# Presentation: 310691

## 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:
- 48-week, randomized, DB, placebo
- 224 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 data
- 93 of first 100 self-reported illnesses verified by   visiting physician
- self-reported illnesses thereafter (unverified)
- _Primary endpoint_: at least one infectious disease symptom within household for each 1-month period

## Larson et al. 2004

- 	_test group_                                       _control_
- training					training
- antimicrobial products* 	    	plain products
- weekly phone calls			weekly phone calls
- monthly visits (adherence) 	monthly visits
- quarterly 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**

## 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:
- Randomized, 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 neighborhoods
- Soap 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 impetigo
- _Endpoint_: incidence of acute respiratory infection, impetigo, diarrhea

## Luby et al. 2005

- _Test group_		_Placebo group_		_Control group_
- Triclocarban soap	plain soap			..............
- HW training		HW training			school 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
- 	 	-before food prep & eating
- 	 	-before feeding infants
- 		-also to bathe once daily with soap

## Study Results (Luby)

_**Mean incidence (episodes/100 person-weeks)**_
-                                 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

## Study Interpretation

- Handwashing plus bathing with soap reduces respiratory infection, diarrhea, and impetigo
- Reduction in disease is simply due to handwashing/bathing with _soap_ (plus HW promotion)
- No 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”

## Study Limitations (Luby)

- study 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 alone

## 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:
- 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):
- 		   1st 4-weeks	   Control	   Sanitizer
- Days illness                 105	   70 (P<.001)
- # students              	     57	   31
- Days absent/pupil        1.84        2.26
- 		 	                                                                                                                                         2nd 4-weeks	   Control	    Sanitizer
- Days illness           	     63 		  28
- # students              	     37		  17
- Days absent/pupil         1.70              1.65

## Study Limitations

- 	clustered, no randomization
- 	no placebo (ie no bland pump spray)
- 	unblinded
- 	no specified length of time for wash
- 	test group monitored, but not control
- 	test group advised to wash more often
-    single site
- 	Are illness rate differences due to monitoring and 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 demo)
- _test groups_                              _control groups_
- education				   education
- sanitizer 				      .........
- HW demo and test		                 .........
- 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:
- 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 illness

## Sandora et al. 2005

-      _test group_                           _control_
- sanitizer				usual practice
- biweekly hand hygiene             biweekly healthy education material	           	diet material
- not monitored			not monitored

## Study Results (Sandora)

- 			            _GI Illness_	        _Respiratory Illness_
- 			          _C _    	       _I_		 _C_		 _I_
- Total		         117	    135         828		974
- Person-days	60413   69118	60413	69118
- Incidence rate     0.06	    0.06	0.42		0.43
- Secondary ill       18	     10	           202		241
- # susceptible       1549	     1810	 8525		9648
-  patient-days
- Incidence rate      0.35	      0.17*	 0.72		0.72
- *P=0.08 vs Control, but 0.03 post 7-variable adjustment
-  C=control group, I=intervention group

## Study Limitations (Sandora)

-    not blinded
- 	hand sanitizer use not monitored
- 	hand sanitizer combined with education
-    no placebo sanitizer for control group
- 	low initial participation: of 647 eligible 	    		families, only 292 randomized
-    unclear whether adjustment for 7 variables
-     was pre-planned or post-hoc
- 	Note: clinical significance of secondary GI illness reduction 10 vs. 18 unclear

## Lee et al. 2005

- _Design_:
- Observational, uncontrolled, prospective cohort study in families in Boston area over 18 months
- Randomly selected
- At least 1 child< 5 years old
- At least 1 child in child care for 10 hours/week
- Recruitment from 5 pediatric practices, 250 families each practice
- Analyze predictors of secondary transmission of illness
- _Endpoint_: rate of secondary respiratory and GI illness per 		susceptible person-month

## Study Results (Lee)

- 	208 (of 1250) families available for analysis:
- 1545 respiratory illness (1099 primary, 446 secondary)
- 360 GI illness (297 primary, 63 secondary)
- secondary 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 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?**