THE QUEST FOR CLINICAL BENEFIT
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THE QUEST FOR CLINICAL BENEFIT. Steven Osborne, M.D. Medical Officer Division of Over-The-Counter Drug Products. Nonprescription AC Meeting March 23, 2005. Key Issues. Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?. Key Issues.

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Hca ndac05

THE QUEST FOR CLINICAL BENEFIT

Steven Osborne, M.D.

Medical Officer

Division of Over-The-Counter Drug Products

Nonprescription AC Meeting

March 23, 2005


Key issues
Key Issues

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


Key issues1
Key Issues

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


Monograph antiseptics
Monograph 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 antiseptics1
Monograph Antiseptics

  • Quaternary Ammonium Compounds

    • Benzalkonium chloride (Zephiran)

  • Phenol Derivatives

    • Carbolic acid

  • Chloroxylenol (PCMX)

  • Triclocarban

    • Safeguard soap


Antiseptic antimicrobial spectrum cdc 2002
Antiseptic Antimicrobial Spectrum (CDC 2002)

Group Gram PositiveGram NegativeSpeed of Action

Alcohols +++ +++ Fast

Chlorhexidine +++ ++ Intermediate

Iodine Compounds +++ +++ Intermediate

Iodophors +++ +++ Intermediate

Phenol Derivatives +++ + Intermediate

Triclosan +++ ++ Intermediate

Quaternary AC + ++ Slow

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

+ fair


Citizen petition and comment
Citizen 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 procedures
Healthcare Procedures

  • Invasive Procedures:

    • Surgery

    • Catheters, IVs

  • Non-Invasive procedures

    • Reduce nosocomial infections with handwash

    • Reduce respiratory and GI illness with handwash


Antiseptics references
Antiseptics 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 limitations
Summary 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 examples
Study Examples

  • Maki et al. 1991 (catheter infections)

  • Luby et al. 2002 (impetigo)


Maki et al 1991
Maki 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


Maki et al 19911
Maki et al 1991

  • 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


Maki et al 19912
Maki et al 1991

  • 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 2002
Luby 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 20021
Luby 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 scrubs
SURGICAL SCRUBS

  • Surgical hand scrubs

    • 300 articles screened for clinical benefit

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


Study examples1
Study 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 examples2
Study 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 2002
Parienti 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 review
HANDWASH 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 references
HANDWASH 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 review
Patient 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


Patient preop literature review1
Patient PREOP Literature Review

  • Majority of studies performed in animals

    • None of the studies found link between colony forming units (CFU) of bacteria and SSIs


Patient preop literature review2
Patient PREOP Literature Review

  • 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 review3
Patient 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 literature
Study 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
Cronquist et al. 2001

  • Bacterial counts (log10):


Study literature1
Study 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


Key issues2
Key Issues

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


Key issues3
Key Issues

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


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