1. Nonprescription Drugs AC Meeting October 20, 2005 1 THE QUEST FOR CLINICAL BENEFIT Steven Osborne, M.D. Medical Officer Office of Nonprescription Drug Products

2. Nonprescription Drugs AC Meeting October 20, 2005 2 THE QUEST FOR CLINICAL BENEFIT Does the Clinical Evidence Link use of Consumer Antiseptics With Clinical Benefit?

3. Nonprescription Drugs AC Meeting October 20, 2005 3 Consumer Antiseptics We will examine the data from: ● Citizen Petition 16 ● FDA’s literature search Try to determine if there is a clinical benefit from: ● specific antiseptic ● hygiene method (e.g. handwashing alone or with training, with disenfectants)

4. Nonprescription Drugs AC Meeting October 20, 2005 4 CP16 References 31 Articles and Abstracts Most relate to professional use—previously discussed 25 articles: weight of evidence was not persuasive for clinical benefit of consumer antiseptics 2 microbial risk assessment 2 describe other models 2 hand sanitizers in school (discuss Guinan et al, Dyer et al) Overall, no link between use of any particular antiseptic and a reduction in infection rates

5. Nonprescription Drugs AC Meeting October 20, 2005 5 Summary of Study Limitations Not designed to assess contribution of active ingredient to effectiveness of product Not designed to assess single ingredient effectiveness vs. hand hygiene alone Lack of standardization of product use Bacterial transfer studies not correlated with clinical outcome Applicable to a healthcare setting and not a consumer use setting

6. Nonprescription Drugs AC Meeting October 20, 2005 6 Handwash Studies FDA literature search: Larson et al. 2004 (antibacterial ingredients in home vs. infection symptoms) Luby et al. 2005 (handwash, bathing vs.respiratory infection, diarrhea, impetigo)

7. Nonprescription Drugs AC Meeting October 20, 2005 7 Larson et al. 2004 Design: 48-week, randomized, DB, placebo48-week, randomized, DB, placebo 224 households inner city NY, at least 3 people, 1 preschool224 households inner city NY, at least 3 people, 1 preschool weekly calls, monthly and quarterly visits, 31-page validated form for home hygiene practices and illness dataweekly calls, monthly and quarterly visits, 31-page validated form for home hygiene practices and illness data 93 of first 100 self-reported illnesses verified by visiting physician93 of first 100 self-reported illnesses verified by visiting physician self-reported illnesses thereafter (unverified)self-reported illnesses thereafter (unverified) Primary endpoint: at least one infectious disease symptom within household for each 1-month period

8. Nonprescription Drugs AC Meeting October 20, 2005 8 Larson et al. 2004 test group control trainingtrainingtrainingtraining antimicrobial products* plain productsantimicrobial products* plain products weekly phone callsweekly phone callsweekly phone callsweekly phone calls monthly visits (adherence) monthly visitsmonthly visits (adherence) monthly visits quarterly visits (symptoms) quarterly visitsquarterly visits (symptoms) quarterly visits *Antimicrobial products: liquid triclosan soap, quaternary ammonium hard surface cleaner, oxygenated bleach detergent, liquid kitchen spray Note: both groups received a non-antimicrobial dish liquid and bar soap

9. Nonprescription Drugs AC Meeting October 20, 2005 9 Study Results Rates of at least one infectious disease symptom for each household

10. Nonprescription Drugs AC Meeting October 20, 2005 10 Study Interpretation (Larson) Adjusted and unadjusted relative risks for each symptom show no advantage of antibacterial product use in reducing infections Symptoms likely reflect viral illnesses Use of multiple antimicrobials (antiseptic + disinfectants) would have confounded assessment for any single antiseptic Cannot assess whether use of antiseptics would reduce transmission of bacterial infections

11. Nonprescription Drugs AC Meeting October 20, 2005 11 Luby et al. 2005 (Karachi Soap Health Study) Design: Randomized, DB, placebo-controlled trial in 36 neighborhoods, 906 households (300 test, 300 placebo, 306 control) in PakistanRandomized, DB, placebo-controlled trial in 36 neighborhoods, 906 households (300 test, 300 placebo, 306 control) in Pakistan HW promotion (slides, video, pamphlets) to soap neighborhoods, school supplies to control neighborhoodsHW promotion (slides, video, pamphlets) to soap neighborhoods, school supplies to control neighborhoods Soap randomized to intervention households (1.2% triclocarban soap or non-medicated). Free soap supplied and replenished, 90g bars, identical-appearance for both groupsSoap randomized to intervention households (1.2% triclocarban soap or non-medicated). Free soap supplied and replenished, 90g bars, identical-appearance for both groups Field workers assessed illness, physician corroborated impetigoField workers assessed illness, physician corroborated impetigo Endpoint: incidence of acute respiratory infection, impetigo, diarrheaEndpoint: incidence of acute respiratory infection, impetigo, diarrhea

12. Nonprescription Drugs AC Meeting October 20, 2005 12 Luby et al. 2005 Test groupPlacebo groupControl group Triclocarban soapplain soap………….. HW trainingHW trainingschool supplies field workers visited control & intervention groups weekly: encouraged children >30 months in test and placebo groups to wash hands (wet, lather 45 seconds, rinse, dry on clothing): -after defecation -after defecation -before food prep & eating -before food prep & eating -before feeding infants -before feeding infants -also to bathe once daily with soap

13. Nonprescription Drugs AC Meeting October 20, 2005 13 Study Results (Luby) Mean incidence (episodes/100 person-weeks) Coryza Diarrhea Impetigo Coryza Diarrhea Impetigo Antibacterial soap 7.32 * 2.02 * 0.61 * Plain soap 6.87 * 1.91 * 0.62 * Control 14.78 4.06 0.94 *=95% C.I of difference from control excludes zero Note: triclocarban effective against some strep, but less activity against gram neg bacteria or viruses neg bacteria or viruses

14. Nonprescription Drugs AC Meeting October 20, 2005 14 Study Interpretation Handwashing plus bathing with soap reduces respiratory infection, diarrhea, and impetigoHandwashing plus bathing with soap reduces respiratory infection, diarrhea, and impetigo Reduction in disease is simply due to handwashing/bathing with soap (plus HW promotion)Reduction in disease is simply due to handwashing/bathing with soap (plus HW promotion) No added benefit from triclocarban in soapNo added benefit from triclocarban in soap “Antibacterial soap did not provide a health advantage over plain soap for any of the health outcomes in our study”“Antibacterial soap did not provide a health advantage over plain soap for any of the health outcomes in our study”

15. Nonprescription Drugs AC Meeting October 20, 2005 15 Study Limitations (Luby) study personnel and participants not masked to soap intervention (though blinded to antibacterial vs plain)—could have under-reported illnessstudy personnel and participants not masked to soap intervention (though blinded to antibacterial vs plain)—could have under-reported illness bathing and overall promotion confounds attempt to attribute effect to handwashing alonebathing and overall promotion confounds attempt to attribute effect to handwashing alone

16. Nonprescription Drugs AC Meeting October 20, 2005 16 Hand Sanitizer Examples CP16 and FDA literature search: Dyer et al. 2000 (reduction in school absenteeism) Guinan et al. 2002 (reduction in school absenteeism) Sandora et al. 2005 (hand sanitizer at home vs. respiratory and GI illness) Lee et al. 2005 (alcohol gels at home and illness transmission)

17. Nonprescription Drugs AC Meeting October 20, 2005 17 Dyer et al. 2000Design: 10-week, open-label, crossover, 1 school 420 students ages 5-12, grouped by class (30/class), 7 classes test, 7 control no randomization, unblinded illness GI or respiratory, per parents test sanitizer: SAB (surfactant + benzalkonium Cl) Endpoint: incidence of illness absenteeism

18. Nonprescription Drugs AC Meeting October 20, 2005 18 Dyer et al. 2000 all students: 30 min talk on germs & HW, video wash with non-medicated soap before eating, after bathroom, prn test group control trainingtraining non-medicated (NM) soapNM soap sanitize entering class, …….. after sneeze or cough rub 0.25 ml SAB in hands, …….. fingertips & nails until dry Monitored not monitored

19. Nonprescription Drugs AC Meeting October 20, 2005 19 Study Results Student Absence Data (2-wk washout): 1 st 4-weeks Control Sanitizer 1 st 4-weeks Control Sanitizer Days illness 105 70 (P<.001) # students 57 31 Days absent/pupil 1.84 2.26 2 nd 4-weeks Control Sanitizer Days illness 63 28 # students 37 17 Days absent/pupil 1.70 1.65

20. Nonprescription Drugs AC Meeting October 20, 2005 20 Study Limitations clustered, no randomizationclustered, no randomization no placebo (ie no bland pump spray)no placebo (ie no bland pump spray) unblindedunblinded no specified length of time for washno specified length of time for wash test group monitored, but not controltest group monitored, but not control test group advised to wash more oftentest group advised to wash more often single site single site Are illness rate differences due to monitoring and number of times washing?

21. Nonprescription Drugs AC Meeting October 20, 2005 21 Guinan et al. 2002 Design: 3-month, open-label, 5 private schools, ~2 test & 2 control/school 290 students, grades K-3, grouped by class (15/class), 9 classes test, 9 control no randomization, unblinded teachers collected data on illness: cold, flu, GI (per parents or child) test sanitizer: alcohol-based instant sanitizer with aloe Endpoint: incidence of illness absenteeism: number of episodes of illness per child per month

22. Nonprescription Drugs AC Meeting October 20, 2005 22 Guinan et al. 2002 all students: 10 min talk on HW, video, pamphlet (no demo)all students: 10 min talk on HW, video, pamphlet (no demo) test groups control groupstest groups control groups education educationeducation education sanitizer ………sanitizer ……… HW demo and test ………HW demo and test ……… not monitored not monitorednot monitored not monitored

23. Nonprescription Drugs AC Meeting October 20, 2005 23 Study Results 277 episodes absenteeism in control group, 140 in test group lower absenteeism in 23 of 27 months in test group (P<0.001) 50.6% fewer episodes of absenteeism in test group (P<0.001)

24. Nonprescription Drugs AC Meeting October 20, 2005 24 Authors’ Conclusions Successful HW program includes: ● administrative support ● 1-hour hand hygiene in-service ● hand sanitizers in classrooms and bathrooms

25. Nonprescription Drugs AC Meeting October 20, 2005 25 Study Limitations no comparison to plain soap not randomized, unblinded homogeneous population home variables not assessed (sibling health, smoking, healthcare visits, home hygiene) student’s actual HW/sanitizing not observed, tallied, or assessed test group received HW training—authors note similar study showed only 19.8% lower absenteeism in a control group given HW training

26. Nonprescription Drugs AC Meeting October 20, 2005 26 Sandora et al. 2005 Design:Design: –5- month, randomized, open-label, controlled trial –292 families, 1 child age 0.5-5 years old in day care –26 child care centers randomized –excluded if using hand sanitizer daily test sanitizer: alcohol-based instant sanitizer with aloe primary outcome: rate of secondary respiratory and GI illnessprimary outcome: rate of secondary respiratory and GI illness

27. Nonprescription Drugs AC Meeting October 20, 2005 27 Sandora et al. 2005 test group control test group control sanitizerusual practicesanitizerusual practice biweekly hand hygiene biweekly healthy education material diet materialbiweekly hand hygiene biweekly healthy education material diet material not monitorednot monitorednot monitorednot monitored

28. Nonprescription Drugs AC Meeting October 20, 2005 28 Study Results (Sandora) GI Illness Respiratory Illness GI Illness Respiratory Illness C I C I C I C I Total 117 135 828974 Person-days60413 691186041369118 Incidence rate 0.06 0.060.420.43 Secondary ill 18 10 202241 # susceptible 1549 1810 85259648 patient-days patient-days Incidence rate 0.35 0.17* 0.720.72 *P=0.08 vs Control, but 0.03 post 7-variable adjustment C=control group, I=intervention group C=control group, I=intervention group

29. Nonprescription Drugs AC Meeting October 20, 2005 29 Study Limitations (Sandora) not blinded not blinded hand sanitizer use not monitoredhand sanitizer use not monitored hand sanitizer combined with educationhand sanitizer combined with education no placebo sanitizer for control group no placebo sanitizer for control group low initial participation: of 647 eligible families, only 292 randomizedlow initial participation: of 647 eligible families, only 292 randomized unclear whether adjustment for 7 variables unclear whether adjustment for 7 variables was pre-planned or post-hoc was pre-planned or post-hoc Note: clinical significance of secondary GI illness reduction 10 vs. 18 unclear

30. Nonprescription Drugs AC Meeting October 20, 2005 30 Lee et al. 2005 Design: Observational, uncontrolled, prospective cohort study in families in Boston area over 18 monthsObservational, uncontrolled, prospective cohort study in families in Boston area over 18 months Randomly selectedRandomly selected At least 1 child< 5 years oldAt least 1 child< 5 years old At least 1 child in child care for 10 hours/weekAt least 1 child in child care for 10 hours/week Recruitment from 5 pediatric practices, 250 families each practiceRecruitment from 5 pediatric practices, 250 families each practice Analyze predictors of secondary transmission of illnessAnalyze predictors of secondary transmission of illness Endpoint: rate of secondary respiratory and GI illness per susceptible person-month

31. Nonprescription Drugs AC Meeting October 20, 2005 31 Study Results (Lee) 208 (of 1250) families available for analysis: 1545 respiratory illness (1099 primary, 446 secondary)1545 respiratory illness (1099 primary, 446 secondary) 360 GI illness (297 primary, 63 secondary)360 GI illness (297 primary, 63 secondary) secondary transmission rates 0.63 respiratory, 0.35 GIsecondary transmission rates 0.63 respiratory, 0.35 GI IRR = 0.6 (C.I. 0.4-0.9, P=0.01, not adjusted for multiple comparisons) for use of alcohol gelsIRR = 0.6 (C.I. 0.4-0.9, P=0.01, not adjusted for multiple comparisons) for use of alcohol gels

32. Nonprescription Drugs AC Meeting October 20, 2005 32 Study Limitation (Lee) Observational Uncontrolled Not designed to assess alcohol efficacy (or any other antiseptic) as a primary endpoint P values<0.05 may not be significant: not adjusted for multiple comparisons

33. Nonprescription Drugs AC Meeting October 20, 2005 33 Summary Data from CP16 and literature review shows: a clinical benefit from HW no added benefit from triclocarban soap no definitive proof of benefit from use of hand sanitizers for handwashing compared to plain soap

34. Nonprescription Drugs AC Meeting October 20, 2005 34 Key Issue Does the Clinical Evidence Link use of Consumer Antiseptics With Clinical Benefit?