Nonprescription AC Meeting March 23, 2005 THE QUEST FOR CLINICAL BENEFIT Steven Osborne, M.D....

Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005

THE QUEST FOR CLINICAL BENEFIT

Steven Osborne, M.D.Medical Officer

Division of Over-The-Counter Drug Products

2Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005

Key IssuesKey Issues

• Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?



• Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?


Monograph AntisepticsMonograph Antiseptics

• Alcohols (ETOH and IPA)– Purell Handrub

• Chlorhexidine (CHG) 2% and 4% Aqueous– Hibiclens and Hibiprep

• Iodine or Iodophors (PI)– Tincture of iodine and povidone-iodine (Betadine)

• Triclosan– Gojo Antimicrobial Lotion Soap


Monograph AntisepticsMonograph Antiseptics

• Quaternary Ammonium Compounds– Benzalkonium chloride (Zephiran)

• Phenol Derivatives– Carbolic acid

• Chloroxylenol (PCMX)

• Triclocarban– Safeguard soap


Antiseptic Antimicrobial Spectrum Antiseptic Antimicrobial Spectrum (CDC 2002)(CDC 2002)

Group Gram Positive Gram Negative Speed of ActionAlcohols +++ +++ FastChlorhexidine +++ ++ IntermediateIodine Compounds +++ +++

IntermediateIodophors +++ +++ IntermediatePhenol Derivatives +++ + IntermediateTriclosan +++ ++ Intermediate Quaternary AC + ++ Slow

+++ excellent, ++ good, but does not include entire bacterial spectrum, + fair


Citizen Petition And CommentCitizen Petition And Comment

• Industry Coalition--Soap and Detergent Association (SDA) and Cosmetic, Toiletry, and Fragrance Association (CTFA): Citizen Petition and Comment to the TFM

–Submitted references–Requested FDA lower efficacy

standards


Healthcare ProceduresHealthcare Procedures

– Invasive Procedures:• Surgery•Catheters, IVs

–Non-Invasive procedures•Reduce nosocomial infections

with handwash•Reduce respiratory and GI illness

with handwash


Antiseptics ReferencesAntiseptics References

• Industry Coalition: Citizen Petition and Comment to the TFM:

• 155 Articles and Abstracts • 58% HW, 26% PP, 16% SS• Weight of evidence of clinical benefit

not persuasive for changing current efficacy criteria• No link between surrogate endpoints

and infection rates


Summary Of Study LimitationsSummary Of Study Limitations• Surrogate endpoints not correlated with

clinical outcome• Not randomized• No placebo control• Retrospective• Multiple confounders• Inadequately powered• No statistics• Lack of standardization of product use• Irregular patterns of data collection• Failure to address a TFM indication


Study ExamplesStudy Examples

• Maki et al. 1991 (catheter infections)

• Luby et al. 2002 (impetigo)


Maki et al 1991Maki et al 1991

• Randomized study in 668 subjects with IV catheters–all catheters CV or arterial–2% CHG, 10% PI, 70% IPA– then every other day. No other

agents applied



• Endpoints:– Local infection rate (>15 CFUs)• 2.3% for CHG, vs 7.1% (alcohol) and

9.1% (PI), P=0.02

– Bacteremia• 10 total• CHG (1), alcohol (3), PI (6), P=0.18



• No correlation between reduction in bacteria with infection rates

• Application of antimicrobial post- catheter insertion limits ability to relate to monograph application


Luby et al 2002Luby et al 2002

• Double blind, randomized study of antibacterial soap in 241 households in Karachi, Pakistan

• Triclocarban soap, bland soap, standard practice group

• Primary outcome was incidence of impetigo


Luby et al 2002Luby et al 2002

• Triclocarban soap 43% less impetigo than standard practice (P=0.02)

• Triclocarban 23% less impetigo than than bland soap (P=0.28)

• Bland soap 24% less impetigo than standard practice (P=0.21)

• Needed 70% increase in sample size


SURGICAL SCRUBSSURGICAL SCRUBS• Surgical hand scrubs–300 articles screened for clinical

benefit

–None conclusively linked reduction in bacteria with reduction in infection rates


Study ExamplesStudy Examples• Bryce et al 2001–70% IPA leave-on» in-use hospital evaluation» 70 scrubs by surgeons»15 ml product used over 3 min

–Endpoint: post-op bacterial counts

– IPA agent comparable to 4% CHG and 7.5% PI in reducing bacteria–No infection rates studied


Study ExamplesStudy Examples

– Parienti et al. 2002• Hand-rubbing with alcoholic leave-on

solution and 30-day surgical site infection (SSI) rate• Randomized, crossover equivalence

trial (75% alcohol, 4% PI, 4% CHG)• 6 surgical services, 4287 pts


Parienti et al. 2002Parienti et al. 2002

• Alcohol hand-rub, PI and CHG as hand-scrub• SSI 2.44% alcohol vs. 2.48% with

PI+CHG• Scrub time compliance better with

alcohol rub (313 sec vs 287 sec, P=0.01)

• SSI micro not provided• Surgeon not blinded (reported SSI)


HANDWASH Literature ReviewHANDWASH Literature Review

• Literature review of healthcare personnel Handwashes 1994-2004–222 studies reviewed for clinical

benefit or efficacy–None showed a definitive link

between bacterial reduction and reduction in infection rates


HANDWASH ReferencesHANDWASH References• Swoboda et al. 2004, 3-Phase, 15

month evaluation incorporating an electronic monitor (monitor, voice-prompt, monitor)–Compliance improved by 35%, 41%

in Phase 2 and 3 –MRSA or VRE colonization rates

19%, 9%, 11%


Patient PREOP Literature ReviewPatient PREOP Literature Review

• 400 articles screened• Searched for bacterial log

reduction data post-scrub compared with pre-scrub, then …..–Searched for SSI rate in same

reference



–Majority of studies performed in animals •None of the studies found link

between colony forming units (CFU) of bacteria and SSIs



• Secondary topic: Is there a minimum number of bacteria in a wound that predisposes to infection?

• 100,000 bacteria (105)–May vary with type of bacteria


Patient PREOP Literature ReviewPatient PREOP Literature Review• 100,000 bacteria “threshold” for infection

– Kass 1957:• 2000 patients with pyelonephritis had

>100,000 • 100% of symptomatic patients with

UTI had >100,000

– Krizek et al. 1967• 94% graft success when pre-graft

bacteria <100,000/ gram tissue


Study LiteratureStudy Literature

• Cronquist et al. 2001–609 neurosurgery patients•Craniotomy• Ventriculo-Peritoneal (VP) shunt

–Pre-scrub and post-scrub bacterial counts from head, back


Cronquist et al. 2001

Head Back

Pre-scrub 4.13 2.39

Post-scrub 0.62 0.54

• Bacterial counts (log10):


Study LiteratureStudy Literature

• Cronquist et al. 2001

• 20 SSIs –19 from craniotomies–Staph species, P. acnes

• No correlation between pre-scrub or post scrub counts and SSIs



• Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?



• Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?

Nonprescription AC Meeting March 23, 2005 THE QUEST FOR CLINICAL BENEFIT Steven Osborne, M.D....

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