1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

                         JOINT SESSION WITH THE

 

                 NONPRESCRIPTION AND DERMATOLOGIC DRUGS

 

                           ADVISORY COMMITTEE

 

 

                                VOLUME I

 

 

 

 

 

 

 

 

 

 

 

 

                       Wednesday, March 23, 2004

 

                               8:00 a.m.

 

 

 

 

 

 

 

 

                       Hilton Washington DC North

                           620 Perry Parkway

                         Gaithersburg, Maryland

                                                                 2

 

                        P A R T I C I P A N T S

 

      Alastair Wood, M.D., Chair

 

      Shalini Jain, PA-C, Executive Secretary

 

      Committee Members:

 

      Michael C. Alfano, DMD, Ph.D., Industry

      Representative

      Terrence F. Blaschke, M.D.

      Ernest B. Clyburn, M.D.

      Frank F. Davidoff, M.D.

      Jack E. Fincham, Ph.D.

      Sonia Patten, Ph.D.., Consumer Representative

      Wayne R. Snodgrass, M.D., Ph.D.

      Robert E. Taylor, M.D., Ph.D., F.A.C.P., F.C.P

      Mary E. Tinetti, M.D.

 

      Special Government Employee (Voting):

 

      Michele L. Pearson, M.D.

 

      Government Employee Consultants (Voting):

 

      John S. Bradley, M.D.

      John M. Boyce, M.D.

      Ralph B. D'Agostino, Ph.D.

      Thomas R. Fleming, Ph.D.

      Elaine L. Larson, R.N., Ph.D.

      James E. Leggett, Jr., M.D.

      Jan E. Patterson, M.D.

 

      FDA Participants:

 

      Tia Frazier, R.N., M.S.

      Charles Ganley, M.D.

      Michelle Jackson, Ph.D.

      Susan Johnson, Pharm.D., Ph.D.

      John Powers, M.D.

      Curtis Rosebraugh, M.D.

      Debbie Lumpkins, Team Leader

                                                                 3

 

                            C O N T E N T S

 

      Call to Order and Introductions

         Alastair Wood, M.D., Chair                              4

 

      Conflict of Interest Statement, Shalini Jain, PA-C

         Acting Executive Secretary                              8

 

      Issue Overview, Susan Johnson, Pharm.D., Ph.D.            10

 

      Regulatory History of Healthcare Antiseptic Drug

         Products, Tia Frazier, R.N., M.S.                      21

 

      Testing of Healthcare Antiseptic Drug Products,

         Michelle Jackson, Ph.D.                                31

 

      Microbiological Surrogate Endpoints in Clinical

         Trials of Infectious Diseases, John Powers, M.D.       54

 

      Antiseptic and Infection Control Practice,

         John Boyce, M.D., Yale School of Medicine             106

 

      Prevention of Surgical Site Infections,

         Michelle Pearson, M.D., CDC                           127

 

      Question and Answer Period                               163

 

      Open Public Hearing:

                Steven C. Felton, Ph.D.                        204

                J. Khalid Ijaz, DVM, Ph.D.                     211

          The Quset for Clinicaql Benefit

                Steven Osborne, M.D.                           214

      OTC-TFM Monograph Statistical Issues of Study

         Design and Analysis, Thamban Valappil, Ph.D.          224

 

      Industry Presentation:

         The Value of Surrogate Endpoint Testing for

            Topical Antimicrobial Products,

            George Fischler                                    250

 

      Statistical Issues in Study Design,

         James P. Bowman                                       276

 

      Committee Discussion                                     299

 

                                                                 4

 

                         P R O C E E D I N G S

 

                    Call to Order and Introductions

 

                DR. WOOD:  Let's get started.  Welcome to

 

      the Over-the-Counter Advisory Committee.  Let's

 

      begin by going around the table and everybody

 

      introducing themselves, and we will start on this

 

      side, Charlie.

 

                DR. GANLEY:  Charley Ganley, Director of

 

      OTC.

 

                DR. POWERS:  John Powers, Lead Medical

 

      Officer for Antimicrobial Drug Development and

 

      Resistance Initiatives in the Office of Drug

 

      Evaluation IV.

 

                DR. ROSEBRAUGH:  Curt Rosebraugh, Deputy

 

      Director, OTC.

 

                DR. JOHNSON:  Sue Johnson, Associate

 

      Director, OTC.

 

                DR. LUMPKINS:  Debbie Lumpkins.  I am a

 

      Team Leader in OTC.

 

                DR. DAVIDOFF:  I am Frank Davidoff.  I am

 

      an internist and editor emeritus of Annals of

 

      Internal Medicine and a member of the OTC

 

                                                                 5

 

      committee.

 

                DR. FLEMING:  Thomas Fleming, Chair,

 

      Department of Biostatistics, University of

 

      Washington.

 

                DR. FINCHAM:  Jack Fincham, professor at

 

      the University of Georgia, College of Pharmacy, and

 

      I am a member of the committee.

 

                DR. CLYBURN:  I am Ben Clyburn.  I am an

 

      internist at Medical University of South Carolina

 

      and a member of the committee.

 

                DR. BRADLEY:  I am John Bradley, a

 

      pediatric infectious disease doctor from Children's

 

      Hospital, San Diego, and I am a member of the

 

      Anti-Infective Drugs Advisory Committee.

 

                DR. PATTERSON:  Jan Patterson, Infectious

 

      Diseases and Infection Control, University of Texas

 

      Health Science Center, San Antonio and South Texas

 

      Veterans Healthcare System.

 

                MS. JAIN:  Shalini Jain, Acting Executive

 

      Secretary for today's meeting.

 

                DR. PATTEN:  Sonia Patten.  I am the

 

      consumer representative on the panel, and I am an

 

                                                                 6

 

      anthropologist on faculty at Macalester College in

 

      St. Paul, Minnesota.

 

                DR. SNODGRASS:  Wayne Snodgrass,

 

      pediatrician and clinical pharmacologist at the

 

      University of Texas Medical Branch.

 

                DR. LARSON:  Elaine Larson, from the

 

      School of Nursing and School of Public Health at

 

      Columbia University, in New York.

 

                DR. TAYLOR:  Robert Taylor, Chairman,

 

      Department of Pharmacology, Howard University, in

 

      Washington, internist and clinical pharmacologist.

 

                DR. BLASCHKE:  Terry Blaschke, internist,

 

      clinical pharmacologist, Stanford, member of the

 

      committee.

 

                DR. TINETTI:  Mary Tinetti, internist,

 

      Yale University and member of the committee.

 

                DR. D'AGOSTINO:  Ralph, D'Agostino,

 

      biostatistician from Boston University, consultant

 

      to the committee.

 

                DR. LEGGETT:  Jim Leggett, infectious

 

      diseases at Portland Medical Center and Oregon

 

      Health Sciences University, and I am a member of

 

                                                                 7

 

      the Anti-Infective Drugs Advisory Committee.

 

                DR. ALFANO:  I am Mike Alfano, New York

 

      University College of Dentistry, industry liaison

 

      to NDAC.

 

                DR. WOOD:  And I am Alastair Wood and I am

 

      the Chairman of the NDAC and Associate Dean at

 

      Vanderbilt.

 

                So, let's get started.  Shalini, do you

 

      want to read the conflict of interest statement?

 

      While she is digging that up, the weather has

 

      caught us and the first speaker from CDC is stuck

 

      in Atlanta--the story of people's life in the

 

      Southeast.  So, what she is going to do, she is on

 

      her way back to her office and she is going to

 

      e-mail us slides and then we will try and project

 

      the slides later in the morning, with her talking

 

      to us over the telephone.  So, that will be a

 

      nightmare I suspect.

 

                [Laughter]

 

                That means we will time shift everything

 

      up and then probably, depending on how she gets on,

 

      we may have the question and answer period  for the

 

                                                                 8

 

      first ones a little bit earlier and take an earlier

 

      break and then come back to hear her, depending on

 

      how the technology is behaving.  Shalini, go ahead.

 

                     Conflict of Interest Statement

 

                MS. JAIN:  The Food and Drug

 

      Administration has prepared general matters waivers

 

      for the following special government employees who

 

      are attending today's meeting of the

 

      Nonprescription Drugs Advisory Committee on the

 

      microbiologic surrogate endpoints used to

 

      demonstrate the effectiveness of antiseptic

 

      products used in healthcare settings.  The

 

      committee will also discuss related public health

 

      issues, trial design and statistical issues.

 

                This meeting is held by the Center for

 

      Drugs Evaluation and Research.  The following

 

      meeting participants have waivers:  Dr. Jan

 

      Patterson, Dr. Sonia Patten, Dr. Thomas Fleming,

 

      Dr. John Boyce, Dr. Ralph D'Agostino and Dr. John

 

      Bradley.

 

                Unlike issues before a committee in which

 

      a particular product is discussed, issues of

 

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      broader applicability such as the topic of today's

 

      meeting will involve many industrial sponsors and

 

      academic institutions.  The committee members have

 

      been screened for their financial interests as they

 

      may apply to the general topic at hand.  Because

 

      general topics impact so many institutions, it is

 

      not practical to recite all potential conflicts of

 

      interest as they apply to each member.  FDA

 

      acknowledges that there may be potential conflicts

 

      of interest but, because of the general nature of

 

      the discussions before the committee, these

 

      potential conflicts are mitigated.

 

                With respect to FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Michael Alfano is participating in this meeting as

 

      a non-voting industry representative, acting on

 

      behalf of regulated industry.  Dr. Alfano's role on

 

      this committee is to represent industry's interests

 

      in general and not any one particular company.  Dr.

 

      Alfano is Dean, College of Dentistry, New York

 

      University.

 

                In the event that discussions involve any

 

                                                                10

 

      other products or firms not already on the agenda

 

      for which FDA participants have a financial

 

      interest, the participants' involvement and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose product they may wish to comment

 

      upon.  Thank you.

 

                DR. WOOD:  Thanks a lot.  Let's go

 

      straight on to the first presentation from Susan

 

      Johnson.  Susan?

 

                             Issue Overview

 

                DR. JOHNSON:  Good morning.

 

                [Slide]

 

                My name is Susan Johnson and I am the

 

      Associate Director of the Division of OTC Drug

 

      Products.  On behalf of the division, I would like

 

      to welcome the members of the Nonprescription

 

      Advisory Committee and the Anti-Infective Advisory

 

      Committee and our other guests.  As I am sure the

 

      committee members would agree, the bulk of the

 

                                                                11

 

      background package as a metric of the challenge

 

      that we face today is certainly significant, and we

 

      certainly appreciate everyone making as much

 

      headway as they could with that background package.

 

                We very much appreciate all of your

 

      assistance today.  There is a wide variety of

 

      issues to discuss and so you will see the

 

      representation of the committee being broadened

 

      from NDAC to include the Anti-Infective committee

 

      members, and we appreciate everyone's attendance,

 

      as well as our consultants.

 

                I will just be providing a brief

 

      introduction to the regulatory issues associated

 

      with the efficacy of OTC healthcare antiseptics.

 

                [Slide]

 

                The OTC healthcare antiseptics include

 

      three categories of drug products, the healthcare

 

      personnel handwashes; surgical hand scrubs; and

 

      patient preoperative skin preparations that are

 

      used to scrub the skin prior to surgery.

 

                [Slide]

 

                FDA's current approach to the evaluation

 

                                                                12

 

      of healthcare antiseptic efficacy assumes that

 

      healthcare antiseptics play a critical role in

 

      infection control, and Dr. Michelle Pearson and Dr.

 

      John Boyce will discuss this role in additional

 

      detail.  However, the efficacy of individual

 

      products must be demonstrated to meet regulatory

 

      requirements.  FDA's current regulatory standards

 

      are based on actual product performance and have

 

      been supported in previous public discussions such

 

      as this one.  Ms. Tia Frazier will explain more

 

      about the regulatory history of these products.

 

                FDA currently determines the efficacy of

 

      healthcare antiseptics using a surrogate endpoint,

 

      and that is used as the reduction in a log                              

 

                                                                     10 count

 

      of bacteria from the site of the test product

 

      application.  Dr. Michelle Jackson, from the

 

      Division of OTC, will discuss how the standard is

 

      used in the test methodology.

 

                [Slide]

 

                This meeting has been convened because we

 

      have received citizen petition requests to change

 

      the threshold criteria for bacterial reduction.  We

 

                                                                13

 

      wish to present our review for your consideration

 

      of the efficacy data in the literature for these

 

      products.  We are asking that the advisory

 

      committee provide input about the standards that

 

      FDA needs to have in place to make regulatory

 

      decisions.

 

                [Slide]

 

                What are some of the factors that can

 

      influence efficacy of the healthcare antiseptics?

 

      This is by no means an exhaustive list but is

 

      intended to give you an idea of why product testing

 

      is required to demonstrate efficacy.

 

                The first group of factors I am going to

 

      discuss are associated with the actual product.

 

      The active ingredient obviously affects efficacy.

 

      The spectrum of activity for each individual active

 

      ingredient is tested in associated testing criteria

 

      in vitro.  The potency or dose response of the

 

      active ingredient shall also be taken into

 

      consideration, although in some cases it is not

 

      well known.

 

                The formulation of the product can impact

 

                                                                14

 

      its efficacy and influence that to increase or

 

      decrease efficacy so the concentration and dose

 

      delivered to the site and vehicle and other

 

      inactives in the products can affect efficacy.  One

 

      thing that influences efficacy quite a bit is how

 

      the product is actually used, and that is led in

 

      large part by the way the product is labeled.

 

                [Slide]

 

                Other factors that influence efficacy of

 

      healthcare antiseptics include actual use

 

      parameters, adherence to the labeling and other

 

      practice standards and actual implementation of

 

      both labeling and practice standards.

 

                There are many patient parameters that can

 

      affect the efficacy of these products, including

 

      things like health status which influences the risk

 

      for infection, as well as the type of procedure

 

      that is being conducted.

 

                Resident and transient bacteria, resident

 

      bacteria being normal flora and transient bacteria

 

      being those sorts that are introduced during

 

      healthcare processes, can affect efficacy as well. 

 

                                                                15

 

      The amount of bacteria that is delivered and that

 

      resides on the skin, either prior to or that is

 

      left residually after product use, is an important

 

      determinant of overall efficacy.  Virulence of the

 

      bacteria that exists on the skin affects efficacy

 

      as well.  A small amount of bacteria can be present

 

      and provide a great risk of infection.

 

                [Slide]

 

                FDA in general assesses efficacy using

 

      randomized, controlled trials for the most part.

 

      These provide analytical strength and can be

 

      designed to control for multiple confounders.

 

      Critical to the design of controlled trials is the

 

      selection of active and vehicle control, and we

 

      will be discussing that later today.

 

                [Slide]

 

                The endpoints that are normally used in

 

      randomized, controlled trials are clinical or

 

      surrogate endpoints.  Randomized, controlled trials

 

      typically use clinical endpoints because the

 

      relevance is more evident.  In some situations the

 

      difficulty and expense of conducting clinical

 

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      trials is very important to industry.  An

 

      alternative to clinical endpoints is surrogate

 

      endpoints, and Dr. John Powers will later discuss

 

      the scientific and regulatory precedent for using

 

      surrogates.  Just as a reminder, and I am sure you

 

      have gleaned this from your reading already, but

 

      the current standards for OTC healthcare antiseptic

 

      efficacy are surrogate endpoints.

 

                [Slide]

 

                The factors that should be considered when

 

      using a surrogate to assess healthcare antiseptic

 

      efficacy include validity.  We acknowledge from the

 

      outset of this discussion that there is limited

 

      information about the links between clinical

 

      outcomes and efficacy and use of the surrogates to

 

      determine efficacy.  Dr. Steve Osborne will discuss

 

      the literature surrounding this question a little

 

      bit later.

 

                The existing trials in the literature are

 

      not designed to validate our practice standards.

 

      Instead, our practice standards and use of

 

      surrogate are based on the use of antiseptics in

 

                                                                17

 

      practice and our experience with marketed drug

 

      products.

 

                Test methodology is also an important

 

      factor to consider when using surrogates.  Test

 

      methodology should evaluate the conditions of use,

 

      largely directed by the labeling or the intended

 

      labeling.  The test methodology to evaluate

 

      healthcare antiseptics with surrogates needs to

 

      characterize the tolerability of drug products.

 

      While we are talking primarily about efficacy

 

      today, the tolerability of these drug products is a

 

      major safety concern and does come up as part of

 

      the testing methodology.  Test methods do need to

 

      be standardized with regard to all inherent

 

      procedures.

 

                [Slide]

 

                Other factors that should be considered

 

      when using surrogate endpoints are the decision

 

      thresholds and, as I have said, the current

 

      criteria are based on the NDA performance of

 

      existing approved products.  We suggest that any

 

      changes to these criteria on decision thresholds

 

                                                                18

 

      should be data driven.

 

                Analysis of test data is critical, and

 

      later today Dr. Thamban Valappil will be discussing

 

      the analysis of these data.  His talk is predicated

 

      on the previous discussions that we will be having

 

      about validity methods and thresholds, and he will

 

      talk about the need to evaluate the response of

 

      test products in the context of variability in both

 

      test methods and in patient response.

 

                [Slide]

 

                Epidemiologic studies do provide

 

      information for healthcare antiseptics.  They

 

      provide actual use information on large populations

 

      and can often be used to suggest practice

 

      standards.  They are often used to generate

 

      hypotheses to be later studied in randomized,

 

      controlled trials.  But they are relatively

 

      insensitive to treatment differences and changes in

 

      things like threshold criteria.  So, using them to

 

      extrapolate for regulatory decision-making is of

 

      limited value.

 

                [Slide]

 

                What specifically are we asking the

 

      advisory committee to address?  First, can we

 

      continue to rely on surrogate markers to assess

 

                                                                19

 

      healthcare antiseptic efficacy?  I would like to

 

      remind the committee, as we will several times

 

      today I am certain, that we have the need for

 

      ongoing assessment and decision-making of these

 

      products so we do need to have standards in place

 

      now and in the near future, as well as into the

 

      distant future.

 

                If surrogates can be applied, at least in

 

      the short term, is there compelling evidence to

 

      change our surrogate efficacy criteria now?  What

 

      is the best way to analyze the efficacy data?  And,

 

      what labeling information would be helpful for

 

      clinicians to understand product efficacy and

 

      potentially to compare among different products?

 

                With that, I will turn it over to Tia

 

      Frazier, who is a regulatory project manager in the

 

      Division of OTC Drug Products, and she will be

 

      discussing regulatory history.

 

                DR. WOOD:  Just before you take that slide

 

                                                                20

 

      off, there is sort of an underlying assumption

 

      there, which I think is right but I just wanted to

 

      articulate that there is a sort of regulatory

 

      inertia which is that in the absence of evidence we

 

      shouldn't change criteria.  Is that fair?  I am not

 

      disagreeing with that, I am just trying to put

 

      number two in that context.

 

                DR. JOHNSON:  Yes, I think that is very

 

      essential to this discussion.  What we have tried

 

      to make clear, and will make clear in other

 

      presentations, is that the surrogates are based on

 

      as much information as we have had prior to the

 

      mid-'70's, when this regulatory mechanism was

 

      invoked, until now.  There still is not a body of

 

      evidence, while we are asking you to assess that

 

      body of evidence and whether you think that compels

 

      us to change.  So, there are standards in place and

 

      we think that those standards are based on the

 

      information that has been available to this point.

 

      At this point we are reconsidering the standards

 

      and we do think, and we are suggesting to the

 

      committee that any change in the standards should

 

                                                                21

 

      be data driven.

 

                DR. WOOD:  Just to summarize, so what you

 

      are saying is that you don't want the committee

 

      particularly to consider the quality of the data

 

      supporting the standards; you want the committee to

 

      consider the quality of the data supporting a

 

      change in the standards.

 

                DR. JOHNSON:  Well, I think it is both but

 

      our concentration is really on the latter part of

 

      that.

 

                DR. WOOD:  All right, thanks.  The next

 

      speaker will be Tia Frazier.

 

                    Regulation History of Healthcare

 

                        Antiseptic Drug Products

 

                MS. FRAZIER:  Good morning.

 

                [Slide]

 

                I am Tia Frazier, and I am a project

 

      manager in the OTC Division, and I will briefly

 

      review the regulatory history of the monograph for

 

      OTC healthcare antiseptic drug products.

 

                [Slide]

 

                The monograph includes both consumer and

 

                                                                22

 

      professional use products.  Today we are addressing

 

      issues related to the professional use products

 

      included in the monograph, which we call the

 

      healthcare antiseptics.  I will start first by

 

      defining the healthcare antiseptics.  There are

 

      three recognized uses, that Susan has already told

 

      you about, included in the tentative final

 

      monograph.  These are patient preoperative skin

 

      preparations used to cleanse patient skin prior to

 

      surgery; surgical scrubs which are used by

 

      operating room personnel prior to performing

 

      surgery; and healthcare personnel handwashes which

 

      are the soaps and leave-on products that are used

 

      by all personnel in healthcare settings prior to

 

      contact with patients.

 

                [Slide]

 

                We have two different mechanisms for

 

      regulating OTC healthcare antiseptics.  Companies

 

      can submit new drug applications, which we call

 

      NDAs, for specific drug products to the FDA.  Data

 

      provided in NDAs remains confidential.  The second

 

      mechanism that we have for regulating these

 

                                                                23

 

      products is the OTC drug monograph review process.

 

      Products submitted to the monograph review are

 

      judged on the safety and efficacy of their

 

      individual active ingredients.  The data review for

 

      monograph drug products is public.

 

                [Slide]

 

                Just to add to this brief description, I

 

      will also tell you that the OTC drug monograph

 

      review began in 1972.  At that time, and for some

 

      years later, the agency made determinations about

 

      the safety and efficacy of over 200,000 OTC

 

      products that were on the market at that time.  We

 

      have reviewed 700 active ingredients in 26

 

      therapeutic categories with the help of expert

 

      panels.

 

                [Slide]

 

                The advisory review panel reviewed and

 

      made recommendations on ingredients and products to

 

      further the development of a drug monograph.  FDA

 

      then categorizes ingredients considered in the

 

      monograph review according to their safety and

 

      effectiveness for a particular use described in the

 

                                                                24

 

      review.  I won't say much more about how we

 

      categorize and evaluate ingredients since the focus

 

      of today's meeting is on the effectiveness criteria

 

      that we use to evaluate this particular group of

 

      professional use products.  The OTC review panel's

 

      recommendations are then published in an advance

 

      notice of proposed rule-making, or ANPR.

 

                [Slide]

 

                After the ANPR is published we consider

 

      public comments as we develop a tentative final

 

      monograph, or TFM.  A TFM is FDA's proposed

 

      monograph.

 

                [Slide]

 

                FDA usually receives more data and public

 

      comments on any TFM that we publish.  Typically, we

 

      publish a final monograph after a tentative final

 

      monograph.  In this case, we published a second

 

      tentative final monograph in 1994 after the first,

 

      which was published in 1978.

 

                [Slide]

 

                We, at FDA, have the current view that

 

      antiseptics do play a pivotal role in the practice

 

                                                                25

 

      of infection control today.  We operate from the

 

      presumption that antiseptics can decrease the

 

      number of organisms on the surface of the skin and

 

      this probably reduces the spread and development of

 

      nosocomial infections.

 

                Based on this presumption, we adopted

 

      surrogate endpoints, measurements of log reductions

 

      on the skin surface that are intended to indirectly

 

      measure the effectiveness of antiseptics that we

 

      regulate.  This is the reason that FDA and the

 

      European regulatory bodies selected this particular

 

      surrogate endpoint, the reduction of the organisms

 

      on the skin surface, to evaluate the effectiveness

 

      of these products.

 

                [Slide]

 

                The advisory review panel recommended in

 

      1974 that we use surrogate endpoints to measure

 

      antiseptic effectiveness.  To date, unfortunately,

 

      we still have not figured out how to design a

 

      clinical study that can measure the contribution of

 

      an antiseptic in reducing the likelihood of

 

      contracting or spreading nosocomial infection. 

 

                                                                26

 

      With any luck, today Dr. Pearson will explain later

 

      why designing studies like this is so difficult.

 

                [Slide]

 

                So, now I am going to go into the history

 

      of the monograph as it relates to the surrogate

 

      endpoints.  The first defined surrogate endpoint

 

      for patient preoperative skin preparations appears

 

      in our 1974 ANPR.  It was also incorporated in the

 

      first tentative final monograph which, I said, was

 

      published in 1978.  Then the panel recommended a

 

      3-log reduction in organisms on the surface of the

 

      skin as the requirement for patient preoperative

 

      skin preparation.  At that time, NDA products were

 

      often approved for patient preoperative skin

 

      preparation indications based on their ability to

 

      meet a 3-log reduction and the monograph simply

 

      adopted this commonly used NDA standard.

 

                It is important to realize that the

 

      effectiveness criteria used today to evaluate

 

      products marketed under the monograph are really

 

      based on the effectiveness criteria often applied

 

      to NDA products.  NDAs, of course, can be approved

 

                                                                27

 

      with alternate clinical endpoints and are not

 

      necessarily bound by the monograph standards.

 

                [Slide]

 

                Moving on to the surgical hand scrub

 

      criteria, the history on this is that Hibiclens is

 

      an NDA product that was approved in 1975 based on a

 

      new surrogate model developed to evaluate surgical

 

      scrubs.  FDA incorporated the effectiveness

 

      criteria applied to Hibiclens surgical scrub into

 

      the developing antiseptic monograph.  These

 

      criteria were published in our second tentative

 

      final monograph, on June 17, 1994.

 

                Hibiclens is often included as a positive

 

      or active control in testing designs for antiseptic

 

      products.  Because these are laboratory tests,

 

      companies are required to include a positive

 

      control arm using an approved product like

 

      Hibiclens to ensure that the tests are conducted

 

      correctly.

 

                [Slide]

 

                The current 3-log reduction criteria

 

      proposed for healthcare personnel handwashes in the

 

                                                                28

 

      second tentative final monograph was based on FDA's

 

      evolving understanding of what the NDA products

 

      under review at that time could achieve.

 

                [Slide]

 

                As I have said before, this monograph is

 

      unusual because there are two tentative final

 

      monographs associated with it.  In 1994 we elected

 

      to publish a second tentative final monograph

 

      rather than a final monograph to allow for public

 

      comment on the new testing requirements.  The

 

      current proposed testing requires in vitro studies

 

      of the product spectrum and kinetics of

 

      antimicrobial activity and of the potential for the

 

      development of resistance.  We also require in vivo

 

      studies of effectiveness under conditions that we

 

      think simulate how the product is actually used in

 

      that healthcare setting.

 

                Another unusual aspect of this monograph

 

      is that it requires in vitro and in vivo testing

 

      not only for the approval of new products but also

 

      for the approval of new formulations.  We require

 

      this testing to be done because changes in the

 

                                                                29

 

      inactive ingredients or dosage forms can affect the

 

      product's effectiveness.

 

                [Slide]

 

                Products are required to meet key

 

      attributes important to their performance in

 

      healthcare settings.  We state that a healthcare

 

      personnel handwash should be persistent if

 

      possible.  We would like it to be non-irritating,

 

      fast acting and be able to kill a broad spectrum of

 

      organisms as well.

 

                Persistence, or the ability to have a

 

      residual effect for some time after the product is

 

      used, is also an attribute that we would want a

 

      surgical scrub or a patient preoperative skin

 

      preparation to have as well.

 

                [Slide]

 

                We have had two prior public discussions

 

      about these effectiveness criteria.  We discussed

 

      performance testing at an advisory committee

 

      meeting in 1998.  This was a general discussion

 

      only and we did not present questions for the

 

      committee to vote on.  Then in 1999 we held a

 

                                                                30

 

      public feedback meeting to hear the industry

 

      coalition present an alternative model or framework

 

      for evaluating antiseptics.  Dr. Jackson will cover

 

      the effectiveness criteria proposed by this

 

      industry coalition in her presentation that follows

 

      mine.

 

                [Slide]

 

                I think everyone here today would agree

 

      that it is critical that FDA ensures it uses the

 

      right criteria to evaluate antiseptic products.

 

      There are many dangers we can imagine might occur

 

      if we allow ineffective products to be sold and

 

      used in hospitals.  We need these products to work.

 

      The OTC and anti-infective divisions admit that the

 

      effectiveness criteria we currently use are not

 

      based on data from clinical studies.  We recognize

 

      this as a limitation of our current standards.

 

                The divisions recently reviewed available

 

      scientific data on topical antiseptic products used

 

      in healthcare settings.  We searched for data that

 

      could be used to support effectiveness standards

 

      for this class of products.  Our review of more

 

                                                                31

 

      than 1,000 studies submitted by industry and picked

 

      up through our own literature search is included in

 

      the committee background packages.  Dr. Steven

 

      Osborne will present the results of his review and

 

      evaluation of a section of those references that

 

      address clinical benefit later on this morning.

 

                [Slide]

 

                The monograph for OTC healthcare

 

      antiseptic drug products is in the tentative final

 

      monograph or proposed rule stage.  We are in the

 

      process of writing a final rule, and we need your

 

      recommendations on what the effectiveness criteria

 

      should be in order to finalize this monograph.

 

                Now I would like to introduce my

 

      colleague, Dr. Michelle Jackson, who is a

 

      microbiology reviewer in the Division of

 

      Over-the-Counter Drug Products.  She will review

 

      the testing methodologies used to evaluate these

 

      products.

 

             Testing of Healthcare Antiseptic Drug Products

 

                [Slide]

 

                DR. JACKSON:  My talk will focus on the

 

                                                                32

 

      testing criteria for healthcare antimicrobial drug

 

      products, and currently the development and

 

      standardization of protocols regarding the testing

 

      criteria for healthcare antiseptic drug products

 

      are based on earlier NDA review process.

 

                [Slide]

 

                My presentation will discuss where we are

 

      with the proposed monograph requirements in regards

 

      to clinical simulation testing procedures for

 

      healthcare personnel handwash, surgical hand scrub

 

      and patient preoperative skin preparation, and the

 

      use of surrogate endpoints, also referred to as log

 

      reductions, with the three healthcare professional

 

      products.  Then I will go over the industry

 

      coalition's position of wanting to use alternative

 

      criteria.                [Slide]

 

                During the early stages of the antiseptic

 

      NDA review process standardized protocols did not

 

      exist.  However, the agency requires standardized

 

      and reproducible methods, therefore, as the NDA

 

      review process evolved clinical protocols used

 

      throughout the NDA review process also evolved into

 

                                                                33

 

      protocols now recommended in the tentative final

 

      monograph.

 

                So, what makes a good clinical simulation

 

      test method?  It should simulate as close as

 

      possible the actual use conditions.  Ideally,

 

      clinical simulations should include design

 

      characteristics such as test product, also referred

 

      to as final formulation; the test product contains

 

      the active antimicrobial agent; a vehicle control

 

      arm is the test product without the active

 

      antimicrobial agent and vehicle, and negative

 

      control that shows how much contribution of

 

      reduction is due to just the mechanical action of

 

      washing the hands.

 

                A current trial design in TFM does not

 

      recommend inclusion of a vehicle for healthcare

 

      personnel handwash and patient preoperative

 

      testing.  The active control arm is also referred

 

      to as the positive or internal control.  The active

 

      control is used to assess the reproducibility of

 

      the clinical simulation studies and also used to

 

      validate the study.  This standard is usually a

 

                                                                34

 

      chlorhexidine gluconate containing product.

 

      Clinical simulations should also measure the

 

      desired product performance.  This simulation

 

      testing generates the surrogate endpoints and it

 

      should also be reproducible.

 

                I will briefly go over the three testing

 

      criteria for healthcare personnel handwash,

 

      surgical hand scrub and patient preoperative skin

 

      testing.

 

                [Slide]

 

                For healthcare personnel handwash, the

 

      label indicated use is handwash to help reduce

 

      bacteria that potentially can cause disease.  The

 

      products are used by healthcare professionals on a

 

      daily basis up for to 50 handwashes per day.  The

 

      testing process predicts the reduction of organisms

 

      that may be achieved by washing the hands after

 

      handling contaminated objects or caring for

 

      patients.  Here we are focused on the removal of

 

      transient organisms.  The testing process is

 

      designed for frequent use and it measures the

 

      reduction of transient organisms after a single use

 

                                                                35

 

      or multiple uses to initial baseline level.

 

                The studies are designed to demonstrate a

 

      cumulative effect of an antiseptic, meaning that

 

      the product gets better and better in reducing the

 

      bacterial load on the hands.  Thus, the products

 

      are considered broad spectrum, fast acting and, if

 

      possible, persistent.  The TFM surrogate endpoints

 

      propose a 2-log reduction for the first wash and a

 

      3-log reduction for the 10th wash.

 

                [Slide]

 

                For the inclusion criteria subjects

 

      participating in the studies must be between the

 

      ages of 18-69, generally in good health, and have

 

      no clinical evidence of dermatosis, open wounds,

 

      hangnails or other skin disorders.

 

                The subjects are excluded if they have

 

      been diagnosed with having medical conditions such

 

      as diabetes, hepatitis, or having an immune

 

      compromised system, subjects having any sensitivity

 

      to antimicrobial products, pregnant or nursing

 

      women also would be excluded from participating in

 

      a study.

 

                For the healthcare personnel handwash

 

      there is a one-week washout period where subjects

 

      are instructed to use a non-antimicrobial product,

 

                                                                36

 

      such as soaps, deodorant and shampoos, and avoid

 

      bathing in chlorinated pools and hot tubs.

 

                [Slide]

 

                The outline of the test procedure includes

 

      a test practice wash using bland soap.  This

 

      basically removes any oils and dirt from the hands,

 

      and the bacteria counts are compared to the

 

      baseline counts.  The hands are contaminated with

 

      Serratia marcescens and immediately sampled, and

 

      the baseline is determining the number of organisms

 

      on the surface of the skin prior to using an

 

      aseptic product.

 

                The handwashing schedule involves ten

 

      washes performed on one day.  At the first wash the

 

      hands are contaminated and washed with the test

 

      product.  The hands are then sampled for microbial

 

      counts.  Eight additional washes are performed, and

 

      at the tenth wash the hands are sampled for

 

      microbial counts and the product must achieve a

 

                                                                37

 

      specific log reduction after the first and tenth

 

      washes.  The repetitive hand washing aspect of the

 

      study design is intended to mimic the repeated use

 

      of a product in hospitals.  The repetitive washing

 

      is also used to measure the cumulative effect, and

 

      cumulative effect is a progressive decrease in the

 

      number of microorganisms recovered following the

 

      repeated application of the test product.

 

                [Slide]

 

                Once the hand washing procedure is

 

      completed, the subject's hands are decontaminated

 

      by sanitizing the hands with 70 percent alcohol.

 

      The purpose of this is to destroy any residual

 

      Serratia marcescens left on the skin.  Typical

 

      handwashing procedures involve contaminating the

 

      hands with a microorganism, Serratia marcescens.

 

      The hands are rubbed together for 45 seconds, and

 

      the hands are held away from the body and allowed

 

      to dry for a few minutes.

 

                [Slide]

 

                Once the hands are dry, a specific amount

 

      of test product is dispensed into the cupped hands

 

                                                                38

 

      and the next step is to lather and wash all over

 

      the surface of the hands and above the wrists.

 

      After the completion of the wash, the hands and

 

      forearms are rinsed under regulated tap water with

 

      a temperature of 40 degrees Celsius for 30 seconds.

 

                [Slide]

 

                The hands are then placed in plastic bags

 

      and sampling fluid is added to the bag containing

 

      neutralizers.  Neutralizers are reagents that stop

 

      the antimicrobial reaction.  Sampling should occur

 

      within five minutes after each wash.  The bags are

 

      tightly secured above the wrist with a strap.  The

 

      hands are massaged for one minute, paying

 

      particular attention to the fingers and underneath

 

      the nails.

 

                [Slide]

 

                An aliquot of the sampling fluid is

 

      aseptically withdrawn from the bag and transferred

 

      immediately to dilution tubes.  The microbial count

 

      determination is performed by surface plating and

 

      this is done within 30 minutes of sampling.  The

 

      plates are incubated for two days at 30 degrees

 

                                                                39

 

      Celsius.

 

                [Slide]

 

                This diagram depicts the colony forming

 

      units, CFUs, from two dilution plates.  CFUs are

 

      then converted into log counts.  Serratia

 

      marcescens produces a red pigment color for easy

 

      identification, and it distinguishes itself from

 

      the normal flora of the hands that appear white or

 

      yellowish on agar plates.  Here, I want to

 

      emphasize that we are just counting bacteria.

 

                [Slide]

 

                Here the industry coalition suggest a 1.5

 

      log reduction for the first wash, and suggest

 

      eliminating the tenth wash.  We require the test

 

      product to show a cumulative effect, that is an

 

      evaluable attribute, that shows a progressive

 

      decrease in the number of organisms recovered

 

      following repeated application of a test product.

 

                [Slide]

 

                For surgical hand scrub the indication use

 

      is to significantly reduce the number of organisms

 

      on the skin prior to surgery.  These products are

 

                                                                40

 

      used to reduce the resident and eliminate the

 

      transient flora of the hands of surgeons and

 

      surgical personnel, thus reducing the incidence of

 

      post-surgical site infection.

 

                The testing process is designed to measure

 

      the immediate and persistent reduction of resident

 

      organisms after a single or repetitive treatment.

 

      Here there is no artificial contamination of the

 

      hands, and the testing of the surgical hand scrub

 

      involves multiple test product use and repeated

 

      measurements of the bacterial reduction.  These

 

      antiseptics are considered broad spectrum, fast

 

      acting and persistent.  The TFM surrogate endpoints

 

      propose a 1-log  on day 1 for the first wash; 2-log

 

      on day 2 at the second wash; and 3-log on day 5 at

 

      the 11th wash.

 

                [Slide]

 

                The subjects are selected through the

 

      inclusion/exclusion criteria for surgical hand

 

      scrub testing.  A 14-day or 2-week washout period

 

      is required.  Soon after the washout period the

 

      baseline counts are determined, and they are

 

                                                                41

 

      sampled two times, first on day one and the second

 

      estimate includes one of the three options.  On day

 

      3 and 5, 5 and 7, or 3 and 7.

 

                Subjects with a baseline greater than or

 

      equal to 5 logs after the first and second baseline

 

      estimates will qualify for the study testing

 

      period.  So, no sooner than 12 hours and no longer

 

      than 4 days after completion of the baseline

 

      determination subjects perform the initial scrub

 

      with the test product.  The surgical hand scrub

 

      testing requires a total of 11 scrub washes over a

 

      5-day period.  The sampling occurs on day 1, day 2

 

      and day 5.

 

                The reason we test 5 days is that the

 

      procedure mimics typical usage and permits the

 

      determination of both immediate and long-term

 

      bacterial reduction.  Each day the antimicrobial

 

      soap is used it produces a greater effect due to

 

      the persistence of minute residues left from the

 

      previous scrub.  This effect is called cumulative

 

      effect, and that is the reason why we test for 5

 

      days.

 

                [Slide]

 

                An amount of the test product is dispensed

 

      according to the manufacturer's labeling

 

                                                                42

 

      instructions.  The soap is distributed all over the

 

      hands and two-thirds of the forearms.

 

                [Slide]

 

                The hands are then scrubbed according to

 

      the manufacturer's directions, and if no directions

 

      are provided the TFM requires two five-minute scrub

 

      procedures.  A scrub brush is used to scrub the

 

      hands including the nails, the fingers, and

 

      interdigital spaces of the hands.

 

                [Slide]

 

                A lab technician will don sampling gloves

 

      on the subjects.  One-third of the hands in a

 

      treatment group is sampled immediately.  The gloves

 

      remain on the test subjects' hands for either three

 

      hours or six hours prior to sampling.  Enumeration

 

      of bacterial flora three hours after the scrub is

 

      conducted in order to demonstrate continued

 

      effectiveness of the product during the time

 

      required for a surgical setting.  The enumeration

 

                                                                43

 

      of bacterial flora six hours after the scrub is

 

      conducted to demonstrate the suppression of

 

      bacterial counts over a period of time chosen as

 

      representing the maximum duration of most surgical

 

      procedures, that is, on average most surgeries will

 

      not last greater than six hours and, if so,

 

      surgeons usually rescrub.

 

                [Slide]

 

                A specified amount of sampling fluid then

 

      is added to the glove pan, and the gloves are

 

      fastened securely above the wrist and strapped, and

 

      the hands are then massaged for one minute, paying

 

      particular attention underneath the nails.

 

                [Slide]

 

                An aliquot of the sampling fluid is

 

      aseptically withdrawn from the glove and

 

      transferred immediately to dilution tubes

 

      containing neutralizers.  A microbial count

 

      determination is performed by surface plating, and

 

      this is done within 30 minutes of sampling. The

 

      plates are incubated for two days at 30 degrees

 

      Celsius.

 

                [Slide]

 

                Here the industry coalition agrees with

 

      the 1-log reduction for the first wash.  They

 

                                                                44

 

      suggest eliminating the second and 11th wash.  They

 

      suggest that persistence of antimicrobial activity

 

      should not be a requirement for surgical hand

 

      scrub.  We require an assessment of persistent

 

      activity in case there is a tear in the surgeon's

 

      glove, and it is assumed that the persistent effect

 

      will prevent the multiplication of resident flora

 

      on the gloved hand, thus preventing contamination

 

      of the surgical field.

 

                [Slide]

 

                For the patient preoperative skin

 

      preparation or surgical prep labeled for the

 

      indicated use helps reduce bacteria that

 

      potentially can cause skin infection.  These

 

      antiseptic products must be fast acting, broad

 

      spectrum and persistent and, statistically reduce

 

      the number of organisms on intact skin.  They are

 

      designed for use by healthcare professionals to

 

      prep the patient's skin prior to invasive surgery

 

                                                                45

 

      or prior to injection.  These indications, however,

 

      do not cover more specific indications such as

 

      catheter insertions and open wounds.

 

                The testing process measures the immediate

 

      and persistent reduction of resident bacteria after

 

      a single treatment.  The TFM surrogate endpoint

 

      proposed a 1-log reduction for pre-injection; 2-log

 

      for the abdomen or dry site; and 3-log for the

 

      groin or moist site area.

 

                [Slide]

 

                The subjects are selected through the

 

      inclusion/exclusion criteria for patient preop

 

      testing.  A 14-day washout period is required, and

 

      no bathing 24 hours prior to the baseline

 

      screening.  We want to try to obtain a high

 

      bacterial count for the baseline.  The TFM

 

      recommends the baseline screening counts for

 

      pre-injection to be greater than or equal to 3

 

      logs.  The TFM recommends that baseline screening

 

      counts for the common surgical sites for both dry

 

      and moist site areas, and the sites are to present

 

      bacterial populations large enough to allow the

 

                                                                46

 

      demonstration of bacterial reduction for up to 2

 

      logs centimeters squared for the abdomen sites and

 

      up to 3 logs centimeters squared on the groin

 

      sites.

 

                [Slide]

 

                For the abdominal site testing a 5 X 5

 

      treatment site area is marked on the skin using a

 

      permanent marker.  The template is divided into

 

      four quadrants for baseline, 10 minutes, 30 minutes

 

      and 6 hours sampling.

 

                [Slide]

 

                The baseline sampling is performed using

 

      the cylinder sampling technique.  A sterile

 

      scrubbing cup is held firmly against the skin over

 

      the site to be sampled.  The scrub solution

 

      containing neutralizers is placed into the cup and

 

      scrubbed with moderate pressure for one minute

 

      using a sterile rubber-tipped spatula.  This

 

      procedure is also used for sampling for the

 

      treatment site.

 

                [Slide]

 

                The application of the prep formulation is

 

                                                                47

 

      applied to the testing area.  For 30-minute and

 

      6-hour sampling sites a sterile gauze is placed

 

      over the prep area to help prevent microbial

 

      contamination.  The gauze pad is held in place by

 

      the sterile teeth dressing.

 

                [Slide]

 

                The treatment samples are taken from the

 

      site areas using the cylinder sampling technique.

 

      A similar procedure is also used for testing the

 

      groin site area.

 

                [Slide]

 

                Here the industry coalition agrees with

 

      the 1-log reduction at the pre-injection site, and

 

      they suggested that only a 1-log reduction should

 

      be required for the abdomen site and a 6-hour

 

      persistent is not needed.  For the groin site a

 

      2-log reduction should be required and a 6-hour

 

      persistent is not needed.

 

                [Slide]

 

                FDA has received objections to the TFM

 

      proposed effectiveness criteria through comments in

 

      a citizen's petition.  Industry contended that the

 

                                                                48

 

      current performance criteria for healthcare

 

      antiseptics are overly stringent.  They claim that

 

      two category ingredients, alcohol and iodine, and

 

      one NDA approved ingredient, CHD, cannot pass the

 

      current testing requirements.  They claim that all

 

      antiseptic products only need to be effective after

 

      a single use, and they also do not want to meet the

 

      persistence requirement.

 

                [Slide]

 

                This table summarizes the bacterial log

 

      reduction in industry's proposal for the healthcare

 

      antiseptic compared to FDA current standards for

 

      final formulation for healthcare personal handwash,

 

      surgical hand scrub and patient preoperative skin

 

      preparation I just reviewed.  Over the years the

 

      industry coalition has made several proposals for

 

      the revised effectiveness criteria.

 

                For the healthcare personal handwash, it

 

      should be effective following a single use.  A

 

      cumulative effect should not be a requirement.  For

 

      surgical hand scrub, it should be effective

 

      following a single use and also a cumulative effect

 

                                                                49

 

      should not be a requirement.  And for patient

 

      preop, the pre-injection and abdomen dry site a

 

      1-log reduction is suggested, and for a worst-case

 

      scenario such as the groin site area, it should

 

      need a 2-log reduction.

 

                [Slide]

 

                We are aware the surrogate endpoints lack

 

      the clinical validation of a test method and

 

      performance criteria.  They do not measure the

 

      level of residual bacteria on the skin and

 

      virulence of the residual bacterial is not factored

 

      into the log reduction determination.  We realize

 

      that we are just measuring the mean log reduction.

 

                The criteria is based largely on earlier

 

      NDA performance and we have approved over 20 NDAs

 

      based on using surrogate endpoints.  These criteria

 

      are consistently applied to monograph products and

 

      many NDAs.  Industry has deviated from following

 

      the TFM in regards to variability in testing

 

      procedures such as scrub techniques and lab

 

      analysis, and it is not compared to vehicle or

 

      active control.  We will later hear from Dr.

 

                                                                50

 

      Valappil regarding improving statistical analysis

 

      that could be applied to the existing criteria.

 

                [Slide]

 

                Overall, it is impossible to compare the

 

      data across studies due to the vast differences and

 

      methodologies that were used, and other limitations

 

      such as the following:  The majority of the studies

 

      were designed as product comparisons; studies were

 

      not designed to assess the product's ability to

 

      meet the TFM effectiveness criteria.  There were

 

      significant variations in how the studies were

 

      conducted; different testing procedures were used;

 

      and neutralizer validation data were not generally

 

      provided.  More than half the data submitted did

 

      not include neutralizers in the testing procedures,

 

      which can result in artificially high log

 

      reductions.  Generally, sample sizes were small in

 

      the studies and there was a limited number of

 

      subjects included in the testing procedure.  And,

 

      alcohol alone did not meet the 10th wash 3-log

 

      reduction.  However, most were able to meet the

 

      3-log reduction of the first wash.  We are

 

                                                                51

 

      currently evaluating the alcohol leave-ons and

 

      alcohol gel products.

 

                [Slide]

 

                This slide was included to show that other

 

      countries also use surrogate endpoints.  The

 

      European performance criteria for handwash require

 

      that the test product mean log reduction factor

 

      should be greater than soap that has an average

 

      reduction log of 2.8.  The performance criteria for

 

      hand rub require that the test product mean log

 

      reduction factor should be equal to or greater than

 

      60 percent isopropyl alcohol that has an average

 

      reduction log of 4.6.

 

                [Slide]

 

                In summary, we measure bacterial log

 

      reduction and testing methodology for healthcare

 

      personnel handwash, surgical hand scrub and patient

 

      preop.  These log reductions are used as surrogate

 

      endpoints to evaluate effectiveness.  How should we

 

      analyze this data?

 

                Later this morning we will hear from Dr.

 

      Valappil a presentation on statistical analysis for

 

                                                                52

 

      healthcare and aseptic drug products.  You will

 

      also hear from Dr. Steve Osborne who will discuss

 

      the relationship of these outcomes and

 

      corresponding reduction in the incidence of

 

      nosocomial infections in healthcare settings where

 

      the product use remains undefined.

 

                [Slide]

 

                We are aware of the limitations of these

 

      test methods, and we assume that the incidence of

 

      infections as related to current use of existing

 

      products and lowering these standards may increase

 

      the infection rates.  We need research to validate

 

      these surrogates, and we need to have products on

 

      the market now and in the use of actionable

 

      criteria in the meantime.  That concludes my

 

      presentation.

 

                DR. WOOD:  Mike, you approached me earlier

 

      about some confusion about the data.  Do you want

 

      to comment on that at this stage?

 

                DR. ALFANO:  Yes, I have been advised that

 

      industry is not recommending removal of the 6-hour

 

      persistence requirement but, rather, the cumulative

 

                                                                53

 

      effect requirements.  Apparently, that came about

 

      because of some confusion over a table that the

 

      industry submitted.

 

                DR. WOOD:  Can you put slide 12 back up?

 

      Is that the one that we are talking about here, on

 

      page 6?  Is that where the confusion is?

 

                DR. ALFANO:  Actually, it was brought to

 

      my attention versus the questions that we are to

 

      answer today, which is on the last page of the

 

      agenda.

 

                DR. WOOD:  I was just trying to clarify

 

      these slides.  So, there is no confusion about what

 

      industry's position is on the slides?  Is that

 

      right?

 

                DR. ALFANO:  That is correct.

 

                DR. WOOD:  Well, I think there is

 

      actually.  Somebody seems to want to comment.

 

                DR. FISCHLER:  George Fischler, manager of

 

      microbiology for the Dowell Corporation,

 

      representing the STA-CTFA coalition.  Yes, there is

 

      some confusion.  On this slide, yes, where it says

 

      surgical hand scrub, there is an asterisk and

 

                                                                54

 

      patient preoperative skin preparation, an asterisk.

 

      Industry has not recommended the removal of the

 

      6-hour persistence criteria.  The only criteria

 

      that we recommended approval for is the cumulative

 

      effect.

 

                DR. WOOD:  Okay.  Well, let's come back to

 

      discussing that later.  I am even more confused now

 

      but let's go on to the next speaker.

 

                DR. JACKSON:  The next speaker is John

 

      Powers.  He is the lead medical officer in the

 

      Antimicrobial Drug Development and Resistance

 

      Division, and he will discuss the biological

 

      surrogate endpoints in the clinical trials of

 

      infectious disease.

 

            Microbiological Surrogate Endpoints in Clinical

 

                     Trials of Infectious Diseases

 

                DR. POWERS:  Thanks, Michelle.

 

                [Slide]

 

                Today I am going to discuss issues related

 

      to microbiological surrogate endpoints in clinical

 

      trials of infectious diseases.  Some of the members

 

      of the Anti-Infective Drugs Advisory Committee

 

                                                                55

 

      won't be surprised by any of this since this is an

 

      issue that has come up in infectious disease trials

 

      over and over again.  So, I am going to try to

 

      discuss just some of the general points that have

 

      to do with selecting surrogate endpoints in these

 

      types of trials.

 

                [Slide]

 

                The first thing I am going to talk about

 

      is differentiating what we do in clinical practice

 

      and how one develops clinical practice guidelines

 

      with what one actually does in a clinical trial,

 

      and how those are very different situations.  Then

 

      what I would like to do is define our terms and

 

      talk about what is an endpoint; define what a

 

      clinical endpoint and surrogate endpoints are and

 

      differentiate those from biomarkers.  One of the

 

      things you will hear often, and probably we will

 

      make the mistake today, is using the term surrogate

 

      markers rather than surrogate endpoints, which is

 

      rather non-specific and causes some confusion.

 

                Then we will talk about the utility of

 

      surrogates in clinical trials and differentiating

 

                                                                56

 

      surrogate endpoints from surrogates as risk

 

      factors, which is an entirely different

 

      consideration.  I will talk about some of the

 

      strengths and limitations of surrogate endpoints

 

      and then, finally, relate all of that information

 

      to the use of surrogates in the setting of topical

 

      antiseptics.

 

                [Slide]

 

                What we do in clinical practice is we are

 

      using drug products that are already proven to be

 

      safe and effective and, hopefully, we are not

 

      experimenting on our patients; we are using the

 

      products in a way where they are already shown to

 

      work.

 

                In clinical practice we impose several

 

      interventions on patients and hope they get better.

 

      We are not really concerned with why they get

 

      better when we do all that stuff to them, only the

 

      fact that they get out of the bed and they leave

 

      the hospital cured.  We develop treatment

 

      guidelines to help us describe the use of the

 

      products based on whatever the best available

 

                                                                57

 

      evidence is, and a lot of current treatment

 

      guidelines actually put grades on the evidence

 

      where you will see A-1 all the way down to D that

 

      talk about whether it is from randomized,

 

      controlled trials versus observational evidence as

 

      well, but optimally these treatment guidelines are

 

      based on randomized, controlled trials.  When that

 

      data is not available we oftentimes have to put

 

      things into these guidelines based on the best

 

      available evidence that we have.

 

                The unfortunate thing is that sometimes

 

      these guidelines then become the reason for not

 

      getting the data from randomized, controlled trials

 

      because people will come to us and say the

 

      guidelines say this, therefore, you can't do a

 

      trial to evaluate it.  And, that is probably not

 

      what the people who alter these guidelines actually

 

      are intending.

 

                This differs from clinical trials which

 

      are experiments in human beings to determine if

 

      drug products are safe and effective.  Clinical

 

      trials differ from clinical practice in that we are

 

                                                                58

 

      using the scientific method.  We are trying to hold

 

      as much as possible constant, except for the

 

      interventions, so that we can apply the outcomes to

 

      causality related to the interventions themselves,

 

      which is very, very different from clinical

 

      practice.  So, how we do this is often to use

 

      concurrent controls which is something that we do

 

      not do in clinical practice.  In clinical practice

 

      we look at what the patient is at baseline and

 

      compare what happens at the end.  That is not what

 

      we do in clinical trials where we are comparing

 

      what happens at the end in patients who receive the

 

      test product versus a control.

 

                These clinical trials are, hopefully, to

 

      provide the evidence for formulation of practice

 

      guidelines and, as I said, hopefully, it is not

 

      vice versa where the guidelines determine that we

 

      can or cannot do a clinical trial.  But the big

 

      issue in clinical trials is that we need to

 

      determine some yardstick to determine if products

 

      are safe and effective.  How are we going to

 

      measure those products to make that kind of

 

                                                                59

 

      assessment?  That is really what we are asking

 

      today.

 

                And, the reason for this slide is to sort

 

      of outline the real question today.  We are not

 

      questioning whether handwashing is important or

 

      whether handwashing should be done in clinical

 

      practice.  What we are asking today is how do we

 

      develop a yardstick to determine which products are

 

      safe and effective to use in handwashing.

 

                [Slide]

 

                So, let's define some of the terms that we

 

      are going to use today.  An endpoint is a measure

 

      of the effect of an intervention on an outcome,

 

      outcome being defined, for instance, as success or

 

      failure in a clinical trial in the treatment or

 

      prevention of a disease.  Again, it is important to

 

      realize that what we are talking about here is a

 

      disease.  We are not preventing someone getting an

 

      organism on their skin.  What we are really trying

 

      to look at is does that prevention of getting an

 

      organism on the skin, in turn, result in prevention

 

      of disease.

 

                But whenever we are picking an endpoint we

 

      have several questions that we have to address.

 

      The first one is what are we going to measure?

 

                                                                60

 

      Obviously, this should be clinically relevant to

 

      the disease in question.  We are not going to ask

 

      if your left earlobe hurts when we are trying to

 

      evaluate something that has to do with foot pain.

 

                The next question is how to measure it?

 

      And, we should be able to measure differences

 

      between therapies, should they exist, and that gets

 

      to this issue of the yardstick and that we need to

 

      be able to differentiate effective from ineffective

 

      products.

 

                The next issue is when do we actually

 

      measure it?  If we apply a product and come back in

 

      two years and then try to determine if there are

 

      differences between the patients we are probably

 

      not going to see a whole lot in a non-lethal

 

      illness.

 

                The next question is how much to measure,

 

      what magnitude of difference actually makes a

 

      difference to patients?  A lot of this has to do

 

                                                                61

 

      with sample size.  We could take a product that is

 

      99 percent effective and show that it is

 

      statistically different than a product that is 90

 

      percent effective if we studied thousands and

 

      thousands of patients.  So, it gets to the issue of

 

      clinical significance versus statistical

 

      significance.

 

                Then, one of the big issues I am going to

 

      ask you to talk about today is when we get some

 

      results, how do we analyze those results so that we

 

      can logically draw conclusions from them?

 

                [Slide]

 

                This is a cartoon from the New Yorker,

 

      which sort of outlines the issue in choosing

 

      endpoints that are relevant to patients.  Here

 

      there is a doctor who has just done an endoscopy on

 

      a miserable patient, and the doctor says

 

      congratulations, the endoscopy was negative;

 

      everything is perfectly all right.  So, according

 

      to the surrogate endpoint of what the doctor saw on

 

      the endoscopy, the patient feels great but the

 

      patient is saying my symptoms bother me.  I am

 

                                                                62

 

      worried and concerned.  I can't exercise; I can't

 

      eat.  My whole life is affected.  So, that gets to

 

      the difference between measuring a surrogate and

 

      measuring what the patient actually feels.

 

                [Slide]

 

                This seems sort of redundant but it is

 

      probably important to define what a disease

 

      actually is.  In these terms we are talking about a

 

      constellation of signs and symptoms experienced by

 

      the patient.  Although infectious diseases are

 

      caused by pathogenic organisms, those result in a

 

      host response and it is actually the host response

 

      that causes a lot of the symptoms that we see.

 

                When we are talking about surrogates we

 

      often hear about Koch's postulates.  Well, these

 

      fulfill Koch's postulates so the surrogate must

 

      work in the setting of an endpoint of a clinical

 

      trial.  But Koch's postulates relate to proving the

 

      cause of a disease, that a pathogen actually causes

 

      that particular illness, and Koch's postulates were

 

      never designed to measure the effect of an

 

      intervention.  It is very important in our

 

                                                                63

 

      discussion today to separate out cause from effect

 

      which are two different considerations.

 

                One of the issues we always talk about is

 

      that patients seek the care of clinicians because

 

      they have symptoms when they have a disease, not

 

      because of the presence of an organism.  So, a

 

      patient may come and say, doctor, I have this

 

      terrible cough I can't get rid of it.  They don't

 

      come in and say, doctor, I have mycoplasma in my

 

      respiratory tract.  Although that may be the cause

 

      of it, the reason patients come to see us is for

 

      relief of symptoms.

 

                In prevention trials, on the other hand,

 

      we are actually seeking to prevent those symptoms

 

      from ever occurring, but still here we are talking

 

      about the relevant endpoints being those actual

 

      symptoms that patients may encounter.

 

                [Slide]

 

                So, what is the difference between

 

      clinical endpoints and surrogate endpoints?  We are

 

      so used to using surrogates that sometimes we call

 

      things clinical endpoints that are, in fact,

 

                                                                64

 

      surrogates.   The definition of a clinical endpoint

 

      is actually fairly simple.  It is measures of how

 

      the patient feels, functions or survives, and a

 

      simple way to think of it is anything that measures

 

      something other than that is a surrogate endpoint.

 

      For instance, clinical endpoints would be measures

 

      of mortality or resolution or prevention of

 

      symptoms of a disease.

 

                On the other hand, surrogate endpoints are

 

      laboratory measurements or physical signs used as a

 

      substitute for a clinical endpoint.  Fever is a

 

      surrogate endpoint.  Fever does not necessarily

 

      measure how the patient feels.  Although fever may

 

      make the person feel terrible, what we really want

 

      to measure is the person feeling terrible not what

 

      the level of the temperature is but we are so used

 

      to using this in infectious disease trials.  But

 

      other things like culture results, which we are

 

      going to talk a lot about today, chest x-rays,

 

      histology or even data like pharmacokinetic

 

      information are all surrogate endpoints and need to

 

      be correlated with what is actually clinically

 

                                                                65

 

      happening to the patient.

 

                The important part here, as discussed at

 

      NIH Biomarkers Definition Working Group, published

 

      in 2001, is that surrogate endpoints by themselves

 

      do not confer direct clinical benefit to the

 

      patient and we need to make that link.  This is

 

      also reiterated in the International Conference on

 

      Harmonization, ICH E9 document.  The International

 

      Conference on Harmonization is a group consisting

 

      of U.S., Japanese, European regulators and members

 

      of the pharmaceutical industry.

 

                [Slide]

 

                So, how do we differentiate biomarkers

 

      from surrogate endpoints?  Biomarkers are any set

 

      of analytical tools that are used to assess

 

      biological parameters so it is a big, broad

 

      category.  Biomarkers are useful for many other

 

      purposes other than surrogate endpoints in trials.

 

      This is why the term surrogate marker isn't really

 

      very helpful to us because we can use these

 

      biomarkers for any number of things.  One may be as

 

      a diagnostic tool.  We can use the test as

 

                                                                66

 

      inclusion criteria to define the disease based on

 

      the presence of organisms.  Differentiating

 

      diagnosis from endpoint is a very, very important

 

      process.  As members of our Anti-Infective Drugs

 

      Advisory Committee that are here will tell you, we

 

      have had several advisory committees for instance

 

      addressing acute otitis media in children and acute

 

      bacterial sinusitis in children and adults where we

 

      have tried to make the distinction between needing

 

      microbiologic data to diagnose that the person

 

      actually has the disease, but how useful it is as

 

      an endpoint is an entirely different consideration.

 

                We can also use biomarkers to describe the

 

      mechanism of action of the drug and the effect on

 

      the organisms of an antibacterial or antiviral

 

      product is really the mechanism by which it

 

      achieves its effect, not necessarily the goal of

 

      therapy alone.  We have certainly been told by a

 

      number of sponsors--the direct quote, all

 

      antibiotics do is affect organisms.  Well, that is

 

      true but that is the mechanism by which they do

 

      what they do, not the goal of why we give them to

 

                                                                67

 

      patients in the first place.

 

                The third thing is that biomarkers can be

 

      a risk factor for acquiring the disease.  For

 

      instance, we know that colonization with a

 

      particular organism is a risk factor for getting an

 

      infection.  That doesn't mean that risk factors end

 

      up being the same thing as an endpoint.  Also, some

 

      of these things can be risk factors for outcome.

 

      They can indicate disease prognosis and how poorly

 

      or well the patient is going to do.  For instance,

 

      HIV viral load and CD4 counts in HIV--we can look

 

      at those to actually predict how a patient is going

 

      to do down the line. Then, finally, biomarkers can

 

      be used as surrogate endpoints, which are different

 

      from the previous four things we talked about.

 

                [Slide]

 

                The word surrogate comes from the Latin

 

      root surrogatus, which means to choose in place of

 

      another, or to substitute or put in place of

 

      another.  So, what we are doing with a surrogate

 

      endpoint is actually substituting microbiologic

 

      outcomes in patients for clinical outcomes.  One of

 

                                                                68

 

      the problems in looking at this is that

 

      investigators have looked at people only who have

 

      failed and then tried to relate clinical and

 

      microbiological outcomes in only the failures.  But

 

      we need to look at these correlations both in

 

      people who succeed and people who fail, which is

 

      pivotal in these clinical trials to prove drug

 

      efficacy.

 

                [Slide]

 

                Surrogate endpoints are very useful.  They

 

      can be used in early drug development as proof of

 

      principle that the drug has some biological

 

      activity, and they can be used in selecting

 

      candidates to go on and study in future phase 3

 

      trials.  They are also useful in phase 3 trials

 

      when the surrogate endpoint can be measured sooner

 

      in time than the clinical endpoint.  The obvious

 

      example of this is HIV trials, which I will go into

 

      in a little more detail.

 

                When the clinical endpoint events are more

 

      rare it allows us to complete a trial with a

 

      smaller sample size.  In other words, if the effect

 

                                                                69

 

      on the surrogate endpoint is quite large and the

 

      effect on the clinical endpoint is small, we can do

 

      a trial with a smaller amount of patients in a

 

      shorter amount of time.  Of course, this is all

 

      predicated on knowing that the surrogate actually

 

      predicts clinical outcomes.

 

                Some examples of where the agency has

 

      allowed surrogates and they have been used

 

      successfully are things like lowering cholesterol

 

      which, in turn, has been shown to prevent

 

      cardiovascular disease; lowering blood pressure to

 

      prevent cardiovascular disease; and perhaps the

 

      best example is suppression of HIV viral load as a

 

      surrogate endpoint in the prevention of either

 

      AIDS-defining events or death in the treatment of

 

      HIV and AIDS.

 

                [Slide]

 

                In this example what we see is a

 

      three-dimensional graph.  On the right-hand side

 

      there are CD4 counts which actually are predictors

 

      of the host's immune response.  On the other axis

 

      is the viral load, or HIV RNA concentration.  On

 

                                                                70

 

      the upward axis there is the three-year probability

 

      of patients progressing to AIDS.  You can see from

 

      this that as the person's CD4 count declines and as

 

      the HIV viral load goes up, the risk of developing

 

      AIDS-defining events and death also goes up.  So,

 

      both HIV viral load and CD4 counts are predictors

 

      of what is going to happen to the patient

 

      independently.

 

                The interesting thing about this is that

 

      this is measuring the organism but CD4 count is

 

      also measuring the host's immune response.  HIV is

 

      very unique in that the virus itself blunts the

 

      host's immune response so one of the things that

 

      complicates the measurement of surrogates is that

 

      measuring the surrogate itself often doesn't

 

      measure what is happening to the person.  So, viral

 

      load is very unique in that the virus itself knocks

 

      out the immune response and takes that piece out of

 

      the equation.

 

                [Slide]

 

                So, HIV viral load and CD4 counts are also

 

      a good example of the difference between risk

 

                                                                71

 

      factors and endpoints.  Both HIV viral load and CD4

 

      counts are risk factors for disease progression to

 

      HIV and AIDS, as I showed you on the previous

 

      slide, however, only HIV viral load functions well

 

      as a surrogate endpoint, much better than CD4 count

 

      does in clinical trials.

 

                Seven of eight trials with a positive

 

      effect on CD4 count also showed a positive effect

 

      on progression to AIDS or death.  But the effect in

 

      6/8 trials that had a positive effect on CD4 count

 

      also showed a negative effect on AIDS progression

 

      or death.  This again gets back to the issue that

 

      you cannot cherry-pick which studies you like.  You

 

      need to look at both success and failure of the

 

      surrogate to be able to get an overall assessment

 

      of what is going on here.  If we only looked at

 

      these studies we would think that CD4 count was

 

      great as a surrogate endpoint.

 

                This also gets to the issue that how you

 

      use the surrogate is very important.  It may be

 

      that CD4 count would function as a decent surrogate

 

      endpoint if we followed patients for longer periods

 

                                                                72

 

      of time than we follow the viral load because it

 

      just may be that the CD4 count may not change fast

 

      enough over the time that we measure it in a

 

      clinical trial to be very useful.  But if we

 

      measured it for longer, that may be a different

 

      story.

 

                [Slide]

 

                What are some of the strengths and

 

      limitations then of evaluating surrogates?  Part of

 

      this is the logic string we go through as related

 

      here to topical antiseptic products.  We know

 

      colonization with organisms precedes infection and,

 

      therefore, the surrogate may be useful as a risk

 

      factor for disease.  We know that these organisms

 

      can cause infection and result in a host response.

 

      So, the logic is that since the organisms cause

 

      infection, eliminating or decreasing the organisms

 

      should result in positive clinical outcomes for

 

      patients.  This seems very logical.  It seems very

 

      objective and reproducible.  But the question is,

 

      is it correct?

 

                This article by DiGruttola, and Dr.

 

                                                                73

 

      Fleming is a co-author on this, talks about are we

 

      being misled in terms of looking at these

 

      surrogates?  What we just did up here was an

 

      example of the old Arthur Conan Doyle Sherlock

 

      Holmes deductive reasoning.  We worked backwards

 

      from the end and said, well, it must be caused by

 

      this.  However, what we do in clinical trials is

 

      inductive reasoning.  We start off with a

 

      hypothesis and we test the hypothesis.  So, we need

 

      to test this logic to see if it is actually true.

 

      One of the seminal articles on surrogates was

 

      written by Prentice where he actually says that in

 

      a given clinical trial we need to test does the

 

      intervention have an effect on the clinical outcome

 

      and, in the same trial, does that intervention also

 

      have an effect on the surrogate so that we can link

 

      the two together?

 

                [Slide]

 

                Well, why may it be that an intervention

 

      having an effect on a surrogate which, in turn, has

 

      an effect on the clinical does not predict what

 

      actually happens to the patient?  And there are

 

                                                                74

 

      five potential reasons why this may happen.

 

                The first is that there may be unmeasured

 

      harms caused by the intervention which actually are

 

      not picked up by just measuring the surrogate.

 

                The second is that there may be unmeasured

 

      benefits, that the intervention actually does

 

      something good that is not measured by the

 

      surrogate and actually has a better clinical

 

      outcome than predicted by the surrogate.

 

                The next issue is that there may be other

 

      pathways of disease that result in a clinical

 

      endpoint that have nothing to do with the

 

      intervention that you applied.

 

                Finally, there are issues with how we

 

      measure the surrogate and how we measure the

 

      clinical endpoint.  Let's go through each one of

 

      those one at a time.

 

                [Slide]

 

                As I said, surrogates may not take into

 

      account unmeasured harm and benefits.  This gets to

 

      the issue of we cannot just look at whether a

 

      surrogate correlates with a clinical endpoint

 

                                                                75

 

      because, even if there are these unmeasured harms

 

      and unmeasured benefits, there will still be an

 

      association between the surrogate endpoint and the

 

      clinical endpoint.  It will be, however, that that

 

      association is not predicting the net clinical

 

      outcome in patients because it is not taking into

 

      account these other unmeasured benefits and harms.

 

                It is not too hard to understand why this

 

      occurs because the body actually has a finite

 

      number of processes to accomplish the things it

 

      wants to accomplish.  So, giving a drug product is

 

      still giving a foreign antigen to the body which

 

      may affect processes other than the ones that we

 

      actually intended to affect in the first place.  We

 

      know that, for instance, in antimicrobial products

 

      what we are really trying to affect is the organism

 

      which, in turn, has a positive effect on the host.

 

      The reason why we get adverse events is that all of

 

      these products have some effect on the host that is

 

      unintended in terms of adverse events.

 

                [Slide]

 

                What are some examples of unmeasured

 

                                                                76

 

      benefits?  Well, there may be effects of the drug

 

      other than eradication of the organism.  Actually,

 

      this is a misnomer.  We constantly use this term

 

      "eradication" but what we really mean is that we

 

      have suppressed the organism to below a level of

 

      detection.  If we think that we are actually

 

      sterilizing somebody's body, we really are fooling

 

      ourselves.  There may be sub-inhibitory effects of

 

      antimicrobials on the organisms.  Even though those

 

      organisms are present, they can't do what they

 

      normally do in terms of invading.  It may be that

 

      we don't need to kill the organisms to actually

 

      have some effect on the ultimate outcome and,

 

      again, that may be because we are having other

 

      effects, other than killing, that do something to

 

      the organism.  Then, again, there may be direct

 

      effects of the antimicrobials on the host immune

 

      system.  These articles that I have shown up here

 

      are actually things that talk about the effect of

 

      antimicrobial products on white cell phagocytosis

 

      and other processes on the human immune system.

 

                There also may be unmeasured harms in

 

                                                                77

 

      terms of deleterious effects on the host that may

 

      promote infection.  For instance in topical

 

      products, if a product actually would cause

 

      micro-breaks in the skin that would not be visible

 

      to either the infection or the patient that may

 

      allow more invasion of organisms to cause wound

 

      infections.  We also may have replacement of one

 

      organism with another.  We get rid of the one

 

      organism we are worried about and, nature abhors a

 

      vacuum, and something else comes in its place that

 

      is actually worse than what we got rid of.  There

 

      may be other sources of infection, other than those

 

      affected by the drug.

 

                [Slide]

 

                Are there some examples of where we have

 

      seen this happen in the past?  The answer is yes.

 

      This is why we have such pause when evaluating

 

      surrogates.  For instance, last year the FDA

 

      approved rifaximin as a treatment for travelers

 

      diarrhea.  If one evaluates the rate of negative

 

      cultures from the stool in rifaximin compared to

 

      placebo, there was no statistical difference

 

                                                                78

 

      between the number of organisms at the end of

 

      treatment in the stool in patients who received the

 

      drug versus those who did not.

 

                Regardless of that, there was still

 

      decreased time to resolution of diarrhea with

 

      rifaximin compared to placebo.  You could say,

 

      well, that means rifaximin isn't acting as an

 

      antibacterial agent; it is doing something else, it

 

      is decreasing GI motility.  Well, if that is the

 

      case, then why did rifaximin have an effect on some

 

      organisms like E. coli, but not on diarrhea caused

 

      by other organisms like Campylobacter?  If it was

 

      just acting as a motility agent it should have

 

      equal effects on everything.  So, perhaps this drug

 

      is doing something to the organisms other than

 

      killing them.

 

                Other examples of unmeasured harms--well,

 

      a classical example of this is the dose escalation

 

      trial of clarithromycin that was studied at 500,000

 

      and 2,000 mg for disease due to Mycobacterium

 

      avium-intracellulare in patients with AIDS.  When

 

      we looked at that dose response, the higher doses

 

                                                                79

 

      had higher rates of negative blood cultures for

 

      MAI.  However, those higher doses also had higher

 

      mortality in terms of the clinical outcomes.  So, a

 

      better microbiologic outcome actually resulted in a

 

      worse clinical outcome in this trial.

 

                [Slide]

 

                Are there also other pathways of disease

 

      that may be unaffected by the intervention?  Do we

 

      have an example of that?

 

                [Slide]

 

                Well, several trials showed decreased

 

      rates of colonization in the nose with Staph.

 

      aureus with intranasal mupirocin.  However, three

 

      trials now done in the last several years show that

 

      prevention of infections with mupirocin, the

 

      clinical outcome, was not lower in patients than

 

      placebo even though there was a dramatic effect in

 

      terms of negative cultures done from the nose with

 

      this particular product.  One hypothesis for why

 

      this may not be effective is that Staph. aureus is

 

      on numerous sites on the body other than just your

 

      nose and we may not be affecting that just by

 

                                                                80

 

      putting a product on one site in the body.

 

                [Slide]

 

                The next issue is with accuracy of how the

 

      surrogate is measured.  One of the things that we

 

      constantly hear about surrogates is that they are

 

      reproducible.  Well, reproducibility talks about

 

      precision, but the example you can think about here

 

      is how to differentiate precision from accuracy.

 

      If I take a bow and arrow and I shoot it at a

 

      target I can hit the same spot on the target all

 

      the time, but it may be way far away from where the

 

      bulls eye actually is.  So, even though we are

 

      getting reproducibility, are we getting accuracy?

 

      Are we getting the correct inference?  This has to

 

      do with what, when, how and the magnitude of what

 

      is measured for that particular surrogate.

 

                [Slide]

 

                The culture techniques that we use for

 

      bacteria are based on methodology actually from the

 

      late 1800's.  We know that there is inherent error.

 

      For instance, if we take the exact same colony of

 

      organisms and measure it two separate times we can

 

                                                                81

 

      get minimum inhibitory concentrations for a

 

      particular drug that are actually off by one or two

 

      tube dilutions jut by testing it a second time.

 

      So, we know that there is some inherent error here.

 

                There are a lot of issues with

 

      microbiological outcomes.  For instance, what is

 

      the patient population that we sample?  What is the

 

      sampling technique that was used?  What was the

 

      methodology used to get the culture?  Actually, I

 

      see Al Sheldon sitting in the back.  When he used

 

      to work for us he gave a great talk last year on

 

      diabetic foot infections where we talked about how

 

      superficial cultures from the foot may not tell us

 

      anything related to deeper cultures from the foot

 

      in diabetic infections, and that methodology is

 

      very important.

 

                When is the culture performed?  On therapy

 

      cultures may be very misleading because when we

 

      take a sample we are actually taking the antibiotic

 

      with it and putting it onto the culture plate as

 

      well, which may give false-negative cultures.

 

                How often do we sample, and what is a win?

 

                                                                82

 

      What is the criteria for classifying that this

 

      organism is there or not?  Do we have an all or

 

      nothing approach that says bug present/bug not

 

      present?  Or, do we so something like HIV viral

 

      load where we have a quantitative assessment of how

 

      much organism is present?

 

                [Slide]

 

                The quantitative assessment may be very

 

      important, as I show on this graph.  On the bottom

 

      axis we have time where we can make a baseline

 

      measurement and on therapy measurement and what

 

      happens when a drug is gone after the study is

 

      over, compared to microbial load.  If one patient

 

      starts out at a higher level than the other

 

      patient, they both may decrease simultaneously at

 

      exactly the same rate, but if we make an on therapy

 

      assessment this patient may still have a positive

 

      culture and this one does not just because we have

 

      gone below some level of detection of how many

 

      organisms we can actually detect.  Does that mean

 

      that these two patients are really different?  We

 

      don't know.  It may just be a factor of how many

 

                                                                83

 

      organisms we were actually able to detect.  If we

 

      only looked at an on therapy assessment, that may

 

      not tell us what happens after the drug is removed

 

      from the body.  In one patient the bugs may come

 

      roaring back because all we did was suppress them.

 

      In the other patient it may continue to decline and

 

      we get rid of the organism altogether.

 

                [Slide]

 

                One of the issues that I am sure we will

 

      talk about today is this issue of practicality, and

 

      practicality is in the eye of the beholder when it

 

      comes to clinical trials.  People have said because

 

      it is difficult to measure the clinical endpoint we

 

      should just rely on surrogates, which is very

 

      difficult logic in terms of perhaps needing to do a

 

      better job of actually measuring clinical

 

      endpoints.  An inaccurate measurement of clinical

 

      endpoints does not justify the use of unvalidated

 

      surrogates.

 

                [Slide]

 

                For example, there is a recent article,

 

      and there has been an ongoing debate in the

 

                                                                84

 

      Clinical Infectious Disease journal about the

 

      utility of catheter tip decolonization which, in

 

      this study, are claimed to be validated as a

 

      surrogate endpoint for clinical trials in

 

      prevention of catheter-related bloodstream

 

      infections based on the correlation of the two

 

      endpoints.  What they did, however, in these trials

 

      is they defined a bloodstream infection in some of

 

      these trials as a positive blood culture and a

 

      positive culture of a catheter tip.  So, this

 

      correlation is highly dependent upon the definition

 

      of the clinical endpoint.

 

                Dr. David Patterson, from the University

 

      of Pittsburgh, wrote in about one of these studies

 

      and said, residual antimicrobial activity in the

 

      removed catheter sufficient to prevent growth from

 

      the cultured catheter segments would substantially

 

      reduce the apparent rate of catheter-related

 

      bloodstream infections--and I put the emphasis on

 

      there--could it be that use of these coated

 

      catheters impregnated with antibiotics prevents

 

      growth from catheters in the microbiology

 

                                                                85

 

      laboratory but does not eliminate the clinical

 

      syndrome of catheter-related bloodstream infection?

 

                So, a more rational use of an endpoint

 

      here would be all people that have positive blood

 

      cultures and symptoms of a clinical infection, not

 

      just those who have to have a positive catheter tip

 

      because that is circular reasoning.

 

                One of the issues we always get into at

 

      the FDA is what gets published is all the

 

      successes, and people will look at those and say,

 

      look, there is this great correlation.  What is

 

      missing, and there has also been a lot in The New

 

      York Times recently, is about negative trials.

 

      What is missing is the data the FDA sits on showing

 

      where those surrogates did not work.  We have had

 

      several examples now, both in catheter tip

 

      decolonization and in products that are actually

 

      put on topically around the catheter site, where

 

      they had a dramatic effect on decolonizing the

 

      catheter and no effect at all relative to placebo

 

      in preventing bloodstream infections.  I cannot

 

      enlighten you anymore than that because this is

 

                                                                86

 

      proprietary information and we can't share it, but

 

      the interesting thing sitting at the FDA is you

 

      always wish that you could talk about the negative

 

      examples but, unfortunately, we can't share those.

 

                [Slide]

 

                One of the other issues with correlating a

 

      surrogate is how well does it actually predict

 

      outcomes?  A perfect correlation would be a slope

 

      of 1 in terms of evaluating the surrogate related

 

      to clinical success so an 80 percent success rate

 

      with a surrogate would result in an 80 percent

 

      success rate in the clinical outcomes.  But we

 

      don't expect that to happen, especially in

 

      prevention trials where we know that a good number

 

      of people on these trials will achieve no benefit

 

      from the product.  So, what we want to look at is

 

      what is the actual correlation between the

 

      surrogate and the clinical outcome.

 

                [Slide]

 

                The other thing that is very important is

 

      that the correlation may differ from drug class to

 

      drug class or from drug product to drug product,

 

                                                                87

 

      and this may actually be highly misleading in terms

 

      of what we actually measure.  For instance, let's

 

      take drug A and drug B that have two different

 

      correlations in terms of the clinical and the

 

      surrogate.  If we did then a measure of drug A and

 

      drug B in terms of the surrogate, it appears here

 

      that drug B is better than drug A in terms of the

 

      outcome with the surrogate.  But if these two

 

      slopes of the correlation are different what

 

      actually is misleading is that in reality drug A is

 

      actually better than drug B in terms of clinical

 

      success so the surrogate actually flip-flops these

 

      and misleads us in terms of telling us why would

 

      these slopes be different.

 

                That gets back to the five things we

 

      actually talked about.  Unmeasured harms,

 

      unmeasured benefits and those other things may be

 

      why these products have different correlations.  We

 

      actually did this with otitis media and showed that

 

      the spread of lines here actually goes from 0.4 all

 

      the way down to 0.1 for various different drug

 

      products.  So, saying that this won't occur--we

 

                                                                88

 

      have actually seen places where this correlation is

 

      actually all over the map for various drug

 

      products.

 

                [Slide]

 

                Finally, there are regulatory issues with

 

      surrogate endpoints.  Traditional approval is based

 

      on surrogate endpoints only in cases where the

 

      endpoint is already validated to predict clinical

 

      benefit.  However, there is an accelerated approval

 

      clause in the Code of Federal Regulations based on

 

      surrogate endpoints for serious and

 

      life-threatening diseases, otherwise known as

 

      Subpart H.  This is where a surrogate endpoint is

 

      reasonably likely to predict clinical outcome.

 

      However, this part of the Code of Federal

 

      Regulations requires confirmatory post-approval

 

      trials based on the clinical endpoint to prove that

 

      what we saw with the surrogate is actually true.

 

                The important thing to note today is that

 

      this clause actually came out in the mid-1990's and

 

      what we are talking about today is a monograph that

 

      started out in the early 1970's.  So, if you ask

 

                                                                89

 

      the question, well, why doesn't the monograph jive

 

      with what we are saying up here, it is because we

 

      are talking about something that happened 20-30

 

      years before this regulation.

 

                [Slide]

 

                Let's relate all of the stuff we just

 

      talked about with surrogates to the issues related

 

      to topical antiseptics.  Are there some potentials

 

      for unmeasured harms with topical antiseptics?

 

      Well, we may have unintended effects on microscopic

 

      breakage in the skin which may actually result in a

 

      greater clinical infection rate.  We know this can

 

      happen, for instance, in trials that examine

 

      peri-operative shaving.  This trial by Seropian,

 

      done in the American Journal of Surgery in 1971,

 

      actually showed a 5.6 percent rate of postop

 

      infection with shaving compared to a 0.6 percent

 

      rate without shaving.  So, we know that there can

 

      be unintended effects.

 

                If you go back and look at the hypothesis

 

      of that trial, it was exactly what we are trying to

 

      say today, clipping hair off may decrease the

 

                                                                90

 

      amount of bacteria near the wound and, therefore,

 

      should result in a decrease in infections.  It

 

      didn't; it did the exact opposite because of

 

      unintended harms that they didn't think about until

 

      after the trial was done.  It is always fascinating

 

      to see how someone's hypothesis changes after the

 

      actual results come out.

 

                Also, the effects on common pathogens may

 

      be less than that on the marker organisms on the

 

      skin.  Michelle Jackson showed you that what we are

 

      measuring here is resident microbial flora in two

 

      of the three indications and we are contaminating

 

      people with Serratia marcescens in another.

 

      Serratia marcescens is not a common cause of skin

 

      infection so the question is does predicting an

 

      effect on Serratia tell us anything about staph.,

 

      strep., E. coli, enterococci and the other common

 

      causes of infection?

 

                Also, there is this issue of are we

 

      selecting resistance to systemic antimicrobials by

 

      using these topical antibiotic products?  This

 

      really is something that deserves its own whole

 

                                                                91

 

      discussion, but there is some evidence at least in

 

      the test tube that there may be afflux pumps which

 

      confer resistance to both topical products and to

 

      the systemic antimicrobials simultaneously, at

 

      least in E. coli and Pseudomonas.  People have

 

      questioned what is the clinical relevance of that

 

      but that really is the question, isn't it?  Once

 

      again, it is how does that surrogate predict what

 

      is going to happen clinically?  I always think it

 

      is fascinating when you don't want to use a

 

      surrogate, all of a sudden it is not relevant.

 

      When you do want to use a surrogate, we will accept

 

      everything we want to believe about it.

 

                So, can there be unintended benefits?

 

      Well, it may be that some of these products have

 

      positive effects other than those on the organisms.

 

      It does something to the host immune system that

 

      actually results in a decreased infection rate,

 

      more than we would predict by what it does to the

 

      bug.  Also, could the effects on common pathogens,

 

      like staph. or strep. be greater than on something

 

      like Serratia?  So, it may be a better benefit than

 

                                                                92

 

      what we think.

 

                [Slide]

 

                Are there other mechanisms not affected by

 

      the intervention?  Well, at least in terms of

 

      patient preop, for that indication we can look at a

 

      study that was done by Brown et al. in 1989 at the

 

      University of Virginia.  The data that we are

 

      obtaining from this surrogate is really from the

 

      most superficial layers of the stratum corneum of

 

      the epidermis.

 

                [Slide]

 

                Here is an anatomical picture of the skin.

 

      What you see here is that the top 30 layers of the

 

      skin are this dead, keratinized layer called the

 

      stratum corneum of the epidermis.   What is down

 

      here is the stratum germinativum where these cells

 

      come from.  The cells die off.  They become highly

 

      keratinized at the stratum granulosum layer which

 

      forms a barrier between this and the stratum

 

      corneum.  What we are measuring in these trials is

 

      what is way up here.

 

                [Slide]

 

                So, what is way up there is right here on

 

      this graph.  This is actually from the CDC

 

      guidelines on prevention of surgical infections.

 

                                                                93

 

      What we are worried about is infections here, here,

 

      here and here.  So, the real question is does doing

 

      something up here do something down here in terms

 

      of affecting the organisms?

 

                [Slide]

 

                This group in Virginia actually did a very

 

      elegant experiment with a methodology that was

 

      developed by Pincus in 1952.  What they did was

 

      they took regular old cellophane tape and they

 

      showed that by putting cellophane tape and

 

      stripping it off the skin you can take one layer of

 

      that stratum corneum off at a time.  They evaluated

 

      this in 12 different sites on the body, and they

 

      showed that these 12 different sites in the body

 

      had highly variable colony counts of organisms

 

      depending upon whether you are looking at the arm,

 

      the back or other sites.

 

                They also showed that the number of

 

      colonies decreased over the top five layers of the

 

                                                                94

 

      stratum corneum but then stabilized in the

 

      remaining 20 layers of the stratum corneum.  So,

 

      there were more organisms up at the top than there

 

      were in the lower layers of the stratum corneum.

 

                But then they did something very

 

      interesting.  They took alcohol and decolonized the

 

      area that they had stripped, put a gauze pad over

 

      it and came back 18 hours later.  They then did

 

      plasmid profiles on the coagulase-negative

 

      staphylococci that were there at the beginning of

 

      the experiment and there 18 hours later and saw

 

      identical plasmid profiles for those staphylococci.

 

                So, they hypothesized that this indicates

 

      a reservoir for these organisms that may be below

 

      the stratum corneum, in the hair follicles and

 

      sebaceous glands of the dermis so where infection

 

      may come from is actually from the organisms that

 

      are lower down.  This is one of the reasons why we

 

      give systemic antimicrobials as perioperative

 

      prophylaxis, trying to affect those organisms that

 

      may be down deeper in the dermis.

 

                We also know that studies in perioperative

 

                                                                95

 

      systemic antimicrobials show that if the antibiotic

 

      isn't around at this layer at the time you get

 

      operated on they will not be effective.  For

 

      instance, you cannot give the antibiotic two

 

      seconds before you make the surgical cut because

 

      they will not affect the subsequent infection rate.

 

                [Slide]

 

                Then there are all the issues with

 

      measurement of the surrogate, which we are going to

 

      talk about today.  Are we actually measuring the

 

      surrogate in a population that we are going to use

 

      it in?  No, we are not.  We are measuring healthy

 

      volunteers, not healthcare workers or patients.

 

                As we already discussed, the organisms

 

      measured are not necessarily those that cause

 

      infection.  Is the timing of these measurements

 

      relative to the disease process we are actually

 

      trying to prevent?  That gets at this issue of do

 

      we need to get persistent effect or not; how long

 

      do we have to look for that; and how long should we

 

      look for it?  For instance, we know that some

 

      patients may undergo prolonged surgery.  Surgeries

 

                                                                96

 

      may last hours and hours so an immediate effect is

 

      not the only thing we want to look at.

 

                Are the conditions of testing the same as

 

      those that would be encountered in real-life

 

      situations?  And, what happens with variations in

 

      the methodology?  One of the things that is

 

      interesting at the FDA is that you will see people

 

      submit things that say I am using the such-and-such

 

      method approved by the CDC or the NIH.  But it is a

 

      modified method.  I always joke I am a modified

 

      millionaire movie star; I am just not a movie star

 

      and I don't have a million dollars.  So, modifying

 

      the method--it is no longer the method.  So, we

 

      need to take into account that changing the method,

 

      even if we have a valid surrogate, may actually

 

      change the correlations between the surrogate and

 

      the clinical outcomes.

 

                The next question is what log reduction is

 

      clinically significant?  And, how do we analyze

 

      those numbers obtained on log reductions?  Dr.

 

      Thamban Valappil is going to go through a great

 

      talk that actually walks through some of these

 

                                                                97

 

      issues with how do we analyze the numbers.

 

                [Slide]

 

                What is the data showing correlation of

 

      reduction of bacteria with a decrease in infection

 

      rates?  Steve Osborne is going to go through our,

 

      believe me, exhaustive, over 1,000-paper literature

 

      search.  You should have helped us out with this;

 

      that was a thrill!

 

                What does the dose-response curve look

 

      like for infection rates and numbers of bacteria?

 

      Is it a threshold effect, or is it a continuous

 

      variable, and is it the same for all types of

 

      products?

 

                [Slide]

 

                What do I mean by dose response?  Down on

 

      the bottom it should read numbers of bacteria on

 

      the skin, not change in numbers of bacteria.  On

 

      the Y axis we have rates of infection.  What we

 

      want to know is does the dose-response curve look

 

      like this?  Sorry, this doesn't show up very well

 

      but it is a straight line.  Or, does the

 

      dose-response curve look like this?  The first

 

                                                                98

 

      straight line is a continuous variable.  The more

 

      organisms there are, the more infections patients

 

      get.  The curved line is really a threshold effect

 

      that we talk about.  At some certain level of

 

      bacteria people are more likely to get infected and

 

      below that level they are less likely to get

 

      infected.

 

                Why is this important for us?  Well, if we

 

      look at a linear correlation between numbers of

 

      bacteria and rates of infection, what we will see

 

      is that the decrease of the numbers of bacteria by

 

      this much will actually result in a corresponding

 

      decrease in the number of infections by some

 

      amount.

 

                [Slide]

 

                On the other hand, if it is a sigmoidal

 

      threshold type effect, what we will see is that

 

      that same, exact change in the number of bacteria

 

      if it is on the flat part of the curve results in

 

      very little change in infection.  So, this gets to

 

      what does a 3-log reduction actually mean?  If this

 

      is 10                                       7 and this is 104 that is a

3-log reduction but

 

                                                                99

 

      we are on the flat part of the curve so there is

 

      very little effect on what happens to the patient.

 

      If we go from 10                                                        

4 to 101 that is a 3-log reduction

 

      too but if we are on the steep part of the curve

 

      that may be telling us something very, very

 

      different.  So, where you start may be as important

 

      as what the delta change is, and we don't have any

 

      information to tell us what this dose response

 

      actually looks like.

 

                [Slide]

 

                What I would like to leave you with then

 

      is sort of the thought process we have had to go

 

      through for the last several months in terms of

 

      trying to look at this.  The first question you

 

      have to ask is what kind of endpoint are you going

 

      to pick to evaluate these products?  Are we going

 

      to pick a clinical endpoint or a surrogate

 

      endpoint?  Ideally, there would be the data right

 

      here that links the clinical and the surrogate

 

      endpoint together, and Steve Osborne is going to

 

      talk about our attempts to actually make that kind

 

      of a link.

 

                The second question is what are we

 

      actually going to measure?  Let me get back to this

 

      issue of practicality.  As I said earlier,

 

                                                               100

 

      practicality ends up being in the eye of the

 

      beholder.  One of the things you will hear about is

 

      that it takes more patients to do these clinical

 

      trials than it does to the surrogate endpoint

 

      trials.

 

                Well, size is actually an issue but size

 

      really relates more to the time that it takes to do

 

      a trial which, let's be honest, relates to cost to

 

      do the trial.  One of the questions you have to ask

 

      when you are getting into this debate is how much

 

      does it cost to do it wrong?  How much does it cost

 

      the patients if we don't get this information and

 

      we don't actually know whether these products are

 

      effective?  That side of the equation needs to be

 

      factored in as well.

 

                The other issue that comes up is ethics.

 

      Ethics are only if you are denying somebody a

 

      proven effective treatment.  What we are trying to

 

      evaluate here is are these things proven effective

 

                                                               101

 

      or not, so we need to keep that in mind when we are

 

      discussing the ethics issue.  When we talk about

 

      clinical trials the endpoint is very simple, it is

 

      infection in patients.  On the other hand, with the

 

      surrogate we are looking at numbers of bacteria.

 

                Then we need to talk about how do we

 

      design these studies and how do we define success.

 

      Well, the definition of success, again, with the

 

      clinical endpoint is much simpler actually.  It is

 

      just the percent of patients that don't get an

 

      infection.  However, when we talk about selecting

 

      an endpoint for a surrogate we have several

 

      decisions to make that Thamban is going to go

 

      through.  Do we look at mean log reductions, median

 

      log reductions, the percent of subjects who meet

 

      some log reduction?  And, where do you get this

 

      information from?  Well, actually optimally it

 

      would be from a clinical trial that evaluated both

 

      of these things simultaneously.

 

                Finally, how do we analyze the results

 

      that we get?  Again, it is much simpler in a

 

      clinical trial.  We just compare it with a

 

                                                               102

 

      concurrent control.  This is one of the issues when

 

      people point to the studies, and Steve is going to

 

      go through this in some detail, they say we already

 

      know these things work.  There is no concurrent

 

      control.  What these things are is quasi

 

      experimental studies where they took what we were

 

      doing last year and they applied something new in

 

      the hospital and said, look, my infection rate went

 

      down.

 

                What that ignores is natural changes in

 

      baseline infection rates that may occur.  Even

 

      though the trials say, well, we didn't do any other

 

      interventions on these patients, you know in the

 

      real world and, hopefully our AIDAC members can

 

      enlighten us on this, when you have an outbreak of

 

      some particular organism you do not do one

 

      intervention.  You cohort patients together; you

 

      start using gowns and gloves on those people; you

 

      do a lot of other interventions that really call

 

      into question what was the cause of why the

 

      infection rate went down.  Was it just related to

 

      the product that you used?

 

                So, here we would make this comparison and

 

      either design these as superiority or

 

      non-inferiority trials, otherwise called

 

                                                               103

 

      equivalence trials, that show that the product is

 

      no worse than something that is already out there.

 

                On the other hand, there are a lot more

 

      complex decisions with a surrogate endpoint.  Do we

 

      say that these things meet some threshold that we

 

      set?  If so, where does that threshold come from?

 

      Where does the data come from to say?  And, do we

 

      still need some comparison with a control given the

 

      variability in the method?  Michelle Jackson showed

 

      you on one of her slides that at least that article

 

      in The Journal of Hospital Infection, based on the

 

      European methodology which is slightly different

 

      from that that is in the TFM, shows at least a 2 to

 

      2.5 log drop with soap and water all by itself.

 

      So, do we need to look at how these things compare

 

      to some vehicle or another product?  And, again, we

 

      have the choice of superiority or non-inferiority.

 

                [Slide]

 

                To conclude then, surrogate endpoints must

 

                                                               104

 

      not only correlate with clinical outcomes but they

 

      must also take into account unmeasured harms and

 

      benefits; the methodology and uncertainties in

 

      measuring the surrogate; and the appropriate

 

      measurement of the clinical endpoint.

 

                The clinical endpoint for efficacy of

 

      topical antiseptic products would be prevention of

 

      infections but actually the clinical design of

 

      these trials would vary depending upon whether we

 

      are talking about patient preop surgical hand

 

      scrubs or healthcare personnel handwash.

 

                One of the things that I am sure we will

 

      hear about is what Semmelweis did in 1847 was he

 

      showed that medical students who went and examined

 

      corpses with their bare hands and then went and

 

      delivered babies--there was actually a higher rate

 

      of death in the mothers who had their babies

 

      delivered by these medical students than the

 

      midwives who were spared the odious task of doing

 

      the autopsies.

 

                That is not what we are doing today.  We

 

      are not digging our hands into gram-negatives of

 

                                                               105

 

      dead people and then going and operating on

 

      someone.  So, the conditions of Semmelweis were

 

      huge bacterial load, probably with gram-negative

 

      organisms.  So, what Semmelweis showed was that

 

      washing your hands is a good thing.  Semmelweis did

 

      not do a randomized trial of one product compared

 

      to handwashing alone or handwashing compared to

 

      nothing.  We are not debating that Semmelweis was

 

      correct and that you need handwashing.  What we are

 

      debating is handwashing with what, and how do we

 

      determine that that "what" is effective compared to

 

      just maybe plain soap and water?  So, we are going

 

      to discuss further today what is known about

 

      surrogates in the setting of topical antiseptics,

 

      and Steve Osborne is going to go over this clinical

 

      correlation and tell us some more about it.

 

                [Slide]

 

                I would like to leave you with this quote

 

      by the statistician John Tukey which I think really

 

      relates to surrogates:  Far better an approximate

 

      answer to the right question, which is often vague,

 

      than an exact answer to the wrong question, which

 

                                                               106

 

      can always be made precise.  I will stop there.

 

      Thank you very much.

 

                DR. WOOD:  Thanks very much.  It appears

 

      that we still don't have the slides from Michelle

 

      Pearson.  Is John Boyce here?  Yes?  Good, so at

 

      least our next speaker is here.  I suggest that we

 

      take a quick break right now and be back at ten

 

      o'clock and we will start again.  We are hoping to

 

      get Michelle Pearson in before we do the questions.

 

      We will get back at ten o'clock.

 

                [Brief recess]

 

                DR. WOOD:  Let's go to Dr. Boyce and then

 

      we will come back to Dr. Pearson, whose talk we do

 

      now have somewhere in the building, as they say,

 

      but we have been unable to play it yet.  So, Dr.

 

      Boyce?

 

               Antiseptic and Infection Control Practice

 

                DR. BOYCE:  Good morning.  I am having

 

      some Power Point problems today because of a switch

 

      in versions so I hope this is going to work.

 

                [Slide]

 

                First I want to talk a little bit about

 

                                                               107

 

      the importance of hand hygiene in preventing

 

      transmission of healthcare-associated infections.

 

      Most of you know that transmission of

 

      healthcare-associated pathogens often occurs via

 

      transiently contaminated hands of healthcare

 

      workers.  For that reason, handwashing has been

 

      considered one of the most important infection

 

      control measures for preventing

 

      healthcare-associated infections.  Despite this,

 

      the availability of published handwashing

 

      guidelines has not helped, and compliance with

 

      healthcare workers with recommended handwashing

 

      practices has remained low for decades.

 

                [Slide]

 

                This slide shows the percent compliance on

 

      the Y axis in 37 published observational studies of

 

      healthcare worker handwashing compliance.  The main

 

      point here is that compliance rates varied from

 

      about 5 percent to 80 percent.  The second point is

 

      that there is no trend towards improvement over

 

      this more than 20-year period.  So, getting people

 

      to wash their hands as frequently as possible has

 

                                                               108

 

      been a very difficult chore.

 

                [Slide]

 

                In 2002 the CDC published the guideline

 

      for hand hygiene in healthcare settings.  I am

 

      going to briefly mention a few indications for hand

 

      hygiene that are listed.  One is that it is

 

      recommended that we wash our hands with a

 

      non-antimicrobial soap or an antimicrobial soap if

 

      our hands are visibly contaminated with blood, body

 

      fluids or other proteinaceous materials.  If the

 

      hands are not visibly soiled, then the guideline

 

      recommended the routine use of an alcohol-based

 

      hand rub for decontaminating hands in most other

 

      clinical situations.  Alternatively, hands can be

 

      washed with an antimicrobial soap and water in

 

      other clinical situations.

 

                The guideline recommends that healthcare

 

      workers decontaminate their hands before having

 

      direct contact with patients, donning sterile

 

      gloves to insert a central intravascular catheter,

 

      before inserting indwelling urinary catheters or

 

      peripheral IV catheters, and before eating.

 

                [Slide]

 

                It is recommended that we decontaminate

 

      our hands after having direct contact with a

 

                                                               109

 

      patient's intact skin, like taking a blood

 

      pressure; contact with body fluids or wound

 

      dressings if our hands are not visibly soiled;

 

      after moving from a contaminated body site to a

 

      clean body site during an episode of patient care;

 

      after contact with inanimate objects in the

 

      immediate vicinity of the patient; and after

 

      removing gloves.  So, there are a lot of

 

      indications for cleaning your hands.

 

                [Slide]

 

                In fact, the number of hand hygiene

 

      opportunities that healthcare workers have can vary

 

      considerably.  In a large study, done by Dr.

 

      Pittet, they found that the average number of hand

 

      hygiene opportunities per hour of care was 24 in

 

      pediatric units, and the average was 43 per hour in

 

      intensive care units.  In fact, the lack of

 

      sufficient time to actually perform this large

 

      number of handwashing episodes is a major factor

 

                                                               110

 

      influencing poor handwashing compliance.

 

                [Slide]

 

                This slide shows the results of a number

 

      of observational studies where healthcare workers

 

      were observed to see how many times they actually

 

      cleaned their hands.  You can see on your right

 

      that the average number of times per 8-hour shift

 

      was anywhere from 13 times to 26 times in an 8-hour

 

      shift.  So, we are talking about frequent use of

 

      these products.

 

                That sounds pretty frequent but let me

 

      present it another way, in a recent prospective

 

      trial that we conducted that involved 57 volunteer

 

      nurses working in intensive care units, a

 

      hematology-oncology ward and general medical ward,

 

      each nurse carried a portable counting device and

 

      prospectively clicked the counter every time they

 

      cleaned their hands.  On the right you see a graph

 

      that, along the X axis, shows the number of hand

 

      hygiene episodes that these nurses recorded during

 

      a 3- to 3.5-week trial period.  You can see that

 

      most nurses cleaned their hands anywhere from 100

 

                                                               111

 

      to 450 times in a 3- to 3.5-week period.

 

                [Slide]

 

                So, one thing that is very clear is that,

 

      because of the high frequency of use of these

 

      products, providing healthcare workers with

 

      products that are well tolerated is very important.

 

      Poorly tolerated products result in poor compliance

 

      often because of irritant contact dermatitis, as

 

      shown in the picture, where this physician has

 

      bleeding knuckles after using soap and water

 

      handwashing 57 times over a period of a couple of

 

      weeks.  Products that have a high degree of

 

      antimicrobial activity, that is, a high log

 

      reduction, but are poorly tolerated may actually be

 

      counterproductive.

 

                [Slide]

 

                Now, another important issue for which we

 

      have very little information is what level of log

 

      reduction of bacterial counts on the hands is

 

      actually necessary to prevent transmission of

 

      pathogens.  As you know, the efficacy of these

 

      agents is often expressed as a number of log

 

                                                               112

 

      reductions of bacterial counts on the hands of

 

      volunteers, 1, 2 or 3 log reductions for example.

 

                Although the review of the literature that

 

      I did apparently is not as big as what FDA has

 

      actually done, I reviewed over about 700 articles

 

      and couldn't find any evidence regarding the number

 

      of log reductions that are necessary to prevent

 

      transmission of healthcare-associated pathogens.

 

      So, we just don't know how many log reductions we

 

      need.

 

                [Slide]

 

                Another thing for which I think there is

 

      little, if any, data relates to whether or not we

 

      need products that have a cumulative effect.  As

 

      you know, the tentative final monograph requires

 

      that healthcare personnel handwash agents produce a

 

      2-log reduction after the first wash and a 3-log

 

      reduction after the 10th wash, therefore showing a

 

      cumulative effect.

 

                In the review of the literature that I did

 

      I failed to identify any data supporting the need

 

      for a cumulative effect.  As a clinician with 25

 

                                                               113

 

      years of experience working in hospitals, I am not

 

      aware of any evidence that patients who are cared

 

      for in the middle or at the end of a work shift are

 

      at higher risk of infection than those that are

 

      cared for at the beginning of a shift.  I am also

 

      not aware of any evidence that patient care

 

      activities that are performed in the middle or near

 

      the end of a work shift result in greater hand

 

      contamination than those that are performed at the

 

      beginning of a shift.  So, frankly, from the

 

      standpoint of a clinician or of infection control,

 

      I fail to see the logic in requiring a cumulative

 

      activity of this type of product given the way they

 

      are used and the types of patients that we take

 

      care of.

 

                [Slide]

 

                Another thing that actually has changed

 

      since the TFM was originally developed is the

 

      frequency of glove use.  Since the late 1980's

 

      nurses, physicians and other healthcare workers use

 

      gloves far more frequently than they ever did in

 

      the past.  A recent observational survey done of

 

                                                               114

 

      nurses working on a general medical ward found that

 

      these nurses visited patients an average of about

 

      54 times during an 8-hour shift, and they found

 

      that the use of gloves varied depending on the type

 

      of patient care activity.  When the nurses were

 

      going to have contact with body fluids they wore

 

      gloves 86 percent of the time.  If they were going

 

      to have skin contact only, then it was more like a

 

      little over 30 percent of the time that they wore

 

      gloves; even less frequently for equipment contact.

 

      So, in fact, glove use does vary among healthcare

 

      workers but it is certainly far more common than in

 

      the past.

 

                [Slide]

 

                A number of studies, shown here, have

 

      documented that gloves can and do reduce the level

 

      of hand contamination when they are worn.

 

      McFarland looked at hand contamination with C.

 

      difficile and found that 46 percent of healthcare

 

      workers who did not wear gloves contaminated their

 

      hands with C. dif..  No healthcare workers who wore

 

      gloves had C. dif. on their hands.  Olsen and

 

                                                               115

 

      colleagues found that gloves prevented hand

 

      contamination in 77 percent of instances.  Dr.

 

      Pittet found that when no gloves were used and they

 

      measured hand contamination rates, they found out

 

      that the hands were contaminated with 16

 

      CFUs/minute of patient care when no gloves were

 

      used, but only 3 CFUs/minute when gloves were used,

 

      showing the protective effect of gloves.  Finally,

 

      Tenorio et al. found that gloves reduced the risk

 

      of hand contamination by vancomycin-resistant

 

      enterococci by 71 percent.  So, in fact, to the

 

      extent that people do wear gloves during patient

 

      care nowadays, their hands are probably less

 

      heavily contaminated than they were back in the

 

      '60's, '70's and early '80's.

 

                [Slide]

 

                One thing that I thought that I was

 

      supposed to try to address was whether or not there

 

      is any evidence that the products that are

 

      currently on the market have any kind of clinical

 

      benefit in a healthcare setting.  I wanted to

 

      mention this model by Ehrenkranz.  It was a field

 

                                                               116

 

      study that was supposed to reproduce clinical hand

 

      contamination.  Nurses touched the skin of patients

 

      who were heavily contaminated with gram-negative

 

      bacteria.  They then cleaned their hands.  They

 

      either used plain soap and water handwashing or

 

      they used the 63 percent isopropyl alcohol hand

 

      rinse.  After cleaning their hands, the nurses

 

      touched catheter material, like a Foley catheter

 

      type material, and then that catheter material was

 

      cultured on agar plats.

 

                What they found is that bacteria were

 

      transferred from the hands of the nurses onto this

 

      catheter material in 11/12 experiments when plain

 

      soap was used to clean their hands but only 2/12

 

      experiments when the alcohol hand rinse was used.

 

                [Slide]

 

                Now, in terms of clinical trials, which I

 

      think is a major issue as was discussed in part by

 

      the last speaker, this slide shows one sequential

 

      trial of three hand hygiene regimens.  It was done

 

      in the surgical intensive care unit by a very

 

      experienced infection control physician.  They

 

                                                               117

 

      looked at non-medicated soap, 10 percent

 

      povidone-iodine or 4 percent chlorhexidine

 

      gluconate.  Each product was used exclusively in

 

      the ICU for 6 weeks.  Surveillance for nosocomial

 

      infections was performed.  What they found was that

 

      the incidence of healthcare-associated infections

 

      was 50 percent lower during times when the two

 

      antiseptic-containing handwash agents were used,

 

      suggesting that these hand hygiene products that

 

      were available at that time reduced infections

 

      better than plain soap and water handwashing in

 

      this short trial which was only done in one ICU.

 

                [Slide]

 

                This slide discusses a prospective trial

 

      done to compare two hand hygiene regimens.  It was

 

      a prospective trial with a multiple crossover

 

      design.  It was done in three intensive care units

 

      in a university hospital that just happened to have

 

      one of the largest and most highly respected

 

      infection control programs in the country at that

 

      time.  So, they had lots of resources relatively

 

      speaking.  They followed over 1,800 adult patients

 

                                                               118

 

      for nearly 8,000 patient-days at risk.  The two

 

      regimens compared were 4 percent chlorhexidine

 

      gluconate versus a combination regimen of isopropyl

 

      alcohol and a non-medicated soap.  Healthcare

 

      workers were told that when the alcohol and

 

      non-medicated soap were available they were

 

      supposed to use the alcohol routinely for cleaning

 

      their hands.

 

                [Slide]

 

                What they found was that the number of

 

      patients who developed a healthcare-associated

 

      infection was 96 in the chlorhexidine time period

 

      and 116 when the alcohol and plain soap were

 

      available.  So, the incidence density was lower

 

      with the 4 percent chlorhexidine.  The number of

 

      healthcare-associated infections was 152 during

 

      periods when the 4 percent chlorhexidine was used

 

      compared to 202 when the combination regimen was

 

      available--again, a lower rate with the 4 percent

 

      chlorhexidine.  Infection rates were significantly

 

      lower in 2/3 ICUs when the chlorhexidine was used.

 

                [Slide]

 

                Despite this being planned by a very

 

      experienced and highly respected individual, with a

 

      large team working with him, this clinical trial

 

                                                               119

 

      ran into some problems.  First of all, the overall

 

      compliance of healthcare workers, as shown on the

 

      left, was not the same during the two trials.  It

 

      was about 42 percent compliance when the

 

      chlorhexidine was available versus 38 percent when

 

      the other regimen was available in the units.  The

 

      difference was actually statistically significant.

 

                Another important problem that emerged,

 

      despite this trial being well planned and designed,

 

      was that the volume of the products used varied

 

      significantly.  The amount of soap and isopropyl

 

      alcohol used when available was significantly lower

 

      than the volume of chlorhexidine used when that

 

      product was available.  Even though healthcare

 

      workers were told they should use the isopropyl

 

      alcohol routinely when available, for reasons that

 

      are not either understood or discussed by the

 

      authors, the healthcare workers hardly ever used

 

      the alcohol.  So, this trial was really more a

 

                                                               120

 

      comparison of 4 percent chlorhexidine against plain

 

      soap and water for the most part.

 

                So, one problem with this trial is that it

 

      is very difficult to control the activities of all

 

      these healthcare workers in all these ICUs over an

 

      8-month period, and to get them all to do exactly

 

      the same thing and to do it with exactly the same

 

      frequency.

 

                [Slide]

 

                From the eyes of a beholder here who works

 

      in a hospital, that is one of the problems with

 

      clinical trials.  When you use a nosocomial

 

      infection rate as the outcome measure for efficacy

 

      of hand hygiene agents, there are many, many

 

      confounding variables including host factors; the

 

      rate of importation of organisms from nursing homes

 

      or other sites into the hospital and onto the

 

      wards; the level of compliance of healthcare

 

      workers with recommended hand hygiene, with

 

      recommended barrier precautions, how frequently

 

      they follow guidelines for central line placement

 

      and for ventilator-associated pneumonia prevention.

 

                                                               121

 

      If you are talking about surgical site infections

 

      you have to worry about the skill of the surgeon;

 

      whether or not prophylactic antibiotics were used

 

      and timed appropriately; and whether or not any

 

      active surveillance cultures are being done on the

 

      wards where the studies are being conducted.

 

                So, from my viewpoint, there are so many

 

      confounding variables that that, in and of itself,

 

      makes the clinical trials extremely difficult to do

 

      and extremely costly.  To me, it seems like the use

 

      of surrogate endpoints to assess efficacy of hand

 

      hygiene products still has merit.

 

                [Slide]

 

                I want to mention a little bit more about

 

      clinical benefit.  None of the things I am going to

 

      mention are carefully controlled, prospective

 

      trials partly for all the reasons I have just

 

      mentioned.  This one publication involved a surgeon

 

      whose hands, but not other body parts, were

 

      colonized with a virulent strain of Staphylococcus

 

      epidermidis that caused an outbreak of surgical

 

      site infections related to cardiac surgery.  This

 

                                                               122

 

      surgeon was using a noon-antimicrobial soap for a

 

      preoperative scrub because of previous problems

 

      with hand dermatitis so he followed the

 

      recommendation of his dermatologist.

 

                An epidemiologic investigation that

 

      included case control studies and molecular typing

 

      clearly implicated the surgeon as the source of

 

      this outbreak, and we told him he had to stop doing

 

      cardiac surgery and to start using a 4 percent

 

      chlorhexidine gluconate surgical scrub.  After he

 

      did so the outbreak terminated and we did not see

 

      that strain any further in cardiac surgery

 

      infections, demonstrating that the antimicrobial

 

      soap that was available didn't appear to have

 

      benefit.

 

                [Slide]

 

                An outbreak of vascular surgery-related

 

      surgical site infections occurred when an operating

 

      room was not provided standard povidone-iodine.

 

      The surgeons were used to using preoperative

 

      surgical hand scrubs.  The vascular surgeons in the

 

      hospital decided to use plain soap for hand

 

                                                               123

 

      scrubbing before surgery, while other surgeons used

 

      a 2 percent iodine with 70 percent alcohol for

 

      preoperative hand scrubbing.  Hand scrubbing with

 

      plain soap was significantly associated with the

 

      occurrence of this outbreak of surgical site

 

      infections and reinstitution of povidone-iodine

 

      hand scrubbing terminated the outbreak, again

 

      suggesting that this povidone-iodine product had

 

      value in reducing surgical site infections.

 

                [Slide]

 

                Of course, the CDC guideline for hand

 

      hygiene was published in 2002 and the guideline

 

      recommends routine use of alcohol-based hand

 

      sanitizers for cleaning hands before and after

 

      patient contact as long as the hands are not

 

      visibly contaminated.

 

                [Slide]

 

                Not long after the guideline was

 

      published, actually in January of 2003, the Joint

 

      Commission on Accreditation of Healthcare

 

      Organizations sent out a sentinel event alert to

 

      hospitals and recommended that hospitals comply

 

                                                               124

 

      with the CDC's new hand hygiene guideline.  So, I

 

      think both the Joint Commission and CDC are

 

      standing behind the guideline.

 

                [Slide]

 

                This study was done where a 70 percent

 

      ethanol hand gel was introduced hospital-wide into

 

      the hospital.  A multidisciplinary program to

 

      improve hand hygiene was carried out.  During the

 

      following 12 months the alcohol hand product was

 

      used an estimated 440,000 times by healthcare

 

      workers and they found a consistent reduction in

 

      the proportion of all methicillin-resistant Staph.

 

      aureus that was hospital-acquired during the

 

      12-month period.

 

                [Slide]

 

                This slide shows the impact of one of

 

      these alcohol hand sanitizers on the hand hygiene

 

      compliance in our hospital.  Compliance rate is

 

      shown on the Y axis.  Observational surveys

 

      conducted by the same infection control

 

      practitioners each time revealed that, by having

 

      this new alcohol hand gel available and promoting

 

                                                               125

 

      its use and educating people about it, the overall

 

      hygiene compliance improved from 38 percent to 63

 

      percent, and the proportion of all hand hygiene

 

      episodes which were performed using the alcohol

 

      hand gel, which is shown in the red part of the

 

      bars, increased significantly.

 

                Not shown on this slide is the fact that

 

      the proportion of all methicillin-resistant Staph.

 

      aureus--let me put that another way, the proportion

 

      of all Staph. aureus isolates that are due to

 

      methicillin resistance in our hospital levelled off

 

      about the time that survey 2 was done, and actually

 

      decreased by 5 percent over the following year and

 

      a half.  This decrease in MRSA in our hospital

 

      occurred during the same time frame when MRSA

 

      continued to increase in prevalence in the

 

      hospitals that participate in CDC's National

 

      Nosocomial Infection Surveillance program, or NNIS.

 

      Although it is rather crude data, we think that the

 

      hand hygiene program probably has helped reduced

 

      MRSA in our hospital as well.

 

                [Slide]

 

                In conclusion, conducting clinical trials

 

      to assess the efficacy of healthcare personnel

 

      handwash products is, in fact, extremely difficult,

 

                                                               126

 

      expensive and, as far as I am concerned, largely

 

      not practical.  If they are to be done, they are

 

      going to be very expensive.

 

                Widespread experience with currently

 

      available products, combined with some of the

 

      epidemiologic studies that I mentioned, provide

 

      some evidence of their clinical benefit in

 

      healthcare settings.  Multiple studies have shown

 

      that promoting the routine use of alcohol-based

 

      hand santizers, when combined with educational and

 

      motivational material, can improve hand hygiene

 

      practices among healthcare workers.

 

                [Slide]

 

                There are no published data that I am

 

      aware of demonstrating that cumulative activity of

 

      healthcare personnel handwash agents or surgical

 

      scrub products results in lower rates of

 

      healthcare-associated infections.  Removal from the

 

      market of hand hygiene products that are currently

 

                                                               127

 

      in widespread use in healthcare facilities would,

 

      in fact, disrupt national efforts to improve hand

 

      hygiene practices among healthcare workers.  So, I

 

      personally would hope that there is no regulatory

 

      action that ends up removing a lot of the current

 

      products from the market because I am convinced,

 

      again on a personal level, that they do have value.

 

      Thank you.

 

                DR. WOOD:  We have received Dr. Pearson's

 

      slides from the wilds of Atlanta and we think we

 

      can show them.  Is that right?

 

                MS. JAIN:  Yes.

 

                DR. WOOD:  Unfortunately, sort of like CNN

 

      breaking news, because the slides are just in we

 

      don't have a handout.  We are going to have her on

 

      the phone.  Dr. Pearson, can you hear us?

 

                DR. PEARSON:  I can.

 

                DR. WOOD:  As you go through the slides,

 

      Dr. Pearson, if you tell us when you want to change

 

      to the next slide, we will be able to do that.

 

      Let's go.

 

                 Prevention of Surgical Site Infections

 

                DR. PEARSON:  Good morning and thanks to

 

      the meeting organizers for tolerating my

 

      inconvenience and thank you for the opportunity to

 

                                                               128

 

      present on the topic.

 

                [Slide]

 

                What I hope to do in the next few minutes

 

      is really to talk about some of the epidemiologic

 

      complexities of looking at the effectiveness of any

 

      preventive measure, whether it be cutaneous

 

      antiseptic or other preventive measures, using

 

      surgical site infections as the context for that

 

      discussion.  Next slide.

 

                What I am going to do is first provide an

 

      overview of what we know about the epidemiology of

 

      surgical site infections, including the incidence

 

      and risk factors for infection.  I will talk next

 

      about some of the preventive strategies that have

 

      been shown to decrease that risk; highlight some of

 

      the current surveillance systems for monitoring the

 

      incidence of surgical site infections; and conclude

 

      with talking about how we, here at the CDC, go

 

      about developing our policies and recommendations

 

                                                               129

 

      for prevention of healthcare-associated infections,

 

      such as SSIs.  Next slide.

 

                Just to give you a little bit of an idea

 

      of why this is an important topic and to frame it

 

      with some numbers, it is estimated that somewhere

 

      in the neighborhood of 20 million inpatient

 

      surgical procedures are done each year in the

 

      United States, and 2-5 percent of these procedures

 

      are complicated by a surgical site infection.

 

                Based on our surveillance system, surgical

 

      site infection is the second most common

 

      healthcare-associated infection, comprising about a

 

      quarter of all of the infections reported to CDC.

 

      These infections come not only at a cost to the

 

      patient but also a cost to the healthcare delivery

 

      system.  These infections result in anywhere from

 

      an additional week of hospital stay and they cost

 

      anywhere from $400 to $2,600 per infection, and

 

      these total well in excess, and approaching in some

 

      instances, close to a billion dollars a year in

 

      terms of healthcare dollars.  Next slide.

 

                In terms of the way we define or look at

 

      surgical site infections at CDC, we classify them

 

      either as incisional surgical site infections, and

 

                                                               130

 

      those include superficial infections which involve

 

      the skin and the underlying subcutaneous tissue, or

 

      deep incisional surgical site infections which

 

      involve the underlying soft tissue as well.

 

      Obviously, the most severe and costly infections

 

      are those that involve the underlying organ or

 

      organ space surgical site infections and those

 

      involve really any part of the anatomy other than

 

      the incision that might have been opened or

 

      manipulated during the procedure.  Next slide.

 

                This is a cross-sectional schematic to

 

      illustrate just a little bit more clearly an

 

      abdominal wall that shows the various

 

      classifications.  As you can see, a superficial

 

      incisional SSI would involve the skin and the

 

      subcutaneous tissue.  A deep incisional SSI would

 

      extend down into the fascia and the muscle.  The

 

      organ space surgical site infection, obviously,

 

      would include the organs in that surrounding

 

                                                               131

 

      tissue.  Next slide.

 

                Now, when we look at the organ or the

 

      potential sources for the pathogens that result in

 

      a surgical site infection, overwhelmingly these

 

      arise from the patient's own endogenous flora.

 

      There are also secondary sources for the pathogens

 

      that result in a surgical site infection.  Those

 

      can result from pathogens that are available in the

 

      operating room theater environment.  They may

 

      result from operating room personnel that are in

 

      and around the surgical field or, not uncommonly,

 

      at the head of the table of the anesthesiologist.

 

      Less commonly, these infections may result from

 

      seeding of the operative site from a distant site

 

      of infection.  Next slide.

 

                If we look at the microbiology of the

 

      surgical site infections--and this slide is

 

      somewhat dated but suffice it to say that the

 

      distribution of these pathogens is still

 

      predominantly--the primary organism are

 

      staphylococcal infections, not surprisingly because

 

      these arise primarily from the patient's own

 

                                                               132

 

      endogenous flora.  The predominance of these

 

      pathogens is Staph. aureus, and then with certain

 

      procedures like cardiac surgery, and more recently

 

      we have been looking at some data from prosthetic

 

      joint infections, and it appears that staphylococci

 

      now account for in the neighborhood of around 50

 

      percent of the infections causing surgical site

 

      infections.  We have also seen an increase in the

 

      proportion of those staph. infections that are due

 

      to resistant organisms, such as

 

      methicillin-resistant Staph. aureus.  Next slide.

 

                Less commonly, SSIs may be due to some

 

      unusual pathogens, such as the ones shown on this

 

      slide that are typically due to either contaminated

 

      products or solutions that are used in and around

 

      the surgical site, or to colonized healthcare

 

      workers, again, that might be part of the surgical

 

      team.  When you see clusters of infections that are

 

      due to these unusual pathogens you should think of

 

      a common source, such as the contaminated vehicle

 

      or potentially the colonized healthcare worker who

 

      is disseminating the organism.  Next slide.

 

                Regardless of where the organism arises,

 

      the pathogenesis of a surgical site infection can

 

      kind of be distilled into this numerical formula

 

                                                               133

 

      and relationship shown here.  That relationship

 

      really is a combination of the dose or the amount

 

      of bacterial contamination at the surgical site

 

      infection, the virulence of the colonizing or

 

      contaminating organism, and then the underlying

 

      sort of resistance of the host.  Those three

 

      factors are really give rise to the risk of

 

      surgical site infection.  Next slide.

 

                If we look at some of the epidemiologic

 

      factors that have been associated with influencing

 

      the risk of acquiring a surgical site infection,

 

      they can be broadly categorized into those that are

 

      host- or patient-related factors, such as age, body

 

      mass index, obesity, the presence of diabetes and,

 

      as we will see later it may not just be a patient

 

      who is labeled with diabetes but having

 

      hyperglycemia at the time of surgery, the

 

      nutritional status of the patient, whether the

 

      patient has a prolonged preoperative stay, again,

 

                                                               134

 

      whether there is infection at a remote site at the

 

      time of surgery, and whether the patient is on

 

      immunosuppressive medication such as steroids, or

 

      whether the patient is a smoker or uses nicotine.

 

                Some of the procedural factors that have

 

      been associated with influencing the risk of

 

      surgical site infection are things like hair

 

      removal or shaving, the duration of the procedure,

 

      surgical technique, the presence of foreign bodies

 

      such as drains, and things like the appropriateness

 

      or inappropriateness of antimicrobial prophylaxis.

 

      Next slide.

 

                What I am going to do now with the next

 

      series of slides is talk a little bit about some of

 

      these modifiable factors in terms of things that we

 

      recommend, or things that are recommended, to be

 

      done to minimize or moderate the risk of a patient

 

      acquiring a surgical site infection.  Next slide.

 

                There are a number of randomized,

 

      controlled trials showing the benefit of

 

      perioperative prophylaxis and I won't belabor you

 

      with those data.  The feeling is that this is

 

                                                               135

 

      probably one of the most important things that we

 

      can do in terms of modifying risk of infection.

 

      When we talk about antimicrobial prophylaxis we are

 

      really referring to a brief course, most commonly a

 

      single dose, of an antimicrobial agent that is

 

      given just before the operation begins.

 

      Antimicrobial prophylaxis is not intended as

 

      therapy.  It really is a preventive strategy ,and

 

      it really should be used as an adjunctive

 

      preventive measure and not really used to supplant

 

      basic things like aseptic technique and some of the

 

      other basic principles of preventing surgical

 

      infection.

 

                Now, antimicrobial prophylaxis, as I said,

 

      has been studied in a number of procedures, a

 

      number of well done randomized, controlled trials

 

      and it is shown that its use, if done

 

      appropriately, can decrease the risk of surgical

 

      site infection at least 5-fold.  Next slide.

 

                But surgical prophylaxis--again, to show

 

      you how complex this whole issue is, is not a

 

      matter of just giving an agent and giving the right

 

                                                               136

 

      agent, but also giving it at an appropriate time.

 

      Now, this slide summarizes a study done by Classen,

 

      and I think it is one of the more classic studies

 

      looking at the importance of timing of

 

      antimicrobial prophylaxis in terms of its efficacy

 

      in preventing surgical site infection.

 

                What Classen did was actually study nearly

 

      3,000 elective clean and contaminated surgery.  He

 

      looked at the timing of the antibiotic and its

 

      influence or relationship to the risk of infection.

 

      If you look at what he called early antimicrobial

 

      prophylaxis, that is antibiotics given 2-24 hours

 

      before incision, the rate of infection in that

 

      cohort was 3.8 percent.  If he looked at

 

      antibiotics that were given postoperatively, that

 

      is 3-24 hours after incision, the rate of infection

 

      was 3.3 percent.  If he looked at antibiotics that

 

      were given within 3 hours after the incision, the

 

      rate of infection was 1.4 percent.  Lastly, the

 

      rate of infection was lower for antimicrobial

 

      prophylaxis that was given within 2 hours of the

 

      incision, 0.6 percent.  So, again, it is not just a

 

                                                               137

 

      matter of giving prophylaxis and giving the right

 

      agent, but this issue of timing is critically

 

      important.  Next slide.

 

                This next series of slides talks not only

 

      about this notion of giving antibiotics at a

 

      critical point before incision, but talks about the

 

      impact of prolonged surgical prophylaxis.  This is

 

      a study that was a prospective study that looked at

 

      a cohort of CABG patients.  They looked at those

 

      patients who received antibiotic prophylaxis within

 

      48 hours of the procedure and those for whom the

 

      prophylaxis was continued for greater than 48 hours

 

      after the procedure.  Next slide.

 

                They looked at two outcomes, not only the

 

      incidence of surgical site infection but also the

 

      likelihood of acquiring a resistant organism if a

 

      surgical site infection did occur.  Interestingly,

 

      what they found is that nearly half of the patients

 

      received antimicrobial prophylaxis greater than 48

 

      hours after the procedure.  Again, antimicrobial

 

      prophylaxis is intended to be given around the time

 

      of incision to get the maximal sterilization, if

 

                                                               138

 

      you will, of the surgical site.  But here we see

 

      that at least in half the cases patients are

 

      getting prophylaxis beyond two days after the

 

      surgery.

 

                What they found is that the incidence of

 

      infection in this cohort of patients really was no

 

      different if antibiotic prophylaxis was

 

      discontinued within 48 hours or if it was continued

 

      for greater than 48 hours.  But, interestingly, the

 

      rate of acquiring a resistant pathogen was 60

 

      percent higher in those patients who received

 

      prolonged antimicrobial prophylaxis.  So, again,

 

      antimicrobial prophylaxis and its influence on SSI

 

      is not only getting the right agent but getting it

 

      within the right interval and discontinuing it as

 

      soon as possible following the surgical procedure.

 

      Next slide.

 

                Another area that I think is particularly

 

      intriguing as to the complexity of things that

 

      would have to be considered or controlled for in

 

      looking at SSI risk is this whole issue of glucose

 

      control and perioperative management of

 

                                                               139

 

      hyperglycemia.  This slide actually summarizes a

 

      prospective study that was done in a group of

 

      diabetic patients who were undergoing cardiac

 

      surgery, over nearly a decade at one hospital.

 

                They had two groups of patients.  Again,

 

      this is a prospective intervention trial with a

 

      pre- and post-design.  The control patients were

 

      those who had received sort of the traditional

 

      therapy with their glucose being measured and

 

      monitored intermittently, and being given

 

      subcutaneous insulin.  What they called the treated

 

      group were patients who were placed on a continuous

 

      IV insulin drip for the immediate operative period

 

      and for up to 48 hours postoperatively.  Next

 

      slide.

 

                The outcomes were that they looked at the

 

      levels of blood glucose that were below 200 mg/dL,

 

      and that was sort of the target level, within the

 

      first two days postoperatively.  The other outcome

 

      obviously was the incidence of surgical site

 

      infection, and they focused on deep SSIs.  What

 

      they found is that in the group who got traditional

 

                                                               140

 

      management using subcutaneous insulin on a PRN

 

      basis the rate of surgical site infection was 2

 

      percent as compared with the 0.8 percent in those

 

      patients who were managed with a continuing IV

 

      drip.  This difference was highly statistically

 

      significant.

 

                Now, there have been some subsequent

 

      studies that have looked at sort of the prevalence

 

      of patients who are hyperglycemic who don't carry

 

      the diagnosis or label of diabetes.  Again, this

 

      notion of perioperative glucose management probably

 

      has broader implications beyond just the diabetic

 

      patient population.  Next slide.

 

                Another sort of titillating article that

 

      is summarized here and I think alludes to some of

 

      the complexity of this issue is this notion of

 

      perioperative oxygenation, the theory being that

 

      better oxygenated tissues are less likely to be at

 

      risk or be prone to developing an infection.

 

                This was a study that was published in the

 

      New England Journal in 2000.  It was a randomized,

 

      controlled, double-blind trial that looked at a

 

                                                               141

 

      relatively small group, 500 patients who were

 

      undergoing colorectal surgery.  Again, I want to

 

      emphasize that this was colorectal surgery.  The

 

      intervention was that patients were randomized to

 

      receive either 30 percent or 80 percent inspired

 

      oxygen during and for up to 2 hours following the

 

      surgical procedure.

 

                Now, what they found is that the incidence

 

      of surgical site infection was 5.2 percent in those

 

      who received higher 32 percent versus 11 percent in

 

      those who received 30 percent oxygen.  That

 

      difference was statistical significant.

 

                There has been a more recent study that

 

      came out in JAMA, and I did not summarize that

 

      here, looking at a more heterogeneous population of

 

      patients undergoing intra-abdominal procedures,

 

      again, randomizing them to receive 70 percent

 

      oxygen versus 30 percent inspired oxygen.  That

 

      study concluded that there was not only no

 

      beneficial effect to a higher level of inspired

 

      oxygen but, in fact, there might be some

 

      detrimental consequences.  In fact, they found a

 

                                                               142

 

      higher rate of surgical site infections in those

 

      people who got more oxygen.

 

                I say this to say again that this

 

      difference might be in part attributable to the

 

      population that was studied in terms of procedures.

 

      So, a lot of these things have to be factored in,

 

      in terms of trying to extrapolate findings from one

 

      cohort to another--not only what the intervention

 

      was but the population and the procedure that was

 

      studied.  Next slide.

 

                What about the issue of antisepsis and

 

      antiseptics?  Probably, as you have heard from Dr.

 

      Boyce, a lot of the studies around the efficacy and

 

      the benefits of antiseptics really use bacterial

 

      count on scans and the amount of cutaneous flora

 

      remaining after their use as the primary outcome

 

      measure.  When we look at hard outcomes or harder

 

      outcomes in terms of patient outcomes, data becomes

 

      much thinner.

 

                These are just summarizing some data, and

 

      these are admittedly older studies and, you know,

 

      these studies to be done today are much more

 

                                                               143

 

      difficult for a variety of reasons, but these three

 

      studies summarize data looking at surgical site

 

      infection rate with patients receiving preoperative

 

      showers versus those not getting showers.  The

 

      earliest study was in the '70's where the rate

 

      among those who did not get showers was 2.3 percent

 

      versus 1.3 percent.  In the subsequent two studies,

 

      in the 1980's, the actually the difference was

 

      quite closer.

 

                Again, I think some of these studies,

 

      although they did not show a statistically

 

      significant difference, may be confounded by

 

      failure or inability to control for a lot of the

 

      factors that we mentioned up to this point.  But,

 

      also, I am not convinced that these studies were