1. 1 Community-Based Studies of Consumer Antiseptics FDA Nonprescription Drug Advisory Committee Meeting Allison E. Aiello, PhD, MS Assistant Professor of Epidemiology University of Michigan-School of Public Health Center for Social Epidemiology & Population Health

2. 2 Outline Literature Review Methodological Issues Summary and Future Research Needs

3. 3 Overall Goal Estimate the reduction in risk attributed to specific hand hygiene products: –Plain soap handwash –Antiseptic soap handwash Triclosan,Triclocarban –Hand sanitizers Alcohol-based Non-alcohol based hand sanitizers –Benzalkonium chloride

4. 4 Methods Use of earlier systematic review articles: –Aiello, AE & Larson, EL. (2002) What is the evidence for a causal link between hygiene and infections? Lancet Infect Dis. Vol.2 –Curtis, V & Cairncross, S. (2003) Effect of washing hands with soap on diarrhoea risk in the community: a systematic review. Lancet Infect Dis. Vol.3 –Meadows, E & Le Saux, N. (2004) A systematic review of the effectiveness of antimicrobial rinse-tree hand sanitizers for prevention of illness-related absenteeism in elementary school children. BMC Pub Health.(4)50 PubMed database search for other articles from 1980 to 2005 –Key word combinations: hygiene, infection, soap, washing, handwashing, community, alcohol, antibacterial, triclosan, day care, school, hand sanitizer

5. 5 Methods Continued Inclusion Criteria: –Outcome: Culture confirmed infection, symptoms of infection, or absenteeism associated with infectious illness –Study Design: Community based Intervention or cross-over study with or without formal randomization –Intervention arm provided »Plain soap (not identified) »Antiseptic soap »Alcohol-based hand sanitizer »Non-alcohol hand sanitizer

6. 6 Number of Studies Meeting Criteria Soap (plain/unidentified) N=8 Antiseptic Soap N=5 Alcohol-Based Hand Sanitizers N=9 Non-Alcohol-Based Hand Sanitizers N=2

7. 7 Plain or Unidentified Soap Versus Control (N=8) YearAuthorsTitleJournal 1982Khan M.Interruption of shigellosis by hand washingTrans R Soc Trop Med Hyg 1989Han A. & Hlaing T.Prevention of diarrhoea and dysentery by hand washingTrans R Soc Trop Med Hyg 1991Wilson J, et al.Hand-washing reduces diarrhoea episodes: a study in Lombok, Indonesia Trans R Soc Trop Med Hyg 1996Shahid N, et al.Hand washing with soap reduces diarrhoea and spread of bacterial pathogens in a Bangladesh village J Diarrhoeal Dis Res 1996Pinfold J & Horan NMeasuring the effect of a hygiene behavior intervention by indicators of behavior and diarrhea disease Trans R Soc Trop Med Hyg 2002Luby S, et al.The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan Am J Trop Med Hyg 2004Luby S, et al.Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan JAMA 2005Luby S, et al.Effect of handwashing on child health: a randomized controlled trial Lancet

8. 8 Plain or Unidentified Soap (N=8): Study Methods Overview Formal randomization (n=3) –Soap form: Bars (n=8) –Reported plain or non-medicated soap (n=4) –Unknown soap type (n=4) Educational component –Wash hands at critical points (n=7) Hygiene promotion seminar (n=3) Washing of dishes (n=1) –Follow regular routine (n=1)

9. 9 Plain or Unidentified Soap (N=8): Study Methods Overview Outcomes: –Diarrhea Incidence/Risk (n=6) Prevalence, Healthcare Visits Culture confirmed Shigella sp. –Impetigo (n=2) –Skin and eye disease (n=1) –Runny nose, cough, and pneumonia (n=1)

10. 10 Plain or Unidentified Soap (N=8): Study Methods Overview Exposure measurements –Measured Soap use or Hand Washing (n=6) Controlled for confounding or reported balance on covariates (n=7)

11. 11 Plain or Unidentified Soap (N=8):Results Reduction in Diarrhea Incidence (n=6) All Results Statistically Significant (P < 0.05)

12. 12 Plain or Unidentified Soap (N=8): Results Continued Other significant findings: –Luby, S. et al. (2005) Lancet 51% reduction in cough or difficulty breathing 54% reduction in coryza (runny nose) 50% reduction in pneumonia 34% reduction in impetigo Null findings: –Luby, S. et al. (2002) Am J Trop Med Hyg 25% reduction in total impetigo (p=0.21) –No prompting of change in hygiene

13. 13 Plain or Unidentified Soap Type (N=8): Summary of Results Reduction in incidence of diarrhea ranged from 30% to 89% –Median reduction: 53% –Similar reduction range for other outcomes

14. 14 Plain or Unidentified Soap Type: Study Design Issues Most studies prior to 2004 lack formal randomization Not possible to mask participants or interviewers Only two studies used techniques to control for clustering Limited measurement on hygiene / soap use Varying definitions of symptoms and reporting methods across studies All studies were conducted outside of USA –High risk populations Difficult to tease apart the effect of soap use from that of hygiene education –Only one study asked participants to follow regular routine

15. 15 Plain or Unidentified Soap Type (N=8): Conclusions Consistent reductions observed –regardless of varying methods and study populations Plain soap in conjunction with proper hygiene is effective in reducing diarrheal illness in high risk populations

16. 16 YearAuthorTitleJournal 2002Luby S, et al.The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan Am J Trop Med Hyg 2004Larson E, et al.Effect of antibacterial home cleaning and handwashing products on infectious disease symptoms Ann Intern Med 2004Luby S, et al.Delayed effectiveness of home-based interventions in reducing childhood diarrhea, Karachi, Pakistan Am J Trop Med Hyg 2005Luby S, et al.Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan JAMA 2005Luby S, et al.Effect of handwashing on child health: a randomized controlled trial Lancet Antiseptic Soap Versus Plain Soap or Control (N=5)

17. 17 Antiseptic Soap (N=5): Study Methods Overview Comparison Groups: –Antiseptic Soap versus Plain Soap (placebo) (n=2) –Antiseptic Soap versus Plain Soap (placebo) and versus Control Group (nothing) (n=3) Formal randomization (n=3) –Soap form: Bars (n=4) (1.2% triclocarban) Liquid (n=1) (0.2% triclosan) Educational component –Washing hands at critical points (n=3) –Follow regular routine (n=2)

18. 18 Antiseptic Soap (N=5): Study Methods Overview Outcomes: –Diarrhea Incidence/Risk (n=3) –Impetigo (n=2) –Pneumonia (n=1) –Symptoms of infection (n=2)

19. 19 Antiseptic Soap (N=5): Study Methods Overview Measured Soap use and/or Hand Washing (n=4) –Masked participants and interviewers (n=4) Among placebo groups only Controlled for confounding or reported balance on covariates (n=5)

20. 20 Antiseptic Soap vs. Plain Soap: Reduction in Diarrhea Incidence (n=2) 10% Reduction* 6% Higher** Larson (2004) United States, Families Luby (2004) Pakistan, Children *Not statistically significant ** Not statistically significant and not designed or powered to make this comparison

21. 21 Antiseptic Soap vs. Plain Soap: Reduction in Incidence of Other Symptoms / Infections (n=3) No results were statistically significant

22. 22 Antiseptic Soap versus Control Group (No Soap Provided in Control Group) Reduction in Incidence of Impetigo and Diarrhea (n=3) All results statistically significant (P < 0.05) Impetigo Diarrhea

23. 23 Antiseptic Soap: Summary of Results Antiseptic Soap vs. Plain Soap (n=3) –No statistically significant differences for all infectious symptoms Antiseptic Soap vs. Control Group (no soap) (n=2) –Reduction in incidence of diarrhea ranged from 29% to 50% Similar to reductions associated with use of plain soap

24. 24 Antiseptic Soap: Study Design Issues Study Design Limitations –Possible viral or parasitic etiology for symptom definitions –High risk groups Study Design Strengths: –All studies used techniques to control for clustering –All studies measured baseline hygiene information Hygiene practices over duration of the study (n=1) Product monitoring (n=2) –Three studies masked participants and/or interviewers Use of a placebo plain soap (n=3) –Extensive follow-up for symptoms

25. 25 Antiseptic Soap: Conclusions Lack of evidence that antiseptic soaps provide a benefit beyond plain soap in community setting in US and Pakistan –Diarrhea –Impetigo –Other infectious symptoms When compared to a control group (no provision of plain soap or hygiene education) –Antiseptic soap with hygiene education is an effective intervention for reducing impetigo and diarrheal illness in high risk groups

26. 26 YearAuthorsTitleJournal 1990Butz A, et al.Occurrence of infectious symptoms in children in day care homesAm J Infect Control 1994Kotch J, et al.Evaluation of an hygienic intervention in child day-care centersPediatrics 1999Falsey A, et al.Evaluation of a handwashing intervention to reuce respiratory illness rates in senior day-care centers Infect Control Hosp Epidemiol 1999Uhari M & Mottonen M An open randomized controlled trial of infection prevention in child day-care centers Pediatr Infect Dis 2000Hammond B, et al.Effect of hand sanitizer use on elementary school absenteeismAm J Infect Control 2002Guinan M, et al.The effect of a comprehensive handwashing program on absenteeism in elementary schools Am J Infect Control 2003White C, et al.The effect of hand hygiene on illness rate among students in university residence halls Am J Infect Control 2004Morton J & Schultz A Healthy hands: use of alcohol gel as an adjunct to handwashing in elementary school children J Sch Nurs 2005Sandora T, et al.A randomized, controlled trial of a mulifaceted intervention including alcohol-based hand sanitizer and hand-hygiene education to reduce illness trasmission in the home Pediatrics Alcohol-Based Hand Sanitizers (N=9)

27. 27 Alcohol-Based Hand Sanitizer (N=9): Study Methods Overview Comparison Groups: –Alcohol + Education versus Control Group (nothing) (n=6) –Alcohol + Education versus Control Group (education) (n=2) –Alcohol versus Control Group (nothing) (n=1) Formal randomization (n=4) Cross-over (n=2) Alcohol form: Hand rinse (n=1) –60% isopropyl alcohol Disinfectant (n=2) –63% isopropyl alcohol, 70-90% ethanol and isopropanol Foam Instant hand sanitizer (n=5) –60-62% or unknown

28. 28 Alcohol-Based Hand Sanitizer (N=9): Study Methods Overview Outcomes: –Gastrointestinal illness (n=3) –Upper respiratory illness (n=3) Viral Respiratory Illnesses (n=1) –Symptoms of infection (n=3) Absence related

29. 29 Alcohol-Based Hand Sanitizer (N=9): Study Methods Overview Measured Alcohol use (n=3) –Supplies (n=3) Frequency of use (n=1) –Total hand hygiene practices (n=1) None masked participants or interviewers –One study collected illness data from masked parents of children in the study Controlled for confounding or reported balance on covariates (n=4)

30. 30 Alcohol-based Hand Sanitizer Reduction in Diarrheal Illness (n=3) * All P < 0.05, Statistically Significant Reduction * * *

31. 31 Alcohol-based Hand Sanitizer Reduction in Respiratory Illness (n=4) *P < 0.05, statistically significant ** Not statistically significant * **

32. 32 Alcohol-based Hand Sanitizer Symptoms of Infection (n=4) * All P < 0.05, Statistically significant reduction * * * *

33. 33 Alcohol-based Hand Sanitizer: Summary of Results Reductions in diarrheal illness ranged from 48% to 71% Similar to reductions associated with use of plain soap Most Reductions in respiratory illness were not statistically significant –3%-20% Infectious symptoms / absence ranged from 9% to 43% –Variable definitions and reporting

34. 34 Alcohol-based Hand Sanitizer: Study Design Issues Study Design Limitations –Unknown etiology for symptom definitions –Variability in definition of symptoms and reporting methods –Not balanced on education intervention –Lack consistent measurement of alcohol use and other hand hygiene practices (soap use?) –Difficult to employ masking –Only one study controlled for clustering

35. 35 Alcohol-based Hand Sanitizer: Conclusions Alcohol-based hand sanitizers in conjunction with hygiene education can effectively reduce diarrhea and general infectious symptoms in the community setting –Alcohol alone? There is less evidence of effectiveness for reducing upper respiratory infections

36. 36 Future Research Needs Assess the effect of antiseptic soaps and alcohol-based hand sanitizers in culture confirmed viral and bacterial infections studies Assess the benefit of alcohol-based hand sanitizers in groups with similar baseline levels of hygiene education –Better control of confounding factors –Analytical techniques that accommodate clustered data –Further household level studies

37. 37 Conflicts of Interest Statement and Acknowledgements Consulted for Pfizer in September Thanks to Dr. Elaine L. Larson