numbers of microorganisms recovered following repeated application of a test product.

7. 7 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Courtesy of Hill Top Research Inc. Inoculation of S. marcescens Rub all over surface of the hands (45 seconds) Allow to air dry

8. 8 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Courtesy of Hill Top Research Inc. Add antimicrobial test formulation Lather and wash all over surface of the hands Rinse hands (30 secs)

9. 9 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Courtesy of Hill Top Research Inc. Hands are placed in plastic bags Add sampling fluid* Bags are tightly secured above the wrist Hands are massaged for 1 minute *Neutralizers: chemical reagent used to inactivate microbiocidal properties of an antimicrobial agent.

10. 10 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Courtesy of Hill Top Research Inc. Aliquot of sampling fluid is withdrawn & diluted in dilution fluid* Surface plating* within 30 minutes of sampling (Microbial Enumeration) * Neutralizers are incorporated

11. 11 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Courtesy of Hill Top Research Inc. Colony forming units (CFUs) of S. marcescens from two dilution plates S. marcescens produces a red pigment

12. 12 Nonprescription Drugs AC Meeting March 23, 2005 Healthcare Personnel Handwash Handwash Industry Coalition’s Proposal Reduction (log 10 ) FDA TFM Proposal Reduction (log 10 ) Wash 11.52 Wash 10*No criteria3 * Cumulative Effect: progressive decrease in the numbers of micro- organisms recovered following repeated application of a test product.

13. 13 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Label Indication: Significantly reduces the number of microorganisms on the skin prior to surgery. Reduces incidence of post- surgical infections. Testing Process: Measures immediate and persistent reduction after single or repetitive treatments. Bacterial Reduction (log 10 ) 1-log CFU / Day 1 – Wash 1 2-log CFU / Day 2 – Wash 2 3-log CFU / Day 5 – Wash 11 TFM Endpoints:

14. 14 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Methodology Inclusion / Exclusion Washout period for 14 days Baseline week 1234567 Testing week 1 1 scrub 2 3 scrubs 3 4 5 1 scrub 3 and 5 5 and 7 3 and 7 1 Sample Day 1 Sample Day 2 Sample Day 5 Days Baseline count > 1.5 x 10 5 12 hrs – 4 days before initial testing

15. 15 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Courtesy of Hill Top Research Inc. Dispense amount in accordance with the manufacturer’s labeling

16. 16 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Courtesy of Hill Top Research Inc. Perform scrub in accordance with the manufacturer’s directions Scrub the hands including the nails, fingers, and interdigital spaces

17. 17 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Courtesy of Hill Top Research Inc. Donning sampling gloves Post Treatment Sampling: - One third of the hands in a treatment group are sampled immediately - Remaining hands wear gloves 3 hrs and/or 6 hrs prior to sampling

18. 18 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Courtesy of Hill Top Research Inc. Add sampling fluid* Fasten glove securely above the wrist Massage for 1 minute * Neutralizers are incorporated

19. 19 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Courtesy of Hill Top Research Inc. Aliquot of sampling fluid is withdrawn & transferred to dilution tubes* Surface plating* within 30 minutes of sampling (Microbial Enumeration) * Neutralizers are incorporated

20. 20 Nonprescription Drugs AC Meeting March 23, 2005 Surgical Hand Scrub Surgical Scrub Industry Coalition’s Proposal Reduction (log 10 ) FDA TFM Proposal Reduction (log 10 ) Wash 11 (No persistence criteria) 1 (persistence*) Wash 2No Criteria2 Wash 11No Criteria3 * 6-Hour Persistence: prolonged or extended antimicrobial activity that prevents or inhibits the proliferation or survival of microorganisms after product application.

21. 21 Nonprescription Drugs AC Meeting March 23, 2005 Patient Preoperative Skin Preparation Label Indication: Helps reduce bacteria that potentially cause skin infection. For the preparation of the skin prior to surgery. For the preparation of the skin prior to injection. Testing Process: Measures immediate and persistent reduction after single treatment. Bacterial Reduction (log 10 ) 1-log CFU / pre-injection 2-log CFU / abdomen (dry site) 3-log CFU / groin (moist site) TFM Endpoints:

22. 22 Nonprescription Drugs AC Meeting March 23, 2005 Patient Preoperative Skin Preparation Methodology Inclusion / Exclusion Washout period for 14 days No bathing 24 hrs prior to baselines Baseline screening counts – Pre-injections > 1.0 x 10 3 – Large enough to show > 2 log for Abdomen (dry site) > 3 log for Groin (moist site)

23. 23 Nonprescription Drugs AC Meeting March 23, 2005 Preoperative Skin Preparation (Abdominal Site) Patient Preoperative Skin Preparation (Abdominal Site) Courtesy of Hill Top Research Inc. 5”x 5” Area baseline30 min 10 min6 hrs

24. 24 Nonprescription Drugs AC Meeting March 23, 2005 Patient Skin Preparation (Abdominal Site) Patient Preoperative Skin Preparation (Abdominal Site) Courtesy of Hill Top Research Inc. Baseline sampling Cylinder sampling technique Add sampling fluid containing neutralizer

25. 25 Nonprescription Drugs AC Meeting March 23, 2005 Patient Preoperative Skin Preparation (Abdominal Site) Courtesy of Hill Top Research Inc. Application of prep formulation Cover area with a sterile gauze pad

26. 26 Nonprescription Drugs AC Meeting March 23, 2005 Patient Preoperative Skin Preparation (Abdominal Site) Treatment samples are taken from the site area using the cylinder sampling technique Courtesy of Hill Top Research Inc.

27. 27 Nonprescription Drugs AC Meeting March 23, 2005 Patient Preoperative Skin Preparation Surgical Scrub Industry Coalition’s Proposal Reduction (log 10 ) FDA TFM Proposal Reduction (log 10 ) Pre-injection11 Abdomen 1 (No persistence criteria) 2 (persistence*) Groin 2 (No persistence criteria) 3 (persistence*) * Persistence: prolonged or extended antimicrobial activity that prevents or inhibits the proliferation or survival of microorganisms after product application.

28. 28 Nonprescription Drugs AC Meeting March 23, 2005 Industry Coalition’s Comments TFM Criteria ● “overly stringent” ● inappropriate in antiseptic products with proven clinical benefit because they cannot meet the current criteria. - Monograph: alcohol & iodine - NDA: chlorhexidine gluconate ● all antiseptic products only need to be effective after a single use.

29. 29 Nonprescription Drugs AC Meeting March 23, 2005 Performance Criteria Industry’s Proposal Bacterial Reduction (log 10 ) FDA TFM Proposal Bacterial Reduction (log 10 ) Healthcare Personnel Handwash Wash 11.52 Wash 10----3 Surgical Hand Scrub* Wash 111 Wash 2---2 Wash 11---3 Patient Preoperative Skin Preparation* Preinjection11 Abdomen12 Groin23 * Industry has recommended removal of the 6-hour persistence criteria for these products. 1.5 ---- 2 1 1 1 ---

30. 30 Nonprescription Drugs AC Meeting March 23, 2005 Other Considerations for Effectiveness Criteria Surrogate endpoints –lack of clinical validation –level of residual bacteria on the skin not measured –virulence of the residual bacteria not considered Criteria based on earlier NDA data Consistently applied to monograph products Industry deviates from TFM –variability in testing procedure –not compared to vehicle or active control –statistical analysis

31. 31 Nonprescription Drugs AC Meeting March 23, 2005 Industry Coalition’s Proposal Points to Consider Majority designed as product comparisons Few studies used TFM methodology Significant variation in test conduct Neutralizer validation data not generally provided Generally sample sizes were small Alcohol alone (rubs/leave-on) did not meet the 10th wash 3-log reduction

32. 32 Nonprescription Drugs AC Meeting March 23, 2005 Product compared to reference Hand wash –significantly more effective than plain soap –average of 2.8 log* Hand rub (leave-on) –not be significantly less effective than 60% IPA –average of 4.6 log* Product compared to reference Hand wash –significantly more effective than plain soap –average of 2.8 log* Hand rub (leave-on) –not be significantly less effective than 60% IPA –average of 4.6 log* * Kampf and Ostermeyer, J Hosp Infect (2002) 52: 219-224. European Performance Criteria

33. 33 Nonprescription Drugs AC Meeting March 23, 2005 Summary of Testing Methodology We measure bacterial log reduction on the testing methodology for healthcare personnel handwash, surgical hand scrub, and patient preop. These log reductions are used as surrogate endpoints to evaluate effectiveness. How should we analyze this data? The relationship of these outcomes and a corresponding reduction in the incidence of nosocomial infections in the healthcare setting where the products are used remains undefined.

34. 34 Nonprescription Drugs AC Meeting March 23, 2005 Concluding Remarks Aware of limitations of test methods Assume incidence of infection: –related to current use of existing products –lowering these standards may increase infection rates Need research to validate these surrogates Need to have products on the market and the use of actionable criteria in the meantime