1. Nonprescription AC Meeting March 23, 2005 THE QUEST FOR CLINICAL BENEFIT Steven Osborne, M.D. Medical Officer Division of Over-The-Counter Drug Products Steven Osborne, M.D. Medical Officer Division of Over-The-Counter Drug Products

2. Nonprescription AC Meeting March 23, 2005 2 Key Issues Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?

3. Nonprescription AC Meeting March 23, 2005 3 Key Issues Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?

4. Nonprescription AC Meeting March 23, 2005 4 Monograph Antiseptics Alcohols (ETOH and IPA) –Purell Handrub Chlorhexidine (CHG) 2% and 4% Aqueous –Hibiclens and Hibiprep Iodine or Iodophors (PI) –Tincture of iodine and povidone-iodine (Betadine) Triclosan –Gojo Antimicrobial Lotion Soap Alcohols (ETOH and IPA) –Purell Handrub Chlorhexidine (CHG) 2% and 4% Aqueous –Hibiclens and Hibiprep Iodine or Iodophors (PI) –Tincture of iodine and povidone-iodine (Betadine) Triclosan –Gojo Antimicrobial Lotion Soap

5. Nonprescription AC Meeting March 23, 2005 5 Monograph Antiseptics Quaternary Ammonium Compounds –Benzalkonium chloride (Zephiran) Phenol Derivatives –Carbolic acid Chloroxylenol (PCMX) Triclocarban –Safeguard soap Quaternary Ammonium Compounds –Benzalkonium chloride (Zephiran) Phenol Derivatives –Carbolic acid Chloroxylenol (PCMX) Triclocarban –Safeguard soap

6. Nonprescription AC Meeting March 23, 2005 6 Antiseptic Antimicrobial Spectrum (CDC 2002) Group Gram Positive Gram Negative Speed of Action Alcohols +++ +++ Fast Chlorhexidine +++ ++ Intermediate Iodine Compounds +++ +++ Intermediate Iodophors +++ +++ Intermediate Phenol Derivatives +++ + Intermediate Triclosan +++ ++ Intermediate Quaternary AC + ++ Slow +++ excellent, ++ good, but does not include entire bacterial spectrum, + fair Group Gram Positive Gram Negative Speed of Action Alcohols +++ +++ Fast Chlorhexidine +++ ++ Intermediate Iodine Compounds +++ +++ Intermediate Iodophors +++ +++ Intermediate Phenol Derivatives +++ + Intermediate Triclosan +++ ++ Intermediate Quaternary AC + ++ Slow +++ excellent, ++ good, but does not include entire bacterial spectrum, + fair

7. Nonprescription AC Meeting March 23, 2005 7 Citizen Petition And Comment Industry Coalition--Soap and Detergent Association (SDA) and Cosmetic, Toiletry, and Fragrance Association (CTFA): Citizen Petition and Comment to the TFM –Submitted references –Requested FDA lower efficacy standards Industry Coalition--Soap and Detergent Association (SDA) and Cosmetic, Toiletry, and Fragrance Association (CTFA): Citizen Petition and Comment to the TFM –Submitted references –Requested FDA lower efficacy standards

8. Nonprescription AC Meeting March 23, 2005 8 Healthcare Procedures –Invasive Procedures: Surgery Catheters, IVs –Non-Invasive procedures Reduce nosocomial infections with handwash Reduce respiratory and GI illness with handwash –Invasive Procedures: Surgery Catheters, IVs –Non-Invasive procedures Reduce nosocomial infections with handwash Reduce respiratory and GI illness with handwash

9. Nonprescription AC Meeting March 23, 2005 9 Antiseptics References Industry Coalition: Citizen Petition and Comment to the TFM: 155 Articles and Abstracts 58% HW, 26% PP, 16% SS Weight of evidence of clinical benefit not persuasive for changing current efficacy criteria No link between surrogate endpoints and infection rates Industry Coalition: Citizen Petition and Comment to the TFM: 155 Articles and Abstracts 58% HW, 26% PP, 16% SS Weight of evidence of clinical benefit not persuasive for changing current efficacy criteria No link between surrogate endpoints and infection rates

10. Nonprescription AC Meeting March 23, 2005 10 Summary Of Study Limitations Surrogate endpoints not correlated with clinical outcome Not randomized No placebo control Retrospective Multiple confounders Inadequately powered No statistics Lack of standardization of product use Irregular patterns of data collection Failure to address a TFM indication Surrogate endpoints not correlated with clinical outcome Not randomized No placebo control Retrospective Multiple confounders Inadequately powered No statistics Lack of standardization of product use Irregular patterns of data collection Failure to address a TFM indication

11. Nonprescription AC Meeting March 23, 2005 11 Study Examples Maki et al. 1991 (catheter infections) Luby et al. 2002 (impetigo) Maki et al. 1991 (catheter infections) Luby et al. 2002 (impetigo)

12. Nonprescription AC Meeting March 23, 2005 12 Maki et al 1991 Randomized study in 668 subjects with IV catheters –all catheters CV or arterial –2% CHG, 10% PI, 70% IPA – then every other day. No other agents applied Randomized study in 668 subjects with IV catheters –all catheters CV or arterial –2% CHG, 10% PI, 70% IPA – then every other day. No other agents applied

13. Nonprescription AC Meeting March 23, 2005 13 Maki et al 1991 Endpoints: –Local infection rate (>15 CFUs) 2.3% for CHG, vs 7.1% (alcohol) and 9.1% (PI), P=0.02 –Bacteremia 10 total CHG (1), alcohol (3), PI (6), P=0.18 Endpoints: –Local infection rate (>15 CFUs) 2.3% for CHG, vs 7.1% (alcohol) and 9.1% (PI), P=0.02 –Bacteremia 10 total CHG (1), alcohol (3), PI (6), P=0.18

14. Nonprescription AC Meeting March 23, 2005 14 Maki et al 1991 No correlation between reduction in bacteria with infection rates Application of antimicrobial post- catheter insertion limits ability to relate to monograph application No correlation between reduction in bacteria with infection rates Application of antimicrobial post- catheter insertion limits ability to relate to monograph application

15. Nonprescription AC Meeting March 23, 2005 15 Luby et al 2002 Double blind, randomized study of antibacterial soap in 241 households in Karachi, Pakistan Triclocarban soap, bland soap, standard practice group Primary outcome was incidence of impetigo Double blind, randomized study of antibacterial soap in 241 households in Karachi, Pakistan Triclocarban soap, bland soap, standard practice group Primary outcome was incidence of impetigo

16. Nonprescription AC Meeting March 23, 2005 16 Luby et al 2002 Triclocarban soap 43% less impetigo than standard practice (P=0.02) Triclocarban 23% less impetigo than than bland soap (P=0.28) Bland soap 24% less impetigo than standard practice (P=0.21) Needed 70% increase in sample size Triclocarban soap 43% less impetigo than standard practice (P=0.02) Triclocarban 23% less impetigo than than bland soap (P=0.28) Bland soap 24% less impetigo than standard practice (P=0.21) Needed 70% increase in sample size

17. Nonprescription AC Meeting March 23, 2005 17 SURGICAL SCRUBS Surgical hand scrubs –300 articles screened for clinical benefit –None conclusively linked reduction in bacteria with reduction in infection rates Surgical hand scrubs –300 articles screened for clinical benefit –None conclusively linked reduction in bacteria with reduction in infection rates

18. Nonprescription AC Meeting March 23, 2005 18 Study Examples Bryce et al 2001 –70% IPA leave-on »in-use hospital evaluation » 70 scrubs by surgeons »15 ml product used over 3 min –Endpoint: post-op bacterial counts –IPA agent comparable to 4% CHG and 7.5% PI in reducing bacteria –No infection rates studied Bryce et al 2001 –70% IPA leave-on »in-use hospital evaluation » 70 scrubs by surgeons »15 ml product used over 3 min –Endpoint: post-op bacterial counts –IPA agent comparable to 4% CHG and 7.5% PI in reducing bacteria –No infection rates studied

19. Nonprescription AC Meeting March 23, 2005 19 Study Examples –Parienti et al. 2002 Hand-rubbing with alcoholic leave-on solution and 30-day surgical site infection (SSI) rate Randomized, crossover equivalence trial (75% alcohol, 4% PI, 4% CHG) 6 surgical services, 4287 pts –Parienti et al. 2002 Hand-rubbing with alcoholic leave-on solution and 30-day surgical site infection (SSI) rate Randomized, crossover equivalence trial (75% alcohol, 4% PI, 4% CHG) 6 surgical services, 4287 pts

20. Nonprescription AC Meeting March 23, 2005 20 Parienti et al. 2002 Alcohol hand-rub, PI and CHG as hand-scrub SSI 2.44% alcohol vs. 2.48% with PI+CHG Scrub time compliance better with alcohol rub (313 sec vs 287 sec, P=0.01) SSI micro not provided Surgeon not blinded (reported SSI) Alcohol hand-rub, PI and CHG as hand-scrub SSI 2.44% alcohol vs. 2.48% with PI+CHG Scrub time compliance better with alcohol rub (313 sec vs 287 sec, P=0.01) SSI micro not provided Surgeon not blinded (reported SSI)

21. Nonprescription AC Meeting March 23, 2005 21 HANDWASH Literature Review Literature review of healthcare personnel Handwashes 1994-2004 –222 studies reviewed for clinical benefit or efficacy –None showed a definitive link between bacterial reduction and reduction in infection rates Literature review of healthcare personnel Handwashes 1994-2004 –222 studies reviewed for clinical benefit or efficacy –None showed a definitive link between bacterial reduction and reduction in infection rates

22. Nonprescription AC Meeting March 23, 2005 22 HANDWASH References Swoboda et al. 2004, 3-Phase, 15 month evaluation incorporating an electronic monitor (monitor, voice- prompt, monitor) –Compliance improved by 35%, 41% in Phase 2 and 3 –MRSA or VRE colonization rates 19%, 9%, 11% Swoboda et al. 2004, 3-Phase, 15 month evaluation incorporating an electronic monitor (monitor, voice- prompt, monitor) –Compliance improved by 35%, 41% in Phase 2 and 3 –MRSA or VRE colonization rates 19%, 9%, 11%

23. Nonprescription AC Meeting March 23, 2005 23 Patient PREOP Literature Review 400 articles screened Searched for bacterial log reduction data post-scrub compared with pre-scrub, then ….. –Searched for SSI rate in same reference 400 articles screened Searched for bacterial log reduction data post-scrub compared with pre-scrub, then ….. –Searched for SSI rate in same reference

24. Nonprescription AC Meeting March 23, 2005 24 Patient PREOP Literature Review –Majority of studies performed in animals None of the studies found link between colony forming units (CFU) of bacteria and SSIs –Majority of studies performed in animals None of the studies found link between colony forming units (CFU) of bacteria and SSIs

25. Nonprescription AC Meeting March 23, 2005 25 Patient PREOP Literature Review Secondary topic: Is there a minimum number of bacteria in a wound that predisposes to infection? 100,000 bacteria (10 5 ) –May vary with type of bacteria Secondary topic: Is there a minimum number of bacteria in a wound that predisposes to infection? 100,000 bacteria (10 5 ) –May vary with type of bacteria

26. Nonprescription AC Meeting March 23, 2005 26 Patient PREOP Literature Review 100,000 bacteria “threshold” for infection –Kass 1957: 2000 patients with pyelonephritis had >100,000 100% of symptomatic patients with UTI had >100,000 –Krizek et al. 1967 94% graft success when pre-graft bacteria <100,000/ gram tissue 100,000 bacteria “threshold” for infection –Kass 1957: 2000 patients with pyelonephritis had >100,000 100% of symptomatic patients with UTI had >100,000 –Krizek et al. 1967 94% graft success when pre-graft bacteria <100,000/ gram tissue

27. Nonprescription AC Meeting March 23, 2005 27 Study Literature Cronquist et al. 2001 –609 neurosurgery patients Craniotomy Ventriculo-Peritoneal (VP) shunt –Pre-scrub and post-scrub bacterial counts from head, back Cronquist et al. 2001 –609 neurosurgery patients Craniotomy Ventriculo-Peritoneal (VP) shunt –Pre-scrub and post-scrub bacterial counts from head, back

28. Nonprescription AC Meeting March 23, 2005 28 Cronquist et al. 2001 HeadBack Pre-scrub4.132.39 Post-scrub0.620.54 Bacterial counts (log 10 ):

29. Nonprescription AC Meeting March 23, 2005 29 Study Literature Cronquist et al. 2001 20 SSIs –19 from craniotomies –Staph species, P. acnes No correlation between pre-scrub or post scrub counts and SSIs Cronquist et al. 2001 20 SSIs –19 from craniotomies –Staph species, P. acnes No correlation between pre-scrub or post scrub counts and SSIs

30. Nonprescription AC Meeting March 23, 2005 30 Key Issues Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?

31. Nonprescription AC Meeting March 23, 2005 31 Key Issues Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?