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Nonprescription AC Meeting March 23, Key Issues Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?
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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?
3Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Key IssuesKey Issues
• Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?
4Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
5Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Monograph AntisepticsMonograph Antiseptics
• Quaternary Ammonium Compounds– Benzalkonium chloride (Zephiran)
• Phenol Derivatives– Carbolic acid
• Chloroxylenol (PCMX)
• Triclocarban– Safeguard soap
6Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
7Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
8Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Healthcare ProceduresHealthcare Procedures
– Invasive Procedures:• Surgery•Catheters, IVs
–Non-Invasive procedures•Reduce nosocomial infections
with handwash•Reduce respiratory and GI illness
with handwash
9Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
10Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
11Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Study ExamplesStudy Examples
• Maki et al. 1991 (catheter infections)
• Luby et al. 2002 (impetigo)
12Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
13Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Maki et al 1991Maki 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
14Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Maki et al 1991Maki 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
15Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
16Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
17Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
SURGICAL SCRUBSSURGICAL SCRUBS• Surgical hand scrubs–300 articles screened for clinical
benefit
–None conclusively linked reduction in bacteria with reduction in infection rates
18Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
19Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
20Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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)
21Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
22Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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%
23Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
24Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Patient PREOP Literature ReviewPatient PREOP Literature Review
–Majority of studies performed in animals •None of the studies found link
between colony forming units (CFU) of bacteria and SSIs
25Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Patient PREOP Literature ReviewPatient 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
26Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
27Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
28Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Cronquist et al. 2001
Head Back
Pre-scrub 4.13 2.39
Post-scrub 0.62 0.54
• Bacterial counts (log10):
29Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
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
30Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Key IssuesKey Issues
• Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?
31Nonprescription AC MeetingNonprescription AC MeetingMarch 23, 2005March 23, 2005
Key IssuesKey Issues
• Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?