Nonprescription Drugs AC Meeting October 20, 2005 1 THE QUEST FOR CLINICAL BENEFIT Steven Osborne,...

1Nonprescription Drugs AC MeetingOctober 20, 2005

THE QUEST FOR CLINICAL BENEFIT

Steven Osborne, M.D.Medical Officer

Office of Nonprescription Drug Products


THE QUEST FOR CLINICAL BENEFIT

Does the Clinical Evidence Link use of Consumer Antiseptics With Clinical Benefit?


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)


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


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


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)


Larson et al. 2004

Design:Design:• 48-week, randomized, DB, placebo48-week, randomized, DB, placebo• 224 households inner city NY, at least 3 224 households inner city NY, at least 3

people, 1 preschool people, 1 preschool• weekly calls, monthly and quarterly visits, weekly calls, monthly and quarterly visits,

31-page validated form for home hygiene 31-page validated form for home hygiene practices and illness data practices and illness data

• 93 of first 100 self-reported illnesses verified by 93 of first 100 self-reported illnesses verified by visiting physicianvisiting physician

• self-reported illnesses thereafter (unverified)self-reported illnesses thereafter (unverified)Primary endpointPrimary endpoint: at least one infectious disease : at least one infectious disease

symptom within household for each 1-month symptom within household for each 1-month periodperiod


Larson et al. 2004

test grouptest group controlcontrol• trainingtraining trainingtraining• antimicrobial products* antimicrobial products* plain productsplain products• weekly phone callsweekly phone calls weekly phone weekly phone

callscalls• monthly visits (adherence) monthly visits (adherence) monthly visits monthly visits • quarterly visits (symptoms) quarterly visits (symptoms) quarterly visitsquarterly visits

*Antimicrobial products: liquid triclosan soap, quaternary *Antimicrobial products: liquid triclosan soap, quaternary ammonium hard surface cleaner, oxygenated bleach ammonium hard surface cleaner, oxygenated bleach detergent, liquid kitchen spraydetergent, liquid kitchen spray

Note: both groups received a non-antimicrobial dish liquid and bar soap


Study Results Rates of at least one infectious disease symptom for each household


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


Luby et al. 2005 (Karachi Soap Health Study)

Design:Design:• Randomized, DB, placebo-controlled trial in 36 Randomized, DB, placebo-controlled trial in 36

neighborhoods, 906 households (300 test, 300 placebo, 306 neighborhoods, 906 households (300 test, 300 placebo, 306 control) in Pakistancontrol) in Pakistan

• HW promotion (slides, video, pamphlets) to soap HW promotion (slides, video, pamphlets) to soap neighborhoods, school supplies to control neighborhoodsneighborhoods, school supplies to control neighborhoods

• Soap randomized to intervention households (1.2% Soap randomized to intervention households (1.2% triclocarban soap or non-medicated). Free soap supplied and triclocarban soap or non-medicated). Free soap supplied and replenished, 90g bars, identical-appearance for both groupsreplenished, 90g bars, identical-appearance for both groups

• Field workers assessed illness, physician corroborated Field workers assessed illness, physician corroborated impetigoimpetigo

• EndpointEndpoint: incidence of acute respiratory infection, : incidence of acute respiratory infection, impetigo, diarrheaimpetigo, diarrhea


Luby et al. 2005

Test groupTest group Placebo groupPlacebo group Control groupControl groupTriclocarban soapTriclocarban soapplain soapplain soap …………..…………..HW trainingHW training HW trainingHW training school school

suppliessupplies

field workers visited control & intervention groups weekly:field workers visited control & intervention groups weekly:encouraged children >30 months in test and placebo encouraged children >30 months in test and placebo groups to wash hands (wet, lather 45 seconds, rinse, dry groups to wash hands (wet, lather 45 seconds, rinse, dry on clothing):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-also to bathe once daily with soap


Study Results (Luby)Mean incidence (episodes/100 person-weeks)Mean incidence (episodes/100 person-weeks)

CoryzaCoryza Diarrhea Diarrhea ImpetigoImpetigo

Antibacterial soap 7.32 *Antibacterial soap 7.32 * 2.02 * 2.02 * 0.61 * 0.61 *

Plain soapPlain soap 6.87 * 6.87 * 1.91 * 1.91 * 0.62 * 0.62 *

Control Control 14.78 14.78 4.06 4.06 0.94 0.94

*=95% C.I of difference from control excludes zero *=95% C.I of difference from control excludes zero

Note: triclocarban effective against some strep, but less activity against gram Note: triclocarban effective against some strep, but less activity against gram neg bacteria or virusesneg bacteria or viruses


Study Interpretation

• Handwashing plus bathing with soap reduces Handwashing plus bathing with soap reduces respiratory infection, diarrhea, and impetigorespiratory infection, diarrhea, and impetigo

• Reduction in disease is simply due to Reduction in disease is simply due to handwashing/bathing with handwashing/bathing with soapsoap (plus HW (plus HW promotion)promotion)

• No added benefit from triclocarban in soapNo added benefit from triclocarban in soap

• ““Antibacterial soap did not provide a health Antibacterial soap did not provide a health advantage over plain soap for any of the health advantage over plain soap for any of the health outcomes in our study”outcomes in our study”


Study Limitations (Luby)

• study personnel and participants not study personnel and participants not masked to soap intervention (though masked to soap intervention (though blinded to antibacterial vs plain)—could blinded to antibacterial vs plain)—could have under-reported illnesshave under-reported illness

• bathing and overall promotion confounds bathing and overall promotion confounds attempt to attribute effect to handwashing attempt to attribute effect to handwashing alonealone


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)


Dyer et al. 2000

Design:Design:• 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


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• training training• non-medicated (NM) soap NM soap• sanitize entering class, ……..

after sneeze or cough• rub 0.25 ml SAB in hands, ……..

fingertips & nails until dry • Monitored not monitored


Study Results

Student Absence Data (2-wk washout):Student Absence Data (2-wk washout):

11stst 4-weeks 4-weeks Control Control Sanitizer Sanitizer Days illness 105Days illness 105 70 (P<.001) 70 (P<.001)# students # students 57 57 31 31Days absent/pupil 1.84 2.26Days absent/pupil 1.84 2.26

22ndnd 4-weeks 4-weeks ControlControl Sanitizer Sanitizer

Days illness Days illness 63 63 28 28 # students # students 37 37 17 17Days absent/pupil 1.70 1.65Days absent/pupil 1.70 1.65


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 sitesingle site

Are illness rate differences due to monitoring and Are illness rate differences due to monitoring and number of times washing?number of times washing?


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


Guinan et al. 2002

• all students: 10 min talk on HW, video, pamphlet (no all students: 10 min talk on HW, video, pamphlet (no demo)demo)

• test groupstest groups control groupscontrol groups• educationeducation education education• sanitizer sanitizer ……… ………• HW demo and testHW demo and test ……… ………• not monitorednot monitored not monitored not monitored


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)


Authors’ Conclusions

Successful HW program includes:

● administrative support● 1-hour hand hygiene in-service● hand sanitizers in classrooms and bathrooms


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


Sandora et al. 2005

• Design: Design:

– 5- month, randomized, open-label, controlled trial 5- month, randomized, open-label, controlled trial – 292 families, 1 child age 0.5-5 years old in day care292 families, 1 child age 0.5-5 years old in day care– 26 child care centers randomized26 child care centers randomized– excluded if using hand sanitizer dailyexcluded if using hand sanitizer daily

• test sanitizer: alcohol-based instant sanitizer with aloe

• primary outcome: rate of secondary respiratory primary outcome: rate of secondary respiratory and GI illness and GI illness


Sandora et al. 2005

test grouptest group controlcontrol• sanitizersanitizer usual practiceusual practice • biweekly hand hygiene biweekly healthy biweekly hand hygiene biweekly healthy

education materialeducation material diet materialdiet material

• not monitorednot monitored not monitorednot monitored


Study Results (Sandora)

GI IllnessGI Illness Respiratory Respiratory IllnessIllness

C C II CC IITotalTotal 117 117 135 828 135 828

974974Person-daysPerson-days 60413 6911860413 69118 6041360413 6911869118Incidence rate 0.06Incidence rate 0.06 0.06 0.06 0.420.42

0.430.43

Secondary ill 18Secondary ill 18 10 10 202 202 241241# susceptible 1549# susceptible 1549 1810 1810 8525 8525

96489648 patient-dayspatient-daysIncidence rate 0.35Incidence rate 0.35 0.17* 0.17* 0.72 0.72

0.72 0.72 *P=0.08 vs Control, but 0.03 post 7-variable adjustment *P=0.08 vs Control, but 0.03 post 7-variable adjustment C=control group, I=intervention groupC=control group, I=intervention group


Study Limitations (Sandora)• not blindednot 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 low initial participation: of 647 eligible

families, only 292 randomizedfamilies, only 292 randomized• unclear whether adjustment for 7 variablesunclear whether adjustment for 7 variables was pre-planned or post-hocwas pre-planned or post-hoc

Note: clinical significance of secondary GI illness Note: clinical significance of secondary GI illness reduction 10 vs. 18 unclearreduction 10 vs. 18 unclear


Lee et al. 2005DesignDesign::

• Observational, uncontrolled, prospective cohort study Observational, uncontrolled, prospective cohort study in families in Boston area over 18 monthsin families in Boston area over 18 months

• Randomly selected Randomly 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 Recruitment from 5 pediatric practices, 250 families

each practiceeach practice• Analyze predictors of secondary transmission of Analyze predictors of secondary transmission of

illnessillness

EndpointEndpoint: : rate of secondary respiratory and GI illness per rate of secondary respiratory and GI illness per susceptible person-monthsusceptible person-month


Study Results (Lee)

208 (of 1250) families available for analysis:208 (of 1250) families available for analysis:• 1545 respiratory illness (1099 primary, 446 1545 respiratory illness (1099 primary, 446

secondary)secondary)

• 360 GI illness (297 primary, 63 secondary)360 GI illness (297 primary, 63 secondary)

• secondary transmission rates 0.63 respiratory, secondary transmission rates 0.63 respiratory, 0.35 GI0.35 GI

• IRR = 0.6 (C.I. 0.4-0.9, P=0.01, IRR = 0.6 (C.I. 0.4-0.9, P=0.01, notnot adjusted for adjusted for multiple comparisons) for use of alcohol gelsmultiple comparisons) for use of alcohol gels


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


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


Key Issue

Does the Clinical Evidence Link use of Consumer Antiseptics With Clinical Benefit?

Nonprescription Drugs AC Meeting October 20, 2005 1 THE QUEST FOR CLINICAL BENEFIT Steven Osborne,...

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