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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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,

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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?

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

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

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

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,

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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?

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

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

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

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

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,

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

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

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

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

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

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.

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

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

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

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

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

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

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

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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

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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

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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

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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

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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

adequately powered to detect a difference. Next

slide.

Another factor that has been shown to

influence the risk of surgical site infection is

the whole issue of hair removal at the site of

infection. In short, not unlike the story that I

portrayed with antimicrobial prophylaxis, it is not

144

only a matter of do you remove hair or not remove

hair but how you do it, and when you do it. They

are all part of the complexity of influencing the

risk of surgical site infection.

This is a study that, again, is admittedly

old and I am not aware of this kind of study being

done sort of in a more modern era, but if you look

at those procedures where no hair removal was done,

or hair removal was done using a depilatory, the

rate of infection was less than 1 percent. In

those procedures where a razor was used the rate of

infection was nearly 8-9-fold higher in those first

two categories of procedures. It is not

surprising. Razors allow for microabrasions and

nicks in the skin and, obviously, it is not

difficult to imagine how those would be sort of

easy portals of entry for any organisms that are

left on the skin. Again, like I said, it is not

only a matter of do you remove hair and how you do

it but also the timing.

This study also looked at whether shaving

done immediately prior to surgery, within 24 hours

145

of the procedure, or done later or much, much

earlier, before 24 hours of the procedure--was that

associated with a risk. As you can see, there was

a nice step-wise progression with shaving or hair

removal being done close to the procedure being

associated again with the lowest risk. Again, one

can imagine that that may be due to the immediate

effect of skin cleansing. You have the benefit of

perioperative prophylaxis being given in and around

the time of the procedure. So, again, this is

another issue that has multiple layers to it in

terms of influencing the risk of surgical site

infection. Next slide.

I will just say that the issue of clipping

has been looked at in multiple studies, and it

shows that, at least in terms of shaving, the

clipping is associated with a lower risk or

surgical site infection. Next slide.

I won't spend a lot of time on this but I

just put this in to remind me to say that there are

also data that suggest that the attire the surgical

team wears, in terms of scrub suits or types of

146

suits, also may influence the amount of bacterial

count in the operating room at the time of the

procedure. I am not aware of any good data that

link these type of things with hard outcomes like

infection. Next slide.

I put this in to say that sort of the

amorphous grab-bag term of surgical technique

which, at least in epidemiologic studies, often

manifests itself as a higher SSI risk being

associated with a given surgeon is also something

to consider, and actually it is fairly difficult to

measure in an objective way. You know, it includes

things like how they handle tissue; whether they

eradicate dead space; whether they remove

devitalized tissue; whether there are inadvertent

things like entering a viscus; and obviously using

things like foreign devices and leaving those in

like drains and suture material. Again, these are

all things that go under sort of a heading of

surgical technique that are very, very difficult to

measure in a systematic and objective way. Next

slide.

I just want to say that although we

believe the skin is the primary source of the

pathogens that result in surgical site infection,

147

and most of our preventive measures are targeted at

reducing that local contamination, there are things

that are done in terms of the operating room

environment to remove airborne bacteria that might

also contaminate the surgical field.

I just put this up to show that the

American Institute of Architects has established

criteria for maintaining, if you will, the

sterility or the ventilatory and environment

parameters of the operating room. Those things

include certain temperatures, relative humidity,

air circulation and air exchanges. Next slide.

Just to follow on that, there are some

data to suggest that air flow may have a role in

SSI risk. This slide just shows some data, and

again there are some issues with the studies and

whether things were adequately controlled, and most

of this data has been done with clean procedures,

148

particularly orthopedic procedures. This is a

study that looked at 8,000 total hip and knee

replacement. What they looked at was the role of

ultra-clean air, laminar flow, antimicrobial

prophylaxis alone or using those in combination.

What they found is that using laminar flow

was associated with about a 50 percent reduction in

surgical site infection risk among those patients

undergoing total knee and hip replacement.

Antimicrobial prophylaxis had a much larger benefit

in reducing surgical site infection risk, going

from 3.4 percent to 0.8 percent. When you coupled

those, again, the additional benefit of laminar

flow was not as marked compared with that of

antimicrobial prophylaxis. So, again, part of

these things are looking at the attributable

fraction of any of these preventing strategies in

terms of getting your bang for the buck. Next

slide.

One thing that I have been asked by our

colleagues at FDA is what does CDC monitor, and how

does CDC track surgical site infections and many of

149

the things that happen in and around the time of

operation. Next slide.

CDC has essentially three surveillance

systems for monitoring healthcare-associated

adverse events as they pertain to infection. The

one that is really the component that is germane

for this discussion is something called the

National Nosocomial Infection Surveillance system,

of the NNIS system. The NNIS system has been

around for 30 years. It started in 1970. It

measures nosocomial infections in patients who are

critically ill, primarily ICU patients. It also

measures infection in surgical patients. Next

slide.

If we look at the characteristics of the

hospitals participating in the NNIS system, the

NNIS system is comprised of about 300 hospitals.

There are roughly 5,000 to 6,000 hospitals in the

United States so the NNIS system is comprised of

less than 10 percent of the hospitals in the United

States. These hospitals tend to be largely large

academic teaching institutions. Nearly 60 percent

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of them are teaching hospitals. The remaining

group of hospitals has some sort of teaching

affiliation. The hospitals in the NNIS system have

a median bed size of around 360 beds, and there are

no facilities in the NNIS system less than 100

beds. That is important because 50 percent of the

hospitals in the United States are less than 100

beds. So, whether the data we see collected in the

NNIS system are representative of all hospitals I

think is one thing to consider. Next slide.

When we look at the specific data and

variables that are collected in the NNIS system as

they pertain to surgical patients, there is some

basic demographic information like patient age and

gender, their ASA score which is a measure that the

anesthesiology colleagues use for sort of measuring

the severity of illness of patients. They collect

data on wound class; whether the operative site or

the surgical site is related to trauma or not; the

type of anesthesia; whether the procedure is

emergency or elective procedure; the duration of

the procedure; the length of postoperative stay;

151

the infection site; the infections pathogen. Is

there any SSI-related mortality, as well as

hospital demographics. Importantly, this system

does not collect data on many of the processes that

we have talked about in terms of influencing the

risk of surgical site infection. Next slide.

One of the things that the system does is

that it generates rates that can be used as

national benchmarks for institutions to essentially

measure their performance based on a given

procedure, for example CABG or what-not. I think

you have in your handout the most recent NNIS

report that shows the national benchmarks for

various procedures. An important part of coming up

with those numbers is this notion of risk

assessment. Part of that adjusting procedure is

looking at something that is called the NNIS risk

index. Again, that risk index is the composite

score of the American Society for

Anesthesiologists, or ASA, score, the wound class

at the time of surgery and the duration of the

procedure. These are the three variables, at least

152

that have been studied in the NNIS system, that

have been shown to be most predictive of a

patient's risk of developing a surgical site

infection. Next slide.

These are some temporal trends in what we

have observed in terms of surgical site infection

rate over a period of the late 1980's to

approximately 2000. Essentially, this is

stratified by those patients who have procedures

that are low, medium low, medium high and high

risk. What you can see is that the lowest risk

procedures in patients the rate of surgical site

infections is actually quite low and has remained

quite low. There has been a slight downward

decrease in the middle categories, and again some

of those rates are relatively low. But

impressively, there has been a marked decline in

the rate of surgical site infection among the

highest risk procedures and patients. Again, you

know, one question you might have is can you

superimpose on this, or do you know how some of

these various preventive strategies relate to this

153

graph, and we don't have procedure and patient

specific data on who got prophylaxis at the right

time, for example, and the risk of infection. Next

slide.

I think an important thing in terms of

this notion of designing any study or measuring the

effect of any intervention is this notion of having

good surveillance data or good capture of patients

who undergo these procedures. In the NNIS system

all of the patients who are enrolled in the system

and recorded in the system are followed for at

least 30 days postoperatively to monitor for risk

of infection. If the procedure involved an implant

such as a prosthetic joint the period of

surveillance is up to one year for the risk of

infection. These are very, very long periods of

time of follow-up, and I think if you look at many

studies the patients may not all have been followed

for this length of time. Next slide.

Having said that, following patients for

this period of time to meet this definition, it

really has become more complicated if you look at

154

some of the trends of what is happening with

healthcare delivery in the United States. I will

focus your attention on length of stay, which has

decreased at least by a third--and this was based

on 1995 numbers; it is probably even lower now--and

also look at the number of procedures that are

actually being done in patients those have

decreased, again based on 1995 data, by 25 percent.

So, the ability to capture these patients requires

a lot more effort and energy if they are going to

be followed for 30 days postop or, in the case of

an implant, up to one year postoperatively. In

fact, our data would suggest that somewhere around

20 percent or less of the procedures that are

complicated by an SSI is that surgical site

infection detected during the admission where the

procedure was done. Obviously, if the patient is

readmitted because of some organ space infection we

would capture those, but for lesser and some of the

higher volume procedures that are primarily

superficial infections, those people would never

come back to the hospital. So, you have to rely on

155

a strong system of post-discharge surveillance to

capture any untoward event and minor untoward event

such as a surgical site infection. Next slide.

We, at CDC, are actually undergoing a

transition in terms of our surveillance activity.

I alluded to on the other slide that we sort of

have three components to our surveillance. We have

a dialysis surveillance network. We have something

called NaSH, which is the National surveillance

system for healthcare workers, and then we have the

additional NNIS where the focus is on patient

outcome. Those are all being rolled into one

system called the National Healthcare Safety

Network. Next slide.

NHSN, although it has a new name and it is

a hybrid of all of our surveillance systems,

maintains the same goals of the predecessor

systems. The reason for doing this is that NHSN is

going to be a web-based application which we

believe will minimize a lot of the data collection

burden and mangled data entry that the current

system has. We are hoping that this system will

156

also increase the capability to capture electronic

data, whether it be from laboratory information

systems, administrative data bases, operating room

records which capture a lot of the process things

around the surgical patients, as well as pharmacy

data to look at things around prescribing. Next

slide.

Importantly, one of the priority areas for

the National Healthcare Safety Network is really

this notion of including process measures. These

process measures will allow you to link them to

outcomes so, for example, we will be looking at

surgical prophylaxis as the first cut and whether

the patient got the appropriate antibiotic based on

national guidelines for that procedure; whether

they got the antibiotic within a certain time, in

this instance within an hour before the incision;

and whether antibiotics were discontinued within 24

hours of the procedure. That will be able to be

linked to outcomes data on patients. So, we will

have some measure of how process relates to

outcome. Next slide.

The last thing I will talk briefly

about--and I was asked by FDA colleagues to give

you a little bit of a glimpse of how we here, at

157

CDC, go about developing policy around some of

these preventive strategies. Next slide.

We here also have a federally charted

advisory committee, the Healthcare Infection

Control Practice Advisory Committee, whose mission

is really to advise the Secretary of Health and CDC

about issues related to the prevention and the

surveillance of healthcare-associated infection and

related adverse events such as antimicrobial

resistance in healthcare settings. Next slide.

The charge of the committee's activities

and recommendations are really targeted and aimed

toward clinicians, infection control professionals,

regulators, purchasers and public health officials.

The target setting for these guidelines--they were

traditionally geared toward procedures and

practices that occur in acute care settings but now

these guidelines are really aimed to address

procedures and healthcare delivery across the

158

continuum, including outpatient settings, home care

and long-term care. Next slide.

These recommendations are aimed to be

evidence-based, and all of the HICPAC guidelines

are ranked. The recommendations are ranked to show

the strength of the evidence. I won't read through

the definitions of the categories; you can do that.

But essentially there are three broad categories.

The category I recommendations are in large part

based on evidence or well-designed experimental

studies or epidemiologic studies; the category II

recommendations where there may be some suggestive

evidence but this category may be based on expert

opinions; and then the last category is for those

practices for which there is either insufficient

evidence or a lack of consensus regarding efficacy,

in which case the committee would consider that

practice or that recommendation an unresolved

issue. Next slide.

What this does is actually sort of

summarizes the categorization scheme and what it

means regarding evidence and recommended practice.

159

In short, the difference between I-A and I-B is

really the strength of the evidence but, in short,

category I recommendations are those practices for

which there is strong evidence supporting it and

the implementation of that practice essentially is

recommended for all hospitals. Category I-C--we

added this fairly recently--are those things for

which there might be legislation or federal or

state mandates, such as the blood-borne pathogens

standards for example, that says that all hospitals

have to do this. There may or may not be good

evidence supporting this but, because it is

required by regulation, all hospitals must do it.

The category II recommendations, again,

are those practices for which there is good or some

evidence that the practice may be beneficial and

that practice is suggested for implementation in

many, if not all, hospitals. Lastly, the category

of no recommendation are those practices for which

there is insufficient or contradictory efficacy,

that is to say, you might have four studies of

equal quality, two showing a benefit and two

160

showing no benefit, in which case the

recommendation for implementing that practice is an

unresolved issue. Next slide.

Now, we too, as I am sure you advisory

committee and many other advisory committees, have

many challenges in trying to take this

evidence-based approach to developing our policies.

Sometimes we identify subject matter experts who

are not necessarily methodologic experts in terms

of conducting systematic reviews. Systematic

reviews are labor intensive and costly so we often

have resource limitations for doing that.

In our field of infection prevention and

infection control, we don't have a body of

randomized, controlled trials that, say, might be

in the cardiology literature or some of the other

more clinically based specialties so sometimes we

have to rely on observational studies, which in

many instances, by some, are considered a lower

quality of evidence.

Lastly, our user needs, not uncommonly,

outstrip what the available science there is to

161

support or to provide evidence-based

recommendations. This is particularly true when we

look at non-hospital based healthcare settings.

Next slide.

Just to say that our guidelines come in

three parts. The first part really is a

comprehensive synthesis of the literature review

and the research that establishes the scientific

rationale for the recommendations that are

contained in part two. Part two are the summary of

the practice recommendations with categorization.

More recently, we have now added a third part which

outlines or provides three to five what we call

performance indicators or performance measures that

institutions can use to monitor their success in

implementing these guidelines. These three to five

indicators are category I-A recommendations, those

recommendations or those practices that we believe

the data suggest have the strongest impact on

reducing that outcome. Next slide.

To conclude, what I hope I have done is

show you that some of the complexities involved in

162

surgical site infection prevention are some of the

things that have to be considered in designing any

study to look at the effectiveness of any one

strategy. This prevention really is a multifaceted

approach targeting pre-, intra- and postoperative

factors.

Our current surveillance systems really

are limited in that they don't collect data on

perioperative processes. Another thing I think

complicating it that would have to be factored into

any study to look at surgical site infections and

impact of any measure would have to consider the

fact that we have experienced a fairly dramatic

shift in where surgical procedures are occurring,

and that patients are staying in the hospital for a

much shorter period of time. There would have to

be some system in place to capture events that

occur post-discharge or for procedures that are

done outside the traditional acute care setting.

I will also say that in general the

incidence of surgical site infections, in large due

to advances in preventive strategies, is low. So,

163

studies that would look at any intervention would

likely have to have a fairly large sample size.

Finally, some of the prevention practices,

such as hand hygiene, might be very, very difficult

to study using the traditional randomized,

controlled, research design because you wouldn't

randomized someone to do it or not to do it.

I will just conclude by saying that

prevention is, obviously, primary, one of our

primary focuses here, in our division, and many of

the things that I have talked about specifically as

guidelines, HICPAC guidelines, are available on the

web site and that URL is in your handout. I think

I will stop there and let you ask any questions.

Thank you.

Question and Answer Period

DR. WOOD: Thank you. I guess what we

will do is keep you on the line. I am told it will

be technically difficult to do that once we start

questions for other speakers so perhaps we could

have the committee focus first just on Dr. Pearson,

with questions for her.

Did I understand correctly that none of

your surveillance instruments use outpatient

surgical centers? Is that right?

164

DR. PEARSON: You are right. The current

NNIS system does not. The NHSN, which should be

going live in a few months--what it is going to now

do is allow any facility that, for example, does

surgery to report to the system. If you are an

ambulatory surgery center you can also report your

data to the system.

DR. WOOD: But even the large hospitals

that are in the system right now that have

outpatient surgery facilities, where these patients

are not admitted, would not be in the system.

Right?

DR. PEARSON: That is correct.

DR. WOOD: All right. Any questions from

the committee? Yes, Mike?

DR. ALFANO: Thank you, Dr. Pearson. That

was a wonderful presentation. I have a question

about how to potentially explain the increase in

nosocomial infections per 1,000 patient-days. As I

165

think about your database, it was occurring as

managed care was coming in and, obviously, patient

days were getting shorter per procedure. So, I

wonder how much the increase per 1,000 patient-days

relates to the difference in numbers of

patient-days per se, which are going down so that

someone, you know, could have acquired an infection

at a comparable rate but the numbers would make it

appear to be somewhat higher.

Also, a point that I think the Chair was

getting at, there are more outpatient procedures

and I think the tendency is that healthier patients

are done in an outpatient setting which means they

would be less likely to be candidates for

infection. Could you project how much of the

increase could be related to those types of changes

in the inherent system as opposed to actual

problems in hospital-acquired infections?

DR. PEARSON: Yes, let me just challenge a

little bit your initial assertion that they are

increasing. We are actually looking at some

updated numbers. I think most of you are aware of

166

the number two million infections and the like, and

what we have actually seen is that the actual

overall number has gone down over the last decade

or so. I think it is 1.7 or something.

But you are right, what we certainly have

seen and believe is that the people who are in

hospitals or getting inpatient procedures are

sicker than they were a decade ago. So, you have a

population at higher risk for infection so that

certainly plays into the rate that we see.

You are right, consequently the lower risk

patients are sort of skimmed off and are not

getting reflected in these numbers that we are

seeing, but also the people that are actually

getting into the hospital and getting inpatient

procedures are older, sicker, and have many more

co-morbidities than one would have seen before; the

20 year-old is not being hospitalized now. Does

that answer your question?

DR. ALFANO: Yes, thank you.

DR. WOOD: Yes, Jan?

DR. PATTERSON: Michelle, this is Jan

167

Patterson. Could you elaborate on what the CDC

guidelines say regarding the surgical prep

chlorhexidine versus alcohol versus betadine? As I

recall, there is some discussion about the

superiority of chlorhexidine used as an antiseptic

but there is no specific recommendation of one over

the other.

DR. PEARSON: Yes, that is right. The

current guideline actually looks at a variety and

does not recommend one specific product over the

other in terms of surgical site prevention. In a

more recent guideline around prevention of IV

catheter-related infection we did specifically

recommend chlorhexidine as the preferred agent for

cutaneous antisepsis. Povidone-iodine can be used

as an alternative but we did recommend

chlorhexidine preferentially, in large part because

there are now several randomized, controlled trials

and even a meta-analysis which shows that

chlorhexidine was superior to povidone-iodine in

preventing catheter-related bloodstream infection.

I think similar rigor, at least to my knowledge, in

168

terms of those kinds of head-to-head comparisons

for prevention of surgical site infection is not

available.

DR. WOOD: In the absence of any other

questions for you, can you stay on the line? I

guess the sound person can hear you so if you can

hear us you can respond to that if you want. Will

that work?

DR. PEARSON: Yes.

DR. WOOD: All right. Questions for the

other speakers then? Yes, Dr. Larson?

DR. LARSON: Thank you. I would like to

describe what I think is the current cyclical

scenario that we are in right now that may explain

why it is that there is very little evidence, and I

totally agree with that, of a link between log

reduction, how much we need in infection and also

whether the TFM recommended procedures are the

right ones that we should do.

I have been doing funded research on skin

antisepsis since the late 1970's, right after the

first TFM came out. I learned in my first couple

169

of studies that the healthcare personnel handwash

recommended protocol testing in the TFM did not

work for what I wanted to do clinically for several

reasons. First of all, it is very difficult to

reproduce. I learned that in various hands you can

change the results you get simply by changing the

amount of time that you allow to dry--just little,

tiny changes in the protocol can change hugely the

results you get. That was concerning although I

know that the labs that do it, do it very well but

there is a lot of room for variability in the test.

Secondly, we learned early on that by

putting Serratia marcescens on the hands we could

not decontaminate the hands after they were

contaminated, and we found Serratia on our

subjects' hands as far away as six days after

putting it on. And, we felt it was unsafe.

Thirdly, by using paid volunteers, it

really had very little to do with what is going on

in field studies, etc. So, I stopped using the

healthcare personnel handwash protocol in the lab

setting because it simply wasn't clinically very

170

relevant.

So, what happens then is you have three

groups that can possibly fund these studies. There

is industry or there is NIH, or whatever. Industry

can't really do studies with clinical endpoints

because they need to link up then with somebody who

is in a clinical setting. The labs that are doing

the testing, are doing it very well in humans but

not with patients, etc. They can't do studies on

their own with clinical endpoints unless they link

with somebody in the clinical setting. So, that

leaves the researchers in clinical settings, like

me, like John, etc. Then we need to get funding.

We are in academic settings and, you know, we can

get funding from industry but the price of the

studies is prohibitive often and there is not a lot

of incentive to look at clinical endpoints

sometimes.

In the last three years I have been the PI

on three NIH-funded grants to look at skin

antisepsis. Each of those grants costs over a

million dollars. One of them is already published,

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and that was a study in the home setting so it is

not relevant here. That was published in The

Annals of Internal Medicine. The second one, which

was a study comparing alcohol and CHG in neonatal

intensive care units will be coming out in a couple

of months in The Archives of Pediatric and

Adolescent Medicine. The third one, which is

funded again for over a million dollars, is a study

to try to assess the impact of the new CDC hand

hygiene guideline on infection rates in 40

hospitals. However, this is not assessing

efficacy; this is assessing effectiveness.

So, one of the things we need to be clear

about is what is FDA's interest. Are we interested

in assessing efficacy or effectiveness? There is

never going to be a clinical study that is going to

look at efficacy because of all of the confounding

factors, and I will be the first to admit that

every study I have done has a lot of problems

because there are confounders, etc., etc.

Judging from that, I think in some

ways--because we have been dealing with this issue

172

since 1978 and I have been at several of these over

the last decades--in some ways the horse is out of

the barn. Now the Joint Commission has said to

hospitals to get accredited you have to use the

hand hygiene guideline. Therefore, it is not

possible to get permission in clinical settings to

do studies where you are comparing plain soap and

an antiseptic soap because the hospital will not

get accredited. So, it is too late in some ways.

Now, I think what has happened is that

short-term political will has ended up, as it

sometimes does with decisions to not fund the ideal

study--you know, 20 years ago or whatever, if it

were possible to do--has resulted in spending more

money and time than we should have. So, I think

that the published studies will never answer the

efficacy questions in the clinical studies that

need to be done.

My feeling is that our position right now

for this committee is two choices. NIH doesn't

want to keep funding these studies; they are too

expensive. So, either FDA defines an ideal

173

protocol and helps fund the study--and I know you

are not a funding agency--because nobody else will

do it, or we just decide that we are going to look

at safety and efficacy and if a product meets a

certain standard, then we keep it on the market.

But to look at clinical effectiveness, you know,

unless the FDA is going to chip in with a little

bit of money, NIH is not going to keep funding

these studies.

DR. WOOD: Well, I am a lot more

optimistic than that. I am not saying that is what

we should do but if, for example, we recommended

that efficacy studies were required you would find

that industry would get them done in a heart beat.

That has been my experience in the past.

DR. LARSON: Industry is doing the

efficacy studies--

DR. WOOD: No, I am talking about efficacy

in terms of clinical endpoints. There is

certainly, you know, plenty of experience doing

extraordinarily complex trials by industry funding

that have resulted in clear demonstration of

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efficacy or not. And, all of these trials cost

huge amounts of money, certainly many times the

numbers you are talking about. Any other

questions? Yes, Frank?

DR. DAVIDOFF: I was curious how the

initial or the existing recommended log reduction

numbers were chosen because it seems pretty clear

that they were, in a sense, pulled out of thin air.

That is to say, there wasn't good, hard evidence on

which to base them certainly in terms of clinical

endpoints. So, there must have been some logic as

to choosing the 1-log, 2-log, 3-log reductions as

the specific numbers or in a sense threshold

numbers or qualifying numbers to use as the

criteria for judging these products. So, that is

part (a) of the question.

The second, related part is why reductions

were chosen rather than some absolute threshold

number, rather than a relative number like a

change. It seems, sort of from a biological

standpoint or clinical standpoint, that it is not

so much whether you have dropped from a million to

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100,000 bugs but the more important point might be

to get yourself below 100 or some other absolute

threshold.

I was curious how those decisions were

made because, if those are the ones we are going to

stick with, it would be nice to know that there was

at least some reasonably compelling logic behind

those initial decisions.

DR. WOOD: Well, my reading of the

briefing book was that there was not, but does

somebody want to add to that?

DR. LUMPKINS: Yes, I will take a stab.

Basically, the effectiveness criteria evolved based

on our experience with the evaluation of NDA data.

Basically, our effectiveness criteria are based on

our experience with the performance of

chlorhexidine gluconate in studies very similar to

the ones that are in the TFM at this point.

DR. WOOD: But I think what Frank is

asking is, as I understand the briefing document,

you sort of saw what you saw for chlorhexidine and

you used that as a kind of standard moving forward.

DR. LUMPKINS: Right.

DR. WOOD: And what he is asking is was

there any data to link that to a clinical outcome.

176

DR. LUMPKINS: No.

DR. WOOD: Right. Then the second

question he was asking was are there any data that

relate absolute numbers of colony counts, or

something, that would--

DR. LUMPKINS: The unfortunate situation

is that the virulence of these organisms varies.

So, you can pick one but we don't really have a

good handle for most organisms so you would be

forced into a situation where you would pick one

organism arbitrarily which may or may not tell you

something about the general population.

DR. WOOD: Okay. Tom, did you have a

question?

DR. FLEMING: I do, and I would like to

pose it in the context of John Powers' slide number

36. So, if we could take a moment to get that?

DR. WOOD: We will work on getting that

slide up. In the meantime, Mary?

DR. TINETTI: Two quick questions. One,

are there other examples like this where FDA has a

standard for a surrogate that has never been linked

to an outcome? Because the other examples that you

had in your slides, John, were all surrogates that

were linked to a clinical outcome.

177

Number two, these are all log reductions.

Do we have any data on individual people,

percentage of people who respond and don't respond

to these?

DR. POWERS: I think what we usually try

to do and what I tried to put in those slides as

far as timing is that today, in our current

regulatory environment, we would try not to do that

where there was no link. What we like to do for

serious and life-threatening diseases, like for

HIV, is propose a plausible link and then study it.

In HIV there were actually over 5,000 patients in

which that viral load was validated. Actually, we

had an advisory committee on that back in the late

1990's. So, it is important to realize that what I

put up there is that this was developed in the

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1970's before any of our current regulatory

strategies.

DR. TINETTI: I understand that but are

there any other examples? Is this the only

example?

DR. POWERS: Not that I can think off the

top of my head, no. Even if there was, it is not

an example we want to replicate.

DR. WOOD: Yes, Dr. D'Agostino?

DR. D'AGOSTINO: Thank you. With regard

to asking some questions about the design, could

you say once again why the multiple wash is done in

some of the studies? Because the industry is

suggesting dropping it and there must be something

more compelling about that than that it was just

historically done.

DR. LUMPKINS: Unfortunately, a lot about

the design is lost to time and I am not well versed

in it. I can tell you what I believe to be the

case. These are multiple use products. These

studies were intended to simulate the actual use of

the products. I almost feel like they were trying

179

to get more than one piece of information from

these studies, one of them being the effectiveness

over time and the other one being the potential for

irritation.

DR. D'AGOSTINO: In the studies you were

looking at the log reduction. We don't have an

irritation measure that comes out.

DR. LUMPKINS: No, we absolutely don't but

sponsors do routinely gather that information from

those kinds of studies. If you look at the

published literature--

DR. D'AGOSTINO: No, I understand that. I

am just trying to figure out why we see it in the

recommended designs. Thanks.

DR. WOOD: Dr. Taylor?

DR. TAYLOR: I would like to thank the

presenters for their thorough presentations. They

were quite useful to me because after I read most

of the big book I was a bit more confused than I

was before I started it. I still am to some

degree. I think in the initial presentation that

Dr. Susan Johnson made, in slide 10 she pointed out

180

that the current decision thresholds are based on

NDA performance. There decisions regarding these

agents are very complex, as Dr. Powers so

eloquently pointed out. In Dr. Johnson's

presentation, she said any change should be data

driven.

I think if you are going to use that as

your threshold for changes, we are in deep trouble

because I think clinical outcomes versus these

outcomes in these trials are quite different and it

is just a complex situation of a moving target.

So, I just bring that up as a point of beginning

the discussion. I guess my optimism is not that

high that we could actually help you with changes

unless they were very specific things that you

wanted to change.

DR. WOOD: If you could get the slide up

for Dr. Fleming? Tom?

DR. FLEMING: I would like to just expand

slightly on Dr. Powers' eloquent presentation. One

of the very important observations is that when you

are looking at biomarkers, for example here, it is

181

very important to understand whether, for example,

lower levels of bacteria are associated with lower

levels of infection. But it is critical, as should

be clear from this presentation, that that just

gets your foot in the door. That doesn't begin to

validate the biomarker and it is entirely possible,

if not highly likely, that you could then induce

reductions in bacteria and not, in fact, reduce

inductions in the infection rate. In fact, the

correlation that exists there might not even lead

you to be able to conclude that it is a causal

pathway. I think that is expanding a big on what

Dr. Powers was pointing out.

A simple example of this in infectious

disease is mother to child transmission of HIV. We

know that a mother that has a higher level of viral

load has a greater risk of transmitting HIV to her

infant. We know the higher the level of the viral

load, the lower her CD4 count. So, we have strong

correlations between the mother's CD4 count and her

risk of transmitting HIV, and you can intervene

with that mother in the month before labor and

182

delivery and you can give IL2 and that is going to

spike her CD4 and it is going to do nothing to

alter the risk of transmission of HIV because it is

not the causal mechanism by which transmission is

occurring even though CD4 is highly correlated.

In essence, what we need in order to be

able to validate surrogates is precisely on this

slide. You need both columns. You need trials

that establish both the effect of the intervention

on the biomarker, in this case log reductions in

bacteria, and the corresponding reduction in rates

of infection.

Dr. Powers gave a success example of

cholesterol lowering but it is important to drill

down on that success example. Gordon did a

meta-analysis of 50 trials looking at fibrates and

vitamins and diets and showed that it was an

inappropriate surrogate because we were looking at

10 percent reductions in cholesterol that didn't

predict an effect on MI or death. Statins came

along with 40 percent reductions and we did see

benefit, although as Dr. Davidoff pointed out, some

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statins actually might have other mechanisms as

well.

So, the message here is we need an array

of trials that look simultaneously at what the

level of effect is on the biomarker and what the

level of effect is on the clinical endpoint. If

cholesterol lowering is any hint of what might

happen, lower levels of effects on the biomarkers,

maybe a 1-log reduction won't translate into

benefit where higher will. That remains to be seen

but there are precedents for that type of

phenomenon and we are only going to understand it

when we follow this slide and we have studies that

look at both.

DR. WOOD: Right, and just to add to that

and sort of supplement what Dr. Larson was saying,

we are spending as a country billions of dollars on

the implementation of these strategies without

knowing whether they work. So, justifying spending

the money to find out whether they work seems to me

a relatively trivial issue. Jan?

DR. PATTERSON: You know, talking about

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the CD4 count and the viral load and, you know, the

CD4 count not being predictive of the outcome

there, I think it is also an over-simplification to

say that antisepsis that is a clinical endpoint in

decrease of infections in patients because the most

common infections that we see and monitor are

things like surgical site infections, bloodstream

infections, ventilator-associated pneumonias that

we know have multiple other factors that are

probably more important, like the devices

themselves and all those surgical factors that Dr.

Pearson reviewed. But we also know that because of

the mode of transmission of some diseases that can

be transmitted in the hospital--conjunctivitis, for

instance, which we know can spread like wildfire

and can be fatal for immunocompromised patients, we

know that is because people who have it rub their

eyes and then touch patients and touch each other;

and influenza which we know, and we are seeing this

year, can go between patients and healthcare

workers in a hospital, and multi-drug resistant

pathogens, C. dif., all those things--you know, I

185

think that antisepsis question is more pathogen

specific than all these device-related infections

that we typically monitor. So, I think that saying

that the clinical endpoint of infections overall in

patients is a bit of an over-simplification for

looking at antisepsis itself.

DR. WOOD: But isn't that also true in

every disease? If we pick the example of

cholesterol, heart attacks are not just due to

cholesterol elevation; they are due to activation

of endothelial factors, platelet activation, and so

on and so on, all of which eventually summate to an

MI but cholesterol is one risk factor. So, it

seems to me to be true here. We are sort of

discussing this as though this is fundamentally

different from every other issue and I am not

persuaded personally that it is.

DR. PATTERSON: Well, I think that the

device aspect of it--I mean, we know that, for

instance, from bloodstream infections and

ventilator-associated pneumonias,

ventilator-associated pneumonias in particular, the

186

device itself is the major risk factor; the same

thing for urinary catheter infections, but the

infection may be more likely be due to a patient's

own flora rather than, say, a multi-drug resistant

organism that is going around if antisepsis is in

place. So, I think, you know, if we are looking at

the big picture overall of infections it is a

little bit difficult to apply that specifically to

antisepsis.

DR. WOOD: Doesn't that speak to drilling

down more to the infections? For instance, if you

are going to a strategy to prevent eye to patient

transmission you would have a specific strategy for

that. Surgical site infections would be something

different. Ventilator infections would be

something different, like, you know, HIV versus

cholesterol reductions or whatever.

DR. PATTERSON: Well, I think that is one

of the difficulties we have been discussing because

in every outbreak investigation intervention we

don't just do a single factor; we do multiple

things.

DR. WOOD: Right. Dr. Powers I think

wants to respond.

DR. POWERS: I wanted to get to what Dr.

187

Larson said and reiterate this question too. One

of the things when I showed some of the things that

may impact from an intervention going to the

clinical outcome, down at the bottom was other

factors that affect that clinical outcome. If it

turns out that those other factors--and Dr. Pearson

enumerated a number of them--are far more important

than what we are doing with antisepsis, that

answers the question of effectiveness which, in

this setting, is the paramount one. It doesn't

matter if we get rid of the organisms if doing that

has minimal impact on those other mechanisms of

disease which actually result in the actual

clinical outcome. So, saying that we are doing

something--it is circular reasoning, saying doing

something must be effective because we changed the

organisms but all those other confounders makes it

look like it is not. So, I think the effectiveness

question here, as Dr. Larson said, is very

188

important.

The other thing I wanted to get to is the

JCAHO question, having learned all this myself in a

regulatory agency. The Center for Medicare and

Medicare Services contracts to organizations like

JCAHO to accredit hospitals. JCAHO does not stand

by itself and does not make those regulations. We

have actually worked very closely in certain

situations with CMS, and they are very interested

in this issue of do these products work or not

because, as Dr. Wood said, there is an awful lot of

money getting spent in this situation. So, we have

worked with them in other situations, and we have

not discussed this particular one with them in

terms of how do we get this information that we

need in order to be able to know whether what we

are doing is actually effective.

DR. WOOD: Right. Dr. Leggett?

DR. BRADLEY: Two comments, one to

elaborate on what John and Tom have been saying

with respect to trial design and the strength of

the evidence, certainly over the past five to ten

189

years how anti-infective drugs that are

administered systemically are evaluated has become

much more stringent based on animal models, based

on mathematical modeling, in vitro characteristics

of all these anti-infectives on organisms, the

ability of drugs to get to the tissue sites--all

sorts of things. It seems as though the evolution

of this particular field began in the '70's when we

had far fewer tools by which to evaluate things.

In looking through the 1994 Federal

the issues raised by Frank regarding what the

inoculum needs to be to cause an infection, and I

saw some reference to a 1950 article in which a

study was done where volunteers received injections

of staphylococci into the skin to see how much you

need to put in. I don't think you could get that

past our human research committee these days but

animal model studies are now what we use in that

context. I couldn't find the animal models within

those several hundred pages. There was something

on shaved rabbits with iodinated iodine and shaved

190

primate backs, but nothing that you would expect

where there was a surgical animal model which I

think would be very helpful. Even though animals

aren't humans, it would be a first would be a first

step. So, the question is are there any of those

studies that were ever done in animal models that

could help us begin the process?

Secondly, there was some ambiguity on

cumulative effect of these topical antiseptics.

From the presentation that Michelle Jackson made

earlier, on slides 12, 13 and 14 there is a one-day

cumulative effect for healthcare personnel

handwashes where, as I understood it, during one

day there are ten handwashes and they are sampling

at the end of that tenth handwash which shows a

three-log reduction. That is in contrast to the

surgical hand scrub cumulative effect in which

there is a five-day cumulative effect sample. When

people say cumulative effect, those are two huge

differences to me and I am not sure which one we

are talking about.

DR. WOOD: Well, these are the proposed

191

reductions rather than clinical trial demonstrated

effects. Right?

DR. BRADLEY: Industry was saying that one

of them was in error and one of them was correct.

DR. WOOD: The real Dr. Leggett?

DR. LEGGETT: Thank you. First let me

respond to John. Yes, there are animal models for

surgical site infections. I know the Vanderbilt

group has also looked at that in the context of

Staphylococcus aureus producing beta-lactamases

that tend to degrade ceftezole more than others,

and there are mouse models of skin and soft tissue

infections, and that was going to be one of my

points too.

The other thing is in terms of other

animal models, dogs and prophylaxis, when we talk

about timing and tissue levels preceding our use of

ceftezole, you know, in a wide context for surgical

site infections. So, I think that with a little

digging we can find those things.

I wanted to go back to John's slide number

36 again in the context of what Tom talked about,

192

trying to correlate clinical endpoints and

surrogate endpoints and use of neutralizers in the

studies. If we are neutralizing clinicians' hands,

why are we neutralizing for the gloves? If there

is a difference between chlorhexidine and soap and

water, the study that was just passed to us last

week showed that, quote, reduction of CFU is the

same for just soap and water as it was for all the

other products, something doesn't jive there. So,

maybe one of the rationales for which these

products work better in terms of cutting down skin

and soft tissue infections is because there is a

persistent effect or something, and whether the

cumulative effect is just that persistence effect

magnified, it doesn't make a lot of sense

necessarily that you need both of those measures.

I think the problem with these models also

is the same problem we face with antibiotic trials.

Most clinical trials, like cholesterol, are sort of

just the person and the drug. Here we have the

wash, the person and the bugs. So, there are three

things to look at here. If we are going to look at

193

CFU reductions, the clearest thing to look at is

the preoperative scrub because each person is their

own control. Looking at some of the studies were

you would look at ten different people and give

them five different drugs, the confidence intervals

are huge. By taking a mean or median it doesn't

make any sense if somebody gains a log when they

wash their hands and somebody else loses five logs.

I don't think the mean or the median means

anything.

So, I think whatever we do decide about

these trials, we have to make them a lot tighter

and make the analysis a lot more logical. For

instance, if soap and water is our control, so our

placebo effect, and the others don't go beyond

placebo how do we get a delta? I mean, what do we

do in that sort of situation? Tom, you may want to

talk about that.

Finally, I think there is a difference

between resident pathogens and transient bacteria.

Those two questions have to be answered separately

because looking at the resident bacteria from that

194

slide that John showed, and also knowing the

history of having to be greater than 10

5 CFUs per

gram of tissue to create burn infections, it may be

different for certain pathogens, but I think there

probably is more likely to be a sigmoid curve than

a continuous curve.

DR. WOOD: Tom, do you want to respond to

that?

DR. FLEMING: Well, Dr. Leggett raises a

really key question here among many of his

important comments. One of the questions was

whatever we use for our control, soap and water,

whatever it is, can we use a non-inferiority

margin? I think one has been proposed here of

saying you have to rule out 20 percent of the

effect.

First of all, we have to be very clear

about what the effect is in the active comparator.

Secondly, we are doing two things at the same time.

We are using a surrogate endpoint which is

reductions in log, and we are using non-inferiority

trials where we are saying how much can we give up

195

before it is clinically meaningful? I often call

the combination of surrogate endpoints and

non-inferiority trials my worst nightmare because

in most cases I don't have confidence in either

one. I don't have confidence that we know the

surrogate is reliable, i.e., you have to know how

many log reductions do you have to achieve in order

to provide the benefit. Well, to do a

non-inferiority margin I not only have to know

that, I also have to know the function relationship

so well that you can tell me how much I can lose on

that before it translates into a meaningful

increase in infection. Well, as we know, we don't

have data on establishing the surrogate in the

first place, so how can you tell me how much you

can give up on the surrogate effect before it

translates into something clinically meaningful on

the clinical effect of infection rate?

Now that I have the mike, can I just

follow-up on a different issue that relates to some

of the comments? The example that I gave of

mother-child transmission of HIV and CD4 not even

196

being in the causal pathway by which the mother

transmits HIV I think is relevant to our setting

when we look at some of the examples here. When we

look at the perioperative skin preparation, when we

look at the skin-stripping research that Dr. Powers

was talking about, bacterial levels on superficial

skin layers may not be the causal pathway; it may

be at lower levels.

Dr. Patterson raises the question about

the endpoints. She was basically, in my words,

saying there may be multi-dimensional components

that influence this risk and we may be only dealing

with one component. This is reminiscent to me of

severe sepsis discussions where we have multiple

organ failures and we can go after one of those

components and people are complaining about don't

ask me to improve survival because I am only

dealing with one component. Well, if I am dealing

with only one component and that is not

sufficiently multi-faceted to translate into

clinical benefit, then the truth is I haven't

achieved clinical benefit. So, I have to do those

197

trials to find out whether or not this intended

biologic effect translates into truly meaningful

clinical benefit.

DR. WOOD: And we do know that antibiotics

administered prophylactically had a profound effect

here. So, in spite of all the other variables that

are in play--different surgeons, different

everything--they seem to be pretty dramatic.

DR. FLEMING: Could I ask one question?

DR. WOOD: Yes.

DR. FLEMING: Dr. Boyce, in your second to

the last slide you had made the comment that there

are no published data demonstrating the cumulative

activity of healthcare personnel handwash agents

and lower rates of infection. Are we saying here

that absence of evidence is evidence of absence? I

am wondering is there actual data that would

establish that we don't have--what I would really

be interested in is not is there absence of

evidence but is there evidence to indicate that

cumulative activity doesn't result in lower

infection rates.

DR. BOYCE: I am not aware that there is

any evidence of that nature either. I don't think

anyone has looked at the issue of cumulative

198

activity to determine whether it does or does not

impact on infection rates. When you look at what

happens in the hospital, when I go to make rounds

in the morning I want whatever I clean my hands

with to be working at eight o'clock in the morning,

the first wash, and I am not really too concerned

whether efficacy is greater on the 10th wash, which

is what the protocol calls for, or the 20th or 30th

or 40th all in one day, which is what really

happens in the real world. The risk of the

patients developing an infection isn't related to

whether you take care of them after your first wash

or after your 10th wash. So, frankly, I just fail

to not only see any evidence, I fail to see the

logic in requiring a cumulative activity in

something that is used 20, 30 or 40 times a day

during the work shift.

DR. WOOD: But the evidence that any of

the other measures are related to reduction in

199

infection isn't there either.

DR. FLEMING: Let me just probe that. I

think I am going to say the same thing but just to

probe the logic, if I follow what you are saying,

John, the FDA is saying that with the first wash

you want 2-log reduction and with the 10th we want

3, following what you are saying, I would like to

have 3 both times. But what they are saying is 2

and 3, and what I hear you saying is 2 is enough at

the first wash; we don't need the evidence at the

10th. I would justify that conclusion if you

showed me data that indicated that products that

give 2 at the first and 3 at the 10th don't give

added benefit in preventing infection compared to

products that give 2 at the first and 2 at the

10th.

The reality is we don't have data on any

of this, but given that we don't have the data on

any of this it is hard for me to understand how we

can advocate weakening the standard as you seem to

be advocating for the cumulative wash.

DR. BOYCE: I just don't think that the

200

rationale is there for requiring a cumulative

effect.

DR. WOOD: Let's move on. We are not

going to get more data, I don't think. Terry? And

this is the last question before lunchtime.

DR. BLASCHKE: I don't know if it is a

question or not. I think we have heard a lot of

epidemiologic data, and we have read a lot that

certainly supports the idea that both handwashing

and perhaps antibacterial handwashing is

efficacious. What we don't know is if it is

efficacious in every situation. I guess I may be

anticipating some of the discussion that we will

have this afternoon, and I think it goes along with

what you were alluding to, Alastair, and that is

that we may need to look at some sort of studies,

enrichment studies that really allow practical

carrying out of such clinical studies to generate

the kind of data that I think Dr. Fleming is

talking about. One of the things that I think

should be happening internally within the FDA,

perhaps with its advisors, is to try to figure

201

out--you know, rather than looking at population as

a whole where large samples might be required,

really to look at the clinical situations where

transmission via healthcare workers is, in fact, at

a higher frequency than we might actually be

able--I mean, FDA is faced with trying to regulate,

regulate in an even-handed way and on a level

playing field way.

DR. WOOD: Let's break for lunch and be

back at one o'clock. We have greatly overrun this

morning because the talks overran a lot. I have

asked Shalini to get us a timer for this afternoon,

which I will enforce, and I strongly suggest that

the FDA and all the other speakers make sure that

they get these talks into whatever the agreed time

is. In fact, if there are ways to get these talks

reduced, as we have used up so much time this

morning, I think we should try and do that over the

lunch break. So, let's make sure that you don't

overrun and, if possible, underrun because the

timer will be running. Let's be back here ready to

start at one o'clock.

202

[Whereupon, at 12:10 p.m., the proceedings

were recessed for lunch, to resume at 1:00 p.m.]

203

A F T E R N O O N P R O C E E D I N G S

Open Public Hearing

DR. WOOD: We will now begin the open

public hearing but I must first read the following:

Both the Food and Drug Administration and the

public believe in a transparent process for

information gathering and decision-making. To

ensure such transparency at the open public hearing

session of the advisory committee meeting, the FDA

believes that it is important to understand the

context of an individual's presentation. For this

reason, FDA encourages you, the open public hearing

speaker, at the beginning of your written or oral

statement, to advise the committee of any financial

relationship that you may have with any company or

any group that is likely to be impacted by the

topic of this meeting. For example, the financial

information may include a company's or group's

payment of your travel, lodging, or other expenses

in connection with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of

your statement to advise the committee if you do

204

not have any such financial relationships. If you

choose not to address this issue of financial

relationships at the beginning of your statement,

it will not preclude you from speaking.

The first speaker is Dr. Felton. You have

fifteen minutes and the next speaker has five

minutes.

DR. FELTON: Good afternoon.

[Slide]

The title of my talk I guess is difficult

but it is proposal for additional intended uses and

performance criteria for the TFM: Topical

antimicrobials for skin site preparation prior to

the placement of percutaneous medical devices

intended to remain indwelling. It is a fancy way

of saying essentially that if you put a device

through the skin, what performance criteria should

you have for the topical antimicrobial.

[Slide]

I am Steve Felton. I am staff scientist

for BD, a major manufacturer of topical,

pharmaceutical and medical device products.

[Slide]

We have gone over this a lot this morning

so I won't go through it, except for the "and"

205

part. Under patient preoperative skin preps there

is a subheading, pre-injection, the 1-log reduction

in surrogate endpoint. I would like to propose

that we have some kind of performance criterion set

down in the monograph which would include the

information essentially that there is no worse or

non-inferiority performance standard for topical

antimicrobials with regard to risk for infection

for indwelling devices.

[Slide]

I am trying to make this as quick as I

can. Here are some of the examples of the devices

that may be included in this category. You have

short-term peripheral catheters, central venous

catheters, peripherally inserted central catheters,

surgical pins, intraosseous infusion devices,

epidural catheters for chronic pain management and

devices for continuous ambulatory peritoneal

dialysis. If you got an earlier version of my

206

slides, it will have abdominal and that was wrong.

[Slide]

These devices have certain things in

common. They all go through the skin and they keep

the hole from healing after you put them in an

leave them in. These devices can remain in place

for as little as a few hours for short-term

peripheral catheters to literally a year or more.

[Slide]

These devices have significant risk of

infection and there is information to predict the

risk as it relates to the time and/or placement of

the device. Topical antimicrobials applied to the

site prior to inserting the device have been

demonstrated to reduce the risk of developing an

infection and the relative efficacy of the topical

antimicrobials is inversely related to the risk of

infection. By the way, these citations on this

slide at the bottom are the same ones that Michelle

Pearson was referring to earlier in the question

and answer session.

[Slide]

I am going to use the special case of

catheter-related bloodstream infection just to try

to develop my argument for why this is important.

207

This particular group of vascular catheters is used

for administration of fluids, monitoring and

collection of blood samples. These devices have a

significant risk of infection. In the better

hospitals in the U.S. it is usually stated around

3-5 percent. In other institutions in the United

States you are talking about 10 percent. Now I am

dealing specifically with central venous catheters,

of course. You go to Europe and you are talking

about 25-40 percent infection rates. They use the

products a little differently over there.

These infections are not insignificant.

There have been estimates of between 296 million

and 2.3 billion dollars per year in additional

medical costs to treat and otherwise deal with

these infections. Mortality is between 5,000 and

20,000 cases per year.

[Slide]

Topical antimicrobials are critical for

208

placement of these devices. The major cause of

these infections is from skin microorganisms,

although I will say that there are minor causes

such as infusate contamination and also breaks in

the line at the hub, etc. However, the topical

antimicrobials are not intended to deal with those.

In these studies that are shown here, they

have proposed, especially Maki and Widmer, a large

chain of evidence that skin microorganisms not only

initiate these infections by colonizing the skin at

the insertion site, and these bugs are present

there either due to insufficient antisepsis or the

bugs are there because the site is recolonized from

skin bacteria adjacent.

[Slide]

These microorganisms colonize the

subcutaneous and intravascular portions of the

device which, if no intervention occurs, can result

in a local infection. This can then progress to

clinical signs, although in central venous

catheters the clinical signs of local infection are

not so predominant. Sometimes you can have an

209

infection that goes straight to catheter-related

bloodstream infection with full-blown symptoms at

the systemic level, and this does have significant

morbidity and mortality and the added healthcare

expenses. You are talking about $5,000 to $40,000

in the ICU for each one of these incidents.

[Slide]

The CRBSIs have been studied extensively.

I am just going to mention that there are some

methods out there that have been developed and

independently verified that seem to ways to

diagnose catheter-related bloodstream infections,

and investigators have shown that the efficacy of

the topical antimicrobial can be evaluated in a

clinical setting, and the investigators have

compared, for example, alcohol with povidone-iodine

to chlorhexidine in a number of these studies.

These, again, are the same references that Dr.

Pearson referred to.

[Slide]

So, in this presentation I have primarily

discussed central venous catheters as these devices

210

are the most extensively studied. These devices

have significant infection rates, 3-5 percent at

the better institutions, and significant mortality,

5-20 percent of the subjects with clinical CRBSI.

These infections are estimated to increase the U.S.

healthcare cost by 2.3 billion dollars a year, up

to that amount.

However, percutaneous medical devices are

all similar in that they remain in the hole through

the skin barrier. Therefore, any intended use

labeling or performance criteria developed for

CRBSI should be applicable to other percutaneous

medical devices. Unlike the current performance

criteria in the TFM, the efficacy of topical

antimicrobials intended to reduce indwelling

percutaneous medical device infections can be

demonstrated in clinical trials in the intended use

population. Therefore, the TFM should identify the

need for and establish performance criteria for the

clinical evaluation of indwelling percutaneous

medical devices. Thank you.

DR. WOOD: Just help me understand, you

211

are not suggesting--or are you suggesting that you

should not do clinical trials?

DR. FELTON: I am suggesting that for this

particular indication clinical trials are

indicated.

DR. WOOD: Okay. The next speaker is Dr.

Ijaz, who is from Microbiotest. He has five

minutes.

DR. IJAZ: Good afternoon. First of all,

I would like to thank the organizers for providing

me this opportunity to express my views on this

topic, which is hand hygiene and viral surrogates

to demonstrate efficacy of topical agents against

viruses.

What I want to raise here is that we have

been discussing microbiological surrogates but we

have not touched viruses and that is what I want to

raise. I have only five minutes so I will just

make my point very briefly. We know the

significance of viruses, and viruses in general

continue to emerge and re-emerge. If one looks at

the past 30 years, we have seen from the '70's a

212

focus on enteric viruses, hemorrhagic fever

viruses, and in the 1980's retroviruses and in the

'90's, you know, sin nombre and more hepatitis

viruses, and more recently we have seen influenza

virus and SARS emerge.

So, the importance of viruses, from a

morbidity and mortality point of view, globally is

well documented, and these viruses continue to

emerge. Specific to this meeting, in the U.S., 5

percent of nosocomial cases are due to viruses and

greater than 32 percent are in the pediatric wards,

of which RSV is the most common.

Hands play an important role in spread of

many virus infections and proper handwashing by

care givers and food handlers for interruption of

spread of viruses and other type of pathogens is

universally recognized. This has been demonstrated

in intervention experimental studies, as well as

studies conducted in the clinical setting,

particularly dealing with the rotavirus infections

and rhinovirus infections. Infectious viruses have

been recovered from naturally contaminated hands.

213

As a case in point, I can document here these

studies dealing with hepatitis C virus, RSV, rhino

and rotaviruses.

Now, although the FDA's Center for Food

Safety and Nutrition recognizes the significance of

viruses being disseminated by food handlers and

healthcare workers, the role played by hands in

this regard in the TFM has not been addressed, and

that is the issue that I want to raise.

Proper antiseptic procedures for use for

decontamination of hands can interrupt such

disseminations. The question is do viruses survive

on hands? We looked, in a very simple, small

experiment, at the survival of rhinoviruses and

BVDV which is used as a surrogate for hepatitis C

on finger pads contaminated with these viruses. Of

course, all of these studies that I am reporting

here, they have gone through IRB approval. You can

see that both of these viruses may survive well on

the finger pads of human subjects for 20 minutes.

Studies done at the University of Ottawa indicate

that some naked and some animal viruses survive

214

more than an hour on hands.

Here is a commercial from CDC, which we

saw in the morning session as well. When we are

thinking about testing topicals and their activity

against viruses, there are a number of methods

which are out there, and I am picking the one which

I believe is better than the other ones to

demonstrate efficacy of these products. The

methods that I am referring to have been peer

reviewed. The data generated by these methods have

been published in peer reviewed journals and these

methods are also the ones that have been approved

by ASTM.

I am not going to go into details of this

method which deals with the use of finger pads to

study the efficacy of the products.

DR. WOOD: I am afraid your time is up.

Let's move on to the next speaker, who is Dr.

Osborne, from the FDA.

The Quest for Clinical Benefit

DR. OSBORNE: Good afternoon.

[Slide]

I am Steve Osborne, a medical officer in

the Division of Over-the-Counter Drug Products. I

have shortened my presentation per request of the

215

Chair. You will find all the slides in the

handout. I have also shortened how much I am going

to speak about each slide. If there are any

questions, I will be available later. The title of

my presentation is the quest for clinical benefit.

[Slide]

We have heard Tia Frazier and some other

members mention that obtaining clinical data from

clinical trials of healthcare antiseptics can be a

daunting task. Two of the issues that we face at

FDA in evaluating healthcare antiseptics for the

monograph are do clinical trials assessing

infection rates provide definitive evidence of

clinical benefit?

[Slide]

And, does the clinical evidence link

surrogate endpoints with clinical benefit?

[Slide]

First I would like to run through the

216

major categories of healthcare antiseptics and give

a quick example of each. The alcohol symbolizes

ETOH or IPA for isopropyl alcohol found in a Purell

handrub or Purell instant sanitizing handwipe.

Chlorhexidine gluconate, or CHG, is found as 2

percent or 4 percent. The trade name is Hibiclens

or Hibiprep--iodine or iodophor--we all know PI or

betadine. Triclosan is found in the Gojo

antimicrobial lotion soap.

[Slide]

The quaternary ammonium compounds, as an

example there is benzalkonium chloride, known as

Zephiran. Chlroxylenol is found in the wash and

dry towelette; and triclocarban is found in the

common Safeguard soap.

[Slide]

I won't dwell on this slide but it shows

the antimicrobial spectrum of the common antiseptic

categories. It is from the CDC 2002. What the

slide shows is that the antimicrobial spectrum is

broad for most of these products, except for

gram-negative activity with the phenols and

217

gram-positive activity with the quaternary

ammonium. The time frame fast, intermediate or

slow is not exactly defined but for fast you can

think of as seconds; intermediate as seconds to

minutes; and slow as minutes to hours.

[Slide]

The citizen's petition and comments were

submitted to FDA in 2001 and 2003 by the industry

coalition made up of the Soap and Detergent

Association, or SDA, and the Cosmetic, Toiletry,

and Fragrance Association, or CTFA. A citizen's

petition is the process whereby the public or

someone can ask that FDA change the monograph. The

coalition submitted references and requested that

FDA lower the efficacy standards.

[Slide]

Two broad categories were encompassed by

155 abstracts and articles. They were invasive

procedures such as surgery, or non-invasive

procedures such as using a handwash to reduce

nosocomial infections.

[Slide]

Of the 155 articles and abstracts, 58

percent covered handwashes; 26 percent were patient

preop preps; and 16 percent were surgical scrubs.

218

Overall, the weight of the evidence of clinical

benefit was not persuasive for changing the current

efficacy criteria. As a common thread, there was

no link between surrogate endpoints and infection

rates.

[Slide]

This is a summary of some of the

limitations in these studies when you look at them

in the context of our monograph process. Not each

study had each limitation; some had more than one.

The common thread, as mentioned, was that surrogate

endpoints were not correlated with the clinical

outcome. Some of the studies were not randomized.

They might have gone back 30 or 40 years in some

instances. A placebo was not used in some of them

or a control. On occasion they were retrospective,

without a comparator or whatever happened before

that period of time.

Multiple confounders might have been

219

present. You can think of that as when you

introduce a new healthcare antiseptic, for example

a handwash, but at the same time introduce a

training program involving posters, reminders,

brochures, etc., such that when you later try to

look at infection rates you are not sure if what

you have done is simply helped the infection rate

with the antiseptic or whether you have changed the

behavior of the subjects in the test.

Inadequately powered, and we will see that

in one of the studies by Luby. No statistics.

That is not so common in the last few years but it

does make it difficult to test your hypothesis if

that is the case. Lack of standardization of

product use--this is complicated. When you

introduce, for example a handwash, you don't always

have the capacity to regulate how much of the

handwash people use, nor how long they use it in

terms of the washing cycle. Irregular patterns of

data collection--one study looked at 26 hospitals

using a healthcare antiseptic and only 13 returned

data for later analysis.

Failure to address the TFM indication.

This is a complicated thing but if the study is

looking at something that is not specifically the

220

way the TFM has the indication for the handwash

patient preop prep or surgical scrub, then we

cannot use that study in making a regulatory

decision. Examples would be if a healthcare

antiseptic is used in acne applications or, as we

heard earlier, in a patient preoperative shower,

which is not a TFM indication.

I am going to show some examples of

studies from the industry coalition and from three

literature reviews performed at FDA. I would like

to emphasize that these studies are notable

examples trying to analyze the answers to important

clinical questions. They are not being criticized.

However, for one set of the study or other they

have a limitation where, by the design of the

study, we at FDA are not able to use the results

from it to make a regulatory decision for the

monograph.

[Slide]

Maki et al., in 1991, looked at catheter

infections and Luby et al., in 2002, looked at

impetigo. First the Maki study.

[Slide]

It was randomized, unblinded study in 668

subjects with IV catheters, all of which were

221

central venous or atrial. Two percent

chlorhexidine gluconate was compared with 10

percent povidone-iodine and 70 percent isopropyl

alcohol. The agents were applied before insertion

of the catheter and then every 48 hours thereafter

until the catheter was removed.

[Slide]

When the catheter was removed, endpoints

looked at were the local infection rate and

bacteremia. For the local infection rate, it was

designed as greater than 15 colony-forming units at

the catheter tip upon removal, and that is

synonymous with catheter colonization. The

infection rate locally was 2.3 percent for CHG

versus 7.1 percent for alcohol and 9.1 percent for

PI, and that was statistically significant in favor

222

of chlorhexidine gluconate.

The harder endpoint of bacteremia had a

total of 10 cases out of the 668 catheters. This

is a rare occurrence, in other words. One was

found with CHG, 3 with alcohol, 6 with

povidone-iodine, and the difference was not

significant. As you can see, when you have a low

incidence of an endpoint it is difficult sometimes

to show a difference between products.

[Slide]

However, there was no correlation between

reduction of bacteria at the site of the catheter

insertion with the resulting infection rate in the

individuals receiving the catheter, and therein

lies the limitation if you try to apply it to what

we need at FDA.

The application of the antimicrobial

post-catheter insertion limits the ability to

relate to a monograph application, which is to

apply the product, insert the catheter and then

perhaps later simply to look at infection rates.

Applying it every 48 hours confounds the result.

[Slide]

Luby, I am going to pass over because of

time.

223

[Slide]

Dr. Michelle Jackson, who we heard from

earlier, performed a literature review on surgical

hand scrubs. Over 300 articles were screened for

clinical benefit. None conclusively linked

reduction in bacteria with reduction in infection

rates.

[Slide]

Examples are Bryce et al., 2001, that

looked at a 70 percent isopropyl alcohol leave-on

product in 70 scrubs by surgeons, the people who

know how to do the scrubbing. This was an in-use

hospital evaluation and 14 mL of the product was

used over 3 minutes and compared to 4 percent CHG

and 7.5 percent PI in reducing bacteria. The

endpoint was postop bacterial counts on the hands

of the surgeons. No infection rates were studied

in the patients.

[Slide]

Parienti et al., 2002, performed a

hand-rubbing with alcohol leave-on solution and

looked at the 30-day surgical site infection rate

later. This was a randomized, crossover

equivalence trial comparing the 75 percent alcohol

leave-on product with the standard 4 percent PI and

224

4 percent CHG as surgical scrubs. Six surgical

services and 4,287 patients were looked at.

[Slide]

The surgical site infection rate was 2.44

percent with alcohol versus 2.48 percent with the

combination of PI pus CHG. That was not

significantly different. The scrub time compliance

was better with the alcohol rub. So, that goes

along with what some other people have said, that

the alcohol might be better tolerated. Surgical

site infection microscopic was not provided, and

the surgeon who reported the surgical site

infection in the patient was not blinded.

[Slide]

Another member of our division, Dr. Collen

Kane Rogers, performed a literature review of

225

healthcare personnel handwashes from 1994 to 2004,

and 222 studies were reviewed for clinical benefit

or efficacy. None showed a definitive link between

bacterial reduction and reduction in infection

rates.

[Slide]

An example of an interesting study is

Swoboda et al., 2004. This was a 3-phase, 15-month

evaluation incorporating an electronic monitor,

that is, to see if the patients were actually

washing their hands and then to voice prompt and

remind them to do so. So, approximately a 6-month

monitoring period, followed by voice prompt, and

then a monitoring period was conducted. Compliance

with handwashing improved by 35 percent in the

second phase versus the first, and by 41 percent in

the third phase versus the first. Patients were

colonized--not necessarily sick but colonized by

either methicillin-resistant Staph. aureus or

vancomycin-resistant enterococcus in 19 percent of

the initial phase, 9 percent of the second, 11

percent of the third phase, indicating that perhaps

226

there was a trend towards lower colonization.

Again, you don't know though whether this is a

change in behavior but that is what the study was

looking at.

[Slide]

Another member, Dr. Peter Kim, from the

Division of Anti-Infective Drug Products, looked at

400 articles in the patient preoperative

literature, and in this review searched for

bacterial log reduction data post scrub compared

with pre-scrub, and then in the same article,

searched for surgical site infection rates.

[Slide]

The majority of these studies were

performed in animals and that answers the question

brought up by a panel member earlier. None of

these studies found a link between colony-forming

units of bacteria in surgical site infections.

[Slide]

A secondary topic looked at in this review

addressed the question is there a minimum number of

bacteria in a wound that predisposes to infection?

227

This is a 100,000 bacteria or 10

5 rule that we have

all heard about through the years. Of course, this

may vary with the type of bacteria, 10

5 Staph. epi.

is not the same, of course, as even 100 shigella.

[Slide]

On this threshold for infection, Kass, in

'57, looked at 2,000 patients for pyelonephritis

and found all of them had over 100,000 bacteria,

and a similar thing with UTI patients.

Krizek, in 1967, showed a 94 percent graft

success rate when the pre-graft bacterial count was

less than 100,000/gram of tissue. That was brought

up earlier by a panel member. And, the rate would

go as low as a 20 percent graft success if there

were more than 100,000 bacteria/ gram.

[Slide]

From this review, Cronquist et al. has an

interesting study in 2001 of 609 neurosurgery

patients undergoing craniotomy or

ventriculo-peritoneal VP shunt. This study looked

at pre-scrub and post-scrub bacterial counts from

the head and the back.

[Slide]

From the head, pre-scrub was 4.13 log and

from the back 2.39 log of bacteria. Post-scrub was

228

0.63 and 0.54. The agents used in this study were

PI scrub followed by isopropyl alcohol wipe off and

then a PI paint.

[Slide]

Twenty surgical site infections were

noted, 19 from the craniotomies, and these involved

mostly staph. species and Propionibaceterim acnes.

No correlation was found between the pre-scrub or

the post-scrub counts in surgical site infection

rates. Remember from that slide that all of these

counts were less than 105.

[Slide]

So, I return to two key issues FDA faces,

do clinical trials assessing infection rates

provide definitive evidence of clinical benefit?

[Slide]

And, does the clinical evidence link

surrogate endpoints with clinical benefit? These

are issues for the panel to discuss.

I would like to next introduce Dr. Thamban

Valappil, from the Office of Biostatistics in the

Division of Biometrics III, who will discuss some

of the statistical issues.

DR. WOOD: Thanks very much for getting

that done so quickly.

229

OTC-TFM Monograph Statistical Issues

of Study Design and Analysis

DR. VALAPPIL: Thank you, Dr. Osborne.

Good afternoon.

[Slide]

I am Thamban Valappil, statistician in the

Division of Biometrics III.

[Slide]

Now I will go over some of the statistical

issues and limitations of the study design and

analysis in the OTC TFM monograph. The outline of

my presentation is as follows: introduction;

summary of statistical issues; current TFM trial

design and analyses with surrogate endpoints;

statistical issues of study design and analyses;

options for trial design and efficacy criteria

230

using surrogate endpoints.

[Slide]

Introduction--previous presentations on

issues involved in validating surrogate endpoints,

in the absence of clinical trials data, FDA still

needs to address current products under review.

This talk discusses issues related to analysis of

data obtained on surrogate endpoints. It does not

address clinical relevance of statistical findings

or differences in analysis of data based on

surrogate endpoints.

[Slide]

Now I am going to discuss briefly the

summary of statistical issues. The primary

endpoint is the log reduction in bacterial counts

from baseline. It is a surrogate endpoint and its

clinical relevance has not been validated, as I

said earlier.

Data analysis and variability

issues--there are a couple of different ways we can

look at the data. One way is using the binary

endpoint, which is the percent of subjects who meet

231

the threshold log reduction and the other one is

using log reduction in bacterial counts. However,

in each of them there are advantages and

disadvantages.

Log reductions are continuous, numerical

data with relatively large variability. The

current TFM recommends mean as the measure to

analyze the spread in the data. However, median

would be another possible option although it is not

mentioned in the current TFM.

Study design and controls--currently, a

non-comparative study design has been used in which

the test product is not directly compared to the

active control. Vehicle and active controls are

mentioned in the current TFM, however, the role of

these controls is not well defined.

[Slide]

This table shows a brief layout of what is

available in the current TFM. Use of various

controls is mentioned under the surgical hand scrub

section of the monograph. But for preoperative

skin preparations and healthcare personnel handwash

232

only active control is recommended.

For comparing the mean log reductions

t-tests are recommended. Under preoperative skin

preparations, a confidence interval approach based

on the difference in success rates between the test

product and the active control has also been

documented.

However, it is important to note that in

the current TFM the efficacy criteria do not use

any of these statistical tests, except using the

mean log reductions to meet a threshold value. The

last column displays the sample size required for

each of these documents.

[Slide]

A brief layout of the current TFM

recommendations are as follows. TFM currently

recommends randomized and blinded trials, also

recommending use of active, vehicle and/or placebo

controls. However, in the current TFM a

non-comparative study design is used in which the

test product is not directly compared to the active

or vehicle control. Mean log reduction meeting the

233

threshold log reduction has been used to

demonstrate efficacy.

[Slide]

Although vehicle and placebo controls are

mentioned in the current TFM, the majority of the

NDAs only have test product and active control

arms. Active controls have only been used for

internal evaluation of the study methods. Efficacy

assessment does not include a direct comparison of

test product performance to active control, vehicle

or placebo controls.

[Slide]

Statistical issues of study design and

analysis--currently, the TFM recommends using log

reduction from baseline as the primary endpoint and

it can be influenced by few extreme observations.

As a suggestion, we could discuss median log

reduction as another possible option. Median is

less sensitive to extreme log reductions or

outliers. It is shown here in parentheses as the

current TFM does not specify it.

[Slide]

The efficacy criteria in the current TFM

are based on point estimates and do not include

confidence intervals to evaluate variability.

234

Consequently, a few extreme observations can

potentially drive the efficacy results.

[Slide]

Now let us look at this figure which shows

the log reduction in bacterial counts using the

threshold approach. This is just an example to

illustrate the potential problems if the

variability of the data has not been considered.

Here the threshold is set to logs, as marked by the

blue dotted line. There are 18 subjects and 14/18,

78 percent, of the subjects, marked in red, have

failed to meet the threshold. As you can see, only

4 subjects, marked in blue, are basically driving

the results to meet the required log reduction.

Instead of mean, if we use the median, which is 1.7

log, this study would have failed to meet the

threshold log reduction.

[Slide]

Now let us look at a few examples to

235

illustrate the importance of controlling

variability and the roles of active and vehicle

controls. In this figure, for illustrative

purposes, if we look at the point estimates, as

done based on the current TFM, the test product may

seem better than the active control however, when

we consider variability, the confidence interval

for the test product and the active control

overlaps, as you can see in the next figure.

[Slide]

As you can see here, the confidence

intervals for the active control and the test

product overlap and both are better than vehicle.

As Dr. Powers has pointed out, it is not how you

define the threshold but how you analyze the that

data is important.

For simplicity, in this figure the

confidence intervals of the individual products are

displayed rather than the confidence intervals

around the treatment differences. It should be

noted that demonstrating superiority in this

situation is a mechanism to control variability but

236

that does not address the issue of clinical

relevance. Let us take another example.

[Slide]

Here the confidence interval for the test

product and the active control overlaps and it

meets the threshold based on the current TFM.

However, if we introduce the vehicle control the

test product appears no better than vehicle.

Therefore, it is important to incorporate a vehicle

or placebo control in the trial design.

[Slide]

The current TFM has recommended using

binary outcomes, however, the efficacy criteria are

not based on binary outcomes. Accordingly, a

subject will be classified as a success or a

failure based on meeting the threshold log

reduction.

These are advantages and disadvantages in

using this approach. The advantages are that the

outcome will be centered on number of subjects and

not on organisms, which provides greater confidence

that it is meeting the threshold. Also, the effect

237

of variability will be reduced. However, one

disadvantage will be that this method does not

differentiate the magnitude of log reductions among

those who meet the criteria for success.

[Slide]

Let us look at this example. In this

figure, based on binary outcome, 90 percent of the

subjects, marked in blue, meet the threshold

reduction and provide greater confidence that it is

meeting the threshold compared to the small chart,

as you can see in the upper left-hand corner, in

which only a few subjects meet the threshold.

[Slide]

Now let us consider one of the agency

approved study data. This table is based on an NDA

approved for surgical hand scrubs. All met the

required log reduction except for active product

number 2 on day 5. Also, the success rates widely

vary among the 3 products and mask the difference

among the median and mean. On day 2, if you

notice, the success rate goes from 100 percent for

the test product to 45 percent for the active

238

control product number 2, as highlighted. however,

they all meet the required mean log reduction. You

will also notice that if the success rate is

higher, mean and median does not make much of a

difference. But if the success rate is low, the

median is much more conservative since it is not

influenced by extreme outliers.

[Slide]

Sample size issues--in the current TFM

sample size is estimated based on allowing a test

product to be as much as 20 percent worse than the

active control in the mean log reduction. However,

the basis for the 20 percent margin is not clearly

stated. Majority of the current submissions do not

follow the recommended sample size as specified in

the TFM and only use a sample size of about 30

subjects per treatment arm.

[Slide]

There are several issues that need to be

addressed before the design and efficacy criteria

are discussed. The various issues are, issue

number one, how to analyze the data obtained on the

239

surrogate endpoint of log reductions in bacteria.

Issue number two, how to take into account

the variability in the data collected when

measuring effect of the product.

Issue number three, how to take into

account the variability in the test methodology.

[Slide]

Now let us go through the issues in

detail. The first issue is how to analyze the data

obtained on the surrogate endpoint of log

reductions in bacteria. There are three options,

mean, median and percent of subjects who meet the

threshold. Please note that these are all for

discussion.

As we know, mean log reduction can be

easily influenced by extreme observations.

However, median log reduction is less sensitive to

outliers or extreme observations. For percent of

subjects who meet the log reduction criteria the

outcome is centered on number of subjects who meet

the threshold and may provide incentive to study

conditions of use that provide highest success

240

rates. Also, it provides greater confidence that

it is meeting the threshold.

[Slide]

The next issue is how to take into account

the variability in the data collected. There are

two options. Option one, we can examine the

outcomes as defined on the previous slide with a

threshold for lower bound of the confidence

interval. There is a pro and con in using this

method. The pro in using this will be an

improvement over examination of point estimates

alone. The con is that it does not take into

account the variability in the method.

The second option is to examine confidence

intervals around the treatment difference between

the test product and some control. Her the pro is

that it allows for examination of variability in

the methodology across treatment arms. The con is

that it may require a larger sample size for

products with lower success rates.

[Slide]

Issue number three, how to take into

241

account variability in the test methodology. There

are two options. Option one is equivalence or

non-inferiority showing that the test product is no

worse than the active control by some clinically

meaningful margin. The pro is that it allows for

comparison with an active control treatment to rule

out loss of effect relative to active control. The

con is that it lacks constancy of effect of active

control in previous studies, possible overlap of

effect of active and test product with the vehicle

and, hence, no basis to select a clinically

meaningful non-inferiority margin.

The other option is to test for

superiority of test product to the vehicle and

superiority of active control to the vehicle. The

pro is that given lack of constancy of effect with

both active control and vehicle control, it allows

internal validity of comparisons. The con is that

it may require a larger sample size than current

TFM standards. How large a sample size will depend

on the product efficacy over the vehicle.

[Slide]

Controlling variability in test

methodology--to address these issues, let us

consider a 3-arm trial design which includes the

242

vehicle, the active control and the test product.

It is important to note that the test product and

active control both demonstrate superiority to the

vehicle. Also, it is important to note that there

are multiple sampling times and, accordingly, there

is multiple hypothesis testing involved. The

superiority of the test product will be

demonstrated only if all tests are statistically

significant.

[Slide]

This figure shows the sample size

requirement for the superiority test over the

vehicle using a binary endpoint. As success rates

increase, as you can see in the figure, and the

treatment difference over the vehicle is large, the

required sample size is much less.

For example, if the success rate for the

test product is 90 percent and the treatment

difference compared to vehicle is 10 percent, then

243

a sample size of 199 subjects per treatment arm is

required. Similarly, for a 20 percent treatment

difference, 62 subjects, and for a 30 percent

treatment difference, 32 subjects are required per

treatment arm. Therefore, the message is that more

effective products require smaller number of

subjects.

[Slide]

With this, I conclude my presentation and

thank you for your attention. Now I would like to

thank Dr. Daphne Lin, Statistical Team Leader and

Acting Deputy Director of the Division Biometrics

III, for her valuable contributions. Thank you.

DR. WOOD: Could you put slide 13 back up?

I don't understand why you would ever want to do a

non-inferiority trial for a surrogate like this. I

mean, surely you would always do it against

vehicle.

DR. VALAPPIL: I am not proposing a

non-inferiority trial. This is just an example to

illustrate--

DR. WOOD: Yes, I mean, the reason you

244

normally would do a non-inferiority trial is where

it would be unethical to do a study.

DR. D'AGOSTINO: This is not a

non-inferiority. The active is just for internal

validation. The active doesn't have to be compared

against the test.

DR. WOOD: Oh, I see.

DR. D'AGOSTINO: It is confused I think

the way he has it, but isn't it just--

DR. WOOD: Let me rephrase the question.

It seems to me there is no justification for ever

not doing a study in a surrogate where you don't

have just the vehicle as the control. All these

numbers on your last slide look pretty trivial to

me given the numbers we see in other studies, and

this is a very easy study to do so I don't see what

the issue is here.

DR. FINCHAM: Alastair, may I ask a

question?

DR. WOOD: Yes.

DR. FINCHAM: On your slide 16 you go

through study number 1. Is this hypothesis data?

DR. VALAPPIL: No, this is real data.

This is the data collected from one of the NDAs we

have approved.

245

DR. FINCHAM: Is it confidential or is it

not referenced because of that?

DR. VALAPPIL: I cannot address the study.

DR. WOOD: So, where is the vehicle

control there? DR. VALAPPIL: Actually,

number two is the vehicle control; but it is not

actually vehicle.

DR. WOOD: That is a study you received

that didn't have a vehicle control in it? Is that

right?

DR. VALAPPIL: The purpose of this slide

is to show you the difference in the mean and

median, and also to find out the difference in the

success rates.

DR. POWERS: You are pointing out an

important point, there are no vehicles in these and

that is what Dr. Wood is actually asking.

DR. WOOD: I thought that was the question

I was asking and I am getting a very confused

246

answer. Are you looking at studies here that do

not contain vehicle control? Yes or no? Yes. Is

that right?

DR. D'AGOSTINO: But can I ask a question?

Are you suggesting that in the future studies

should be done with the real vehicle, or are you

saying that what you are calling a vehicle is

somehow or other a low-level active?

DR. VALAPPIL: No, no, that is not what we

are proposing, but I think it would be better to

have the vehicle incorporated in the trial design

so we know what is the product effect compared to

the test product.

DR. WOOD: Put up slide 7 again. As I

read what you have there, it says the current

TFM--maybe I am reading it wrong--recommends that

you can do a study just with active control. Am I

reading that wrongly?

DR. VALAPPIL: No. What I was trying to

tell you is that--

DR. WOOD: No, wait, are we reading that

wrongly? Can you do a study right now with just

247

active control?

DR. JOHNSON: Yes.

DR. WOOD: Yes is the answer.

DR. D'AGOSTINO: But you don't have to

contrast the active with the test. You ask the

question does the active exceed the threshold and,

if it does, you say you have internal validation.

Then you ask does the test exceed the threshold,

and you never make the comparison of active with

the test. Is that right?

DR. JOHNSON: That is correct also.

DR. WOOD: I guess that is the point I am

making, it is crazy.

DR. D'AGOSTINO: Can I just jump in here?

If you do a test where you have the vehicle, the

active and the test, you look at the active versus

vehicle; you look at the test versus vehicle; and

you hope both of those are significant. At that

point, you still also need the log reduction for

the clinical, but we don't know what clinical

significance means because we don't know how to tie

it, but that would be one possibility. Then you

248

would have to do that for every single time period.

DR. VALAPPIL: Right.

DR. WOOD: We can take questions for all

of these now. Any other questions?

DR. FINCHAM: I don't think our speaker

ever got the chance to answer the question that was

asked. Could he do that?

DR. VALAPPIL: Yes, what was the question,

please? DR. FINCHAM: Well, I think

everybody else answered the question that was meant

for you but I don't think you answered the

question. I don't think he had a chance.

DR. VALAPPIL: If you can repeat the

question I will be able to answer that.

DR. WOOD: Which question? Sorry?

DR. FINCHAM: Well, I think that you both

have dealt with it and you referred to the slide

that is up there now, and I just didn't know

whether you agreed with what was answered.

DR. POWERS: Can I help with this? There

are several options within the TFM as to what you

can do. Believe me, it is confusing to us too. In

249

the statistical section of the TFM it states that

you can do essentially what is a non-inferiority

trial based on a surrogate endpoint with a 20

percent margin. In other places in the TFM it

states that you just need to meet a log reduction.

So, what it really does is present you

with several options. There is also one part in

the TFM that says you can also use vehicle but it

doesn't tell you what to do with the information

and the vehicle. So, if it is confusing to you, it

is because it is confusing and there are several

options put out there and it does not specify which

one you should use.

DR. WOOD: It is always reassuring to not

be uniquely confused I guess. All right, any other

questions?

DR. SNODGRASS: I just have a brief

comment. It sounds like we should go back to the

"paperwork reduction act." You know, you just go

back to the drawing board and get rid of the past

TFMs and you start over.

DR. WOOD: It is two o'clock; don't get

250

too ambitious!

[Laughter]

All right, let's move on to the next

speaker, and the next two speakers are going to

present the industry's view, and the first speaker

is George Fischler, and we are generously going to

give each of you 23 minutes, which is one minute

more.

Industry Presentation

The Value of Surrogate Endpoint Testing for Topical

Antimicrobial Products

DR. FISCHLER: And just to start this off,

how do you think we feel?

[Slide]

Good afternoon. I am George Fischler, the

manager of microbiology for the Dial Corporation.

[Slide]

Today I am speaking on behalf of the Soap

and Detergent, and Cosmetic, Toiletry and Fragrance

Association Industry Coalition. The SDA/CTFA

coalition has previously submitted several detailed

comments and has had extensive interchange with FDA

251

in response tot he June 17, 1994 tentative final

monograph, the TFM, for healthcare antiseptic drug

products. I will be speaking on the value of

surrogate endpoint testing. I will then be

followed by Jim Bowman of Hill Top Research, who

will talk on statistical issues. We will then be

happy to answer any questions.

[Slide]

During this time, the science surrounding

topical antimicrobial skin antiseptics has

continued to advance. Much of the original

analysis done on the use of healthcare antiseptic

drug products was developed in the 1970's. Both

infection control practice and test methodologies

have undergone changes, and the testing and

evaluation of these products must be done in the

light of current practice.

The coalition has been at the forefront of

much of this evolution. While the basic

perspective of the coalition has not fundamentally

changed since 1995, we believe that our current

position and recommendations, updated to include

252

new information, data and further validation of

test methods outlined in the TFM, are well-grounded

in the latest science. Our recommendations do not

represent a lowering of efficacy standards but,

rather, matching surrogate endpoints with current

practice, and this is a very important point. We

appreciate the opportunity to summarize our

perspective and look forward to continuing dialog

towards finalizing a monograph that establishes

appropriate test methodology and performance

criteria representative of a threshold of clinical

effectiveness for this important category of

healthcare drugs. Our presentation will cover the

following topics.

[Slide]

A basic premise of the monograph system is

that certain, well-defined categories of drug

products that have been determined as safe and

effective may be marketed without FDA pre-approval,

as compared to the NDA system which requires that

individual formulated drugs undergo separate review

and approval prior to marketing. A key challenge

253

of the monograph that addresses healthcare

antiseptics is the determination and demonstration

of efficacy for a category of drug products that

encompasses several distinct active ingredients

across a range of indications.

[Slide]

Our first key point is that definitive

randomized and controlled clinical trials,

typically used to assess therapeutic benefit are

not practical in measuring the prophylactic

benefits of topical antimicrobial products.

[Slide]

Investigators in this area have stated

that definitive, classical, prospective, randomized

and controlled clinical trials typically used to

assess therapeutic benefits are not practical in

measuring prophylactic benefits of antimicrobial

products.

[Slide]

Human clinical trials have a number of

issues that can blur any potential efficacy result

and can cause the size of the study to become so

254

large that it is impractical, impossible or

unethical to conduct. For example, the incidence

of infection should be directly related to a

specific dose of organisms that causes a particular

infection. We have heard a lot about that today.

Nmerous mitigating factors influence whether an

infection can become established, including the

immunological status of the host, the route of

infection, direct or indirect transfer of the

infectious agent, etc., and we heard a lot more of

these confounding factors here today.

In addition--and this, again, is a key

differentiator particularly of handwashing--the

primary target of antiseptic handwashing is not the

individual using the product. Rather, it is to

prevent the transmission of pathogens within a

relatively large specific population, healthcare

providers, thus improving public health. Within

that context, many factors not directly related to

the efficacy of the product must be considered,

primary amongst them being compliance. It is

paramount in the development of antiseptic

255

handwashes or rubs that acceptance, whether through

convenience or mildness, is always an important

consideration when formulating such products.

Manufacturers have made significant improvements in

dispensing systems, product forms such as foams,

and the mildness profile of products meant to be

used repeatedly. In addition, many manufacturers

have sponsored studies aimed at looking at ways to

improve hand hygiene compliance.

All of these factors make it

difficult--and I think that is an

understatement--to calculate the level of bacterial

reduction needed to demonstrate the benefit from

the use of primarily prophylactic agents. For

these and other reasons, alternatives to classical,

prospective, randomized and controlled clinical

trials must be used for evaluating these topical

antimicrobials.

Fortunately, there is a substantial body

of scientific evidence that demonstrates the public

health and clinical benefit of using topical

antimicrobial products in healthcare settings.

256

Such a benefit has been demonstrated repeatedly

through studies of bacterial transmission and

infection rate reduction. These data allow for

determination of effectiveness by benchmarking

current antimicrobial products.

[Slide]

Our second key point is that standardized,

defined and peer-reviewed test methodologies ensure

reliability, reproducibility and comparability of

test results. For the purposes of a monograph, it

is necessary to establish efficacy methodology and

criteria that ensure effectiveness of topical

antiseptics. Surrogate testing provides such a

methodology. Such testing encompasses both in

vitro and in vivo methodologies, and extensive

comments have previously been submitted to the FDA

on their validity. We shall be presenting some of

these data from the published literature, and some

of these will be repeats of what you heard so I

will jump through them rather fast but there are

some key points to bring out from them. It is

apparent that over the years many different and

257

incomparable test methods have been used to assess

effectiveness. The efficacy of topical

antimicrobial products can be defined as the

prevention or reduction of risk of bacterial

transmission.

[Slide]

The FDA, in 1978, found that the reduction

of the normal flora, both transient and resident,

has been sufficiently supported to be considered a

benefit. The only determination that remains,

therefore, is how much of a reduction in microbial

flora will be required to permit claims for the

various product classes.

Thus, the agency has previously embraced

reduction of skin flora by a prespecified amount as

a valid surrogate endpoint for the efficacy of

topical antimicrobial products in a clinical

setting. Healthcare personnel handwashes or

waterless hand rub preparations are largely

designed for the removal of transient

microorganisms from the skin. These products are

used in a clinical setting in an uncontrolled

258

manner, with little regard for the dosage, the

amount applied during handwashing, exposure time,

repeat interval, or the amount of water used if the

product is intended to be used with water.

Due to the nature of product use,

demonstration of efficacy in these products in an

actual use setting would be, by definition,

uncontrolled and, therefore, poorly suited for

study by classical methods. Therefore, these

products are tested in a controlled manner by

procedures such as the ASTM Healthcare Antiseptic

Handwash test, the E1174, or in Europe by the

EN-1499 and EN-1500 handwash and hand rub methods

that similarly employ surrogate endpoints.

[Slide]

Although the basic ASTM E1174 framework

has been in use for many years and has served as

the basis for approval of many currently marketed

NDA products, researchers have modified it, and we

have heard a lot about that, and the method itself

has undergone rigorous review within ASTM and

several improvements to minimize test variability

259

have been instituted. The importance of complete

and immediate neutralization of active ingredient

is foremost among these changes. Incomplete or

delayed neutralization can have the effect of

overestimating ingredient efficacy. This is shown

by a study that looked at a direct comparison of

test versions.

[Slide]

The test versions were the current ASTM

method, as it is published in ASTM, the ASTM method

as it was published prior to 1994, which is a

method that was used for many of these NDAs, and

the method as published in the 1994 TFM. I will

compare three primary parameters, inoculum

application, neutralization and timing of the

baseline enumeration.

I am going to take a little time to go

through this slide because I think this is very

important to understand. In the first column we

have the inoculum addition. The current ASTM

method calls for applying the inoculum to the hand

in 3 1.5 mL aliquots. This is the culture of

260

Serratia marcescens. That is done in order to

minimize variability in the baseline because it is

very difficult to keep 4.5 mL or 5 mL of liquid in

the hand without spilling some into the sink. So,

applying it in smaller amounts helps give you a

baseline that is much less variable.

The timing of the baseline

measurement--this is particularly important when it

comes to the 1994 TFM method as written. As you

heard Michelle Jackson talk this morning, the way

the test is done is that a cleansing wash is

performed to familiarize the subjects with the wash

procedure. Following that, the hands are

inoculated with the Serratia. In the 1994 TFM, as

it is written, it is then followed by another

cleansing wash and after that the baseline is then

calculated.

The way the ASTM method reads is that the

baseline is taken following the familiarity wash

and then the inoculum. You can see the result that

that has in reducing the baseline by almost 3 logs.

So, you are starting at a very different point with

261

the TFM method than you are with either of the ASTM

methods.

Again, neutralization--a very important

point because, again, the goal of this test, of any

test, is as good as it can be to mimic what goes on

in real life. I think we would all agree that

ultimately the answer is that no test can mimic

what goes on in real life but you have to try and

minimize the variability so that at least the data

that you are getting is valuable.

Given that people wash their hands for a

very short period of time, 15 seconds, 30 seconds

at the most I think if you are lucky in a

healthcare personnel handwash setting, that is the

time point that you have to assess because

immediately following that wash the provider could

go on to do whatever activity they are assigned to.

So, neutralization must occur in the test

immediately following the wash procedure. This is

done in the current method by including a chemical

neutralizer in the recovery fluid. This

essentially stops the activity of the active

262

ingredient within a time frame similar to what one

sees in washing and rinsing their hands.

In the previous ASTM method and in the TFM

method neutralizer was not added until sometime

later until the dilution series was created and the

samples were taken to the lab. This can occur

anywhere from 10, 20, 20 minutes to half an hour

after the actual wash procedure.

I don't have the data up here but another

study was done. It was presented as a poster at

ASTM in, I believe, 2002 that demonstrated with

chlorhexidine gluconate that delaying

neutralization by approximately 15 minutes

increased its apparent efficacy after an initial

wash by over 1 log.

So, if we look at the results from the

handwashing, the first wash and the final wash, we

can see that in the current ASTM method compared to

the former ASTM method there is a slight

over-expression following the final wash. We would

like to see a greater over-expression after the

first wash but I think the lab we had do this was

263

too good and they immediately got to the samples.

You can see that following the TFM method you can't

even compare the results. So, this makes it

incomparable.

The last column is an important point. It

is an analytical assessment of how much

chlorhexidine gluconate was extracted into the

recovery fluid following the wash procedure was

measured. While the numbers vary somewhat, the

important point here is that all three of those

numbers are above the MIC value of chlorhexidine

gluconate against Serratia marcescens. Therefore,

one has to assume that some activity is going on

unless neutralization occurs immediately.

[Slide]

None of these results, however, changes

actually in-use effectiveness of the product, and

only serves to highlight the importance of

determining the appropriate test parameters, as

well as maintaining test consistent.

Sickbert-Bennet, in a 2004 paper, looked

specifically at the ASTM E1174 and the effect that

264

some test variables, such as product volume and

drying time, can have on the effectiveness of

alcohol.

The key take-away from this slide is that

as alcohol is currently used, and admittedly the N

is very small but these results have been repeated

in various laboratories around the country. The

white bar represents 3 grams of alcohol. To give

you a sense of what that is, for those familiar

with either the wall dispensers or pumps, that

pretty much represents 2 full pumps out of either a

wall dispense or a hand dispenser. That is 3

grams.

DR. WOOD: These are two people? Is that

what that is?

DR. FISCHLER: Yes. The 7 gram amount

would then represent something around 5 pumps from

a wall dispenser or a hand pump. You can see that

you can achieve a 3-log reduction with the use of

alcohol, but the question is are people pumping the

alcohol 5 times out of a dispenser, or is the 3

gram amount more realistic of actual practice?

Also to give you a comparison, it takes

approximately 30 seconds to a minute on average,

and some people are faster and some people are

265

slower, for 3 grams of alcohol to evaporate from

the hands. It can take potentially up to 10

minutes for 7 grams of alcohol to evaporate. So,

you can see no one is going to stand around for 10

minutes waiting for the alcohol to evaporate.

[Slide]

So, when the key parameters that can

affect data are understood, an evaluation based on

the reduction of marker organism contaminating the

hand, such as Serratia marcescens or E. coli, is an

appropriate way to measure effectiveness. Instead

of relying on subject normal flora, these methods

control the number of microorganisms on the hand by

intentionally inoculating them with a known number

of bacteria. In addition, these studies control

the dosage, the exposure time to the antimicrobial,

as well as other factors.

[Slide]

Our next key points are that surrogate

266

endpoint testing provides meaningful and

appropriate tools to determine the threshold

efficacy criteria for topical antimicrobial

products, and the published literature represents a

body of scientific evidence supporting that the

proposed microbial reductions reflect clinical

benefit and, importantly, represent current

infection control practice.

The SDA/CTFA coalition agrees with the

agency that the use of surrogate endpoints to

assess clinical effectiveness is a valid mechanism

for ensuring that products are efficacious.

Surrogate endpoint testing has been used in

situations where there is a known benefit, and

where standard validated methods have been

developed that simulate product use conditions, or

where testing and proving a clinical claim would

prove to be impractical or unethical.

With surrogate endpoints it is possible to

demonstrate a significant incremental benefit from

the use of topical antimicrobial products. The

SDA/CTFA industry coalition has previously

267

submitted data on surrogate endpoints that

represent clinical effectiveness based on the

scientific literature. We agree that while many of

the cited studies lack some or the elements found

in traditional clinical trials, such as personnel

education and training data, incomplete product

blinding or specific formulation information, taken

as whole, they represent a body of scientific

evidence supporting specific microbial reductions

and, importantly, represent current infection

control practice. The surrogate endpoints that

have been proposed were determined from controlled

test methods and correlate to a threshold of

effectiveness.

[Slide]

Now I am going to focus on each of the

healthcare categories, starting with the healthcare

personnel handwash. The results from healthcare

personnel handwash studies show that a reduction of

approximately 1.2 to 2.5 log

5 is achievable

following a single application, and correlate with

the literature on benefits of preparations

268

containing ingredients such as ethanol or

triclosan.

I am going to go through these very fast

since we have heard about them and we are all aware

of the shortcomings that all of the published

literature has. But it is important to get some

key points from some of these.

[Slide]

This was a study in 1995 that looked at

determination of an outbreak of MRSA in a ward

through the use of a 0.3 percent triclosan

handwash. While not a direct comparison of the

product literature, the product used in the study

demonstrates a 1.7-log reduction following an

initial application and 1.9 following subsequent

applications.

[Slide]

A study by Webster in 1994 similarly

looked at the introduction of a handwash to

eliminate colonization of MRSA cases. A gradual

elimination of MRSA was noted and, as a side

benefit, fewer antibiotics were found to have been

269

prescribed--again, not direct cause and effect but

another link in the chain.

[Slide]

Hilburn and these next two alcohol studies

looked at the use of alcohol as an infection

control tool and, again, while not correlating

directly, there is strong incidental evidence that

the use of the alcohol led to a 36 percent

reduction in infection rates over a 10-month period

compared to the previous period.

[Slide]

Fendler, in 2002, did a similar study

looking at the use of ethanol in a facility

compared to regular protocols, and noted a 30

percent reduction in infection rate where hand

sanitizer was used.

[Slide]

Dr. Boyce talked at length about

Doebbeling so I won't go into that a lot but,

actually, what is important to note here is the

comparison of alcohol, a product that does not

provide either persistence or a cumulative effect

270

compared to chlorhexidine gluconate that does.

Although there were a lot of issues with the study,

not the least of which was the use of the product

and how much product was used, in a matched pair

analysis the authors did find that the difference

was directional but statistically significant.

[Slide]

The data supports our previous

recommendation that a 1.5 log reduction--and this

is based primarily on our review of the alcohol

data in amounts as it is used in infection control

practice--is sufficient to demonstrate benefit.

The necessity for demonstration of persistence or a

cumulative effect following several applications of

product that is designed for multiple routine

applications throughout the day has not been

demonstrated. Maybe I should take a moment here to

talk a little bit about persistence versus

cumulative effect since I think there seems to be a

little confusion on the issue.

Persistence is really a demonstration that

after a single use typically you have reduced the

271

resident flora to a certain level and that they do

not rebound to a level above what they were when

you started. A cumulative effect is very

different. It is an application-based phenomenon

and looks at what happens after multiple uses of a

product rather than what happens over a specific

period of time. The definition that Michelle

Jackson gave is correct for cumulative effect. It

is an apparent reduction in the recovery of

organisms. Now, whether that is due to persistence

or some other factor hasn't really been well

explored. But there is a difference between the

two of them. Persistence is time based and

cumulative effect is application based.

[Slide]

Surgical scrub products are used by

healthcare personnel immediately prior to donning

sterile gloves for the performance of invasive

procedures to reduce or eliminate transmission of

microorganisms from their hands to the patient.

As with healthcare personnel handwashes,

surrogate endpoints utilizing a test such as the

272

ASTM for surgical hand scrub methods have been

established for the surgical hand scrubbing in

deference to the impracticality of clinical trials

to demonstrate reduction of patient infections. In

this case, the rate of infection is thought to be

very low so any clinical trial would be extremely

large and difficult to control. A placebo control

would be unethical in this situation so an active

control would have to be employed, thus, further

decreasing the theoretical differences in infection

rates between groups for the study and increasing

the sample size. The literature does contain some

comparisons between active ingredients, and the

coalition has previously presented information that

supports initial microbial reductions of 1 log of

the resident hand flora, with the flora remaining

at or below the initial level, and this is

persistence after six hours from baseline. So, in

our recommendation we are recommending the

demonstration of persistence, not of cumulative

effect.

[Slide]

There are two studies--we heard about one

of them but I am going to use them for a different

purpose, and that is that they both compare alcohol

273

and, again, we have heard alcohol is a product that

does not provide either persistence or a cumulative

effect, compared with products that do, either

povidone-iodine or chlorhexidine gluconate. In

this case, the comparisons are made and I believe

are valid in both Parienti and Bryce in that no

difference was seen between current practice, which

involves the product that did provide a cumulative

effect, and a product, alcohol, which did not.

[Slide]

The clinical use of preoperative skin

preparations to reduce the incidence of surgical

site infections is the most completely tested of

the clinical indications contained in the TFM. It

has long been considered unethical to even attempt

a surgical procedure through intact skin without

first cleansing the site, preferably with an

antimicrobial formulation.

Given the clinical evidence and the

274

current standards of care at the time that the 1978

TFM was drafted, the agency acknowledged that the

value of the effective skin antisepsis prior to

surgery and established surrogate endpoints

utilizing the ASTM E-1173 preoperative skin prep

method. The coalition suggests that the groin

performance criterion of 3 log

10 does not correlate

with clinical effectiveness and, in fact, may be

unrealistic due to a low bacterial population at

that skin site in the general population. The

coalition has previously presented information that

supports microbial reduction of 2 log

10 on the groin

within 10 minutes of use, and again that

persistence with no rebound of the resident flora

over a 6-hour period, as indicative of clinical

benefit.

In one study, and in particular I am going

to use this study to also illustrate a point which

is that, while it was a comparison of a new skin

preparation with a standard 4 percent chlorhexidine

gluconate skin prep, two things emerged from the

study. One, it was extremely difficult to find a

275

population that met the baseline criteria set in

the TFM. The other point is that the active

control product, the 4 percent chlorhexidine

gluconate, did not achieve the log reduction

required from the TFM. It achieved a 2.5 log

reduction following 10 minutes of application.

[Slide]

One of the performance criteria, addressed

under patient preoperative skin preparation in the

TFM, is the pre-injection skin preparation

performance criterion of 1-log reduction of skin

flora within 30 seconds of use. The coalition

agrees that this is a suitable surrogate endpoint

for clinical efficacy for this indication.

Clinical trials for this indication would

be possible but impractical. As with the previous

indications, injection site infections are a rare

occurrence and would require a multiple-day

follow-up period to assess the infection rate.

Therefore, the surrogate endpoint for these studies

is a reasonable alternative.

[Slide]

In conclusion, we would like to emphasize

the following key point. The efficacy criteria of

healthcare antiseptic drug products should be

276

appropriately set to reflect the performance of

currently recognized effective products. Thank

you. Now I would like to introduce Jim Bowman who

will address some issues on statistics.

Statistical Issues in Study Design

DR. BOWMAN: Good afternoon.

[Slide]

I am Jim Bowman, technical director,

biostatistician at Hill Top Research. I too

represent the CTFA/SDA coalition. I have been

asked to summarize the statistical issue at hand.

[Slide]

Log reduction criteria has historically

been based on point estimates with no set

requirements for sample size. It is understood

that variability needs to be considered, and there

are several ways to take that into account.

[Slide]

Here are two examples that come from other

277

OTC monographs. From the sunscreen monograph, a

mean value is calculated and then the standard

error is used to calculate the SPF value for

product labeling.

From the antiperspirant monograph, in

order to label a product as an antiperspirant the

tested mean value must be statistically

significantly greater than 20 percent sweat

reduction.

[Slide]

Our objective is to obtain a mean value

greater than or equal to a certain log reduction.

With point estimates manufacturers have

historically conducted studies with sample sizes

they deemed appropriate, and submitted data to the

FDA. With statistical criteria being utilized,

i.e., statistically greater than a specific number,

appropriate sample sizes are a function of the

variability of the data.

[Slide]

We have conducted data reviews and

statistical simulations using data from hands and

278

looking into the variability. This review

consisted of data from 13 studies conducted with an

active material, and simulations were conducted to

better understand that variability. Our conclusion

was that if statistical criteria are to be

utilized, then lower criteria will be necessary to

achieve the same level of efficacy based on our

data review.

[Slide]

For an example we can look at the

antiperspirant monograph. The OTC antiperspirant

monograph requires statistically significantly

greater than 20 percent reduction. However, this

requires point estimates of sweat reduction to be

greater than 25 percent to 30 percent reduction in

order to achieve the level of benefit mandated.

[Slide]

Historically, the FDA and industry have

relied on point estimates. All recommendations

from the coalition have been based on point

estimates. However, if statistical significance is

required, then lower log reduction criteria are

279

necessary to achieve the same level of efficacy

based on our data review. We would like to work

with the FDA on setting these criteria for specific

indications at specific time points. Thank you for

your time. George will now summarize.

DR. WOOD: Just before you step down, can

you put up slide 23 from the last talk? I have a

statistical question on it. This has been offered

to remove one of the criteria. So, what was the

sample size in this study, and what was the size of

the difference that you could exclude, and at what

power?

DR. FISCHLER: I have to refer to the

paper for that.

DR. WOOD: Well, this is being offered as

one of the key pieces of evidence.

DR. BOYCE: I am not sure, but I think

they are in that range of 1,500 to 1,800 patients

in both arms of the study so there were over 3,000

patients that underwent surgery during the trial.

DR. WOOD: And what was the size of the

difference?

DR. BOYCE: The difference between the two

arms was about 0.04 percent, in other words, no

significant difference and it was considered to be

280

an equivalence trial.

DR. WOOD: So, it was set up with some

sort of power calculation in advance?

DR. BOYCE: Yes, I believe so.

DR. WOOD: But we don't know what that

was?

DR. BOYCE: I have the reference here.

DR. FISCHLER: And I have the paper.

DR. WOOD: The second part was it was

possible then to do a clinical study. So, you feel

that this was an adequately powered study to show a

non-inferiority outcome and it only needed 3,000

patients.

DR. BOYCE: I think that was the

conclusion that the authors arrived at.

DR. OSBORNE: Dr. Wood, just to review the

exact data from that study, there were 4,287

patients, divided roughly equally into the three

groups, the alcohol hand rub, the PI and the CHG.

281

The surgical site infection rate was 2.44 percent

for the alcohol versus 2.48 percent for the

combined group of PI and CHG. What more can I give

you?

DR. WOOD: That is fine.

DR. OSBORNE: That is where the 0.04 came

from that Dr. Boyce mentioned.

DR. WOOD: And Tom can calculate that on

the back of an envelope, and probably already has.

Frank?

DR. DAVIDOFF: What was the confidence

interval of the difference?

DR. WOOD: I don't know.

DR. DAVIDOFF: Isn't that the key

question?

DR. WOOD: Do we know that?

DR. BOYCE: I don't know the confidence

interval.

DR. BLASCHKE: It had to be pretty small

if the difference was 0.04 between the products and

they were statistically significant.

DR. DAVIDOFF: That is how you can talk

282

about meaningful exclusion of differences. Without

that, it is real tough to do that.

DR. WOOD: All right, let's let him

finish.

DR. FISCHLER: I will be very quick in

rapping up. In summary these are our points.

[Slide]

Definitive prospective, and controlled

clinical trials are not practical in measuring the

prophylactic benefit of antimicrobial products.

Again, I think we have to look at these as three

different types of antimicrobial products, the

healthcare personnel handwashes, the surgical

scrubs and the preoperative preps.

I am just going to make one point which is

if you look at those three and you start with the

preop prep--I forget who said this in their

presentation, but in a preop prep the patient

represents their own control. So, you have

basically the smallest denomination. If you look

at surgical scrubs you are not looking at the

benefit being derived from the surgeon, but it is

283

essentially a one-on-one calculation, the surgeon

and the patient. When you move to healthcare

personnel handwashes, you are now trying to look at

what is the benefit derived to a general population

from another population that has used the product?

So, in equivalence it is asking the question what

benefit do the members of the committee seated at

the table derive from the people in the audience

washing their hands?

Standardized, defined, and peer-reviewed

test methodology, such as ASTM methods, encourages

reliability, reproducibility and comparability of

results. Surrogate endpoint testing provides an

appropriate tool to determine threshold efficacy

criteria. The published literature, with all its

shortcomings, supports that the proposed surrogate

endpoints represent clinical benefit. Finally, the

efficacy criteria should reflect the performance of

recognized effective products. And, I will be

happy to answer any questions.

DR. WOOD: Questions from the committee

for the last two presenters? Ralph?

DR. D'AGOSTINO: If I understood the FDA

presentation, the literature was full of studies

that were inconclusive, and we have heard some

284

fairly definitive statements, I thought, with this

presentation. Could the FDA respond to that?

DR. WOOD: Well, I am not sure that I

agree. Some of them had two subjects in them.

DR. D'AGOSTINO: I would have presumed

that the response to my question is going to be

that it is a rosier picture than what is real.

DR. WOOD: Right.

DR. OSBORNE: If there is a request about

a comment on a specific study, I could make a

comment on that specific study.

DR. D'AGOSTINO: Well, the one where the

sample size was 4,000 and you gave the numbers, was

that a well-designed study, well executed?

DR. POWERS: What I was trying to answer

about that previously was that we struggled greatly

with how to interpret non-inferiority trials in

this setting. To look at that study, regardless of

how many patients it has in it, and determine that

285

two things are not inferior to each other means one

of two things: Either both products are effective

in doing something or neither product is doing

anything. The problem is that without the ability

to determine what the magnitude of benefit over

whatever you want to specify as the control is in

that over nothing, it is very difficult for us to

interpret what no difference actually means in this

setting.

So, what we really want to look for is

trials which showed some kind of a difference, and

that was very difficult to find. Then, when you

did look at those trials, many of them actually had

flaws in them in terms of there was no concurrent

control group or other things that made it very

difficult.

So, we did not just look for a p value at

the end. We asked the question of how did you get

to that p value, and that really had a lot--the

buzz word "evidence" has gotten thrown around a lot

here today, and just because you have lots of

studies, does that really mean that that is

286

evidence or not? That is one of the things we

struggled with in a 1,000-paper review.

DR. D'AGOSTINO: It does go back somewhat

to the discussion we had half an hour ago about

vehicle control and positive control and trying to

interpret in that setting, I agree.

DR. WOOD: Other questions for the

speakers? Tom? DR. FLEMING: I come up just

crudely with about half a percent, just to go back

to this slide 23 where you had 2.44 and 2.48 and

you could rule out a 0.5 percent difference but

what does that mean? If you are essentially the

same and you can rule out not more than a 0.5

percent difference, are you the same effective or

are you the same ineffective?

There are several things on your slide,

this last slide. The last point says, and it is

reworded from an earlier conclusion slide where you

had said efficacy criteria should be set to reflect

the performance of concurrently recognized

effective products. What is the effect of

currently recognized effective products? If I know

287

that a currently recognized, effective product

provides a 50 percent reduction in infection risk

and I have a lot of studies that allow me to

understand that I need to achieve a 2.5 log

reduction to achieve that, and the relationship is

if I give up half a log reduction that I am giving

up 10-20 percent protection on infection risk I am

buying into your last statement. Tell me how I

can, in fact, address, based on currently available

data, how much efficacy--or I would call it how

much biologic activity I have to achieve in

reducing log reduction in bacterial load to achieve

clinically meaningful benefit on infection risk.

DR. FISCHLER: I guess not to give you a

smart answer, but I think that is what we are here

to try and determine. I think we are struggling as

an industry with the same issues that clinicians

have been struggling with, which is that we are

operating under a regulatory framework and when we

look at infection control practice today,

specifically highlighting the fact that alcohol

hand rubs have become a key part of infection

288

control, and looking at how alcohol hand rubs are

used in infection control and what does that

translate to in a surrogate endpoint test--and the

determination of whether or not surrogate endpoint

is appropriate or whether or not the test is

appropriate we will set aside for a moment--but

looking at that, if we admittedly go back to the

Sickbert-Bennet with an N of 2 but companies do

have internal data that did repeat that study.

There is probably data on several hundred subjects

doing that exact same study. Most people put 2-3

grams of alcohol on their hands at most and what

got a log reduction in a standardized test to come

up with for that 2-3 gtam amount of alcohol.

The issue that we are all struggling with

here is while that is all well and good, how does

that translate to a clinical benefit? I think we

have heard from pretty much everyone here that no

one can definitively say that any of these log

reductions translates to a clinical benefit in

terms of the way clinical trials are assessed. So,

in my own poor way I guess I am saying what we are

289

trying to do is not lower the efficacy standard but

match. Over probably 20 years of infection control

practice people have been washing their hands in

hospitals and using antiseptic products for over 20

years. Dr. Larson stated it when she said the

horse has left the barn. We are trying to look

back at over 30 years of data and saying what is

going on and what is happening.

So, what we are looking at is current

practice, and if current practice is acceptable,

and I can't answer that, only clinicians can

answer--if compliance is not an issue, if infection

control practice as it is currently performed today

meets the standards of care, then for the products

that are being used we should analyze what

surrogate endpoint test results they achieve in

whatever standardized test we come up with so that

we don't set criteria that essentially will

eliminate the products that are currently being

used for infection control. That is a really

long-winded answer. I don't know if I got to the

heart of your question.

DR. FLEMING: It is a long-winded answer.

I guess my short interpretation of the answer is we

could, in fact, justify using surrogates if, in

290

fact, we had evidence that allowed us to know what

the actual efficacy is of currently used products

or efficacy on prevention of infection, and where

the data were also allowing us to understand how

the influence on bacterial load was causally

leading to what the association is with the

reduction in infection. We lack that evidence--

DR. FISCHLER: Correct.

DR. FLEMING: --therefore, we lack the

ability to draw that conclusion. You went on to

say, well, then we will ask clinicians whether what

we currently have in the real world is adequate.

Dr. Pearson, in her presentation, said we have 2-5

percent infection rates with surgical site

infections. Is that adequate? I think we would

all say it is better than 8 percent; it is not

nearly as good as 0-1 percent. Now the question is

how do we achieve 0-1 percent? What are the

interventions that are out there that are more

291

effective than others? How do we determine how

maximally to use them?

Let me just close by saying you made the

point earlier on that we have a complicated

situation, and that complicated situation is

multidimensional involving immunological host

factors; involving test subjects versus

populations; involving compliance. And, for this

reason, clinical trials are not appropriate. I can

look at a lot of other areas. An area where I am

involved in my own research, which is looking at

vaginal microbicides as a way to prevent

heterosexual transmission of HIV where, clearly,

all of these issues are relevant and many of us are

embarking on major clinical trials to answer the

question as to how these interventions affect

transmission rates. So, this isn't a unique

challenge.

DR. FISCHLER: I guess I would go back to

the regulatory framework within which we have been

operating for the past several years, which is the

world of surrogate endpoints from the FDA's

292

perspective. I think our key challenge, and I

think it is reflected in the questions that the

committee is being asked is, is that the world we

should be in? Is that appropriate? Should we be

moving somewhere else? And, how do we deal with

the situation moving forward because there has to

be common ground somewhere?

DR. WOOD: I think what Tom was also

asking you is this, you are here today proposing a

reduction in the surrogate standard, rightly or

wrongly and I am not arguing with that right now.

What I think the committee would like to hear is

what is your estimate of the clinical outcome of

that reduction in the surrogate standard and point

us to where we would look to see the evidence to

support that.

DR. FISCHLER: I don't know that you would

see a reduction because is practice going to

change? Practice as it exists now will not meet

that standard that is set. So, I guess it is a

question of if you change what is printed on the

page, does that change infection control outcome?

293

Or, as we are suggesting, do you match products?

Do you find a test that everyone can agree on that

adequately measures whatever outcome you are trying

to measure and then determine what the number

should be?

We feel that the number as published in

the monograph has a number of flaws, the cumulative

effect for healthcare personnel handwashes among

other things. We feel that the number, the 1.5 log

reduction reflective of alcohol under use

conditions, is reflective of current practice.

DR. WOOD: That would be terrific if we

had a zero percent infection rate, but we don't

have a zero percent infection rate and, given that,

what has led you to believe that we are currently

in the ideal Nirvana?

DR. FISCHLER: I guess I would ask the

question is zero a number in a biological system?

But besides that, I guess I can't answer the

question of is 2 percent to 5 percent acceptable.

Certainly, the lowest number that is possibly

achievable is the goal. But setting a standard for

294

current products--I guess that is what the

committee has to decide, changing the standard so

that products that are currently used are no longer

available because they do not meet the

standard--will that increase or decrease the public

health?

DR. WOOD: Any other questions?

DR. BRADLEY: Just a clarification. The

TFM from 1994 sets some criteria and guidelines.

Yet it seems in this discussion that the

alcohol-based solutions don't meet the TFM

guidelines, yet they are being used and

recommended. So is it true that the current TFM

guidelines aren't being enforced with these

products? If that is true, then the industry is

asking for a further reduction even though we have

a standard that is not yet being enforced. If we,

as a committee at the end of the day, feel that the

TFM standards should be enforced, then we should

raise the bar from where we are right now.

DR. LUMPKINS: Basically, because the OTC

monograph process is a public rule-making and a

295

multi-stage process, what the agency has decided as

a matter of policy is that we don't enforce

proposals. So, right now, there is not a

requirement for anybody to comply with the TFM.

What the discussion today is about is what

do we finalize and what, at the end of the day,

will everybody need to comply with. That is what

you need to worry about.

DR. WOOD: Jan?

DR. PATTERSON: I just wanted to comment

back on the Parienti study, the surgical site

infections. These are two antiseptics compared to

each other so there is not a control, which I think

was the issue. But I don't think that an IRB

committee would approve the study of surgical

scrubs that didn't involve an antiseptic. And I,

personally, wouldn't want to be a subject in one in

which my surgeon might not have used an antiseptic.

I think there are some practical

considerations like that. Even as was mentioned

this morning, you might be able to do a plain soap

versus an antiseptic for routine patients on the

296

ward but now we have a federal guideline from CDC

that says we should be using antiseptics and also

an accrediting agency advised by federal agencies

tells us this can be monitored. So I think it is

very difficult to talk about comparing antiseptics

to non-antiseptics.

DR. WOOD: Dr. Patten?

DR. PATTEN: I have a question for the

FDA. If the requirements that you are proposing in

your TFM were to be finalized, what sort of a time

frame would be built in to allow the industry to

respond?

DR. LUMPKINS: Once a final rule is

published there is usually a one-year period for

implementation. However, I have to be honest with

everyone involved. In the monographs that we have

developed that have required final formulation

testing, in reality there have been a number of

stays of the final rule to allow industry time to

make adjustments.

DR. WOOD: And some have never got to

final, right? Let's be honest here.

DR. LUMPKINS: Hopefully, we will fix

that.

DR. WOOD: Right, but I mean there is a

297

lot out there that has never got to final. So, it

is not a door that has to be closed. Dr. Larson?

DR. LARSON: Despite all the difficulties

of answering all the questions we have to answer,

and I don't know the answers either, I just want to

point out that this has been a tentative final

monograph, first in '78 and now in '94 so for

decades it has been tentative. In some ways,

patient safety is more at risk by not finalizing

something because now products can be on the market

and there is no regulatory agency that is

overseeing them by force of law. So, even if we

don't all agree on what it should be, I would hope

that it wouldn't stay tentative until after I die,

for example, or until after my career is done

because I have been waiting for 30 years for a

final ruling of some sort and, in the meantime, the

good industries want to do it right and they want

to follow the rules, and they ultimately, I am

298

sure, have the same goal we all do which is to

reduce infections. But right now it is possible

for industry to be out there, selling something

that is inferior, because there are no rules.

DR. WOOD: Mary?

DR. TINETTI: I think we do need to

discuss separately surgical scrubs from the

handwashes. I agree with that. I would think it

would be very difficult to do anything in the

surgical scrub at this point. But for the

handwash, I mean what we are hearing today is that

there is no evidence linking the standards that are

in the TFM with the clinical outcome that we are

interested in. We are hearing that guidelines

exist in JCAHO but guidelines were developed in the

absence of evidence and to now use those guidelines

that were forced because there was lack of evidence

as a reason for not procuring evidence seems to me

a road I certainly would not like to see healthcare

go down.

Certainly, this may be the final

opportunity for us to preclude that from happening

299

and I think there are alternatives to study it.

Yes, it is difficult but a lot of us do research

that is difficult. Difficult is not a reason to

preclude it from happening. Yes, it is going to be

expensive but these are marketed because they say

they do improve the clinical outcomes and the fact

that, yes, we treat the healthcare providers to

help the patients, that is what these are marketed

to do so it seems to me that these studies in that

area are feasible. I think it will be setting

healthcare back to finalize it when there is really

complete lack of evidence.

DR. WOOD: Any other comments? If not,

let's take a quick break and come back at 3:10 and

we will start the final discussion and deal with

the questions. So, 3:10.

[Brief recess]

Committee Discussion

DR. WOOD: To summarize what I think we

have heard so far as we begin the discussion, I

think what we heard--I tried to jot down some notes

here--we heard that there are no adequately

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designed or powered studies to demonstrate the

clinical effectiveness of these topical

antiseptics. Given that, therefore, it is not

surprising that there are no adequately designed

and powered studies that demonstrate the robustness

of any particular surrogate in predicting the

clinical effectiveness of these agents.

As I think Susan or somebody said, the

standards are arbitrary but steeped in history, and

industry clearly believes the current products are

clinically effective but industry wants to lower

the bar for the surrogates because they have

products that can't meet these standards. Industry

has no evidence that lowering the standards for the

surrogates won't impair effectiveness and result in

patients being at increased risk for infections,

again not surprising given the current lack of

clinical correlates for the surrogates in the first

place.

So, I guess I don't see how, in the

absence of data, we can possibly endorse lowering a

standard for which we have no evidence that it is

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clinically relevant and when we can't determine

what would be a safe reduction in that surrogate in

the first place.

Finally, I don't see how industry, or

anyone else for that matter, can argue that if they

believe the current products work, whatever that

means, that products that work less well, again

whatever that means, can possibly be approved

without someone going out and doing a study to

determine the clinical consequences of that

reduction in effectiveness.

So, it occurred to me that a way out of

this dilemma, Susan, was to ask you this question.

We are working around this sort of mish-mash of the

historical precedents, but supposing somebody were

to go out and do a study where they demonstrated

that their product reduced bacteremia--all the

things that we have heard are impossible to do, but

supposing somebody did it, would you approve a

study and give them that as an indication?

DR. JOHNSON: There are a couple of issues

here. Let me put the clinical one aside for just a

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second and talk about the regulatory. Within the

monograph--

DR. WOOD: No, no, I am not talking about

the monograph. I am saying forget the monograph

for a minute. Somebody goes out and does a study

in which they demonstrate that X, Y, Z handwash, or

whichever indication it is, reduces bacteremia in

patients, or some other hard endpoint and you can

pick whichever one you like, would they get an

indication for that and would they be allowed to

promote on that basis?

DR. JOHNSON: We have been asked various

permutations of that question many times from NDA

sponsors, and we have always supported that under

an NDA were they to come up with a clinical design

and conduct a trial that showed that sort of

effect, we would label them accordingly.

DR. WOOD: So, one of the things this

committee could do in addition to answering the

questions is to come up with that as a proposal,

which would get us out of Dr. Larson's very

reasonable point that she wants to live long enough

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to see this finalized. Essentially, it seems to me

there are two tracks we can take. One is to

promote the rational adoption of a regular process,

which would be to find a clinical endpoint and do

that, or not if you can't do it, and the other is

to proceed down the current track.

The attraction of the former, which is the

clinical endpoint, is that clearly any sponsor who

does that and comes out with such an endpoint

trumps everybody who is unable now, they say, to do

that, which would obviously be a very compelling

argument both in the marketplace and hospitals who

purchase these things and, I guess, the JCAHO. So,

that would be a reasonable approach from the

agency's point of view. Is that right? All right.

In that case, let's move on to discussion and who

would like to comment first? Yes?

DR. LEGGETT: I have a question for the

FDA. Suppose we come up with a final monograph,

what happens to the products that are on the market

already?

As a corollary to that, I would like to

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mention this Sickbert-Bennet paper that we got just

this past week, in AJAIC this month I believe. In

table 3 they looked at the log reductions of

Serratia marcescens in the hand hygiene agents,

albeit this is with that 10-second wash because

they document elsewhere in the paper that the

median time of washing hands is 11.6 seconds, or

something like that. In agent A, which is the 60

percent alcohol, the first wash only had a

reduction of 1.15 logs. So, even by the industry's

standards this would not fly. At episode 10 the

alcohol actually had a negative trend; it was less

efficacious after 10 washes, and they had some

theories in the paper. So, with those two

questions, what does the FDA do if you get a final

monograph?

DR. JOHNSON: One of the things that I

would like to do is ask Colleen Rogers to address

the information that she found in doing the

literature search on the handwashes. But as a

general response to your question, the products can

be formulated, as far as we have seen in the

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literature, to be able to accomplish what we have

proposed in the tentative final monograph. This

alert that is being sounded that in general the

products are failing to meet this standard is not

what we have observed in general in NDA

submissions. We don't see data submitted routinely

under the monograph because that is not the way the

process works; it is dissimilar to the NDA in that

regard and it is driven by the literature. So, we

are not seeing the same level of current studies

coming in under the monograph prospectus. But in

reviewing the NDA data, which obviously we can't

present to you, we are seeing that this is not an

across the board uniform problem.

If I could ask Colleen, there is a

difference between the immediate acting alcohol

products and the leave-on products, and the

difference is in formulation and she might want to

comment a little bit more on the data that we

found.

DR. ROGERS: In reference to what Dr.

Johnson was just saying, in looking through the

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literature most of the alcohol-based products are

leave-on products and they are not rinsed off the

skin. Compared to what was presented in the most

recent Sickbert-Bennet paper, those products, for

one, were used for a very short time, 10 seconds,

and most of the other studies that I looked at used

a longer time period for contact with the skin.

Also, if I remember correctly, in the

recent paper, the Sickbert-Bennet paper, they also

rinsed after using an alcohol product, which is not

normally done with an alcohol leave-on product, and

that may have affected the results in that most