1 Community-Based Studies of Consumer Antiseptics FDA Nonprescription Drug Advisory Committee...

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Community-Based Studies of Consumer Antiseptics

FDA Nonprescription Drug Advisory Committee Meeting

Allison E. Aiello, PhD, MSAssistant Professor of Epidemiology

University of Michigan-School of Public HealthCenter for Social Epidemiology & Population Health

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Outline

• Literature Review

• Methodological Issues

• Summary and Future Research Needs

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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

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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

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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

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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

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Plain or Unidentified Soap Versus Control (N=8)

Year Authors Title Journal 1982 Khan M. Interruption of shigellosis by hand washing Trans R Soc Trop Med Hyg

1989 Han A. & Hlaing T. Prevention of diarrhoea and dysentery by hand washing

Trans R Soc Trop Med Hyg

1991 Wilson J, et al. Hand-washing reduces diarrhoea episodes: a study in Lombok, Indonesia


1996 Shahid N, et al. Hand washing with soap reduces diarrhoea and spread of bacterial pathogens in a Bangladesh village

J Diarrhoeal Dis Res

1996 Pinfold J & Horan N Measuring the effect of a hygiene behavior intervention by indicators of behavior and diarrhea disease


2002 Luby S, et al. The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan

Am J Trop Med Hyg

2004 Luby S, et al. Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan

JAMA

2005 Luby S, et al. Effect of handwashing on child health: a randomized controlled trial

Lancet

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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)

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• 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)

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• Exposure measurements– Measured Soap use or Hand Washing (n=6)

• Controlled for confounding or reported balance on covariates (n=7)

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Plain or Unidentified Soap (N=8):Results

Reduction in Diarrhea Incidence (n=6)

84

30

89

62

39

53

0

10

20

30

40

50

60

70

80

90

100

Khan (1982)Bangladesh,

Families

Han (1982)Myanmar , Children

Wilson (1991)Indonesia, Children

Shahid (1996)Bangladesh,

Families

Pinfold (1996)Thailand, Children

Luby (2004)Pakistan, Children

Author (Year) Group

% R

educt

ion

All Results Statistically Significant (P < 0.05)

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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

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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

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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

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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

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Year Author Title Journal

2002 Luby S, et al. The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan

Am J Trop Med Hyg

2004 Larson E, et al. Effect of antibacterial home cleaning and handwashing products on infectious disease symptoms

Ann Intern Med

2004 Luby S, et al. Delayed effectiveness of home-based interventions in reducing childhood diarrhea, Karachi, Pakistan

Am J Trop Med Hyg

2005 Luby S, et al. Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan

JAMA

2005 Luby S, et al. Effect of handwashing on child health: a randomized controlled trial

Lancet

Antiseptic Soap Versus Plain Soap or Control (N=5)

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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)

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• Outcomes:

– Diarrhea Incidence/Risk (n=3)

– Impetigo (n=2)

– Pneumonia (n=1)

– Symptoms of infection (n=2)

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• Measured Soap use and/or Hand Washing (n=4)– Masked participants and interviewers (n=4)

• Among placebo groups only


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Antiseptic Soap vs. Plain Soap:

Reduction in Diarrhea Incidence (n=2)

-8

-6

-4

-2

0

2

4

6

8

10

12

1 2% R

eductio

n

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

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Antiseptic Soap vs. Plain Soap:

Reduction in Incidence of Other Symptoms / Infections (n=3)

No results were statistically significant

-20

-10

0

10

20

30

40

50

60

Cough Coryza Skin/Impetigo

% R

eductio

n

Larson, E.(2004)Luby, S. (2005)Luby, S. (2002)

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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)

43

29

50

0

10

20

30

40

50

60

Luby (2002) Pakistan, Children Luby (2004) Pakistan, Children Luby (2004) Pakistan, Children

% R

ed

uct

ion

Impetigo

Diarrhea

Diarrhea

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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

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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

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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

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Year Authors Title Journal

1990 Butz A, et al. Occurrence of infectious symptoms in children in day care homes Am J Infect Control

1994 Kotch J, et al. Evaluation of an hygienic intervention in child day-care centers Pediatrics

1999 Falsey A, et al. Evaluation of a handwashing intervention to reuce respiratory illness rates in senior day-care centers

Infect Control Hosp Epidemiol

1999 Uhari M & Mottonen M

An open randomized controlled trial of infection prevention in child day-care centers

Pediatr Infect Dis

2000 Hammond B, et al. Effect of hand sanitizer use on elementary school absenteeism Am J Infect Control

2002 Guinan M, et al. The effect of a comprehensive handwashing program on absenteeism in elementary schools

Am J Infect Control

2003 White C, et al. The effect of hand hygiene on illness rate among students in university residence halls

Am J Infect Control

2004 Morton J & Schultz A

Healthy hands: use of alcohol gel as an adjunct to handwashing in elementary school children

J Sch Nurs

2005 Sandora 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)

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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

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• Outcomes:

– Gastrointestinal illness (n=3)

– Upper respiratory illness (n=3)• Viral Respiratory Illnesses (n=1)

– Symptoms of infection (n=3)• Absence related

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• 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


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Alcohol-based Hand Sanitizer

Reduction in Diarrheal Illness (n=3)

* All P < 0.05, Statistically Significant Reduction

71

48

59

0

10

20

30

40

50

60

70

80

Butz, E (1990) US, Daycare Kotch et al, (1994) US, Daycare Sandora et al. (2005) US, Families

Author (Year) Group

% R

educt

ion

*

**

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Reduction in Respiratory Illness (n=4)

*P < 0.05, statistically significant

** Not statistically significant

1517

20

3

0

5

10

15

20

25

Kotch et al,(1994) US,Daycare

Falsey et al.(1999) US,

Elderly Daycare

White et al.(2001) US,University

Sandora et al.(2005) US,Families

Author (Year) Group

% R

educt

ion

*

**

** **

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9

19.8

50

43

0

10

20

30

40

50

60

Uharti and Mottonen (1999)Finland, Daycare

Hammond et al. (2000) US,schools

Guinan et al. (2002) US, Schools Morton & Schultz et al. (2004)US, Families

Author (Year) Group

% R

educt

ion


Symptoms of Infection (n=4)

* All P < 0.05, Statistically significant reduction

*

*

**

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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

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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

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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

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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

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Conflicts of Interest Statement and Acknowledgements

• Consulted for Pfizer in September

• Thanks to Dr. Elaine L. Larson

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