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									  SDA/CTFA Topical
Antimicrobial Coalition
           Presentation to FDA
           Nonprescription Drugs
           Advisory Committee
           March 23, 2005
    AGENDA

       The Value of Surrogate
        Endpoint Testing, G. Fischler
       Statistical Issues in Study Design, J.
        Bowman
       Questions




2               March 23, 2005
The Value of Surrogate Endpoint
Testing for Topical Antimicrobial
            Products


                George Fischler
                The Dial Corporation
    Overview

       Clinical trials
       Standardized test methodology
       Surrogate endpoints




4                  March 23, 2005
    Key Point

       Definitive randomized and controlled
        clinical trials, typically used to assess
        therapeutic benefit are not practical in
        measuring the prophylactic benefits of
        topical antimicrobial products



5                   March 23, 2005
     Larson, E. 1995. APIC Guideline for
     Handwashing and Hand Antisepsis in Health
     Care Settings.



    “Although a definitive, double blind, clinical trial of the
      effects of handwashing with an antiseptic product on
      nosocomial infection rates may be infeasible, it
      appears that, at least in certain high risk situations,
      such antimicrobial products are beneficial.”




6                      March 23, 2005
    Clinical Trial Issues for
    Prophylactic Indications

       Size
       Ethics
       Immunological host status
       Mode of transmission
       Intended beneficiary
        –   Test subject vs. population
       Compliance

7                      March 23, 2005
    Key Point

       Standardized, defined and peer
        reviewed test methodologies ensure
        reliability, reproducibility and
        comparability of test results




8                 March 23, 2005
    FDA, 1978 TFM

       “..the reduction of the normal flora, both
        transient and resident, has been sufficiently
        supported to be considered a benefit. The
        only determination that remains therefore, is
        how much of a reduction in microbial flora
        will be required to permit claims for the
        various product classes.”


9                   March 23, 2005
     Fischler G.E., et al. 2002. The Effect of Modification to
     the ASTM E1174 Healthcare Personnel Handwash
     Method on the Evaluation of Antimicrobial
     Effectiveness

        Three methods
         –   Current ASTM
         –   Pre 1994 ASTM (NDA)
         –   1994 TFM
        Comparison of methods
         –   Inoculum application
         –   Neutralization
         –   Timing of baseline enumeration

10                      March 23, 2005
           Fischler G.E., et al. 2002. The Effect of Modification
           to the ASTM E1174 Healthcare Personnel
           Handwash Method on the Evaluation of
           Antimicrobial Effectiveness

                          Comparison of ASTM E1174 Method and Proposed TFM Method

                                  Timing of  Baseline              1st Wash Final Wash CHG in
                       Inoculum    Baseline   log10                  log10     log10   Recovery
      Test Method       Addition Measurement  /hand Neutralization Reduction Reduction   Fluid

     Current ASTM 3x1.5 ml        After inoculum   9.2172   Immediate     2.4225    3.4453   48 ppm


     Former ASTM         4.5 ml   After inoculum   9.2087   Delayed       2.4622    3.7937   22 ppm

                             After inoculum
       1994 TFM     5 ml      + "cleansing" 6.4942         Delayed        -0.0073   1.1092   43 ppm
                                  wash
     4% CHG Handwash (5 ml product, 15 second wash and 30 second rinse)
     30 subjects per product




11                                  March 23, 2005
     Sickbert-Bennett E. E., et al. 2004. The Effects of Test
     Variables on the Efficacy of Hand Hygiene Agents




12                   March 23, 2005
     Key Point

        Surrogate endpoint testing provides
         meaningful and appropriate tools to
         determine the threshold efficacy criteria
         for topical antimicrobial products




13                   March 23, 2005
     Key Point

        The published literature represents a
         body of scientific evidence supporting
         that the proposed microbial reductions
         reflect clinical benefit, and importantly
         represent current infection control
         practice


14                   March 23, 2005
Healthcare Personnel Handwash
     Zafar A.B. et al. 1995. Use of 0.3% Triclosan to
     Eradicate an Outbreak of MRSA in a Neonatal
     Nursery


        The single additional infection control measure of
         changing the handwash and bathing product to
         Bactistat (0.3% triclosan handwash) was associated
         with the immediate termination of the acute phase
         of the MRSA outbreak.
        Surrogate handwash (ASTM E1174) results (from
         1995 Huntington company literature) indicate 1.7
         log10 following the initial application of 5 mL of
         product and 1.9 log10 reduction after ten
         subsequent applications of 60 seconds duration
         each time.
16                      March 23, 2005
     Webster J., et al. 1994. Elimination of Methicillin-
     resistant Staphylococcus aureus from a Neonatal
     Intensive Care Unit after Hand Washing with Triclosan



        Following introduction of a 1% triclosan handwash, new
         cases of MRSA colonization were monitored for one
         year
        No changes were made to procedures or protocols
        A gradual elimination of MRSA in the ward was noted
         during the 12 month period
        Compared with the previous 12 month period, fewer
         antibiotics were prescribed, and fewer (P< 0.05)
         nosocomial infections recorded
17                     March 23, 2005
     Hilburn J., et al. 2003. Use of Alcohol Hand Sanitizer as
     an Infection Control Strategy in an Acute Care Facility


        Data were collected in one unit of a 500-bed facility over
         a 16 month period during the introduction of an alcohol
         (60% ethanol) hand gel
        Primary infection types were urinary tract and surgical
         site infections
        Infection types and rates demonstrated a 36% reduction
         in infection rates for the 10 month period during which
         the hand sanitizer was in use compared with the previous
         6 month period
        The study concludes that use of an alcohol gel hand
         sanitizer is an effective tool in an infection control
         program
18                       March 23, 2005
     Fendler E.J., et al. 2002. The Impact of Alcohol
     Hand Sanitizer Use on Infection Rates in an
     Extended Care Facility

        Data on infection rate and type were collected in a
         275 bed extended care facility over a 34 month
         period, during which an alcohol (60% ethanol) hand
         gel was used in two units of the facility
        Primary infection types were urinary tract,
         respiratory, and wound infections.
        A 30% reduction in infection rate was found in the
         units where the hand sanitizer was used compared to
         the other units over the 34 months


19                      March 23, 2005
     Doebbeling B.N., et al. 1992. Comparative Efficacy of
     Alternative Hand-washing Agents in Reducing
     Nosocomial Infections in Intensive Care Units

        During an 8 month period a prospective crossover design
         trial involving 1894 patients in three ICUs was
         conducted.
        A comparison of 60% alcohol (isopropanol), with or
         without non-medicated soap, and a chlorhexidine
         gluconate product was made
        152 nosocomial infections were seen when chlorhexidine
         was used, as compared to 202 infections for the
         soap/alcohol combination
        This difference was directional but not significant

20                      March 23, 2005
Surgical Hand Scrub
     Bryce E.A., et al. 2001. An In-use Evaluation of an
     Alcohol-based Pre-surgical Hand Disinfectant



        A prospective trial of a 70% alcohol (isopropanol) pre-
         surgical hand treatment compared to 4% chlorhexidine
         gluconate and 7.5% povidone iodine treatments
        Evaluated both short (< 2 hours) and longer surgical
         procedures
        Found no statistical difference in microbial hand
         counts following the use of any of the treatments for
         cases less than 2 hours
        Matched pair analysis of longer surgical cases also
         found no difference in treatment


22                      March 23, 2005
     Parienti J.J., et al. 2002. Hand-rubbing With an Aqueous
     Alcoholic Solution vs. Traditional Surgical Hand-
     scrubbing and 30-day Surgical Site Infection Rates


        Compared the effectiveness of an alcoholic hand rub
         solution to either a chlorhexidine or povidone iodine
         hand scrub at reducing surgical site infections in a
         randomized trial
        Statistically, no difference was found in infection
         rates between the two procedures in infection rate




23                      March 23, 2005
Pre-operative Skin Preparation
         Aly R. et al. 1998. Clinical Efficacy of a
         Chlorous Acid Preoperative Skin Antiseptic


        Under clinical conditions a comparison of a standard 4%
         chlorhexidine gluconate skin prep was compared to a new
         preparation on both abdominal and inguinal skin sites
        An examination of baseline flora at both sites was undertaken,
         and only subjects whose skin flora met certain criteria were
         included
        The active control product (4% CHG) reduced resident flora by
         less than the required amount (3 log10) proposed in the TFM
         immediately after treatment




25                        March 23, 2005
     Conclusion

        The efficacy criteria should be
         appropriately set to reflect the
         performance of currently recognized
         effective products




26                  March 23, 2005
     AGENDA

        The Value of Surrogate Endpoint
         Testing, G. Fischler
        Statistical Issues in Study
         Design, J. Bowman
        Questions




27              March 23, 2005
Statistical Issues in Study Design



                Jim Bowman
                Hill Top Research, Inc.
     Statistical Issues

        Log Reduction Criteria
         –   Historically based on point estimates (mean)
         –   No requirement of sample size


        Variability needs to be considered
         –   There are several ways to take variability
             into account


29                      March 23, 2005
     Examples from Other
     OTC Monographs

        Sunscreen Monograph
         –   Mean value is calculated and the standard error
             is used to calculate the label SPF value


        Antiperspirant Monograph
         –   Mean value must be statistically significantly
             greater than a certain level (i.e. 20% sweat
             reduction)


30                       March 23, 2005
     Statistical Criteria vs Point Estimate

     – Objective:   mean value > ‘x’ log reduction
         With point estimates manufacturers have
          historically conducted studies with sample
          sizes they deemed appropriate and submitted
          data to the FDA
         With statistical criteria being utilized (i.e.,
          statistically greater than a specific number),
          appropriate sample sizes are a function of the
          variability of the data.

31                  March 23, 2005
     Statistical Criteria vs Point Estimate

        We have conducted data reviews and statistical
         simulations using data at hand looking into the
         variability
        Data review consisted of data from 13 studies
         conducted with an active material, simulations were
         conducted to better understand the variability
        If statistical criteria are to be utilized, then lower
         criteria will be necessary to achieve the same level
         of efficacy based on our data review


32                      March 23, 2005
     Statistical Criteria vs Point Estimate

         OTC Antiperspirant monograph requires
          statistically significantly greater than 20%
          reduction.
         This requires point estimates of sweat
          reduction to be >25%-30% reduction in
          order to achieve the level of benefit
          mandated


33                    March 23, 2005
     Next Steps

        Historically, the FDA and Industry have relied on
         point estimates.
        However, if statistical significance is required, then
         lower log reduction criteria are necessary to achieve
         the same level of efficacy based on our data review.
        We would like to work with the FDA on setting these
         criteria for specific indications at specific time points.



34                        March 23, 2005
Summary
     Key Point Summary

        Clinical trials are not appropriate for assessing
         prophylactic benefit
        Standardized methodologies ensure reproducibility
        Surrogate endpoints are appropriate
        Literature supports that the proposed microbial
         reductions reflect clinical benefit
        Efficacy criteria should reflect the performance of
         recognized effective products


36                      March 23, 2005

								
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