UNITED STATES OF AMERICA

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

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CLINICAL CHEMISTRY AND CLINICAL

TOXICOLOGY DEVICES PANEL

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MEETING

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MONDAY,

NOVEMBER 13, 2000

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The Panel met at 10:00 a.m. in Salons C and D of the Gaithersburg
Hilton, 620 Perry Parkway, Gaithersburg, Maryland, Dr. Martin H. Kroll,
Chairperson, presiding.

PANEL MEMBERS PRESENT:

MARTIN M. KROLL, M.D., Chairperson

DONNA M. BUSH, Ph.D., D-ABFT, Guest/Federal

Liaison

JAMES EVERETT, M.D., Ph.D., Member

CASSANDRA E. HENDERSON, M.D., Member

THOMAS L. KURT, M.D., M.P.H., Consultant

FRED D. LASKY, Ph.D., Industry Representative

SHERWOOD C. LEWIS, Ph.D., Consultant

BARBARA R. MANNO, Ph.D., Member

STANLEY M. REYNOLDS, Consumer Representative

ARLAN L. ROSENBLOOM, M.D., Member

DIANA G. WILKINS, Ph.D., Consultant

VERONICA J. CALVIN, M.A., Executive Secretary

FDA REPRESENTATIVES:

STEVEN I. GUTMAN, M.D., M.B.A., Division

Director

JEAN M. COOPER, M.S., D.V.M., Branch Chief

CLARA SLIVA, M.P.A., Acting CLIA Coordinator

LINDA R. MANLEY, Secretary

PUBLIC SPEAKERS:

BOB AROMANDO, Independent Industry Consultant

KEN BERGER, Lifepoint Corporation

DAVID G. EVANS, National On-Site Testing

Association

DR. CARL M. GOOD, III, Avitar Corporation

LORRAINE HOGAN

DR. HARESH C. JAIN, National Toxicology Labs

DR. JEMO KANG, Princeton BioMeditech

CAROL A. MONGIOVI, Pharmatech

DR. LUANN OCHS, Roche Diagnostics

DR. SALVATORE SALAMONE, Roche Diagnostics

TONY TORANTO, Guardian Angel

C-O-N-T-E-N-T-S

I. Call to Order 4

II\. Opening Remarks 4

III\. CLIA 9

IV\. FDA Presentation 18

V. Open Public Hearing 27

VI\. Open Committee Discussion 42

VII\. FDA Presentation 96

VIII\. Open Public Meeting 113

IX\. Open Committee Discussion 166

XI\. Closing Remarks 247

P-R-O-C-E-E-D-I-N-G-S

(10:07 a.m.)

DR. KROLL: Good morning. I would like all the members of the panel to
please take their seats. My name is Martin Kroll, and I am the Panel
Chair, and we would like to start this meeting. This is a panel meeting
that will discuss and make recommendations on two draft guidelines.

One is the \"Guidance for Prescription-Use Drugs-of-Abuse Assays,
Premarket Notifications.\" And the other is \"Over-the-Counter (OTC)
Screening Tests for Drugs of Abuse: Guidance for Premarket
notifications.\"

I would now like to turn things over to our executive secretary,
Veronica Calvin.

MS. CALVIN: Good morning, and welcome to this meeting. I want to recap
briefly what occurred at the last panel meeting. On March 24th, 2000 the
panel reviewed a PME for Biosite Diagnostics Triage, B-Type Natriuretic
Peptide Test, indicated as an aid in the diagnosis of congestive heart
failure.

The majority of the panel had major concerns with clinical data and
voted 6 to 3 for non-approval. At this time, I would like to welcome our
new industry representative, Dr. Fred Lasky.

I would also like to acknowledge Mr. Stanley Reynolds, who is filling in
for our consumer rep, Ms. Davida Kruger, who is the consumer
representative on the Microbiology Devices Panel. And I would also like
to acknowledge Dr. Donna Bush, who is here from SAMHSA.

Now, if the panel could introduce themselves, starting with Dr.
Rosenblum.

DR. ROSENBLOOM: I am Arlan Rosenblum, O I am an Emeritus Professor of
Pediatrics at the University of Florida, and a member of the panel, a
regular member of the panel

DR. LEWIS: I am Sherwood Lewis, Director of Toxicology at the Office of
the Chief Medical Examiner, State of Connecticut, and I am serving as a
consultant to the panel, having formerly been a voting member of that
panel.

DR. MANNO: I am Dr. Barbara Manno, and I am a professor in the
Department of Psychiatry at the Louisiana State University Health
Sciences Center in Shreveport, Louisiana, and I am a member of the
panel.

DR. KROLL: I am Martin Kroll, and I am a pathologist at the Dallas
Veterans Administration, in Dallas, Texas; and an associate professor of
pathology at the University of Texas, Southwestern Medical School.

DR. KURT: I am Tom Kurt, and I am a founder and medical toxicologist for
the Certified Regional Poison Center in Dallas, called the North Texas
Poison Center, where I am also a clinical professor in the Department of
Internal Medicine.

I am a certified medical toxicologist, a medical review officer, and a
former FDA medical officer and member of this committee from \'94 to
\'98, and now I am a consultant to CCCTDP MDAC.

DR. WILKINS: I am Diana Wilkins, and I am the assistant director of the
Center for Human Toxicology at the University of Utah, in Salt Lake
City. I am also an associate professor of Pharmacology and Toxicology at
the University, and today I am servicing as a consultant to the
committee.

DR. EVERETT: I am James Everett, Medical Director for Madison Memorial
Health Healthcare, in Madison, Florida.

DR. BUSH: My name is Dr. Donna Bush, and I am the Chief of Drug Testing,
Division of Workplace Programs, in SAMHSA.

DR. REYNOLDS: I\'m Stanley Reynolds, and I am a supervisor of immunology
and virology at the Pennsylvania Department of Health, Bureau of
Laboratories, and I am the consumer representative.

DR. LASKY: I am Fred Lasky, the Director of Regulatory Affairs,
Ortho-Clinical Diagnostics, and I am the new industry rep, and this is
my first meeting.

MS. CALVIN: Thank you. And seated at t he end of the table is Dr.
Gutman, and he is the Director of the Division of Clinical Laboratory
Devices. I will now read the conflict of interest statement.

The following announcement addresses conflict of interest issues
associated with this meeting, and being part of the record to preclude
even the appearance of an impropriety. To determine if any conflicts
existed, the agency reviewed the submitted agenda and all financial
interests reported by the committee participants.

The conflict of interest statutes prohibit special government employees
from participating in matters that could affect their or their
employer\'s financial interests.

However, the agency may determine that participation of certain members
and consultants, the need for whose services outweighs the potential
conflict of interest involved, is in the best interests of the
government.

We would like to note for the record that the agency took into
consideration certain matters regarding Drs. Martin Kroll and Arlan
Rosenbloom. These panelists reported unrelated interest with firms at
issue.

Since the interests are unrelated to the issues before the panel, the
agency has determined that they may participate fully in today\'s
deliberations. In the event that the discussions involve any other
products or firms not already on the agenda for which an FDA participant
has a financial interest, the participant should exclude him or herself
from such involvement, and the exclusion will be noted for the record.

With respect to all other participants, we ask that in the interests of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firms whose
products they may wish to comment upon. Thank you and I will turn the
meeting back over to Dr. Kroll.

DR. KROLL: Thank you. Now, we would like to hear about CLIA from Ms.
Clara Sliva.

MS. SLIVA: Hi. I\'m Clara Sliva, and I am the Acting CLIA Coordinator. I
have also \-- I have handouts, and they are up front. If I have not
passed them out to you, there are some more up front. I want to give you
a nine month report.

What I am doing is that for each of our devices panel meetings, I am
just going to make a presentation probably for the first year of CLIA to
update people on what we are doing.

I will talk a little bit about FDA\'s history and the transfer from CDC,
CLIA regulations, FDA\'s accomplishments, CLIA waiver, the CLIA waiver
workshop, and really what are the next steps that we are going to be
taking.

The CLIA regs were issued in 1992, and FDA was assigned the
responsibility for complexity categorization. Between 1993 and 1994, we
actually completed 900 categorizations. But then there were no resources
and funding issues, and the responsibility was delegated back to CDC in
1994.

The CLIA transfer. There was an impetus to change from manufacturers,
and the manufacturers I believe went to Congress and said that there was
confusion and duplication of its efforts.

Congress asked the CDC, HFCA, and FDA for some form of consensus, and
then we signed an inter-agency agreement in February of 1999, because
HFCA actually pays for us to do the categorization. But again, HFCA,
CDC, and FDA, we are all CLIA partners.

We began hiring scientific reviewers and medical officers in the fall of
1999, and we have actually completed all of our hiring in the fall of
2000.

And FDA has a dual challenge. We do an FDA review and a CLIA
categorization review, and always the training is in a continuum. Again,
the key features of CLIA is that it is based on the complexity of the
testing, and not the laboratory site and it applies to virtually all
laboratories.

And if I looked on HCFA\'s home page, it really is about 170,000, versus
12,000 that were previously regulated before CLIA \'88. And the key to
understanding categorization is the analyst and the complexity of the
testing.

Again, CLIA \'88, the law specified that laboratory requirements be
based on complexity, and the regulations were published to implement
CLIA on February 28th, 1992.

Three complexity categories that the FDA regulates, which are
commercially marketed products,

\-- high, moderate, and waived, and waive tests were defined as cleared
by the FDA for home use, are simple and accurate as to whether the
likelihood of erroneous results legible.

The CDC and HCFA actually published a criteria for waiver as a notice of
proposed rule making, because the purpose was to clarify the statutory
criteria for waiver, and then on November 9th, 1997 the CLIA waiver
provisions were revised by Congress, and it said the tests approved by
the FDA for home use are automatically waived.

And then they also changed the one phrase in there, \"simple and
accurate\" to render the chance of an erroneous results by the user
negligible. So it looked at that instance that it was taking it away
maybe from the test and saying can a user perform this accurately. And
then also no reasonable risk of harm if performed incorrectly.

And this was actually put in the Food and Drug Modernization Act, in
Section 123, under biologics, under the biologic exception and not
devices. If you need any more information, that is basically me right
here. I won\'t be there and you can just leave me a message if you want
to call me.

And this is also our fax number, but the web page is really a very
effective way to give out information. Again, we have done really a lot
of accomplishments since we started. On 913 categorized, 797 moderate
and high, again about 75 percent are moderate, and probably about 24
percent are high.

And really only about one percent are waived. We have the waiver
notifications on the CLIA home page, and we also have an administratives
procedures guidance, which was published in August.

The purpose of that is to just give you an idea that if you have an
exempt device, what do you do if it is exempt from 510(k), but it still
needs a CLIA categorization. That is some of the information that is on
there.

Again, you can see that waived is certainly a very small part of it. The
majority of it really is moderate, by far a moderate complexity.

FDA\'s waiver responsibilities. As I said before, that the proposed rule
was published by HCFA and CDC in September of 1995, and they were to
clarify the statutory criteria for waiver. The CLIA committee provided
input into the guidelines for a waiver, and I believe our new panel
chair, Fred Lasky, was part of that. Weren\'t you, Fred?

DR. LASKY: Yes.

MS. SLIVA: So he is not really that new. And so what we did was that
CLIA provided input into the guidelines for waiver, and now the FDA
needed information from the stakeholders to implement new
responsibilities for waiver decisions.

Waive test systems. They are certainly controversial, and waiver labs do
not need to meet national personnel standards, waiver inspections,
proficiency testing. But another thing is that manufacturers really have
shown the technology to be very reliable.

Again, the three paths to waiver. This is the nine by regulation. The
waiver criteria in the notice of proposed rule making, where you would
actually have to meet the criteria published by HCFA and CDC. And then
those cleared or approved by the FDA for over-the-counter or
prescription home use.

Again, the regulation is the dipstick, the spun hemacrits, hemoglobins,
urine pregnancy tests, ovulation tests, and this is where the majority
of tests are the waived category, the nine by regulation. Again, you can
see pregnancy tests are probably the number one. But a growing number of
new tests have been included by the FDA for over-the-counter use, and
this does include drugs-of-abuse and triglycerides, and
estrone-3-glucuronide, HOL cholesterol and microalbumin.

A drug test cleared by the FDA as over-the-counter are automatically
waived, but this, the CLIA regulations are not currently applied to
workplace testing. The delay in implementation applies to employee
workplace testing. rkplace testing. But employee testing for health or
treatment purposes is subject to CLIA.

Again, what is prescription home use, and this was given to us by a
lawyer, and so FDA devices are either over-the-counter prescription, and
prescription home use is a prescription device that the physician
instructs you to use at home, or it is any device that is not used in
the home that is not over-the-counter.

And examples are prothrombin, and that was our first over-the-counter, a
bladder tumor antigen, and hemoglobin A1C, which we just cleared in the
last couple of months.

Again, we had a public workshop, and we needed to obtain additional
comments, and there really were \-- it really represented all of our
stakeholders; the public, the government, inspectors, lawyers,
clinicians, industry, professional lab groups, and medical societies.

There were probably over 300 people present for both days. I thought it
was a wonderful workshop. There was really a lot accomplished. There
were 28 presenters, and we did accept written comments through October
16th.

Why did we have this? It really was that the time was ripe to revisit
the criteria for waiver. The proposed rule is really over five years
old, and FDA needs to re-propose the rule to implement its
responsibility for CLIA, and it is beneficial to all groups to actually
know what criteria you need, and the interest in waive test is very
high.

Where are we? We continue to meet with manufacturers requesting waiver,
and we have a priority on the transition waiver. These are waivers that
are in transition from CDC. There are really about 21 of them that we
are reviewing.

We are putting out or drafting a level one guidance on criteria for
waiver, and this will just give FDA \-- it is a proposed guidance that
gives manufacturers another route to obtain waiver. But manufacturers
may still request waiver based on the criteria in the \'95 proposed
rule.

The guidance on waiver criteria. These are just some of the questions
that we are asking. Is the test simple, meaning does it have simple
characteristics; say something like it only takes five steps.

Can users in waive labs achieve results that are as accurate as results
achieved by moderate and high complexity labs. And are there no
significant differences between lay user and laboratorian; and there are
no significant differences between the lay user and the expected result.

So again the emphasis is not on is the test a perfect test, but the
guidance on criteria is asking the question can the untrained user
repeat and get the same results as a trained professional. But remember
that these are all proposed, and we are going to re-propose the rule.

Well, one thing that I think is really a good part of our guidance is
going to be a data based QC recommendation, because we all know that one
side\'s QC does not fit all, and we do want studies to demonstrate that
there is alternative QC for the advanced technology.

What are we doing? Well, we are still accepting requests for waiver
based on the proposed rule, and we continue to listen and interact with
our stakeholders.

DR. KROLL: Thank you very much. Now, we are going to have the FDA
presentation from Dr. Jean Cooper.

DR. COOPER: Good morning, Mr. Chairman, and panel. My name is Dr. Jean
Cooper, and I am the Chief of the Toxicology and Chemistry Branch in the
Division of Clinical Laboratory Devices.

It is my pleasure to have the opportunity to discuss our revised
drugs-of-abuse guidance documents. The policies set by these guidances
will have significant public health impact. We will discuss the
prescription guidances this morning, and the OTC guidance this
afternoon.

We would like to focus this morning\'s discussion on the proposed study
designs for characterizing device performance. I will summarize the
study design described in the guidance. This guidance differs from
earlier versions in, one, providing examples of study design formats;
and, two, focusing more on characterizing performance around the cutoff.

We would like your comments on the study design as proposed in the
guidance, and we would like you to discuss evaluating tests without
SAMHSA guidelines, including tests to detect drugs with multiple
metabolites, and tests intended to detect members of a large family of
drugs, such as barbiturates and diazepams.

Let\'s begin with some background information. Drugs-of-abuse tests are
intended to detect the presence of drugs-of-abuse or their metabolite
examples. These tests do not indicate whether a person is impaired.

The guidance focuses on testing urine samples for amphetamines,
methamphetamines, cocaine, opiates, cannabinoids, and PCP. The revision
expands the application of the guidance.

The guidance recognizes that most of the studies would also be
appropriate for characterizing other drugs and drugs found in alternate
matrices. The prescription guidance describes study designs used to
characterize the performance of tests that are performed by medical
professionals.

The studies are typically done within the sponsor\'s own facility. The
study results are then put into the products package insert to better
assist the professional in understanding the device performance and
limitations.

The prescription guidance addresses analytical performance by trained
technicians performing the tests in either a central laboratory or by
near-patient personnel performing the tests under the supervision of
professionals.

Performance testing needs to reflect the site in which the device is
intended for use. The guidance outlines the information needed in a 510K
application to support substantial equivalence to other marketed drugs
of abuse-testing devices.

The information used to support clearance includes, but is not limited
to, studies demonstrating the devices\' minimum detection limit, cutoff
concentration method comparison studies, cross-reactivity, interference,
and precision.

The specimen collection process needs to be prescribed, and the guidance
asks that each data set include the following information.

And they are the number of samples in the study, the concentration of
the specimen, the methods used to determine drug concentration, the
number of replicates, the number of operators involved in the study, the
description of the testing facilities, and the qualifications of the
individuals performing the tests. And I would refer you to the guidance
for specifically additional information.

The minimum detection limits are determined by analyzing 20 repeat
determinations of the zero calibrator and calculating the mean and
adding two standard deviation.

The detection limit for a qualitative visually read assay may be
estimated by serially diluting a sample with a known amount of the drug
until the sample no longer renders a positive result.

To reduce the impact of assay imprecision, we suggest that multiple
aliquots at each level be evaluated. Sample concentrations should be
confirmed by analytical techniques, such as a GC/mass spec.

The guidance was revised to help clarify the information provided
characterizing performance around the cutoff. Cutoff concentrations and
applications are generally consistent with a level established by SAMHSA
for the five drugs-of-abuse in urine.

Product applications contain studies to support each cutoff by testing a
statistically valid number of spiked samples with known drug
concentrations equally distributed around the cutoff.

Concentrations at 25 percent above and below the cutoff allow the
reviewer to evaluate the product\'s performance around the SAMHSA
established cutoff.

In the absence of SAMHSA recommendations, the rationale for a cutoff may
be based on analytical studies or scientific literature. Tests intended
to detect drugs with multiple metabolites, and tests intended to detect
a large family of drugs, raise questions related to complex cutoffs.

For example, barbiturates have many related compounds and many
metabolites. A potential review criteria might be to evaluate the
performance around the cutoff using the compound most commonly observed
in urine.

We would like your suggestions on review criteria when addressing
complex cutoffs. The guidance strongly recommends that all or part of
method comparison studies be performed against referenced testing
methodologies.

Comparisons between varying immunoassays often provide limited
information on device performance because of a variable reactivity of
these assays around the cutoff. Most screening tests would agree a
hundred percent of extreme upper and lower drug concentration.

A method comparison using a quantitative record method allows the
reviewer to assess qualitative performance at defined drug
concentrations.

The guidance suggests at least 80 clinical samples be tested per drug.
All positive samples, and any portion of the negatives, should be
characterized by GC/mass spec.

Causery activity is determined by adding drugs with similar molecular
structures likely to cause a test to be positive to drug free urine.
Compound concentrations should reflect those normally seen in subjects.

The guidance suggests if a compound causes a positive reaction, dilute
it until negative results are observed, and report the impact
concentration in the label.

Interference is determined by adding commonly prescribed prescription
drugs, and common OTC remedies, such as acetaminophen and caffeine, at a
minimum concentration of a hundred milligrams per milliliter to see if
the drug alters performance.

Effects on performance due to Ph and specific gravity, or other
properties, needs to be identified. Precision, provisionally read,
qualitative tests, is determined by asserting multiple lots by at least
three operators.

The guidance suggests that each operator evaluate 10 samples for each
level over a minimum of 2 to 3 days. For semi-quantitative assays,
replicate measurements or calibrators is acceptable.

If the device is to be marketed to a point of care settings, studies
should be performed in the hands of personnel without training as
medical technicians or technologists at least three representative
point-of-care sites.

Data should be presented according to site and operator, and information
on education background of operators needs to be included. During
point-of-care studies, the written and verbal information available to
operators should parallel that expected under usual conditions of use.

The prescription drugs-of-abuse guidance document describes the testing
and labeling information needed for clearance, and we have revised the
guidance based on what we have learned from reviewing applications, and
we look forward to hearing your thoughts when you have a question.

Are the suggested study designs in the guidance for the following
performance characteristics appropriate. We would like you to give us
your comments on precision, comparison to GC/mass spec, sensitivity to
cutoff validation, interference, cross-reactivity, and studies for
point-of-care devices.

And our second question is the guidance addresses the five classes of
drugs for which SAMHSA publishes guidelines. The FDA often reviews other
drugs for which there are not SAMHSA guidelines.

What are the appropriate methods for establishing valid cutoffs and
assessing accuracy of these tests? Consider especially tests intended to
detect drugs with multiple metabolites and tests intended to detect
members of a large family of drugs, such as diazepams or barbiturates.
Thank you.

DR. KROLL: Thank you. Do any members of the panel have any questions for
Dr. Cooper?

(No audible response.)

DR. KROLL: No? Then we will proceed, and now we open the floor up for a
public hearing, and these are lawyers who have previously contacted the
executive secretary, and they will address the panel and present
information relevant to this agenda.

Again, we ask the speakers to identify themselves, and please state
whether or not they have any financial involvement with the manufacturer
of the product being discussed or with their competitors.

And we are giving each speaker 10 minutes. So the first speaker we have
on the list is David G. Evans.

MR. EVANS: Hi. Good morning. I am David Evans, and I am the Executive
Director of the National On-Site Testing Association. NOTA is a
consensus group of the manufacturers, users, and distributors of on-site
drug and alcohol tests.

I also have a private law practice where I provide legal assistance to
the manufacturers of drug and alcohol tests, and I have litigated in
these areas, including the U.S. Supreme Court.

When clients come to me, I usually give then one of three answers. I
give them either a yes, that they can do what they want to do; I give
them a maybe pending further research; and sometimes I say no.

If I was representing the FDA, and the issue was presented to me as to
whether or not the FDA had authority to regulate on-site testing other
than the very narrow category of diagnosing it or using it for disease
diagnosis, my response would be, no, you do not have the authority to do
this.

But why do I say that? Well, in looking at the FDA regulations and the
statutory authority of the FDA, looking at the definition of devices, it
is clear that the only authority the FDA has is to regulate devices that
are used for a mediastinal purpose.

Now, let\'s look at the definition. It includes re-agents instruments
and systems intended for use in the diagnosis of disease or other
conditions, including a state of health. But then what is the purpose of
that?

Then it goes on to say that in order \-- which gives you the purpose \--
to cure, mitigate, treat, or prevent disease or sequelae. The FDA has no
lawful jurisdiction over drug testing unless it is used only to diagnose
a disease.

There is case law on this. There is the case of the [U.S. versus An
Article of Drug\...Ova II]{.underline}, out of the [District of New
Jersey]{.underline}. It was affirmed in the 3rd Circuit Court of
Appeals, saying that the product must be used for mediastinal use. That
is the intent of it.

Intended use under the FDA Regulation 21 CFR 801.4 determines whether
these products are medical devices. Now, this afternoon, I am going to
go into detail about the intended uses of these types of products and
show how the intended use does not meet the FDA definition.

The FDA recently tried to regulate cigarettes as a medical device, and
it went up through the court system and up to the United States Supreme
Court, and the FDA was turned down.

The Supreme Court said that an administrative agency\'s power to
regulate in the public interest, no matter how intense that public
interest is, must be grounded in a valid grant of authority from
Congress.

Well, what has Congress and the courts had to say on this issue? Well,
there have been several court cases now under the Americans With
Disabilities Act where people who were given a drug test and then fired
complained that the drug test was \-- because it was positive,
determined that they had a disease.

And the disease was that they were drug users, and therefore they could
not be fired, because that was discrimination. Well, the courts clearly
have said \-- and I am not aware of a single court that has ever held to
the contrary, that a drug test only detects the use of drugs.

It does not detect whether somebody is an addict, or an alcoholic, or
anything else. It just merely means that within a 2 or 3 day period
before the test that somebody ingested drugs. That is not a diagnosis of
a disease.

Congress went on to say again in the Americans With Disabilities Act \--
and this is a direct quote, a test to determine the illegal use of drugs
shall not be considered a medical examination.

That is a statutory holding by Congress.

And I will be going into this in a little more detail later. There are
adequate laws to provide protection to consumers. The FDA not only has
to consider the intent of Congress according to the case law, but the
FDA also has to consider if there are alternatives to FDA regulations.

And we have a lot of laws regulating workplace drug testing programs and
other types of drug testing programs. We have been working with SAMHSA
for several years on this issue, and they are about to come out with
some draft regulations that will provide regulation of on-site testing.

Several States now have laws on on-site testing. There are also other
laws; the Federal Trade Commission laws, Consumer Product Safety
Commission, the U.S. Postal Service, all have laws protecting consumers.

Several State\'s Attorney Generals now have looked at the issue as to
whether or not a drug test, and specifically an on-site drug test, is a
laboratory test or a medical test. They have all come down on our side
of the issue.

They have all said that it is not a laboratory test, and it is not a
medical test. And they didn\'t even get into the issue of intent. They
just looked at some of the other issues involved in this.

I am also concerned that the FDA is seeking to impose confirmatory
testing after an on-site test is used. Where is this going to stop? If
you decide that you have the right to mandate that employees engage in
confirmatory testing, are you then going to decide that they have to use
an MRO.

Are you then going to decide that they have to used a licensed specimen
collector, and on, and on, and on, and on. It is not going to stop. If
you decide that we have to fine tune this to ensure test accuracy, you
can add on other requirements that are going to be very burdensome to
employers.

I am going to have further comments on this afternoon, but I would like
to hear from the FDA where is the problem that needs fixing. I would
like to know what evidence are you basing this on.

We have now been using on-site tests for 10 years. I am not aware \--
and I have written two books on the subject, on the legal aspects of
drug testing, and I am not aware of a single court case in this 10
years, in employment or any other matter, where an on-site test has not
been found to be valid.

And in fact we have several court cases, many of them in the criminal
justice system, where on-site tests and the method of using those
on-site tests, have been found to be valid, where the manufacturer
instructs people on how to use the tests.

And those court cases have specifically mentioned this as an issue, and
these are cases where people have to prove \-- and these are cases that
are already before courts, and they had to use the standards of proof to
prove that these tests were valid.

And I have written testimony that cites all these cases, and I am not
aware of a single case to the contrary. So if there was a big problem
out there, we would have heard from it by now in the courts.

The U.S. Postal Service \-- and I am going to end on this \-- has been
doing about 250,000 on-site tests a year since I believe 1998. They
testified before SAMHSA when they were looking into this issue, and I
suggest that you talk to the U.S. Postal Service.

These are a \-- you now, a large organization, and a quasi-government
organization, and it has been using on-site testing, and they have not
had the issues that the FDA is concerned about.

Mr. Chairman, I have some written testimony, and if I may, I would like
to add it to the record, and I brought 20 copies. So I will give it to
you. Thank you very much, and I will have further comments this
afternoon.

DR. KROLL: Thank you. Before we go on to the next speaker, one of our
panel members just came in, and I would like her to introduce herself.

DR. HENDERSON: Hi. My name is Cassandra Henderson, and I am the Medical
Director of the MIC Women\'s Health Services in New York City. I am also
Chief of the Maternal-Internal Medicine at Our Lady of Mercy Medical
Center in The Bronx.

DR. KROLL: Thank you. Now we are going to go to our next speaker, which
is Mr. Bob Aromando.

MR. AROMANDO: Good morning. I had indicated to the Chairperson earlier
today that I wished to decline my opportunity to speak in the morning
session, and save my comments for the afternoon session.

DR. KROLL: All right. Thank you. Then we will go to our next speaker,
which is Dr. Salvatore Salamone.

DR. SALAMONE: Hi. I\'m the vice president of research and development at
Roche Diagnostic Systems, and I have been at Roche for about 18 years
now, and I have been intimately involved with the development of many
different product lines for drugs-of-abuse testing.

In fact, I was also involved with the first full complete line of
on-site drugs-and-abuse tests, and that was the abuscreen On Trak
System, and we launched that in, what, 1989 or so.

And as I was reading through the draft document, I thought that I might
make some comments on some of the aspects, or some of the points that
were brought up there.

The first point is this whole aspect of clinical samples around the
cutoff. I have talked with people about this in the past, and for a
number of different assays, it is very difficult to procure samples that
have values around the cutoff.

This would be especially true for samples like morphine or cocaine; and
for cannabinoids, yes, you would find more around the cutoff; and with
amphetamines, you would find more around the cutoff.

But it has been our experience that when we submit documents to the FDA
\-- and we don\'t force those analytes that we don\'t have materials
around the cutoff samples, around the cutoff, they ask us to dilute the
samples.

And dilution of samples, clinical samples, drugs-of-abuse samples, is
not like when you dilute a therapeutic drug, or a clinical chemistry
sample. There you get linearity upon dilution.

But with drugs-of-abuse screening tests, the antibodies are designed to
pick up a wide range of metabolites, and when you dilute a sample like
that, you really don\'t get linearity upon dilution, and it makes it
extremely difficult for us to try to hit with values around the cutoff.

So what would be better for us to do, and be m ore informative, would be
to take samples and spike \-- take clinical negative samples, and spike
them with a specific drug that we are interested in, and look at the
performance around the cutoff of those drug standards in those sample
matrices.

It just \-- it does not work out in many cases, and it just makes it
very difficult, and it also makes it very confusing. The other point is
about the detection limits in cutoffs.

The document describes a quantitative test quite well in terms of
detection limits, and it also in the first paragraph talks about \-- I
think it alludes to detection limits in qualitative tests, and it says
this, \"Alternatively, this may be defined as a minimum concentration of
a drug or drug metabolite that is capable of generating a positive
result.\"

Then we go down to study design, and this is on page 8. The way that I
look at qualitative tests is that the cutoff value is the detection
limit, okay? Because in a qualitative test the presence of a drug above
a certain level will give rise to a positive test result.

And if the drug level is below \-- if the drug concentration is below
that level to the visual or to the user, it is a negative result. And it
says here \-- and that\'s why I am confused. It says here under study
design on page 8, \"The detection limit for a qualitative visually read
assay may be estimated by serially diluting a sample with a known amount
of drug until the sample no longer renders a positive result.\"

So does this mean that the detection limit is the cutoff value, or \--
well, it is just confusing, okay? But I think detection limits with a
qualitative test are meaningless if we just use a cutoff value in
whether seeing the presence or absence of the drug.

Okay. The establishment of cutoff. Well, that is another aspect. A lot
of times these cutoff values are marketing driven, and when we develop
different types of tests, especially instrument-based tests, certain
unions require a certain cutoff, and other laboratories require a
different cutoff. And in hospital emergency rooms, they want the most
sensitive tests generally.

And so the only thing that manufacturers can do in terms of establishing
cutoffs is to look at a particular cutoff and make the comparisons with
GC/MS to see if it is a valid cutoff, and how accurate a screening
cutoff is, or how clinically effective a screening cutoff is relative to
GC/MS.

Now, I heard some description about perfect agreement and now I have a
better understanding of that. I guess what we are looking for here is at
what levels in the testing do we get perfect agreement.

And I guess with every amino assay, you can dilute to a certain level or
concentrate to a certain level until you get close to a hundred percent
agreement. In general, the way that we have gone about looking at
precision of these assays, or agreements, was at the 95 percent
confidence level.

We would use a standard and either dilute it or concentrate it to a
point where we would see 95 percent confidence. This is the way that we
have been developing drug tests for the past 18 years.

And this is the SAMHSA requirements, which give that same confidence
interval of 95 percent. I think that would probably be a better way of
going than looking at something at a hundred percent, because the window
would be very large at that point.

As far as additional drugs, I think that has been talked about a bit.
Yes, there are a number of other drugs that aren\'t under the SAMHSA
guidelines that the market needs, and we currently have tests available
for them.

And one other point about multiple lots of re-agents when you are doing
the clinical testing out in the field. I think it is a good idea to do
clinical testing in the milieu of where the test is going to be
performed. It will give a nice assessment of things.

But the point made in the guidance document is that we should use three
different lots of re-agents. That will really put a very large burden on
the manufacturer, because these lots generally are production lots, and
the cycles to make these production lots are quite long.

And to make three different lots, and then to send them out into the
field for testing really puts a lot of strain on the system. And I
don\'t really know if it is necessary. We are under good manufacturing
practices that are very highly regulated.

And when we make pre-production lots or production lots, the performance
of them has to be within specifications of the performance of all of the
subsequent lots.

And so what we would like to ideally see with this type of testing is
that, yes, we allow one lot to go out to be tested, and then our other
lots \-- just like the way we make any of our re-agents, our other lots
are compared to the original lot.

This is the way we have been doing things for years, and the accuracy
that we see, and the variation that we see, is kept to a minimum. I
understand that there may be a concern with a lot of new entrance to
this whole business that it may be necessary to ensure that you get
lot-to-lot reproducability.

But it really does put a burden, especially on the large manufacturers
that have been doing this for many years, and doing it in a very
accurate way. So that is about all that I have to say. Thank you.

DR. KROLL: All right. Thank you. Now we are ready to go to our open
committee discussion, and one way to do this is that we can go around
the table and have each person, each panel consultant, go ahead and give
their comments on this document and see if they can help answer the
questions that the FDA has put before us.

So why don\'t we start with Dr. Rosenbloom. So why don\'t we put up
question number one first from the FDA, and see if we can answer that
question specifically. All right. Why don\'t we start with Dr.
Rosenbloom.

DR. ROSENBLOOM: Well, regarding question number one, I am not an expert
in laboratory. Those are all laboratory questions, and I am going to
defer to those who are.

And so lacking immediate laboratory experience, I will be interested in
those people who are working directly in this area and their comments,
and I will respond to those in addressing this. So I defer to the
laboratory experts in the group.

DR. HENDERSON: Similarly, I will have to defer to my laboratory
colleagues.

DR. LEWIS: Not so much a question as a comment, and I think that the
presentation regarding the sensitivity or the cutoff validation, I have
been wrestling with that very question of what is meant by the limit of
detection, as opposed to the cutoff, when you are talking about the
types of tests where either it is positive or negative, and there is no
numerical value associated with that result as being positive or
negative.

So to me it is either confusing, or a non-existing entity as to the
distinction between cutoff and limit of detection or sensitivity.
That\'s my only comment at this particular moment.

MS. CALVIN: For the record, that was Dr. Lewis, and panel members,
please remember to state your name.

DR. LEWIS: Sorry.

DR. MANNO: Barbara Manno. I am a little confused between the document
and the presentations because by the wording of the document the
document contains the wording for therapeutic use, and it needs to be
very clear on point-of-care testing whether it is for workplace testing,
or whether it is for therapeutic use.

And I agree with Dr. Lewis\' confusion on the limit of \-- on the
wording of limited detection and cutoff. There has to be a difference or
a clear definition of the terminology here.

I was reading again the document last night, and I was reading at the
same time, or during that time, the DOT guidelines. And they make a
point in there on visual read-out tests; that they should be tested
under varying lighting conditions, and I would suggest that that be
considered to be put into this as well.

So that having worked with some of these myself, I know that varying
lighting conditions can give you varying results based on the intensity
or a lack thereof of color at the point of reading. So I would think
that some consideration needs to be given there. Thank you.

DR. KROLL: Thank you. Martin Kroll. One thing or one comment that I
would like to make is that when we look at things like comparison to
GC/MS, which I think is a good idea, as that is always good to know how
much is actually in a sample by some means that we would consider a
reference or almost as a reference method.

So that is an accuracy issue, and we need to clearly separate that out
from precision. And the same thing in terms of sensitivity or cutoff
validation. That we need to clearly separate that out from the precision
issues, even though precision does play a role in evaluating the
accuracy, sensitivity, or cutoff validation.

When I was looking at this document, I actually liked the idea that they
had a separate one for the minimal detection limit, and I do think it is
appropriate to use samples in which in some way we can dilute them down
by using some appropriate matrix.

I take a different view than some people, and that is that I do believe
even on a device that is meant for qualitatively that you can go down to
a very potentially low concentration of drugs or drug metabolite, and
yet your cutoff can still be significantly above that limit of
detection.

Because it is one thing to say that I can detect a certain amount of
drug here, or metabolite, but then you get into other issues, which is,
for example, if the person did take drugs or they were exposed, how did
they get in there.

Is it really important, and what are the probabilities that this person
is potentially going to be, let\'s say, abusing a certain drug. So those
are distinct types of entities.

For many years I was involved in an emergency room where we had people
come in, and you knew that a lot of these people were drug users. But
there was a clear separation; did they use something recently, or is it
something that is sort of hanging around; or is it really not that
important in terms of what we are dealing with today for that person.

And you would like to have your ability to detect the concentration, and
to go below your cutoff. So then you can set your cutoff above that. In
some cases, depending on the situation, the cutoff could be set at a
minimal detectable concentration, but it does not always have to be.

So I think that is important that those two things are separated out.
All right. Those are all the comments that I have for right now.

DR. KURT: I am Tom Kurt, and I would like to point out something that I
don\'t think is on the list, and which has become important in recent
years, and that is adulterants, because adulterants are frequently done
as a pretest.

And since as a medical review officer, there is an adulterant presence,
such as chromium or sodium hydroxide, and that is positive, that is
considered a refusal to test, and the test itself is not performed, and
the person might lose their job.

And so I think that there should be something about the quality,
control, and precision of the adulterant testing that is included in
this if the adulterant testing is indeed performed.

The next under GC/MS accuracy, there are times in my experience where a
non-DOT testing for a specimen has either been discarded, lost, or
contaminated before the GC/MS testing could be performed.

The question then arises is confirmation testing absolutely necessary,
or is the test that is performed absolutely worthless. I think based
upon the SYVA information, that in a test or a study of 20,000 alert
tests, there was a 98.2 percent accuracy of testing of your remit
methods that as a stand alone testing is relatively accurate.

And something should be said \-- instead of categorizing this as a
screening test in these categories, as something more like an initial
test, with GC/MS being necessary or preferred in the situation. Thank
you.

DR. WILKINS: Diana Wilkins. I want to apologize ahead of time because I
am going to ask probably some questions that may have come up at prior
meetings or something, and so being a first-time member, I am not sure
if these have already been discussed.

I just want to mention that I concur with the comments of Dr. Kroll and
Dr. Manno regarding the definitions of terminology for detection limits
and cutoffs for these assays, as well as the lot-to-lot variability with
the color issues and visually read tests.

The one thing that I had a question of is with the issue of comparison
to GC/MS testing as the reference method, I wondered if it has already
been discussed at some point whether or not that could be limited
theoretically to mass spectrometry as the detection method in general.

I am just looking further down the road. There maybe come times when,
for example, a manufacturer or someone else might be looking at a polar
drug or metabolite, and might be interested in using an alternative
method of introducing the sample to the detector, possibly LC/MS, for
example, or capillary LC/MS.

And if it is limited to GC/MS, my concern would be that that really may
not \-- if you strictly use that interpretation \-- allow the
manufacturer to use the best, and most reliable, and accurate method of
establishing sensitivity, or reproducability about the cutoff. That\'s
number one.

And the second thing is that I was curious on whether in the proposed
document that the sponsor was going to need to include the length of
time between sample collection and testing, or whether they needed to
evaluate the stability of samples between the time that a sample might
be collected, wherever that happens to be, and the time that it is
actually received at a laboratory in the documents provided for
submission.

DR. GUTMAN: I would be happy to address and to answer both of those
questions. I don\'t recall \-- and somebody from the group can quality
control me. But I don\'t actually recall a panel meeting where there has
been previous discussion about what the appropriate gold standard or
yardstick is.

There has been a lot of internal discussion with certain submissions
about the novelty of some of the alternative gold standards, and how to
be sure that what you are dealing with is gold and not an alloy of
uncertain proportion.

We could certainly take it under advisement that there be a
liberalization. I don\'t think there was an intent to restrict or to
create any artificial barrier that was a comfort with GC/MS. But
certainly as science changes, and credible alternatives are available,
we wouldn\'t want to be in any way limiting.

We don\'t currently have any requirements, I don\'t believe, either as a
review practice or in the guidance document, that there be information
on duration of storage of the sample. If you would like to put that
recommendation on the table, we would certainly consider it.

DR. EVERETT: James Everett. This particular question I actually agree
with. That is, if any laboratory task is going to be developed, and in
essence in a research laboratory, and then later put into practice,
there should be some perimeters to decide if the test performed as
indicated.

The characteristics listed here, precision, comparison to GC/MC, and
sensitivity, and interference, and cross-reactivity, and studies for
point-of-care, these are studies that get to the heart of whether or not
the device actually works.

The only real thing it seems to me that seems to be left off is
specificity. But in essence I generally agree that with any test that is
going to be used on the public interest, there should be some
performance characteristics.

And I think that these are minimal. And the list, in essence, could go
on and on. But assuming that Mr. Evans is incorrect, and the FDA does
have some authority to regulate these devices, then I agree. I think as
minimal characteristics that these are certainly appropriate.

DR. BUSH: Thank you. This is Donna Bush. I was unsure as an associate
here whether I was to participate directly with comments. Thank you for
that opportunity. My training is as a chemist, first and foremost, and I
concur with several of the other panel members who have reflected on the
list of characteristics here in question one.

In very basic analytical chemistry, they are the minimum essentials to
define an assay, and at the heart of qualitative assays, and I have had
an awful lot of experience in these testing technologies with these
testing technologies, both laboratory based and instrumental read and
visually read, at the heart of that is that you can\'t tell me if
something is there or not unless you know an awful, awful lot about that
assay.

Unless you can be quantitative and specific about every aspect of the
assay, then you can go qualitative. You actually have to be very
defined, very specific, in establishing the criteria about an assay
before you can go general.

It is kind of an oxymoron when you think about it, but for something as
simple as it is or that it appears to be, that\'s how complex it
generally is underneath.

And so I wholeheartedly concur with these as minimum requirements, as
well as with the comments that Dr. Wilkins and Dr. Everett, and other
board members have made about that. Thank you.

MR. REYNOLDS: Stanley Reynolds, consumer rep, and again I would pretty
much agree with the rest of the panel that I don\'t believe the study
design is laid out at this point is unreasonable or unnecessarily
burdensome. And it does give you the minimum amount of information that
you need to make a judgment.

DR. LASKY: Fred Lasky. I have several comments actually. From an overall
prospective, these characteristics I think are appropriate, but let me
go into some of the details, because that\'s where the devil is from a
manufacturer\'s perspective.

First of all, I was interested in Mr. Evan\'s comments, and I was
concerned about some of the directions that it seems that the FDA was
moving in, and his comments were ones that I had not considered and were
beyond my level of expertise.

But let me bring up an issue that is, I think, within my realm of
knowledge, and that is what is contained in the labeling of the device.
And how the manufacturer actually conducts studies in order to support
the submission, and in fact demonstrate that the device is safe and
effective.

Part of that has to do with the intended use of the device. The FDA has
authority to review submissions based only on the intended use that the
manufacturer puts in labeling. Anything beyond that

\-- off-label use, and use, for instance, in workplace drug screening.

If a manufacturer seeks not to have that as an intended use, that is
beyond the realm of the FDA\'s authority for a review based on the FDA
Modernization Act. So I think that has to be considered very carefully.

That being said, let me go on to some of the specifics, in terms of the
technical issues. There is a comment there about the comparison to GC/MC
for accuracy. But there is also an option as I understand it to compare
a device to a predicate, a device that has been cleared or approved for
market by the FDA.

And a question arises is or how are the two comparisons going to be
used. I would suggest that it should be at the option of the
manufacturer to submit data, and then of course there is always
negotiation with the FDA.

And the two options I think would be to compare it to GC/MS as a
standard, and have FDA declare that as an acceptable standard under
their authority, also under the Modernization Act.

And use that comparative study to demonstrate that the new device in
fact compares favorably or in ways known to the GC/MS method, for
instance, in this case which is generally accepted as the most
definitive method for assay, and definitive with a little \"d\" for
those of us who are hung up on standards.

The other is compared to a predicate, if that is appropriate, and in
fact might be more appropriate depending upon what the intended use of
the device is.

I have another comment about cutoff, and I would like to emphasize that
the minimum detection limit is not equivalent to the cutoff. The cutoff
is to determine, based again on the intended use of the device, whether
or not for a qualitative test a sample is positive or negative.

And there again it really depends on what the intended use of the device
is, because there are always uncertainties around the cutoff level, the
simple statistical or random variability that always occurs with any
measurement.

It is not unique to these tests, and if you were going to count a jug of
pennies, there would be uncertainly around the accuracy of that count.
So that really has to be carefully considered.

If you are looking for increased sensitivity, or increased specificity
for patient population, then that\'s how the cutoff should be
determined. And again that is based on the manufacturer\'s intended use,
and has to be decided upon by the manufacturer and by FDA.

Another comment on precision, and as Dr. Salamone mentioned, lot-to-lot
variability is most often best determined and monitored by the
manufacturer within the plant, and is at least to my knowledge always a
consideration when products are released for sale as production
continues, hopefully for a long time from a manufacturer\'s standpoint.

Most often it is not a function of operator use. Most often. And that\'s
because I hate the never and always times of scenarios. But again that
is up to the manufacturer to determine and for FDA to agree to.

So I have some concerns about the recommendations about what sort of
variables have to be considered in the end use test, which by the way I
do agree with. The tests should be looked at in the area of intended us.

And lastly I have just one small comment about specific issues, like
under particular light conditions, which I think is a very valid
comment. But those are the sort of variables that have to be considered
during the design phase of the test.

And there are regulations that in fact manufacturers must adhere to in
order to consider the major points of variability that must be
addressed, mitigated, resolved, or addressed in labeling when a product
goes out.

That\'s not to say that the FDA shouldn\'t ask those pertinent
questions, but also to consider that those are the sort of things that I
don\'t think in a guidance should be specifically noted, but given as
examples. So those conclude my comments at this point.

DR. KROLL: Thank you. What I would like to do is open this back up to
the panel members and see if anybody else has any additional comments.

DR. HENDERSON: Cassandra Henderson. As a clinician, I am very concerned
about any of the testing, and taking care of high risk pregnant women, I
want to understand and be certain that the negative predictive value is
something that I can rely on in taking care of women, and being
concerned about abortion, and pre-term labor, and fetal death, and all
of that.

Can we eliminate the possibility that some of the problems are related
to the use of drugs, immediate or in the immediate past. And I think in
listening to all of my laboratory colleagues that I have just been
educated very much here, and I thank you.

What I am very interested in, I guess, is qualitative analysis. I mean,
quantitative seems to me to be more of a research tool for me as a
researcher when I am evaluating a test.

But when I am taking care of somebody at the bedside, it seems to be the
most important thing is something that would be qualitatively reliable,
whether it is in the dark or in the light, or how that affects it
certainly is of concern.

And then finally the adulterants. We know that a lot of people who are
using substances are using other things, and things that are used on the
street. We are not clear on what else they have taken.

So certainly how the qualitative analysis would be affected by any
adulterants that they might have been exposed to.

DR. KROLL: Thank you. Any other of the panel members have any additional
comments to make?

DR. MANNO: Barbara Manno. I am concerned again about this intended use
of the product. I am hearing things that disturb me as a practicing
forensic toxicologist, and also a member of the Department of
Psychiatry, where I teach people how to interpret drug screens in both
environments.

And, number one, there needs to be something considered for the insert
in the product that you cannot tell the time of use on a qualitative
test. It is either there or it isn\'t there.

If you talk about cutoffs, per se, or \-- well, again, it is getting
back to there also should be something about not only time of use, but
very definitely for those taking qualitative results from an emergency
room setting, let\'s say, where the full intended use would be for a
clinical application in a person with an uncertain history, that those
results later cannot be used in any way to predict based on a
qualitative test performance decrement.

And this bothers me because we have the door open for alternative
matrices to be used. You cannot go from altered performance based on a
qualitative urine, for example; a urine test.

And a lot of the performance that goes along with this issue, for
decrement of performance, we don\'t know a lot about that yet. The only
one we have out there that is tested is alcohol.

We are working as fast as we can that the financial resources in the
research community allow us to work. But it is very difficult and it is
really impossible on a qualitative test in my opinion.

DR. HENDERSON: Cassandra Henderson. That\'s why as a clinician that I am
very concerned about negative values. I want to cross that off the list
of my differential.

Positives I understand. They can be plus-minus, and I don\'t know what
to make of it, and when does she use it, and does she really use it. But
a negative, I would like to be able to be comfortable that that is for
sure.

DR. MANNO: I am agreeing with you.

DR. ROSENBLOOM: Arlan Rosenbloom. I would just like to confirm that I
get involved in a lot of medical legal cases, where people have things
in their urine, and the question always comes up, well, does this really
mean that they have taken up, does it tell you when they took it, and of
course, how much they took.

There is all variables in what you find, but the importance of saying
that if it is there, it really was taken has extremely great
significance and more than just diagnosis, but in a legal context.

DR. LASKY: Fred Lasky. I think this discussion illustrates the point
that one test may not satisfy all of the needs of the community in
general; that if a qualitative drug test was used, for instance, for
workplace monitoring, just in and of itself \-- and I am not reporting
or supporting that.

But in the event that it was, then in that situation, if I was an
employer, I would want to be damn sure that a positive was truly a
positive. And yet in the clinical setting as I am hearing, you want to
be sure that a negative is truly a negative.

And there is always going to be a gray zone somewhere in between, and
depending upon the performance characteristics of that test, that gray
zone may be extremely narrow and very easy to distinguish between a
positive and a negative.

But to my knowledge there are very few \-- some, but very few \-- tests
that in fact offer that sort of a characteristic. So I go back to the
statement that I made earlier about the intended use of the test.

I think that has to be very clear, and the documentation and the data
supporting the test has to be with regard to the specific intended use,
and there are obligations that people who may use the device off-label,
or where the manufacturer did not provide data or information for other
than the intended use, that the obligation reside elsewhere.

DR. KURT: Tom Kurt. I would like to refute David Evans\' comment that
the FDA is an agency only involved in approving tests or drugs, and to
diagnose disease.

Concerning the ADA and the testing that you were pointing out in
disease, the ADA is involved with fitness for duty testing. So if a
person has a positive drug test, that is considered a person who is not
fit-for-duty.

The FDA is involved in approving biologics, such as immunizations, that
protect against disease. It is involved in lowering cholesterol
medicines that are not necessarily diseases in and of themselves, such
as lipitor and other medicines that lower cholesterol levels.

It is involved in the Center for Devices here in reviewing the standards
for rubber gloves that protect people from different substances, but not
necessarily as a diagnosis of disease.

And it is involved in the Center for Veterinary Medicine, and approving
and reviewing animal foods. So those are not necessarily diseases. So
the FDA\'s perview, I think, is a little bit wider than your perception.

DR. EVERETT: Can I respond?

DR. KROLL: I think we will hold that off for now. I think we want to get
the comments from the panel. Any other comments?

DR. WILKINS: I actually don\'t have a comment, but again I have another
question as a panel member, and that is \-- and it does relate to
something that I had not thought about until one of the presenters this
morning, Dr. Salamone, brought it up about the issue of diluting native
urine samples, and that whole issue using to demonstrate the reliability
of the device and the minimum detection limits and such.

And one question I had was that it seems to me that \-- my general
impression is that the availability of clinical specimens is going to be
come increasingly difficult, I think, in the future, because I don\'t
know about in the commercial sector, for example.

But I certainly know in academic institutions that urine, blood,
whatever, is no longer considered biological waste; that you can simply
go ahead and give to someone to be looking at.

It is not even something that many laboratories in that setting could
receive if you understand what I am saying, because that contains
information about an individual, DNA or what have you, that belongs to
that individual.

And so I am just bringing it up that I don\'t know what impact that
plays on here, but I think if there needs to be some mechanism to get
around that, it may involve fortification of urine that is known to be
drug free, with the drug that the test is targeted at, to be able to get
around that.

Again, this may have been an issue that has been discussed at some other
point in time, but I am just mentioning it.

DR. KROLL: Okay. Dr. Rosenbloom.

DR. ROSENBLOOM: Arlan Rosenbloom again. That brings up an issue of all
of the metabolites, and the variability from individual to individual,
which I don\'t pretend to be an expert on.

But I don\'t know if this is going to come up in another of the
questions. I didn\'t see that it would, but the device, the
point-of-care device that I am familiar with that is most relevant here
is the glycohemoglobin that we use in the clinic.

And in order to use that device effectively, we have to with each run
send a specimen or two to the laboratory for confirmation. I was
wondering about quality control as a question here.

It says comparison to GC/MS, but that sounds like it is in the approval
phase rather than in an ongoing point-of-care usage. Maybe we need some
discussion of that issue.

DR. KROLL: Dr. Gutman, can you comment on that?

DR. GUTMAN: Well, I hadn\'t actually thought of it in the context of a
quality control program, where you would run samples at the site, and
samples at the central lab. But anything is fair game, and so any advice
that you have on the quality control that we ought to consider, we would
certainly be willing to hear.

DR. KURT: Tom Kurt. I think that would be important in specimens where
you biologically decay particularly is cocaine, cocaine metabolites.

MR. REYNOLDS: Well, one thing I would like to mention here again, and as
Mr. Evans commented on the workplace testing, and we do have two very
different testing arenas.

And that is where we have clinical testing, where you are going to have
tests being done in hospital labs and clinical laboratories who are
regulated by other agencies, such as CLIA, CAP, Joint Commission, State
agencies.

And then you have workplace testing, where the question comes up if in
any or many of those cases if those labs are regulated at all by any
agency. I know that in Pennsylvania our law considers it to be a
clinical laboratory test, and we don\'t care if it is done in the
workplace, or done for screening, or for job performance, or whatever.
It is a regulated test in Pennsylvania.

And you are governed by our clinical lab regulations, but that may not
be the case in every State. So you do have two very different testing
arenas, and that is another thing that you need to consider.

DR. KROLL: Thank you.

DR. MANNO: Barbara Manno. Going back to the quality control, I agree
with you Dr. Rosenbloom that it is a very important issue. What I hear
some of my colleagues who are using point-of-care testing in a clinical
setting are complaining about is the fact that the point-of-care testing
is expensive to do, as compared to where you can batch process something
in a main lab, which is true.

Given that, they are saying that they are having to run one particular
test with a QC, and one with the donor specimen, the patient\'s
specimen. I think that there has to be some quality control on that;
running a parallel test once a day with that lot would give you some
indication as long as it meets a positive and a negative.

And that would give you two extra that you would have to run, but if you
are in an emergency room setting, for example, you are going to have
very likely more than one patient a day that you would need something
like that on.

That would at the very minimum would be once a day, and then jumping to
once a shift, depending on your workload. But most labs will go with the
same lot number. They try to earmark a lot number for their use for a
year, or the people supplying this, so that you don\'t have so much
confusion and possible difference by lot number.

DR. ROSENBLOOM: Dr. Rosenbloom again. Yes, I think in terms of
practicality, point-of-care testing is very expensive, unless you are
doing a lot of it.

And that that kind of system once a day, or once a lot, or once a shift,
makes sense. I doubt that you would be doing point-of-care testing
otherwise unless you had enough.

DR. MANNO: Well, I am basically agreeing with you that QC is very
important on this subject, and just making some suggestions for
consideration, I think it needs to be given consideration on
presentations.

DR. KROLL: Thank you. Actually, coming back ot the issue of \-- this is
Marty Kroll, back to the issue of cutoff concentration. I have been
reading this over several times, this definition and how it is
established.

And I wonder if in the document it could specify that this is done in a
clearer fashion, depending upon its type of use. I think as some other
people mentioned, the use determines where you want your cutoff to be.

If it is a medical situation, like in an emergency room, you want to
know that \-- you want to detect almost any drug that is there, because
that could become important in terms of how you manage the patient.

In terms of trying to decide if somebody has been using drugs
inappropriately, and you want to do something about their job status \--
and I have been in that situation, you want to make certain that your
positive is probably absolutely certain.

You are not talking about manufacturer\'s competence intervals here. We
are talking about that you want to be certain, like 99.99 percent,
because you are going to do some really nasty things to somebody based
on that result.

And so you want \-- those calls have to be different, and the
probabilities that you work with are different. And I am not saying that
the witness document is written that it is inadequate, but that it may
need to clarify those types of issues so it is dependent on the type of
use.

And when someone goes ahead and forward with the product, they say that
if you are going to use it this way, this is what the cutoff needs to
be, and this is how it is interpreted, and that we know \-- for example,
if we say it is positive, and you are using it in an occupational
setting, that the probability that it is actually a negative is so
remote that it is not going to cause harm.

I mean, we could go back to this old adage that worries clinicians that
what is worse, not having the test, or having a test that is wrong. And
if you work in a lab long enough, you realize having a test that is
wrong, or gives the wrong answer, is sometimes a lot worse than not
having any answer.

Any other comments from the panel on question number one? Let me ask Dr.
Gutman if we have discussed this sufficiently?

DR. GUTMAN: Yes. I would actually like to revisit the issue that Dr.
Salamone raised, and that Dr. Wilkins touched upon, which is whether \--
or what is the appropriate nature or specimens, and it is one that we
have been very hung up about, in terms of trying to get samples that are
more naturalistic.

I would be curious to get a sense for whether the suggestion that was
put on the table \-- I think both in the public panel meeting and by Dr.
Wilkins \-- about using a calibrator control, as opposed to samples,
seems like an reasonable alternative.

I actually do think you have access to samples as long as you are very
careful about de-linking them, but I also recognize that this is
controversial, confusing, and more intense than it might have been a
couple of years ago. So I would be very curious to know how far you
would encourage us to go.

DR. WILKINS: This is Dr. Wilkins again. I think that I had not really
thought about this before the comments this morning, and it seems to me
that again it depends on the intent and what it is that you are trying
to use it for.

I think that if you are fortifying drug free urine in order to determine
a particular characteristic, such as sensitivity, or reproducibility, at
a certain specified cutoff for a certain specified acolyte, then I would
think the use of fortified materials seems appropriate and reasonable.

I think that is a different issue though than looking at the robustness
of the system or the assay on real life specimens that are complex
mixtures of the drug and the metabolites, and everything else.

And I am not sure what the answer to that is, but I think they are two
different issues, and at least in my mind I think that fortifying
materials to specify a performance characteristic for a particular
acolyte seems reasonable.

But that would not answer the question of how well it would do in a true
urine, with a complex mixture of metabolites or other compounds.

DR. LASKY: Fred Lasky. I just want to emphasize something that Dr.
Gutman alluded to; that there are several very critical issues that are
being sort of bandied about between industry clinical laboratories and
the FDA with regard to old samples, historical samples, and whether or
not in fact they will be available for use.

So far no conclusions have been reached, but the thing that I am
concerned about is \-- and as I am sure we all are, is that there will
be two guidances that will be written, one with issues of patient
confidentiality, and historical samples, and their appropriateness for
use.

And other guidances that might require them in order to deal with this
very important issue about metabolites and different pharmacokinetics,
et cetera, et cetera.

And I would just \-- I wouldn\'t say caution, but I guess I would say
plead for all of our sakes that things be done very slowly at this point
until there is agreement between different parts of the agency so that
in fact the right work can go on to address the needs as best as
possible.

I am not sure at this point that it is possible to address all of the
needs satisfactorily, but this story is not over yet.

DR. BUSH: Donna Bush. I would like to amplify a couple of comments that
have come up here towards the end about looking at specimens, and
looking at drugs and metabolites, and looking at spiked samples.

And one example that comes to my mind that I hear a great deal about in
non-Federally regulated workplace drug testing, and the types of testing
technology, whether it be laboratory based, or whether it be
point-of-collection based.

And I will just pick a class of compounds here, and that is the
benzodiazepines, and let\'s warp back a few years, and take a look at
the old classics of the diazepam class, and then let\'s fast forward up
30 years and took a look at the new benzos of the halcyon type.

And I have many puzzled colleagues repeatedly saying to me, well, you
know, I did a benzo test, and I didn\'t detect this compound, and I\'m
like, well, you wouldn\'t. And then I lapse into pharmacokinetic talk.

But in the case of labeling, and again back to the basic analytical
characteristics about an assay, and intended use, so much needs to be
clear and understood by the parties developing the assay, as well as
marketing it to individuals who need to know in hospital settings, and
other settings, about such complex characteristics.

And one size does not fit all for many drug categories, and benzos is
just one example. Thank you.

DR. KURT: As an afterthought \-- Tom Kurt, and I would like to comment
on the cross-reactivity. I did not notice anything said about cigarette
smoking or cigarette smokers, which introduces not only nicotine, but
aldehydes, and other chemicals into the blood. I can think of at least
400.

And I think that something should be determined that cigarette smokers
are tested in the cross-reactivity.

And in addition there are a whole multitude of dietary supplements now
on the market, such as St. John\'s Wort, in which the active ingredient
is hypericum, in which perhaps some exploration should be sought as to
whether it is cross-reactive to any of the drugs-of-abuse.

DR. KROLL: All right. Thank you. Let\'s put a question to \-- and it is
on page 5, and it deals with guidance, and it addresses five classes of
drugs and what not.

So why don\'t we go around the panel, and we will start at the other
end. We will start with Dr. Lasky.

DR. LASKY: I have no comments about this. Thanks.

MR. REYNOLDS: No comments at this time.

DR. BUSH: Donna Bush. I have more questions than I have comments on how
to do this, and I am going to wait for somebody with a sage beginning
point, and I promise I will come back to it. Thank you.

DR. EVERETT: James Everett. This is an interesting question, because
from reviewing past devices, it brings to heart one of the biggest
problems by the time the manufacturer gets here.

And the issue usually is that they have already developed a method for
determining what the valid cutoffs are, and what the accuracy, as well
as the many other variables are.

But the problem really seems to be that there was an earlier
consultation with the biostatisticians for the FDA, and when they
present the data, a lot of times the data has been changed in such a way
that it appears as though the manufacturer still doesn\'t understand why
the data was changed, and to determine whether it was valid, or whether
the information they presented is not really valid at all.

So that when you look at the information to decide whether this is
something where I can say a negative is truly a negative, or is this
something that is positive, and I can truly feel comfortable that it is
positive.

The question really becomes when do you select the method for
determining whether or not the valid cutoffs are truly valid, or if you
are going to select other perimeters.

And these things are usually determined during study design. But many
manufacturers appear as though they generate the data, and then they
went back to find the mathematical test that will match their data, and
that really creates lots of problems by the time that they get here.

So the question is who should select the method for determining a valid
cutoff, and for determining the accuracy of the test. I still think that
is a manufacturer\'s decision. But that decision should be in
consultation with the FDA.

And a lot of times it just gets to be a real stickler for the members of
the panel who truly understand what biostatisticians are about, and
determining whether or not your results are valid, because in many cases
it appears as though the results are not valid.

But then we approve with stipulations to try and make the information
valid. So from my point of view, I think that that decision is still a
manufacturers\' one, but again it should be done in consultation with
the FDA.

And I would like to ask Dr. Gutman whether or not \-- or when do you
encourage the manufacturer to consult FDA for selecting those
appropriate statistical tests?

DR. GUTMAN: Well, we are trying to be more interactive. So we actually
suggest \-- and particularly if there are interesting outstanding issues
about a particular product, we suggest that they come in early.

We are willing to meet with them when it is frankly just a business
idea. We prefer to meet with companies when they actually have defined
objectives and protocols.

We are willing to do review of the protocols, including interactive
review of the protocols. We prefer to review the protocols before the
study has been started or completed, and we like to have guidance,
because that allows us to have to meet less often, because the rules are
sort of public before the game is started.

But we are very interactive, and so if somebody came through either with
an old drug with new applications, or with a new drug, we would be
interested in an early discussion about appropriate end points, design,
and statistics.

DR. EVERETT: Okay. Well, that is basically my viewpoint on this issue.

DR. WILKINS: I\'m Dr. Wilkins again. I am going to sort of take a simple
view of looking at this question, and that is sort of what approach
would you want to use for a drug that wasn\'t \-- that doesn\'t belong
to one of the \-- as we referred to it, the NIDA five, if you want to
call it that way.

And I think the model system that was specified on the previous slide,
in terms of performance characteristics, seems a reasonable approach as
a minimum criteria to shoot for. I think that is very reasonable.

Certainly when there are multiple metabolites present, then that becomes
a complicating factor. But it seems as if the package insert labeling,
and the intent of the product, is to perhaps identify a specific
metabolic, and then define the cross-reactivity with a parent compound
or what have you, that as long as it is clearly specified and defined in
that insert what is being detected, and at what level, then I think the
approach is valid, even when there are multiple metabolites present.

Anyway, I will see what everybody else thinks.

DR. KURT: Tom Kurt. I would like to comment on three areas. First, I
think this is a subject of ongoing review, because, for example, the
opiate level which was increased to 2,000 nanograms per ml of urine, and
then the NIDA five, shows that that is a subject that is something that
should be under a relative constant review or an ongoing nature.

The second is that in the NIDA five we have two substances in which the
metabolites are measured in THC, where you have carboxyl THC, and in
cocaine, you have benzoylectnonine.

The FDA uses the term surrogate marker in the Center for Drugs for drugs
that are metabolized, with those metabolites being surrogate markers of
the drugs.

And I think it would be appropriate to use the term surrogate markers
for drug abuse in this situation. The third is that there are substances
that might be added to this list from time to time. For instance, MDMA,
or metdioxymethamphetamine, or \"Ecstasy\" is now going into a
resurgence, where that might possibly be added to the list, and that\'s
not picked up under the methamphetamine or amphetamine testing.

So I think some kind of a situation where you could have a memorandum of
understanding, or MOU, ongoing with SAMHSA on substances that might need
to be added to the list based upon the current circumstances, such as
MDMA, would be appropriate.

DR. KROLL: Thank you. I am Dr. Kroll. Looking at this, I agree with the
previous comments. I think if you are looking at other drugs besides
this group, you have to make certain that in terms of accuracy that the
methods compare with some other method, where they have a clear
understanding of the metabolites involves, and the pharmacokinetics.

And that they can clearly establish many of the metabolites. Also, if
there are a large number of metabolites, or even just a few, but they
range in value from person to person, that a range of values are used
for metabolites.

When you start looking at large classes of drugs, this actually makes it
more difficult, because there are many different types of metabolites,
and so they have to look at the different types of extremes in these
cases, especially when answering the last part of the question, that if
you pick out barbiturates, how would you pick out the cutoffs.

That again is really very dependent on its intended use, and what type
of statement someone is trying to make, and I think that clearly has to
be identified, in terms of probabilities and the outcomes of using a
particular cutoff. Thank you.

DR. MANNO: Dr. Manno again. Like a previous panel member, I don\'t know
where to start on this, but picking up and coming around the table to
me, I would agree that the list of things on the performance of the test
that we have discussed earlier \-- precision, accuracy, et cetera \--
seem to me to be appropriate for establishing valid cutoffs.

But there again we have to have an open door in establishing cutoffs so
that they can be varied based on clinical experience, whether it is
clinical experience in a true clinical arena, or if it is in the
workplace, and what we are seeing coming out of some of the surveys that
come out of SAMHSA.

On the second part, I think we should not make this too difficult to get
the product to market so to speak when we are having to talk about
detection of drugs and metabolites.

It has been my experience \-- and I have been in the business since it
started \-- from a consumer standpoint in a laboratory that the
companies that are serious about the business are very helpful to the
consumer, in that once they will have some initial compounds, we will
say, that have been checked for detection of particular things.

For example, again, the benzos. They will have a certain list that they
have tested to start with. But as the laboratorians or the user gets
into the continued use of the product, they will keep a very extensive
list of products that have \-- or drugs that have shown interferences or
cross-reactivities.

And they have the help line as we call it in the lab, and they have been
very \-- I have had good luck with using help lines with some of the
larger corporations at any rate.

And knowing at what concentration a product would interfere, another
drug would interfere, or a metabolite might cross-react, that is not in
the product insert.

So if we can keep those lines open with the sponsor of the product, that
is very important. That is all I have at this point.

DR. LEWIS: Sherwood Lewis. Looking at the question of what are
appropriate methods for establishing valid cutoffs and assessing
accuracy of these tests, and focusing simply on the question, I would
say that if the appropriate methods are established for the SAMHSA five,
then these should certainly be appropriate given that, yes, for
barbiturates that you are going to find some distinction as to what
metabolites, and the purpose to which you are putting the test.

But appropriate methods, I think, should in principle be the same,
whether it is for the five previously discussed, or others that may come
along, if I understand the question correctly.

DR. HENDERSON: Again, as a clinician, I don\'t have any comments on the
laboratory tests. But certainly it seems to me that the methods for
establishing cutoffs and accuracy would be very dependent on what the
tests were being used for.

I would certainly echo one of the previous panel members in the
importance \-- and I think it was Dr. Kurt, of the importance of
identifying the new substances that we may be testing for.

Certainly as a clinician, I have been faced with women who have used
\"Ecstasy\" and trying to figure out how to test for that is very
difficult, and as we all know, if you read the paper, every other week
or every other month there are new agents out there that people are
using.

So certainly the changes in what we are testing for need to keep up to
date with what is happening, and to make it more relevant to do the
tests.

DR. ROSENBLOOM: This is Dr. Rosenbloom. I have nothing further to add. I
agree very much with Dr. Lewis\' comments. And I know that there are at
least two people in the room who don\'t know what SAMHSA stands for or
maybe more. Does somebody care to tell me?

DR. BUSH: I will. My name is Donna Bush, and I am from SAMHSA, and so I
know what it means. It is a five letter acronym for \"Substance Abuse
and Mental Health Services Administration.\" Actually, it is six
letters. Since I have the microphone, may I continue?

DR. KROLL: Yes.

DR. BUSH: The FDA in the handout for the draft for \-- not for
implementation, but guidance for prescription drug use, that in that
document, page 10, there is some special notes in there that the FDA put
in there.

There is the rationale for the selection of particular cutoff when no
SAMHSA cutoff is available should be described; support the cutoff
selection, and must be based on sponsor studies and evaluation of
scientific literature.

This really does put an awful lot of burden back on those who are
looking to develop a product, but that burden may be very well placed,
in that they need to know the literature, and they need to know the
experiences of clinicians in many and varied fields, to be able to
market, and to be able to develop and market a product that will be
successful.

So they have a degree of monetary interest in this, and therefore,
communication then with the FDA may be very important, because we may
talk about benzodiazapines as a classic example of one size does not fit
all.

Point-of-collection testing or immunoassay tests, liquid-based
immunoassay tests, for that class of compounds, that is only one
example, and the future is large in front of us. So the burden is heavy
on those who are going to look to develop something applicable, again
for what intended use.

And then again on that special notes, the fifth note down, \"In all
cases, cutoff concentrations should be clinically, as well as
analytically, valid.\" And that springs immediately back into the first
point, where you have to know what is going on with that particular
drug.

How does someone set a cutoff for MDMA assays, one that was mentioned
before. It is something that you wrestle with. It is not intuitively
obvious. How do you look at benzodiazapines in a non-Federal workplace
situation?

So I think it is a lot. There is no one easy answer for this, but I
think that the special notes do contain very good direction for those
who are interested in developing that product.

And then you have got to go to the biostatisticians, and the rest of it,
and back to FDA. Okay. Thank you. That\'s all.

DR. KROLL: Thank you. Let me ask Dr. Gutman if he believes that we have
adequately discussed this question.

DR. GUTMAN: Yes, that\'s fine.

DR. KROLL: Okay. Dr. Lasky has a comment.

DR. LASKY: Yes. I just have one more comment, and I think I would just
like to state that from a manufacturers\' perspective that I agree
particularly with drugs like this that there is a large burden on the
manufacturer, and I also agree that much of that is where it belongs,
where we are responsible for the products that we sell.

The issue, I think, as Dr. Gutman mentioned before is when the
negotiations actually go on. And some of the issues about the clinical
cutoffs, particularly when there might be a new drug out on the street,
and the metabolites and the pharmacologic activity, whether they are in
fact active or inactive, may not be known.

So it may be that the test itself is used for determining the clinical
studies. So it is really a chicken and egg sort of situation. So, we
should not dismiss the fact that if the information is only analytical
that that still might be very appropriate for the test to be available
in commercial use.

And again it depends on what is stated on the label, and I think that is
the key. And in a dynamic situation like drug abuse, and unfortunately
too dynamic, there may be a bit of catch-up, in terms of updating
labeling. It should not take too long.

But also what is in the literature I think is important, and I don\'t
know if the panel is aware, but manufacturers also have a responsibility
to monitor the literature.

And if there are issues about the effectiveness of the device of all
types, then it is up to the manufacturer and the manufacturer has an
obligation to follow through on that, and in fact investigate.

So there is a bit of cycloid issues here. Once the device is on the
market, it is not left as an orphan. There is an obligation to
continuously monitor how it is used and whether or not the indications
are still appropriate.

DR. KROLL: Thank you. Any other comments from the panel?

(No audible response.)

DR. KROLL: Okay. Well, given the hour, we will now break for lunch.

(Whereupon, the Panel recessed for lunch at 12:03 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:13 p.m.)

DR. KROLL: Hello. If the panel members would kindly take their seats, we
can start the afternoon session, please. And this afternoon we will be
discussing the topic related to over-the-counter guidance.

And to begin that discussion will be the presentation by Dr. Jean
Cooper.

DR. COOPER: It is my pleasure to have the opportunity this afternoon to
introduce our revised over-the-counter drugs-of-abuse guidance document.
Revising this guidance was intended to, one, clarify the importance of
confirming test results for drugs-of-abuse tests marketed to consumers.

Two, describe the consumer study needed to characterize performance
around the cutoff. Three, establish the minimum threshold for
performance for OTC products; and, four, expand the consumer survey in
order to determine if the labeling communicated the limitations of the
screening result. Let\'s review some background information.

This morning we discussed study designs to characterize the performance
of tests used by medical professionals. The study results are then put
into the product\'s package insert to better assist the professional in
understanding test performance and limitations.

The OTC guidance then describes the additional study and labeling needed
before drugs-of-abuse test kits are marketed over-the-counter. The
additional consumer studies are used to characterize the performance of
the device in the hands of the consumers.

The studies are designed to evaluate consumer ability to read the
package insert, perform the test correctly, and properly interpret the
results. Labeling for OTC products discusses the need to confirm test
results.

Let\'s discuss confirmation testing. Immunoassay based screening tests
are presumptive tests. Positive tests are intended to be confirmed by
another analytical method, such as Gas Chromatography and Mass
Spectrometry, in order to protect individuals against false positive
results.

The revised guidance recommends that the labeling for OTC products
include a statement under the warning and precaution section. The
statement reads, \"This device is only the first step in a two-step
process to look for the presence of drugs-of-abuse. If your result is
uncertain, you must send the results of the urine sample to the
laboratory to find out whether there are drugs in the sample. The
laboratory test is more accurate than the home test and there is no
extra cost for the laboratory test.\"

We would like your thoughts on this label statement. In support of this
statement, preaddressed shipping materials for sending samples to the
laboratory need to be included in the screening test kid.

The intent of FDA is to make the cost of confirmation testing part of
the cost of the device, to increase the incentive for consumers to
confirm presumptive positives. In the absence of confirmation, linking
preliminary screening to true positive results, requires knowing the
clinical performance of the OTC devices.

Linking analytical performance to the impact on clinical performance,
however, is difficult to establish. Although study designs attempt to
characterize performance of the device at concentrations that are
challenging to the cutoff concentrations of the assay, it is not known
how many samples in an OTC environment are at these concentrations.

It is also difficult to capture all of the physiological conditions and
external interfering substances, such as medications, that could impact
results. Performance around the cutoff varies greatly from one device to
the next.

Additionally, the lot-to-lot variability in visually read unitized
devices is sometimes difficult to control. There are m any variables
that can have an impact on false positives, as well as false negative
results in the OTC environment.

I would like to provide you with the information we do know. Analytical
performance of the devices is variable among manufacturers. In
evaluating the analysis of spiked samples, we have observed that with
some devices the concentration of the target acolyte must drop to 75
percent below the claimed cutoff concentration before all results are
negative.,

In other devices, we have seen that the concentration of the target
acolyte must be 25 to 50 percent above the claimed cutoff concentration
before all results are positive.

Our understanding of clinical performance of drugs-of-abuse assays is
limited to information on the performance of wet chemistry assays used
in reference laboratories.

The performance of wet chemistry automated assays undoubtedly is
superior to that of unitized visually read devices. It is also unclear
how the sample population evaluated in reference laboratories,
predominantly work place samples and drugs of abuse clinics, relates to
the samples that would originate from a consumer environment.

The following anecdotal data reflects results from samples originating
predominantly from workplace environments. What this table reflects is
that with cocaine and marijuana the screening test and the confirmation
test typically relate fairly closely to each other.

With the other drugs-of-abuse, generally this relationship is not so
strong. This data reflects the performance of wet chemistry automated
assays under optimal conditions.

The agency believes that devices used by consumers should be as safe and
reliable as possible. Sponsors of applications for OTC tests currently
include the cost of confirmation testing in the cost of the initial
screening test.

This approach removes cost barriers associated with confirmation
testing, thereby increasing the chance that consumers will confirm their
screening results.

Confirmation testing is expected to minimize the chance of individuals
being falsely accused of using illegal drugs. Others, however, argue
that including the cost of confirmation in the initial test cost does
not compel many consumers to send the samples to the lab, and that it
only adds to consumers\' cost, and may therefore be preventing access to
drug testing by some consumers.

Our intent is to balance the benefits of ensuring more accurate results
to the consumer, versus the possible effects of imposing additional
costs on the original purchase price. We are receptive to other
approaches to establishing a responsible risk-to-benefit ratio.

Let\'s discuss the consumer study. In addition, needing confirmation
testing, OTC applications include a study to determine if consumers can
follow the label directions and interpret the test results.

The consumer study is designed to address accuracy and precision
performed by consumers. A survey and labeling assessment is also given
to assess label readability and to evaluate consumer understanding of
results.

This study was described in the original guidance. The revised guidance
clarifies the information needed to characterize performance around the
cutoff, establishes the minimum threshold for performance for OTC
products, and expands the consumer survey in order to determine if the
labeling communicates the limitations of the screening result.

The guidance was revised to clarify the description of the consumer
study design. Please comment on this design. The consumer study is to be
conducted at three sites.

At least 200 samples per drug are tested by 200 consumers. Samples are
drug-free, spiked with known amounts of drugs. Multiple drugs may be
spiked in a sample to reduce the number of samples.

The concentration of drug in the samples is confirmed by GC/MS. The
range of drug concentrations is chosen to challenge each drug cutoff as
well as the high and low clinically relevant extremes of drug
concentration.

Specifically, the testing is divided into the following format; 20
samples at a low negative concentration; and 30 samples at 50 percent
above the cutoff; 50 samples at 25 percent above the cutoff; 50 samples
at 25 percent below the cutoff; 30 samples at 50 percent below, and 20
samples at a high positive concentration.

Study participants are given on instruction beyond the package insert.
Study participant demographics are provided in the application to
demonstrate whether the participants reflect the population most likely
to use the device.

The challenge at 25 percent above and below the cutoff is intended to
determine how the SAMHSA cutoff compares with the cutoff of the product.
This information also provides the reviewer with a comparison between
the OTC use and professional use under the ideal analytical conditions.

The challenge at 50 percent above and below the cutoff is intended to
determine whether a test gives too many false positives to be marketed
as an OTC product. When multiple consumer study participants interpret a
sample concentration as presumptively positive at 50 percent below the
cutoff, it is not clear how close to background levels the test will
read positive.

Conversely, the challenge at 50 percent above the cutoff determines if
the test is likely to miss true positive samples. Correcting false
readings at 50 percent above and below the cutoff might include fine
tuning consumer labeling to improve interpreting test results or
adjusting product release criteria to reduce misinterpreting the
presence or absence of drugs.

Evaluating the cutoff at these drug concentrations is a revision and we
would like feedback. The guidance indicates that the consumer study
results are not included in the label.

This policy was established because of the difficulties in relaying
technical information to consumers, the lack of clarity about how
analytical performance relates to the device use in the overall
population; and the need to encourage confirmation testing screen test
positive results. We would like to hear your thoughts on this policy.

Let\'s discuss over-the-counter claims. A drugs-of-abuse test is
considered over-the-counter when it is intended to be used in the home,
workplace insurance, or sports settings.

Issues related to consumer ability to use a test and test quality are
similar in all these setting, including concerns about sample integrity
and test accuracy. The need to provide assurance of test accuracy and
reliability applies equally in all of these areas.

FDA will continue to exercise its enforcement discretion with respect to
the use of these products in the law enforcement setting, because there
are protections to ensure sample integrity and test accuracy that are
not generally available in the home, workplace, insurance, or sports
settings.

The additional protections include the use of rules of evidence in
judicial proceedings, and the representation of the person tested
through the judicial process.

Given that OTC claims include settings other than house use, it is
important to note that the drugs-of-abuse tests are intended to detect
the presence of drugs-of-abuse, or their metabolites in samples, but not
whether a person is impaired.

Let\'s now go to the questions. To maximize the likelihood that
confirmation testing will be performed on presumptive positive results,
the FDA has been requesting that confirmatory testing be a mandatory
component in the designing of the screening tests.

The next question, please. Are the studies and labeling guidelines as
outlined in the guidances appropriate for home, workplace, insurance,
sports, and other OTC settings.

Consider that the intended use of drugs-of-abuse tests, generally, are
to indicate the presence of a drug, rather than the impairment of an
individual.

Question 3: The FDA is suggesting that OTC devices render negligible
performance error with spiked samples at concentrations of plus 50
percent and minus 50 percent of the cutoff concentration.

Is this reasonable. If not, not alternative performance criteria would
be appropriate? Next question.

The FDA does not encourage inclusion of performance data in OTC
labeling. Do you feel such information should be included, and if so,
what type of studies should be done to characterize performance well
enough so that it would be meaningful to the consumer? And how should
performance be relayed to consumers in the labeling?

The next question. Is the study design described in the guidance
appropriate for demonstrating performance of the device in the hands of
the lay user? Please consider sample size, use of spiked samples for
consumer studies, concentration range and distribution of the samples,
and size of consumer study.

Next. FDA is suggesting that sponsors conduct only the consumer studies
described in the OTC document, when the device has already obtained
prescription clearance. Are there any other studies warranted?

Next. Should only those devices with SAMHSA cutoffs be eligible to be
cleared for OTC use?

Next. Visually read devices frequently render positive results well
below the claimed cutoff of the assay. For instance, some sponsors might
claim a cutoff of 1000 nanograms per Ml, but their test renders all
positive results at 750 or 500 nanograms per Ml.

Should there be certain performance requirements to support a claimed
cutoff concentration?

Now I would like to talk more generally about substance abuse.
Over-the-counter alcohol tests and drug abuse tests are similar because
of concerns about sample integrity, reliability, and test accuracy.

Confirming test results obtained in the home, workplace, insurance, or
sports settings, and consumer ability to follow label instructions and
interpret test results.

Over-the-counter alcohol tests and drugs-of-abuse tests are different
because intoxication is determined rather than substance exposure.
Confirming results from a test used in a bar or at a party is not
practical.

Samples used in alcohol screening tests are generally replaced, often
with another matrix, to confirm a result.

Time lapses between testing and confirmation may affect interpretation.
The FDA currently regulates alcohol tests intended for medical use.
Tests to determine chronic abuse are considered medical use.

Since 1992, the Department of Transportation has regulated screening
tests in workplaces related to transportation, such as aviation, motor
carrier, rail and mass transit industries.

DOT tests all of the devices that are submitted to them, and those that
pass their requirements are placed in an approved device list. Jobs that
are under the jurisdiction of the DOT require testing of employees that
perform critical jobs to be randomly tested for acute alcohol use.

The tests must be performed with devices from the approved list, and
they must be carried out by DOT trained personnel. The specifications
for the devices are set based on on the specifications for breath
analyzers and are as follows.

At a cutoff of 0.02 percent; with precision /accuracy and blank reading
tests being performed, and to pass this test as described the device
must not have any positive readings at zero, only one false positive at
0.08, and only one false negative at 0.032.

The above test must be performed under the following light conditions.
Under fluorescent lights, incandescent lights, mercury vapor, sodium
vapor, and daylight. In total, 300 assays are performed, resulting in
3000 independent readings.

There is a cigarette smoke interference test that is done, and it is
described in this line. All results must be negative for this test.
There is a high and low ambient temperature tests. To pass, the device
must have only one false positive and only one false negative under
these test conditions.

There is a vibration test, and to pass the device must have only one
false positive, and only one false negative. Based on the number of
tests performed, which is 40, the concentration at which the device is
expected to show no positive results within a 95 percent confidence, is
0.008.

Similarly, the concentration at which the device is expected to show no
negative results with 95 percent confidence is 0.032. Home use tests,
tests sold in bars, tests used in workplaces, tests performed for
insurance use, and tests in sports settings, are not currently
regulated.

Now, we will go to questions. FDA is proposing to include alcohol
testing in the same category as other tests for substance abuse. Are the
same types of studies appropriate for alcohol tests? Should other
approaches, such as the one used by the Department of Transportation, be
considered?

The second question. In what settings is confirmatory testing for OTC
alcohol tests appropriate: home, workplace, insurance, sports, other?

What matrices and what time span between collection of the original
sample and collection of the sample for confirmation would be
appropriate? Thank you.

DR. KROLL: Thank you. Now we come to the part in the program where we
have the open public hearing, and these are people who have previously
submitted their name and contacted the executive secretary.

And they will address the panel and present relevant information to the
agenda. And I would like to ask that each speaker as they come up to
state their name, and whether or not they have any financial involvement
with the manufacturer of the product being discussed or with their
competitors.

And the first person on the list is David Evans. And also each person
has about 7 or 8 minutes.

MR. EVANS: Good afternoon. My name is David Evans, and I am the
executive director of the National On-Site Testing Association. We are
an industry consensus organization composed of the manufacturers, users
and distributors of on-site drug and alcohol tests.

I am also an attorney in private practice, and I provide legal advice to
corporations that do drug testing, and also to the manufacturers of drug
and alcohol tests.

My wife and I are remodeling our house, and we live on a farm, and we
have a pool in the back yard and pastures. And we are putting a new room
on the back of the house, and the builder was there and asked me what I
wanted for windows in the back of the house.

And I wanted a big picture window so that I could see the pool, and see
the pastures, and see everything that is going on there. So I told him,
well, I want a big picture window there.

So then the wife came home, and it turned out that she doesn\'t want a
big picture window. She wants windows that are with small panes in the
back. So I made my arguments to her, and then I heard what she had to
say, and I said yes, dear, and we moved on.

Now, what was my problem? My problem was lack of jurisdiction, and I
would like to bring this to your attention. I think I am in the right
place. This is an advisory panel of the Medical Devices Advisory Panel,
and it seems to me that the jurisdiction that you have is over medical
devices as they are defined in the FDA regulations.

And the medical devices are those that deal with the diagnosis of
disease or other conditions in order to cure, mitigate, treat, or
prevent disease or its sequelae. So that is my humble opinion of your
jurisdiction.

The case law on this \-- and also the regulations say \-- that it is the
intended use of the device is what matters. And my dad was a
psychiatrist, and when I was a kid, I used to go to his office and get
his tongue depressors.

Now, if I took a tongue depressor and put it in the freezer with some
orange juice and made a popsickle out of it, that is not a medical use.
If my dad used it to treat his patients, then it is a medical use.

So a tongue depressor could be considered a medical device, but not as I
intended to use it, as I did from time to time. I also used to make
little houses out of them.

So when looking at your jurisdiction under these laws, you need to look
at the intended use. Now, you may have an argument if a drug test is
used to diagnose a medical condition.

Somebody comes into an emergency room, and they appear to be in an
overdose situation, and you use a test. Even there I would assert that
maybe you wouldn\'t want to spend your time on this issue, because
hospital emergency rooms, doctor\'s offices, are already regulating.

CLIA takes care of a lot of that, and even physicians\' offices in a lot
of states are regulated. A lot of States have clinical laboratory laws.
My good friend, Mr. Stanley, from Pennsylvania, he has a very fine
clinical laboratory law.

And New Jersey does, and Florida does, and California. And by the way,
the California laboratory office has determined that if you use an
on-site test for a workplace purpose, they have no jurisdiction.

Pennsylvania, also, if you use an on-site test for a purely workplace
purpose \-- for example, whether or not to hire somebody or not, they
don\'t have jurisdiction. If you are using it to provide treatment, then
they claim that they do have jurisdiction.

So that I think lays out the jurisdictional issue. Now, I am just going
to focus on the workplace testing, on-site workplace testing, and let\'s
look at the reasons that the employers have given in court for having
drug testing programs in the workplace, and let\'s see if they have
anything to do with medical diagnosis or treatment.

And I have researched all of these, and it is in my book, and you can
read them. The case law cites are in my book. To promote workplace
efficiency, and to ensure the integrity of employees by prohibiting
off-duty or on-duty conduct.

Promote public confidence in the safety or integrity of a particular
job. Prevention of theft, and prevention of blackmail. That was a case
in the [National Treasury Employees Union versus Barrat]{.underline}.
They were Treasury Agents, and that\'s why they wanted to do drug
testing.

Prevent embarrassment to the employer. To promote a drug free society,
and to gather facts about employee drug use and on company operations.
Now, none of those have to do with medical diagnosis or to provide as
the regulation says to cure, mitigate, treat, or prevent disease.

Now, what about the use of an on-site test for other purposes? Certainly
for law enforcement purposes, I think you have already exempted
yourselves out of that one, and I believe there is even a regulation or
something to that effect.

Similarly, if an employer wants to use on-site testing or drug testing
in general to ensure compliance with the workplace policy, the drug free
workplace policy, I don\'t think you have jurisdiction, and the same
thing with schools.

My daughter goes to Hunter and Central Regional High School, in
Flemington, New Jersey, and they have a drug testing program for the
students. The students are subject to discipline if they come to school
under the influence.

And they are given a drug test, and the drug test is used as evidence
for disciplinary purposes, and to ensure compliance of school rules.
Again, there I don\'t think you would have jurisdiction.

The same thing with athletics; to determine whether or not somebody can
participate in athletics, and not whether they get treatment, but to
determine whether they can participate in athletics or not.

And these are really conduct issues, and compliance issues, and not
health issues, okay? And also the Courts that have looked at this issue
have said that if you declare that an on-site test or drug testing in
employment are medical examinations, you are going to have direct
conflict with Congress on the Americans With Disabilities Act.

Now, the reason that Congress exempted testing for illegal use of drugs
is because they did not want drug addicts who are under the influence at
work, and because of a drug test to be able to claim that they are
subject to protection under the disability discrimination laws.

So this is going to cause a conflict with the ADA. Congress has spoken
on this issue, and a recent Supreme Court case that the FDA lost trying
to regulate cigarettes, the Supreme Court said that you must look at the
intent of Congress before the FDA can take an action.

And you also have to look to see if there is any other existing
regulations that would provide protections before you can take action or
exert your authority, no matter how good the cause.

And I believe that you are all people of good faith, and I have heard
nothing here other than that you want to protect people, and you want to
do the right thing, and you want to make sure that these tests are
accurate.

We also share those goals, but again it is a question of the
jurisdiction. We believe that having to impose OTC requirements on all
these uses for on-site tests will be extremely burdensome on our
industry, and it will be extremely burdensome on employers, and it will
be burdensome on athletic events, and insurance companies, and law
enforcement if that goes down.

So that is the reason that we are opposed to it. I would also urge you
to look at the protections that are already in place. Multiple States
have employment drug testing laws. And 7 to 12 million people are now
going to be regulated under the SAMHSA regulations.

They have done a very fine job, and they are already permitting on-site
testing, at least in the last draft that we saw, and they have a final
draft to go through.

And what they are doing is that they are putting their trust in the
manufacturers, and saying the manufacturers will train the users. This
is a model with the Federal Department of Transportation that it has
used for several years, and it has been successful, and we have not had
any real problems. Thank you very much.

DR. KROLL: Thank you. Our next speaker is Bob Aromando.

MR. AROMANDO: Thank you very much. My name is Bob Aromando, and I am an
independent industry consultant, and I do some consulting for some of
the special interest parties that would be adversely affected should
these regulations become a reality.

So I do make that statement quite freely up front.

So I would like to thank everybody here for this opportunity to address
this esteemed panel on the topic of the over-the-counter screening tests
for drugs-of-abuse.

Initially when I heard about this meeting, I was prepared to testify on
the issues surrounding accuracy, reliability, safety, and effectiveness
to this panel.

However, I was very surprised to learn that the OTC draft guidance
document has the potential to implement FDA oversight to the workplace,
insurance, and sports drug testing markets, well outside and beyond any
realm of medical diagnostic assessment, and therefore outside the
oversight of the FDA when you look at the markets that we just mentioned
utilizing an on-site drug test.

Let\'s remind the members of this advisory panel and the audience here
today that the mission of the FDA according to the FDA Modernization Act
of 1997, and that is posted on the website, is to promptly and
efficiently review clinical research, protect the public from ensuring
that foods are safe, and ensure reasonable safety and effectiveness of
devices intended for human use.

And according to the FDA growing responsibilities for the year 2000 and
beyond, the FDA, in quotes, \"review or scrutinize products that are
designed to treat human conditions or diseases.\"

Nowhere in there is it to be interpreted or stated that the FDA must now
render oversight to corporate hiring practices and business management,
criteria that effects inclusion and exclusion of insurance policy
applicants, and criteria for participation in structured sports.

Absolutely nowhere can it be even implied that the FDA has any authority
over there not medically related areas. So why aren\'t were here today
discussing FDA\'s possibility to regulate drug testing in the workplace,
insurance, and sports markets.

My testimony here today contains compelling arguments and justifications
to modify and/or eliminate completely major components of the
over-the-counter draft guidance for pre-market notifications in order to
continue to permit the commercial sale of on-site drug tests, by the
way, which have already been cleared by the FDA for professional use to
the workplace, insurance, and sports testing markets.

The Food and Drug Administration is making two stretch assumptions
relative to the OTC user of a drug test. One, the FDA assumes that
concerns related to OTC use of a drug test are similar in workplace,
insurance, and sports settings.

And, two, the FDA assumes that there should be consistency in its
regulation, if any, of drugs-of-abuse screening tests used in the home,
workplace, insurance, and sports testing settings.

Panel Members, let me assure you that under no conditions whatsoever are
the concerns similar in these markets. As an example, in the workplace
setting, a drug test is used exclusively to assess compliance to a
corporate drug-free workplace program.

It is not used for medical treatment purposes or disease management, or
diagnosis of disease. Corporate entities and businesses in general
utilizing drug testing simply do so to ensure they recruit and hire only
those candidates that are drug free, which is very consistent with any
drug free workplace program.

In fact, the U.S. Government implemented such a drug-free workplace
program in the late 1980s under then President Reagan, and that program
is still in existence today, and has absolutely nothing to do with the
diagnosing of disease, nor the management and treatment of disease.

It is simply a program that drug test eligible employee candidates
intended for hire and nothing more. In an insurance setting, a drug test
is also simply a means by which an underwriter excludes or includes an
individual from subscribing to some form of insurance policy.

In fact, the Supreme Court of the State of New York has previously ruled
overwhelmingly that insurance type testing is not considered a medical
test for diagnostic purposes, and as such would be exempt from the New
York State laboratory statute. That is case law.

In a sports setting, again we have a situation whereby as an example the
NCAA will drug test athletes to assess compliance and/or drug use status
to determine whether or not a policy has been violated and nothing more.

As another example, and I mention back to David Evans\' Huntering
Central High School in New Jersey, implemented on-site random
drug-testing of student athletes simply to assess compliance to the
school\'s anti-drug policy and nothing more.

Now in an OTC or consumer setting, you are likely to have a parent
purchase a drug test because they suspect that their child may be using
drugs. As a parent myself, with two children, this would allow me to get
my children into treatment faster, with the intent of a more effective
rehabilitation outcome.

Here, I grant you, you have oversight. The use of a drug test in an
over-the-counter setting has clear medical related concerns, and as such
should be within the oversight of the FDA.

The use of a drug test in workplace, insurance, and sports, carries no
true diagnostic implications whatsoever. When performed in the
management of probation, parole, prison, drug and alcohol
rehabilitation, compliance to school policies, clearance for a life
insurance policy, or management of workplace policies, drug abuse
screening only provides detection of drug or alcohol use.

It does not assess disease, immediate impairment, or other health
related diagnosis requiring medical judgment or treatment. Drug abuse
testing in these situations is also qualitatively different from testing
for purposes of treatment or diagnosis.

This is because the individual being tested is fully aware of what the
outcome of the test should be. The principles of diagnosis are then
irrelevant for this type of testing. As such, the FDA must defer
oversight of workplace, insurance, and sports testing settings.

In the past, an attempt to regulate workplace drug testing under CLIA
\'99 met with immediate objections, and ultimately was exempted and
placed in moratorium by then Secretary Sullivan.

Thus, in permitting this exemption, HCFA recognized the need for
testing, that has as its purpose the uncovering of behavior that the
U.S. Congress and every State Legislature recognizes to be sufficiently
dangerous to society and its members, to warrant such conduct being
deemed illegal.

The purpose of drug abuse testing in the workplace is to identify
behavior that unquestionably is illegal and clearly constitutes a danger
to the workforce collectively and its individual members.

Furthermore, the FDA cannot assume a role of selective oversight
relative to the workplace setting simply because the test format in
question is that of a point-of-care platform and not lab based.

Currently, a number of drug testing reference labs in this country
running millions of drug tests utilize generic home-brew assays made
from FDA clear products, and absolutely no oversight is enforced or even
considered.

To even consider oversight of an on-site point-of-care drug test in a
workplace setting, while completely ignoring the practice of diluting
drug testing re-agents, is blatant prejudice and bias in favor of
lab-based testing.

This would be viewed clearly as a means to position manufacturers of
point-of-care drug tests at a competitive disadvantage. In conclusion,
the FDA must and should limit its oversight authority specifically in
those areas where a drug test is utilized for diagnosis of disease, for
treatment and/or cure, and in those situations where medical treatment
is required.

Within the confines of workplace, insurance, and sports settings, that
only utilize a drug test to assess compliance to policy, the FDA is
clearly outside the perimeters of its legislative charge.

I would like to thank the panel for this opportunity to voice my
concerns, and I hope that the messages that I have provided in this
forum allow for an informed decision to be made. Thank you.

DR. KROLL: Thank you. Our next speaker is LuAnn Ochs.

MS. OCHS: I\'m LuAnn Ochs, and I am with Roche Diagnostics Corporation,
and I am a regulatory manager there. I am a scientist and not an
attorney, and so I am going to leave the legal issues to the attorneys,
and take a different vain here and address the guidance document itself.

First of all, I would like to compliment the FDA for continuing to
produce guidance documents and for promoting good guidance practices. As
a member of industry, we are very happy to have guidance documents, and
they allow us to participate in FDA\'s new paradigm for product
approval, the abbreviated 510(k).

In case you are not aware, manufacturers are now able to achieve 510(k)
clearances through certification of conformity to recognized standards,
or FDA\'s published guidance documents.

This abbreviated 510(k) program brings much needed efficiencies to the
510(k) process, benefiting both the FDA and industry. Because of these
mutual benefits, we appreciate the opportunity to work with the agency
in the development of guidance.

Regarding the specific guidance for ODC drug products, with only a few
minor comments that we will send in, we agree that this guidance is very
good for obtaining clearances for home use drugs-of-abuse testing
products.

Parts of this guidance may also be appropriately applicable to the other
testing venues as well; workplace testing, insurance, testing, and
sports settings testings.

If the attorneys are able to substantiate that DATs in these settings
are indeed subject to FDA regulation, then Roche would like to offer
these comments on the guidance document.

The guidance document should clearly split apart the regulatory
requirements for home testing, from workplace, insurance, and sports
settings. There are some clear differences in the needs of home users,
versus the other testing settings.

Certainly there are labeling differences between these settings. All
users need to know how to perform the tests and how to interpret the
results, and If the result is indeterminate, then they must be
instructed in the meaning of that result, and the need for a more
accurate confirmatory test.

But then what? For example, home users need additional instruction and
information referring them to their health care professionals for
appropriate counseling and/or treatment.

Let\'s look at the requirement for confirmatory testing. Obviously, this
testing is needed. We manufacturers agree that the accuracy around the
cutoff needs to be improved.

Perhaps need technologies will some day reduce the rates of
cross-reactivities and interferences. And perhaps then we can achieve
Dr. Kroll\'s requested 99.99 percent accuracy.

Cutoff levels are set to identify the drug, while avoiding
cross-reactivities. We understand that Dr. Cooper wants to protect
innocent people from being labeled as drug users. That protection
mechanism is already in place.

The confirmation testing already offers that protection. Also, bear this
in mind. There are no legal levels for drugs-of-abuse. Ethanol testing
was mentioned this morning.

Unlike ethanol, where a level of impairment has been determined, no
level of cocaine, for example, is legal. Presumptive positive results
are due to either the presence of the drug or the presence of an
interference.

Interferences can and will produce false results no matter what the
cutoff. That\'s why these tests must be confirmed. However, there is no
such thing as a false positive result when the drug is present.

It is not okay to have a drug present at a level below the cutoff. It is
still illegal. Yes, we have to protect people from being labeled
positive when no drug is present. But we do not have to protect the real
drug abusers. We must identify them.

This is the inherent difference between these tests and diagnostic
tests. These people know that they have taken the drug, and we are
trying to identify that drug\'s presence. Please remember that
confirmation testing is already required by agencies that oversee
Federal workplace drug testing.

It is mandated by many States, and it is good practice for everyone else
who does this kind of testing to avoid litigation. The guidance document
requires that manufacturers establish a mechanism for lay users to
obtain confirmatory tests.

While we agree that this is needed, we are concerned that in practice
that it may be difficult to achieve. By Regulation 21 CFR 801.109, lay
users cannot order confirmatory tests on their own.

In some States, medical laboratory tests can only be ordered by a
licensed health care professional. I have with me an excerpt from the
Illinois complied statutes, the Illinois Clinical Laboratory and Blood
Bank Act.

And it says that a clinical laboratory shall examine specimens only at
the request of a licensed physician, a licensed dentist, a licensed
podiatrist, a therapeutic optometrist, a licensed physician assistant,
an advanced practice nurse, or an authorized law enforcement agency.

In Illinois, manufacturers cannot order these tests, and although
manufacturers can attempt to set up relationships with reference
laboratories to do the confirmatory testing, for some States this
mechanism will not work.

The home-use intended use is clearly a medical use of the test. The same
is not true, however, for workplace settings. Workplaces can set up
relationships with reference labs because the test is not being used for
medical purposes.

At Roche, we have found that our workplace customers usually already
have relationships with reference laboratories. Often they are locked
into using particular laboratories, and would not be able to use our
certified laboratory as required by the guidance.

For the customers who don\'t have access to a reference lab, Roche
Diagnostics already is implementing a program to provide that access. We
would prefer to offer this program as an optional service to our
customers, and not have it mandated by regulation.

We are concerned that if the FDA expands their oversight to include
workplace, insurance, and sports settings, then these tests will
automatically become considered as medical tests, preventing our
customers from ordering the necessary confirmation testing in some
States.

Certainly the FDA does not intend to restrict the current access to DAT
testing in that manner. We again ask the FDA to focus this guidance to
separately address the needs of the home-users and the differing needs
of the other settings.

Thank you for hearing our concerns today. We will be sending these and
other comments to the guidance document in writing, and I will be happy
to answer any questions.

DR. KROLL: Thank you. The next speaker is Carl Mongiovi.

MR. MONGIOVI: Good afternoon. I am Carl Mongiovi, and I am the vice
president of Phamatech, Incorporated. I do have some monetary interest
in this. They pay me sometimes enough.

Pardon me also if my voice is a little waver. I have been in Mexico and
San Diego, and I am here in the last three days. So I am a little tired,
but we felt that this was important.

I would like to give you a little background. Phamatech was the first
company to get an approval for over-the-counter screening devices. That
was in October of 1998. We are currently in over 30,000 stores.

Our level of sales is approximately 18,000 devices per month, and
because of this intimate knowledge, we have learned a substantial amount
in the last two years, and some of this information I would like to pass
along.

When we did our original submission, we ran over 4,700 tests, with 300
and some participants, and I realize that is a tremendous amount. It was
done to draw attention to the fact that we felt that we could do it, and
we wanted to be the first.

We ended up getting an overall accuracy with that test of 96.6 percent,
and we were surprised by that. We had looked at participants who were in
mental health institutions, drug rehab centers, and we took some Ph.Ds
to see if we could throw them off.

Still, the number came out to almost 97 percent. I heard it said earlier
that in the workplace that the manufacturer trains the technician, and
indeed that is the case for corrections, law enforcement, and several
other arenas.

It\'s that which makes the OTC test for home use so different from the
others. We don\'t go to everyone\'s house to teach them anything. We
give them a directional insert.

The target audience for lay people are individuals that have little or
no experience in diagnostic testing, other than possibly pregnancy tests
or glucose tests.

They seem to have very little patience and they don\'t seem to have a
lot of time to read the directions. Something that we thought that we
had covered very well was the study we produced to do this with so many
numbers, and we thought we took in all the relevant factors, including
education, sex, race, English as a second language, education, regional
diversity.

We forgot one and that was stress, and we are finding that parents do
the darnest things sometimes, and they don\'t often read and they are
impatient.

I found out about this meeting Friday two weeks ago, and I was in Latin
America all last week. I pulled up information and this is one days
worth of confirmation tests that our laboratory did for us, and I just
made copies of them, and took with me on my trip.

And I would like to just sort of tell you what I see. There were 62
samples; 34 positive for THC, and the high was 780 ng/ml. We had four
cocaines, and the highest of those was 11 6,000 ng/ml. We had three
MDMAs, which we could not get, except that our confirmation laboratory
tests that for us.

It is becoming an ever increasing problem, and we are finding a huge
number of these samples. We had eight multiple drugs, and none of them
had more than three drugs in an individual sample. But a lot of multiple
drugs; five methamphetamine/amphetamines.

I believe it is very important for anyone to get a result and be able to
do something with it. confirmation testing is necessary. It is not just
that, yes, he is positive for THC. Was he positive for THC at 25 ng/ml,
or 50 ng/ml, or was it 780 ng/ml.

Certainly the clinical implications are a little bit different. We know
that our tests are not 100 percent accurate. The test is to be used in
the home. It is not for DOT, and not DoD, and the donor and the person
that are running this test have the right to expect an accurate result.

And the only way they are going to get an accurate result is with
confirmation. False results of any kind are going to override any good
that we do with this test. And any incidents of false positives is going
to seriously weaken this emerging category.

It is crass to talk about money, but that is the bottom line. If we
cannot create a product that gives an accurate result, it will fail. It
will be off the shelves and this whole thing will go away.

We feel that confirmation testing is necessary. We feel that the
performance criteria that the test is judged by should be no less than
what we see in the clinical lab.

Indeed, I would offer that and perhaps an over-the-counter test, only be
a test that has been slightly modified from the clinical laboratory, so
that there is enough data to show that it will work.

And finally we found that with confirmation testing we get to close the
cycle. There is a need for individuals to be given an opportunity to
find substance abuse counselors in their area, and the only way they can
find out about that is to call up for that anonymous result.

When they call up, we can simply ask for a zip code, and that closes the
circle. Thank you very much. If there are any questions, I would be
happy to answer them.

DR. KROLL: Thank you. The next speaker is Naresh Jain.

DR. JAIN: Good afternoon, ladies and gentlemen. I am a scientist, and
probably looking at the audience and the members, I am probably the
oldest person standing here.

And naturally with age comes some experience, and experience is that I
have been in this field for over 35 years. I see one of my students is
sitting as a panel member, and I know that I am a forensic scientist for
35 years, and for the last 30 years, I have been doing nothing but
testing drugs-of-abuse.

I was the Chief of Toxicology for L.A. County in 1970, and I started a
laboratory, and I am now the director of a fairly larger drug testing
laboratory specializing in drug testing for law enforcement agencies.

And our contracts includes the California Department of Corrections, and
then send about 2,000 or 3,000 urine samples a day. We have the Federal
Bureau of Prisons contract, and the California Department of Mental
Health, and we do a lot of job seekers, and pre-employment, DOT, and all
that.

And the reason that I am here is primarily \-- and I am surprised that I
am here speaking to this panel for confirmation tasking. This is like
reinventing the wheel.

I mean, we have taken for granted that a scientist, that whatever test
we put on the market, it should be accurate, and it should be reliable.
If we are not doing that, then we are in the wrong business.

The nature of all of these tests, over-the-counter drug tests, are based
on immunoassays. And all immunoassays, if you read just basic chemistry,
basic science, will cross-react with high end of concentrations with
some molecules which are completely unrelated to the drug.

And of course with structurally similar substances, they will react.
What is this argument, and it is hard for me to fathom, and when people
come here and say, oh, we do this \-- and on insurance testing, which I
have heard so much words just now.

It so happens that two weeks ago, I took an insurance policy, and the
doctor came home, and he said that one of the requirements was cocaine
and marijuana tests, and he pulled out his kit, and put my hand in it.

And should I rely on that test? I mean, it has to be confirmed, and so
basically what I am saying is that these screening tests are like API
grouping systems. They can eliminate a suspect, but for confirmation,
you need DNA testing, and that is the best analogy that I can give.

Then we have these \-- with the nature of the technology that we have,
all the over-the-counter medications. You know, dietary supplements,
containing pseudoephedrine and ephedra, all of these will give a
false-positive test.

Then we come down to narcotics. A lot of people use pain killers on
prescription, such as oxycodone, vicodin, and all those things. They
will give a false-positive for morphine, because none of the
immunoassays, or over-the-counter drug tests can distinguish between
those two.

Then as I said, we get a lot of probation department samples from
paroles, and a lot of these units have their \-- they do on-site testing
before they send the samples to us.

We have no control where they get these samples, where they get the
kits. Some are from Roche and some are from Phamatech, and some are from
different manufacturers. We have nothing to do with that.

And we found from the prison population and paroles that we were getting
a high percentage of THC, and could not understand what was happening.
Then further research showed that a lot of these paroles had AIDS.

And they were receiving this medication called sustiva, and that was
giving a cross-reactivity with the THC agent. So, I mean, this is such a
basic thing to go into this thing.

So confirmatory testing, the question with that was whether it should be
limited to GC/MS. No, it should not be limited to GC/MS. Anything
scientifically accepted. GC/MS is the gold standard, and LC/MS would be
equally good.

Something which is accepted by the peers in the scientific community as
giving reliable and accurate tests. I mean, the GC/MS is very good, and
LC/MS would be good, and triple quot would be even better.

But anything that is acceptable to the general scientific community. And
then another question that comes is that like you may get
methamphetamine/amphetamine test, and we would not know. I don\'t think
any test is available for MDMA, or MDA, or MDEA.

Only the confirmation will tell whether it is methamphetamine or
anything. Then we come to where if a parent finds that their child is
taking a drug. Okay. And now the child says, well, dad, I am not going
to use any more.

Well, that\'s true, and so we test him a week later, and again it shows
positive. Is he telling the truth? Maybe. So confirmation testing will
show whether the level of concentration is going down or not.

I mean, how can we in the year 2001 debate this issue that confirmation
testing is not \-- it should be an integral component of any
over-the-counter drug kit, and this should be so mandatory that no
manufacturer is allowed to sell any product which can give false and
misleading results.

Now, coming to anything that is necessary and useful; necessary because
it can eliminate unfair accusation and punishment; and useful because it
can help both the parent and the child establish a dialogue and maybe
form a statement.

And if I have a few more minutes just to partly discuss this?

DR. KROLL: Can you wrap it up in 30 seconds?

MS. JAIN: No. I just wanted to say that because of the spiked urine,
that I have some ideas, because I have been in this field for a long
time. Somebody thought of pooling the samples like we do, because should
I review the samples, you are altering the metrics, because when you
test something, you want to make sure there are metabolites present.

And that\'s because there are a lot of other drugs, and that is a true
test. What we do is when we take and pool samples, one set will contain
10,000 anograms, and sometimes there is 2,000 anograms.

If you pool them together, you can come out to a very close
concentration at a cutoff level without any dilution, and which will
give the true metabolites, and other things. And with alcohol, be
careful, because the 15 minute wait period if it is saliva testing.
Thank you very much.

DR. KROLL: Thank you. The next speaker is Carl Good. And please remember
to limit your comments to seven minutes, and tell us your financial
affiliations.

DR. GOOD: As you said, my name is Carl Good, and I am the vice president
of research and development at Avitar Corporation, and I have a
financial investment there, and I own a few mutual funds, and I don\'t
have much idea what they own, but there could be other aspects.

I would like to say that we really appreciate the opportunity of
speaking before this group, and also would like to say that we very much
appreciate the guidance documents that have been generated, and the
benefit that I think that they provide to all parties concerned.

My background isn\'t legal at all, and I know that there were some
issues raised as far as jurisdiction in the legal area, and I will leave
those to others who are better informed.

What I would like to talk about a little bit today are a couple of
technical aspects that have to do with testing, and our focus as a
corporation is primarily on industrial and forensic insurance and sports
testing, and secondary education testing.

And in these market places one has the opportunity for more extensive
training, and certification of testers within that environment. We as a
company strongly support the requirement for confirmatory testing.

However, including the cost of confirmatory testing, and the price of
the screening test, can create difficulties. With all tests positive or
negative to be confirmed, then the cost of this confirmation testing
using GC/MS and other sophisticated procedures would cause the price of
the consumable to be prohibitively high, and discourage folks from
taking advantage of these drug testing opportunities.

It is also in conflict with current laboratory testing in which only
positives are confirmed. If only positives are confirmed, then the test
may again result in high prices due to the attempt to compensate for
worst-case situations.

We would like to propose that it might be possible to provide each
individual being tested with something perhaps that I incorrectly call a
\"Miranda Rights\" card, so that anyone being tested \-- and again our
focus is primarily on the industrial environment \-\-- would be given a
card saying that you have the right to confirmatory testing, and it
should be borne by the organization that is performing the testing.

This way it would minimize the costs since most tests will be negative,
and focus primarily on confirmatory testing and the positives, assuming
that few people would ask that their negatives tests be confirmed.

I also would like to talk a little bit about perhaps a more technical
area. Our focus is primarily oral fluids testing, which gives the
advantage of direct observation of the testing process, unlike most
urine testing situations, either laboratory based or over-the-counter.

And also by that process in using oral fluids, reduces the opportunities
for substitution or adulteration of the sample. And substituted or
adulterated samples really have a quality of zero.

In the proposed guidelines, there is a section where the individuals who
would be typical customers or typical people operating the tests would
be asked to look at standard samples, and we believe that oral fluids
testing, where your concentration of drug is much lower, that these
ranges of plus or minus 50 percent can be too tight.

For example, a cutoff perhaps for opiates might be in the 10 nanogram
range, and so you would be looking at differences in a qualitative
over-the-counter visually read test of only perhaps a 5 nanogram
difference.

Whereas, if you are looking at cocaine and urine, you are looking at 300
nanograms, and that is plus or minus 150 nanograms for the plus or minus
50 sample.

And for opiates it is a level of 2,000, and it would bee plus or minus a
thousand nanograms. And so we would hope that this type of constraint on
samples to be tested by users in that portion of the guidance be
considered to be widened somewhat for these kinds of samples. Thank you
very much.

DR. KROLL: Thank you. The next speaker is Ken Berger.

MR. BERGER: Good afternoon. I am the vice president of regulatory
affairs and quality systems for Lifepoint, Incorporated, Ontario,
California. We will shortly be commercializing a rapid, on-site product
that will simultaneously test for both alcohol and drugs in saliva.

The Lifepoint test system consists of a small portable instrument, and a
disposable cassette. By testing a few drops of saliva, the system can
provide results for up to 10 anolytes in under 5 minutes.

The specimen and collection, processing, analysis and interpretation, is
completely automated, with no user intervention. Additionally, the
system is self-calibrating, and automatically quality controls the
instrument and the cassette.

As applied to testing for substances-of-abuse, the Lifepoint product
brings the advantages of observable, non-evasive, collection as we just
heard, and quantitative legally defensible results.

This technology should prove to be evidential for alcohol, and be
significantly more sensitive and specific than current on-site or lab
based urine immunoassay drug tests.

The test is completely automated to minimize operator error. In
addition, we anticipate significant cost savings and operational
improvements for testing substances of abuse in the workplace,
insurance, and sports.

We are convinced that saliva is a drug test specimen represents a viable
alternative for drug testing programs. The use of saliva, rather than
urine, makes it possible to address a number of burdensome issues that
have plagued drug testing for years.

The collection of saliva is non-evasive, and unlike urine, few people
find it offensive to provide a saliva sample. Saliva also makes it
possible to conduct and observe collection every time without requiring
anyone to watch a donor urinate.

This significantly reduces the opportunity for adulteration or
substitution, again as we just heard. Because the saliva\'s window is a
detection of several hours, depending on the drug, it makes for an
excellent indicator of under-the-influence status.

This makes it particularly effective as a more accurate post-accident,
reasonable suspicion test, and even fit for duty testing. Additionally,
all urine and saliva-based drug tests are recent use tests, and as such
have the capability to be used for preemployment, random, and return to
duty, testing.

Saliva has already been validated and approved in many States has a
viable specimen for use in the criminal justice system. Law enforcement
officials are specifically allowed by law to use saliva as a specimen
for DUI drug testing purposes in 9 States, while 10 other States allow
the use of other bodily substances besides breath, urine, and blood.

Lastly, several participants in the European-funded Rosita Project have
published the results of their studies, and have defined the perfect
on-site drug test as a saliva-based, instrumented for objectivity and
elimination of user interpretation panel tests, with results in 5
minutes.

Interest in the use of saliva for drug testing purposes is growing
rapidly, and the guideline should not only reflect this, but also be
careful not to inadvertently restrict or discourage the use of saliva.

This is especially true at a time when adulteration and substitution
problems associated with urine testing are beginning to impact the
integrity of the drug testing process overall.

Furthermore, the development of simple, easy to use, drug testing
products, such as the Lifepoint test system, should enhance substance
abuse detection and allow for more reliable, accurate, and faster
testing methods without increasing the costs of such testing.

There is no real attempt to include these new and improved technologies.
The draft guidelines focus on current urine drug tests. Also, while we
acknowledge the need to set guidelines for OTC products and environments
where there are casual, and frequent, and inexperienced users, such as
the home, the application of these guidelines to more routine
professional use in the workplace, sports, and insurance is not
appropriate.

Drug testing in these environments is conducted by trained professionals
under the guidance of SAMHSA, DOT, the International Olympic Committee,
the NCAA, and others as we have heard today.

Additionally, the guideline proposed by the FDA is inconsistent and
disruptive to these current practices, and will add uncertainty and
costs to already established processes.

For example, how and when a confirmation testing is required, when
confirmation testing is required as defined in these environments, the
FDA requirement for automatically including the confirmation test in the
pricing process of an initial test is confusing, and inconsistent with
accepted protocol.

It is critical, therefore, that the FDA take into consideration the
newer technologies and products that will soon be available. These newer
technologies and products will revolutionize substance abuse testing
practices, and finally provide the ability to obtain lab quality results
easily, quickly, and cost effectively, on-site by non-technical users.

It is critical, moreover, that the FDA take into consideration the
guidance that already exists for workplace, insurance, and sports. We
believe that creating duplicate requirements on the user and the
manufacturer by FDA, in conjunction with the proposed DOT and SAMHSA
guidelines will have significant, undesired effects, on drug testing in
general.

There will be increases in costs, and corresponding decreases in the
amount of testing being done. It has been validated numerous times that
testing routinely for drugs is the best deterrent of drug use.

We firmly believe, therefore, that by melding the FDA guidelines with
those of SAMHSA and DOT, this will further promote public health and
safety.

We also strongly recommend that the FDA consider that these environments
are separate and distinct from home OTC. Lastly, and most importantly,
although I am not a lawyer, the FDA\'s charter, as authorized by law,
and not by regulation as we heard earlier, 21 U.S.C, paragraph 393, is
to promote and protect the public health by regulating devices intended
for the use and the diagnosis of disease, and other conditions, or in
the cure, mitigation, treatment, or prevention of disease, and that is
21 U.S.C. 321(h).

The results of tests in the workplace, sports, and insurance are not
used for diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease.

Drug testing in these environments therefore appears to fall outside the
legal charter of the FDA. Thank you for your time.

DR. KROLL: Thank you. The next and final speaker is Tony Toranto.

MR. TORANTO: Ladies and Gentlemen, representatives of the FDA, and
distinguished panelists, thank you for holding today\'s forum, and for
enabling me to address this audience.

My name is Tony Toranto, and I am the proud president and chief
executive officer of Guardian Angel, an amazing company hailing from the
great State of California.

Today I will tell you about Guardian Angel and our mission, and then I
will focus on three issues presented to the panel by the FDA. One,
whether alcohol tests should be in the same category as the various
tests for drugs-of-abuse, including the appropriate standards.

Two, whether the study design in the FDA\'s draft guidance for
drugs-of-abuse is appropriate for alcohol tests; and, three, whether
confirmation testing is appropriate for alcohol tests.

I said before that I am the proud president and CEO of Guardian Angel,
and in my shoes you would be, too. Guardian Angel has a simple mission;
to be the great company that stops drunk driving. To repeat that,
Guardian Angel\'s mission is to be the great company that stops drunk
driving.

In the United States, people drink and subsequently get behind the wheel
an estimated 2.5 billion times each year. These occasions lead to over
1.5 million DUIs, and one million alcohol related injuries, and 16,000
alcohol related deaths.

But who are these people that are getting behind the wheel after
drinking? You may be surprised to know that many of them are social
drinkers. Many of them are no different from you, or from me, or from
our friends.

They may have two drinks with dinner, or maybe three, and then think
they are okay to drive. That\'s where Guardian Angel steps in. We have
developed a product that is a simple alcohol test, and this is it. It\'s
small. It fits right in your wallet, and there is a small test strip,
like a strip of lintless paper.

The user simply inserts the test strip into his or her mouth, and the
test strip changes color to give an estimate of the user\'s blood
alcohol content. It is pretty amazing.

Now, knowledge is power, and Guardian Angel gives people empowering
information. That\'s what we are about, giving people empowering
information to make more informed decisions before getting behind the
wheel.

The intended use of our product, and everything that Guardian Angel
does, is focused on providing people with that empowering information.
The need for products like ours is manifest, and it is with that
background in mind that I address the first of the three issues that I
mentioned earlier.

Should alcohol tests like ours be included in the same category as other
tests for drugs of abuse. What analytical studies are appropriate, and
what standards, such as DOT standards, should be applied.

To be very clear, we are not the same as a test for heroin, or cocaine,
or marijuana for that matter, and we never will be. We are different,
and if regulated \-- and of course you have heard arguments suggesting
that we should not be regulated. We should be subject to different
studies and standards if regulated.

The first and most obvious reason for this is that we do not test for an
illegal substance. There is a huge different between helping law abiding
users to test their alcohol level before driving on the one-hand, and
testing law breakers for the presence on the other.

And there is a huge difference between what we do and testing alcohol
for some medical purpose, like when a patient comes into an emergency
room.

The basic message here is that we should not treat an apple like an
orange. Further weight for this is evident by comparing the historical
progression of tests for drugs-of-abuse to the historical progression of
alcohol tests like ours.

Historically, many tests for cocaine, heroin, and other drugs-of-abuse
were first prescription devices, which are not being tested and adapted
for OTC purposes. Our products simply do not evolve that way. We are an
OTC product first and last.

Again, products like ours are just a different kind of cat. We should
not treat an apple like an orange. The different studies and analytical
standards that apply to products like ours are well articulated.

For years the Department of Transportation has published standards for
alcohol tests. These standards are the valuable model used by makers of
products like ours. These standards are high standards based on sound
methodology.

They are already in place and have withstood the test of time. The DOT
standards should be the model applied to products like ours. There
simply is no need to reinvent the wheel.

The second issue that I will address is the appropriateness of the study
design set forth in the guidance for products like ours. The FDA poses a
question about the use of spiked samples, and the answer here is
straightforward.

The DOT approved spiked samples under its standards, and the FDA already
allows spiked samples for prescription testing of alcohol. So clearly
spiked samples are appropriate for studying tests like ours.

The FDA also poses a question about the appropriate concentration range
and distribution for studying tests like ours. The model in the guidance
for drugs-of-abuse should not be applied to products like ours. We are
different for all the reasons that I already said.

The DOT model should apply, and the DOT model already sets forth
concentration ranges and distributions. Lastly on this issue, the FDA
poses a question about the appropriate size of the study, including the
sample size.

The design set forth in the guidance for drugs-of-abuse contains 6
different cells, and it requires 200 subjects. The DOT model, which is
the right model for us, requires only two cells, plus a zero
concentration control cell.

As a result, we suggested only a third of as many subjects should be
required. The third and final issue that I will address is the
appropriateness of confirmation testing for products like Guardian
Angels.

Simply put, for us confirmation testing makes no sense. Our intended use
is to empower people with information about their alcohol level on the
spot so that they can make more informed decisions about drinking and
driving on the spot.

This is not like testing for the presence of heroin. For our intended
use, confirmation testing at a later point makes no sense at all. It is
neither appropriate nor practical.

If there were circumstances where a user wanted confirmation, labeling
should take care of it. Labeling should advise the user to apply a
different assay, and other approaches just don\'t make sense.

In closing, Ladies and Gentlemen, remember who we are and what we do.
Guardian Angel is the great company that stops drunk driving. Our
mission is noble, and our product important, and our reasoning sound.

The DOT model is the right one to apply, and there is no need to
reinvent the wheel. The agency and this distinguished panel should work
hand-in-hand with Guardian Angel to encourage these types of products.
It is the right think to do. Thank you for your time.

DR. KROLL: Thank you. Now, I am going to go to the open committee
discussion. First what I would like to do is ask Mr. Gutman to give us a
comment or opinion about some of the legal aspects that have been
brought up here, in terms of how our panelists want to discuss or not
discuss them.

DR. GUTMAN: Sure. I would request that the panel actually take the legal
issues off the table. You actually weren\'t assembled here for legal
advice. We probably would have constituted a different panel had we been
interested in discussing legal issues.

So I would ask you to focus on the science and public health. That\'s
not to suggest that legal issues aren\'t important, but they are not
relevant today.

DR. KROLL: Okay. Thank you. And now what I would like to do is per our
discussion is if Dr. Cooper could put some of the questions back up on
the board here for us to consider.

DR. COOPER: There are a total of 10 questions, which is quite a bit more
than this morning, and so we were going to try to see if we could group
some of the questions to try to cover the topic to be efficient.

The drugs-of-abuse questions will be the first eight questions, and then
the two following questions will be on alcohol. Some of the questions
that you answer initially may help with answers further down. But that
is going to somewhat depend on the answers you give.

So I think we perhaps ought to start with number one of the eight for
the drugs-of-abuse.

DR. KROLL: Okay.

DR. COOPER: Do you want me to read the question?

DR. KROLL: Why don\'t you read the question for us.

DR. COOPER: Okay. to maximize the likelihood that confirmation testing
will be performed on presumptive positive results, FDA has been
requesting that confirmatory testing be a mandatory component and design
of the screening test. Are there other approaches that might be equally
effective.

DR. KROLL: All right. I was going to start to my right, but since Dr.
Rosenbloom is temporarily out, I am going to go to the other side of the
room and ask Dr. Lasky to begin.

DR. LASKY: Okay. Thank you. Actually, I have two concerns about the
results of this question, if indeed the confirmation testing was a
requirement. One is that I was thinking about the use of other home
tests, and what the instructions are when the result is provided to a
lay user, like cholesterol testing.

And there the instructions are to consult a physician for further workup
and counseling, et cetera, et cetera. And although certainly
drugs-of-abuse testing have different social connotations, I don\'t see
where there should be anything other than that sort of recommendation.

The other concern that I have is if a confirmatory testing was a
mandatory component of the design of the screening test, then the device
becomes not only the initial device, the over-the-counter test, but also
the confirmatory test.

And that opens from a regulatory standpoint a whole other can of worms.
If I were to develop such a test, would then my confirmatory test, say
GC/MS or whatever it happened to be, would that be subject to FDA
clearance, and would I have to provide labeling, and all other kinds of
information to the agency, even though I have no intent of putting that
device into interstate commerce.

It will just reside in my own reference laboratory, or even more
troublesome, in terms of regulation, if it is a laboratory that I
contract with. So I think that is just extremely difficult, and opening
a Pandora\'s Box, and frankly I don\'t think it is necessary if there is
appropriated advice in the initial labeling of the over-the-counter test
kit.

DR. KROLL: Okay. We will go to Mr. Reynolds.

MR. REYNOLDS: When I looked at this question, the first comment that
came to my mind was who was this really intended for. You know, we have
had some of the industry people make a big distinction between an
at-home test, as opposed to the test which may be used in the workplace.

I could see where possibly you might have a manufacturer selling a kit
who might have some influence perhaps in the work setting, but in a home
setting, for instance, I really don\'t know how you would enforce
something like this.

Now, if a parent decides that a positive is a positive, then what does
the manufacturer of that kit do? So, I am not really sure how you go
about implementing this.

DR. BUSH: Donna Bush. Historically, two tests tend to give you a much
better result than just one. When you have a screening device such as
what we are talking about here, immunoassay-based, they may in fact rule
out negatives.

If they are so prepared, you can rely on the negative results. But
clearly the positive result needs further work, needs further analysis.
So in the past, ideas have been floated about constructing a kit that
would have the ability \-- if you get a screening test result, then have
the capability within that kit to immediately send that specimen on for
confirmation to another site.

That is inherent, because then it is up to the user. If the user reads
that package insert and decides not to send it in, that is there
decision. But clearly the counseling and the information provided in
that package insert tells the individual that more testing is in fact
necessary.

And I see at this point in time, or at this point in time, I am not sure
that I see another approach that is equally effective. Confirmation
tests is essential. So, thank you.

DR. EVERETT: This is James Everett. Clearly as a physician and a
scientist, confirmatory testing is absolutely necessary. You can\'t put,
or perhaps if you recognize the danger of putting these type tests in
the hands of laymen, and they are not a hundred percent accurate, the
resulting effect could be disastrous.

The industry mentioned the cost. It is strictly up to the individual
whether they want confirmation or not, but if a significant number of
people do not send in for confirmation, plus the negative ones have
already paid for it, and then they don\'t know it, then the cost in
essence is offset.

So the amount of cost is irrelevant. The important thing is the public
and the safety. The information we review for approval of medical
devices is tremendous. It is a lot of information and for us it can be
difficult to interpret.

Kindly the FDA provides experts to come in and explain that information
to us. The layman will not have that assistance in understanding exactly
what a positive test really meant, or what the meaning of it really is.

So the only true answer is to have the experts decide whether this is a
truly positive sample, or as opposed to a truly negative one. But in
essence, with every other analytical test we perform as experts, we
always have what is called a gold standard for confirmatory tests. There
is no need to remove that expertise from the layman as well.

DR. WILKINS: Diana Wilkins. I wanted to say that I agree with both Dr.
Bush and Dr. Everett, and with their comments about the confirmatory
testing. And I would just like to make one other additional comment
about that.

That while I realize that it doesn\'t increase the cost of the product,
one concern I have is that with the increasing use of what you might
refer to as unregulated products, unregulated medications, or
supplements, et cetera, by consumers, without an avenue that clearly
makes it apparent to the consumer that that sample or that specimen is
presumptive, I am concerned that without requiring confirmatory testing
that we could end up in a tremendous problem with other products that we
or the manufacturers don\'t anticipate a problem right now, but could
be.

You have an anticipated testing, and whether this cross-reacts with a
home-use device or something, and that is a concern to me. I think if
anything unregulated product use is certainly on the rise, and I don\'t
think that is going to go away.

And without the ability to confirm the presence of that substance in the
urine, I think we are misleading the consumer.

DR. KURT: Tom Kurt. I certainly have been giving consideration to my
fellow panel members, and I would like to comment on some things that
would be just a little bit different.

First, I was concerned about the consumer pre-marketing testing of a kit
that the consumers be a broad range of the population as a whole,
instead all of them being college graduates; that there would be an
educational level that would be polled among them.

Perhaps some of them might be visually impaired, and perhaps some of
them might be older, et cetera. Perhaps some of them might even be
artificially put under stress to see how they function under the
conditions of performing the test.

And in confirmation testing obviously alcohol testing is quite different
than doing confirmation on drugs-of-abuse, where GC/MS, of course, is a
preferred confirmation.

But I would like to point out that Donna Bush pointed out at a previous
panel meeting that the emit tests, or tests of such a nature, are used
as a stand alone test in different situations, such as parole programs,
employee action programs, methadone clinics, et cetera, on a sort of a
serial basis to see whether a person is compliant.

And I think that in certain situations where you have such tests
performed under a very creditable auspices such as a \-- and let\'s say
in this city, Georgetown University Hospital, I would not necessarily
question the result of an emit test performed under those auspices, even
though a GC/MS might be preferred.

I wouldn\'t necessary say that the GC/MS is absolutely necessary under
those circumstances, unless it falls under the DOT perview. I would like
to comment also on the situation of consumers using testing in
situations where you have sports use, home use, clinics. I mean, in an
non-clinical use under non-professional review.

I would say \"caveat emptor\" or let the buyer beware; that if such ever
occurs, let such kits be properly labeled that the user or the buyer be
forewarned, and that any positive tests should be consulted with the
appropriate medical person, such as the family physician, et cetera,
with such a positive test.

DR. KROLL: Dr. Manno.

DR. MANNO: You are skipping.

DR. KROLL: I\'m passing.

DR. MANNO: Just simply at this time addressing one, I concur with Dr.
Bush, Dr. Everett, Dr. Wilkins, on their comments. It seems to me that I
have been here before when we first discussed whether or not guidelines
should be developed.

And I think the concern then was the misleading of the consumer on the
OTC type product, and the education of the consumer. So I really think
that in order to additionally strength the family structure in an
adversarial situation between a parent and a child, I think that for use
in this environment that confirmatory tests have to be available.

They absolutely have to be available, and like Dr. Bush, at this point
in time, I just don\'t see any other way going about making that
available than what we already have. Thank you.

DR. LEWIS: Sherwood Lewis. I certainly agree with the others, as far as
the need for the confirmatory testing. I do have a question which comes
as a result of the thought on my part that what does this say about the
confirmatory testing of negative results.

If, for example, the cost is built into the test, should the user insist
that a confirmatory be conducted even though the test is negative, and
say that they know about the cutoffs, and the sensitivity around the
cutoff and so forth, and say I know this should be positive, even though
it turns out negative, and I want a confirmatory test.

Is that though built into the FDA\'s approach to the labeling and
marketing of the product. Thank you.

DR. GUTMAN: I will respond to that. There is no question that the
configuration can be gained, and that is someone who has a negative
result and has high anxiety could pretend that it is positive, and mail
it in and have it confirmed under this algorhythm.

That\'s not the intent and I would guess that is not a common practice,
but it certainly is a possible practice. So there is no intention if you
were really concerned about false negatives that this might be bad.

There is actually no intention to capture false negatives here. The
intention is to make sure that a false positive does not create a false
label. And just to clarify, we obviously can\'t go into the home with a
shotgun and make anybody do anything.

What is on the table here is the notion that by having this design and
cost built into the up-front review or clearance of the product, that it
will reduce a barrier and make appropriate behavior more likely.

We obviously can\'t actually force anybody, and then can run the test
and use it to diagnose brain cancer if they want.

DR. HENDERSON: I have a couple of comments. One, the notion that the FDA
doesn\'t have jurisdiction over a test that is used in the home is a
little concerning to me, because I would assume that all consumers would
have a right to expect that a product that they buy is safe and
reliable.

And if the FDA were not to certify that or assure that, I am not sure
who would. So I certainly think that the FDA has a role in that.

DR. GUTMAN: No, I didn\'t mean to suggest that we wouldn\'t \--

DR. HENDERSON: No, no, no. The industry is suggesting that the FDA
doesn\'t have any perview over the regulation of such a device.

DR. KROLL: I think we would want to skirt around this issue. We are now
dealing with the legal aspects.

DR. HENDERSON: Okay. The other thing is that if such a device as a
screening test was decided to be really a medical test, and therefore
something that we could look at, I certainly think that after the
screening for the confirmatory, in looking at and paying for it, health
care insurance.

If it was decided that we were using this at home to diagnose drug
addiction, or use of drugs, and they needed to have treatment
afterwards, certainly it would be something that health care insurance
would be interested in, and perhaps would help to flip some of the bill
for the confirmatory test.

I also agree that if we do provide this for home use that there should
be some incentive to follow up with confirmatory testing, and certainly
building the cost of that into it does decrease a barrier, and would
help to increase the use of confirmatory testing.

DR. ROSENBLOOM: Rosenbloom. It is hard for me to imagine not having
confirmation of all positives, not just those at the cutoff. But any
positive.

I think with the negatives that one would have to consider the quality
control that is applied at the point of contact in sports applications
and other applications.

But for the individual user, I would think that they would be well
advised to not just have cutoff positives confirmed, but to have any
positive confirmed, because that\'s where you are likely to see the most
false negatives, are those that are below the cutoff and considered
negative under those circumstances.

DR. KROLL: Okay. Thank you. I am going to ask Dr. Cooper if we could go
to question number two, and if there are any other questions she thinks
that we can group together.

DR. COOPER: I think that there is enough distinction between the two
questions that we need to make this a stand alone question. Are the
studies and labeling guidelines as outlined in the guidance appropriate
for home, workplace, insurance, sports, or other OTC settings.

Consider that the intended use of drug abuse tests generally are to
indicate the presence of drug rather than impairment.

DR. KROLL: Okay. Thank you. Why don\'t we begin with Dr. Rosenbloom.

DR. ROSENBLOOM: What I just said. I think I have pretty much addressed
that. I think that we need QC in those places where they are doing
numerous tests to confirm that negatives in general are true negatives,
and that any positive, not just those at the cutoff, but that any \--
unless it is confirmed that there is a base line, and of course that is
a negative.

But that the zero point is really \-- that there is some reaction, but
it is present in all specimens. But that anything that is positive, and
not just those considered at the cutoff, needs to be confirmed.

DR. HENDERSON: I agree.

DR. KROLL: Dr. Henderson.

DR. LEWIS: Sherwood Lewis. I agree generally that there is one thing
that has been throughout the documents that I have been reading and what
has been presented, a term, which I guess goes under labeling, which
describes the presumptive result as being uncertain.

And I think that this would create a real problem for the lay user,
where instead of using that word presumptive, uncertain is the term that
I have seen used throughout. And I just wonder if that is an appropriate
term to describe the positive test result in a screening modality.

DR. MANNO: Dr. Manno. The main thing on question two that gives me deep
concern is the application of the OTC product to anything that follows
the words appropriate for home.

I think that we have got guidelines for workplace, and I think insurance
is not for treatment. Sports is not for treatment, and so on, and so I
think this needs to be limited to home use.

DR. KROLL: All right. Thank you. Marty Kroll. I was looking at the
labeling guidelines, and I didn\'t see a separation come out for these
different entities.

And I would think that they would actually be used differently in each
place, and I think maybe there could be some language that would address
that.

DR. KURT: Tom Kurt. I would like to comment that I think that any
consumer use test, whether at home or in the sports arena setting,
should have a built-in confirmation as part of the cost of that test, so
that the person does not necessarily misjudge what that result is, or is
unnecessarily penalized in a situation of determining what the
preliminary, or presumptive, or initial test is, I would consider that a
probable positive result, but not necessarily a certain, with near
medical certainly in the result.

I think that there should be differences in the labeling guidelines,
depending upon the circumstances of the distribution of the kid. There
should be an 800 number available for the appropriate parties to call,
and that the people should be advised to consult their immediate medical
advisors.

And that there might be some quality control built into such
disseminated kits by including on a randomized basis a card, for
instance, every 10 to 20 kits to have the person send in to see their
response to doing the test, and the results that they obtained.

DR. WILKINS: Dr. Wilkins. I agree with both Dr. Kroll and Dr. Manno
regarding the labeling guidelines and the issues in my mind become most
important in the issue of home use, because there isn\'t oversight at
some other level.

At least with workplace testing and sports testing, there are other
agencies that set criteria, et cetera, for the type of testing to some
degree. But I think where it becomes very critical is for the at-home
use, and I think that somehow the labeling guidelines, or the guidance
provided for that, should be separated out for those purposes.

DR. EVERETT: James Everett. This is clearly an over-the-counter device,
and the decision to use it in the home, at work, or in some other
environment, the rules in essence should not change. It becomes more
imperative perhaps, of course, if you use an over-the-counter device and
take it to work, and the thing turns out to be positive, and not the
employee has no recourse.

Those types of activities become very important and ensures in essence
that you have a need to make sure that the test is reading accurately or
correctly.

To have this device and not have a background mechanism to make sure
that the device is correct ensures that people will be injured at all
ages \-- children, adults, and those who are somewhat in between being
an adult and a child.

These are usually the kids in the early 20s, and the important thing
about having a test to confirm your answer is to ensure that you are
proceeding on correct information. Anything else is truly presumptive.

And that opens the door to danger, misdiagnosis, misuse, and perhaps
abuse of these types of kids. So again trying to decide what the rules
should be based on where the test is being used employees somewhat of a
fallacy.

And that is that the test is more accurate in one environment than
another, or that it is somebody else\'s responsibility to make sure that
the test is accurate.

The rules for determining whether it is accurate or not should be based
on how the test performs, and not so much whether it is in the hands of
the employer, versus the hands of the parent.

Whether this test is going to be accurate for urine or saliva should be
the same in either environment. So again I don\'t think we should alter
the rules for playing this particular game based on who is doing it,
whether we are expecting the employer to pick up the responsibility for
the accuracy or the manufacturer.

Clearly the manufacturer should absorb some of that responsibility, and
this is a way to ensure that that happens.

DR. BUSH: Donna Bush. I strongly concur with Dr. Everett and his review
of the applicability in all arenas of an accurate test, because a result
of the test is a result of the test, and is a result of the test, no
matter how and where you apply it.

We spoke earlier in the day about the quandary of no result at all,
versus an incorrect result, which is worse. And that applies in whatever
scenario the testing is performed.

So I believe equal weight, equal applicability for accurate and reliable
result, screening, confirmation, initial test, followed by confirmation,
is a necessity.

Also, I think a question was asked are the studies and labeling
guidelines as outlined in these guidances, and I do want to specifically
take a look at what Dr. Cooper had presented concerning the consumer
study designs and I concur with them. That is a very good and nicely
done approach. Thank you. That\'s all.

MR. REYNOLDS: Stan Reynolds. I agree basically with Dr. Bush and Dr.
Everett, in that either the test works or doesn\'t work. It is that
simple, regardless of the setting. And also Dr. Lewis\' comment that I
really don\'t like that term uncertain.

I think that particularly for consumers for at-home use that that is a
confusing term, and should come up with something better, whether it is
presumptive positive, or whatever the term is, but I really don\'t like
that term uncertain.

DR. LASKY: Fred Lasky. First, I would like to qualify what I had
mentioned earlier, because as people are going around the table, I
recognized that everybody was avoiding my comment. I certainly agree
that confirmatory testing in drug analysis is essential.

I was addressing some of the regulatory quagmire that might follow in
the event that confirmatory testing was a required follow-up to an
over-the-counter test. So please be assured that I agree that in an
environment like this that confirming a drug test is important and is in
the best interests of everyone.

I would like to now comment on the question asked about the \-- to
consider that the intended use of the drugs-of-abuse test generally are
to indicate presence of a drug.

In fact, I have serious reservations about that statement because it is
in fact the intended use under different settings that I think is really
the issue that we really need to be troubled about, because uncertainly
certainly is a fact of life, and to minimize that uncertainly is going
to depend on how the test is intended to be used.

For example \-- and we are leaving the legal issues aside, and so we are
talking about the workplace, and insurance, and sports, and other things
like that.

But I want to say right up front that I am not sure that that is within
the realm of what we were talking about. But that being said, let me go
on. If a pilot in the plane that I am going to take back to Rochester,
New York, had a presumptive positive screen test, I would want to be
sure that he was off or out of the cockpit.

However, if an insurance company is using the same drug test, and is
going to prohibit me from getting a new insurance policy, I would want
to be sure that it was a hundred percent sure that that same test would
be positive only 100 percent of the time when in fact somebody \-- I was
going to say I, but somebody had in fact taken or abused the drug.

So here again it is the intended use that we really have to be so
careful about, and how the labeling has to be put forward clearly and
unequivocally, and I think it depends upon the setting and the facts.

Also, it has to be imminently clear when this box or kit is picked up by
a physician or an insurance company, or somebody in the workplace, that
they understand clearly what the limitations are. I don\'t think one
size will fit all in this case.

DR. KROLL: Dr. Rosenbloom.

DR. ROSENBLOOM: I am really confused. I don\'t see a dimes worth of
difference between those two situations, except in terms of timing. I
want that pilot not flying until the test is confirmed.

I don\'t give a damn whether you get your insurance today or a week from
now. Other than the timing, I think that both of those tests demand
confirmation equally. I don\'t see the difference.

DR. KROLL: Okay. Let me thank the panel for their comments. I would like
to take a short break now.

(Whereupon, the panel recessed at 3:06 p.m., and resumed at 3:26 p.m.)

DR. KROLL: I would ask the panel members to resume their seats, please.
I would like to reconvene now. In the interest of \-- or someone asked
me if we could discuss the questions concerning alcohol testing now
because someone has to leave, and wanted to listen to them, and I said
we could probably do that, and we will start with them.

And then we will return to the ones dealing with the other types of
drugs.

DR. COOPER: All right. What we are going to do is present question one
and question two for alcohol, and have the comments be collectively for
question one and question two, rather than do them as two separate
questions.

The FDA is proposing to include alcohol testing in the same category as
other tests for substance abuse. Are the same types of studies
appropriate for alcohol tests and should other approaches, such as the
one used by the Department of Transportation, be considered.

And the question that we are combining that with is in what setting is
confirmatory testing for OTC alcohol tests appropriate, at home,
workplace, insurance, sports, other.

What matrices and what time span between collection of the original
sample and collection of the sample for confirmation would be
appropriate. Thank you.

DR. KROLL: Okay. These are on page 13 of the handouts. You can review
what the actual questions are there. I would like to ask that in the
interest of time can people please keep their comments succinct, but if
you do have something that you want to say, please say it. So let me go
to Dr. Lasky.

DR. LASKY: I don\'t have any comment on this part.

MR. REYNOLDS: I have no comment at this time either.

DR. BUSH: Donna Bush. DOT models work well. Actually, when we are taking
a look at point of collection testing in the SAMHSA workplace arena, the
Federal workplace, we are looking at the NHTSA, National Highway and
Traffic Safety Administration, way of approving and testing on their own
separate and independently the test devices for breath alcohol.

Well, we are looking at that model and later on our point of collection
testing, urine drug testing and oral fluid drug testing, possible assay
kits.

And so there is a model out there that works well for taking a look at
evaluating devices, as well as implementing cutoffs, and confirmation,
screening and confirmation, and DOT has a good model in their workplace
program also.

DR. EVERETT: James Everett. I agree in the sense that I don\'t run into
the same problems, and other physicians that I know, we don\'t tend to
run into the same problems with alcohol as we run into with the other
types of drugs.

So I don\'t think it is necessarily needed to include it in the same
type testing and impose the same type criteria.

DR. WILKINS: Diana Wilkins. I also agree with Dr. Bush\'s comments, and
Dr. Everett\'s comments, and I think we definitely should consider other
approaches, such as the DOT model, because I think at least there we
have some basis or some reference point, some experience to go on
particularly for alcohol.

So I think that that is a reasonable approach to take.

DR. KURT: John Kurt. I agree with Donna Bush\'s point that NHTSA and DOT
have long established the kind of program review devices used in alcohol
testing.

I think it would be helpful for the FDA to have sort of editing
privileges of labeling, or input on the labeling of such devices, but
not necessarily take the lead, because the lead is already well
established.

DR. KROLL: Martin Kroll. I am going to try to answer the things in
question two. First of all, I think for confirmatory testing there, I
think that where it is going to be used for some type of purpose, like
where a punishment is attached, think there should be some type of
confirmatory testing.

I think if you are looking at somebody who is at a bar or some in the
home, and decides or is trying to decide whether or not they have drunk
too much to drive, I don\'t think that needs confirmatory testing.

I think they need to look at that and say what goes over a certain
amount over the certain limit and that could be set fairly low, and that
they would say it is better for me not to drive, and try to deal with
that.

But in other places, the workplace or sports, or insurance, I think that
needs to be handled differently, because the consequences are more
severe.

DR. MANNO: Barbara Manno. I agree with all the comments so far. I would
add one more just general comment to the whole area of alcohol testing.
I heard one of the sponsors plead for not including other
drugs-of-abuse.

I don\'t see where the inclusion of alcohol in any way in a drug kit
that has other drugs of abuse in it for over-the-counter testing
precludes in any way a single test unit that may be out there, just
purely to see if you have had to much to drink to drive.

But I would think that we should use that DOT, or at least consider what
is there already as a pattern to follow. There is a good knowledge base
there.

DR. LEWIS: Sherwood Lewis. I have nothing to add.

DR. HENDERSON: Cassandra Henderson. I don\'t either.

DR. ROSENBLOOM: Arlan Rosenbloom. I agree that a parsimonious approach
and the most efficient would be to use established guidelines, and that
alcohol is a very different testing issue, and database \-- and a well
established database compared to the other substances.

DR. KROLL: Thank you. I would like to go to Dr. Gutman and ask him if
there are any more questions that we have related to this issue.

(Brief Pause.)

DR. KROLL: All right. Let\'s go back to the other drug tests, and I
believe that takes us to questions 3 and 4; is that right?

DR. COOPER: Actually, I believe it is going to be 3 and 8. We are
combining our cutoff questions. The FDA is suggesting that OTC devices
render negligible performance error with spiked samples that
concentrations of plus 50 percent, and minus 50 percent of the cutoff
concentration.

Again, these are drugs-of-abuse questions. And is this reasonable. If
not, what alternative performance criteria would be appropriate.

And visually read devices frequently render positive results well below
the claimed cutoff of the assay. And the caveat is should there be
certain performance requirements to support a claimed cutoff
concentration.

DR. KROLL: All right. Let\'s start with Dr. Rosenbloom.

DR. ROSENBLOOM: Can you start with somebody who is registering faster
than I am?

DR. KROLL: Dr. Henderson.

DR. HENDERSON: Again, I\'m still focusing on negative results. I
certainly think that devices that are read, if they are less likely to
render a positive result because of the cutoff, I would argue that the
cutoff should be moved so as to render it much less likely that you are
going to get a false negative than a false positive.

So I would argue that the devices, the concentrations, the cutoffs,
would be changed so that the spread between what is acceptable and what
the sponsors might produce on their data, would actually be tightened to
increase the likelihood that they are not going to identify somebody as
being positive when in fact they may well in fact be negative.

So I am really concerned about the false negatives.

DR. ROSENBLOOM: I guess I would say the same thing, which is what I have
been saying right along, is that any positive, even if it is below the
cutoff, should be emphatically stated as requiring confirmatory testing
before it is assumed to be negative; just as positive requires
confirmatory testing before a label is placed.

DR. LEWIS: Sherwood Lewis. I think that for the reasons already given
that the plus 50 percent and minus 50 percent are pretty broad, and
could be tightened up for the reasons mentioned.

DR. MANNO: I kind of feel like the 50 percent value is rather tight for
this also. If they are going to stay there, there needs to be some
discussion on the labeling, and the percent of the time that you would
expect to have a frank positive and one is that you might consider
making a suggestion that when it is negative, they might want to test on
another day and another time.

I am not selling over-the-counter drug testing kits, but I am thinking
about the practical application in the home setting. And in terms of
question number 8, I am going to pass on that temporarily.

DR. KROLL: All right. Martin Kroll. I am a little concerned on question
three whether plus or minus 50 percent, and that seems a little liberal
to me. I mean, I just imagine that could be a bit tighter. You need
something that is like a plus or minus 25 percent, or plus or minus 30
percent.

There could be a lot of values that fall within that range and that may
in part depend somewhat on the actual drug that is being looked at. And
on question eight, I didn\'t exactly understand this question real well.

I would expect that there should be performance requirements to support
any claimed cutoff, and it doesn\'t disturb me that much that they can
detect a drug below the cutoff. I would expect that they should be able
to.

But that I would certainly like to look at that. Usually for a
qualitative test of this sort, you are actually in the fairly linear
portion of the curve when you are near the cutoff. So that analytically
they perform fairly well.

And the tests are qualitative because when you go to much higher
concentrations, then you lose the linearity, but you don\'t care because
they are just positive. So I would be interested if the FDA might even
want to look at just how linear they are in this region. That\'s all.

DR. KURT: Tom Kurt. I agree with the previous speakers and would like to
point out that the kits that are being produced should be used exactly
as they are labeled, and that shortcuts or dividing them up so that they
are being used on two specimens, et cetera, is to save funds or a kit
being reused, and rejuvenated with some other re-agents, et cetera, is
not what is supposed to be done. It is supposed to be used exactly as it
is there, with the re-agents contained within.

DR. WILKINS: Dr. Wilkins. With respect to the first question, I think
that I agree with Dr. Kroll that I think, if anything, that I think the
plus 50 percent and the minus 50 percent is somewhat liberal.

I would be more in favor of tightening that rather than widening that
range to minus a hundred percent, or plus a hundred percent. I mean, I
don\'t see the utility of the test or the benefit to the consumer having
quite that broad of a range.

I also might suggest that at least in the guidance document that the
term negligible performance error be clearly defined for this issue,
because I think that leads to a lot of interpretation variability, and
that probably needed to be clearly outlined.

DR. EVERETT: James Everett. Without the later aggression data and some
evidence of what the standard deviation would be, it is difficult to
tell whether the plus or minus 50 percent would include the majority of
samples or actually leave out a significant number of samples.

But routinely a plus or minus 50 percent should include the majority of
samples clearly, as opposed to screening out a lot of samples. I am not
sure if the manufacturers could actually meet such criteria.

And again trying to define what the negligible performance error would
be, again that is difficult to interpret without some data to help
evaluate whether the linear aggression curve actually covers the
majority of data that the test kits would collect, because that is what
you would like to do.

And that is that you would like to be able to put the majority of
samples in that range, and then decide what the deviation should really
be; whether it is a plus or minus 25 percent, or plus or minus 50
percent.

But in essence, to start with, I think a plus or minus 50 is probably
reasonable to start. But I suggest that once a kit is developed and the
data is presented that that would have to be modified.

And then as it relates to question number eight, should there be certain
performance requirements to support a claimed cutoff concentration;
again, you need the linear regression data to determine that. But, of
course, that is standard for any statistical value that you will need
those numbers.

And if you are going to use a cutoff to apply to whether or not a sample
is negative or positive, there should be some data to back that up. So
clearly I am in support of number eight.

That is, there should be some performance requirements to support the
claimed cutoff. You should just pick one out of the air. That kind of
goes without saying.

DR. BUSH: Donna Bush. As to the first question, the FDA suggests that
OTC devices render negligible performance error at plus or minus 50
percent of the cutoff. This is reasonable, and very reasonable.

When you think about what this first initial test is part of, it is part
of a system of confirmation. So you want to get an accurate and reliable
\-- a good feed into the confirmatory process for those that need to be
there, and you don\'t want to miss some that should be going on to
confirmation.

So you don\'t want to miss on the high side, and the more on the low
side that you get going in, you are going to get laboratory confirmed
negatives coming back.

So people are going to have doubt and wonder what is going on here with
how tight that bell curve is around the cutoff. So in a laboratory, plus
or minus 50 percent error would generate the antennae to go up, and for
one to start looking at what is going on in your testing system.

So I think that is applicable also in this type of technology. Visually
read devices. Absolutely. There should be performance requirements to
support the claimed cutoff.

And it is easy to do; whether it be the standard bell curve that goes
back to the days of radio amino assay, and you can talk about linear
ranges of the curves based on many different approaches to finding a
binding criteria. That\'s all.

MR. REYNOLDS: Stan Reynolds. On question three, I agree with Dr. Wilkins
and Dr. Everett that you do need to define your negligible performance
error.

And also the comment that Dr. Henderson made earlier, in that it would
also be good to have positive and negative predictive values, so that
you know in your population how frequently you may be getting a false
positive or false negative.

This is something that you know occurs in one out of every 100 patients,
and you get a false negative, and you have someone that you have a
strong suspicion may be a drug abuser, and you may not accept that
value, and say maybe I need to do additional testing.

If on the other hand it only occurs one in every thousand, you may
accept it. So I think that you need both of these items for number
three.

On question number eight, obviously you have to show how you came up
with your cutoff. I don\'t think that is a question. But the second
question because that if you set your cutoff at a value that is
different from the absolute sensitivity in your system does that really
matter.

In other words, if your system is actually going to be more sensitive
than what you are saying your cutoff is, I don\'t see what the issue is
there.

But you have to be able to document that whatever you have established
your cutoff is that it is reasonable, and you have documentation to
support that.

DR. LASKY: Fred Lasky. I agree with the comments that have been stated,
but I would like to even get a little more specific. The issue with
negligible error, negligible performance error, is a real bugaboo
because when we are developing tests, we think that we have negligible
error, but all too often it seems that when we come up with data, the
FDA disagrees.

And of course the hundreds of times that we don\'t disagree, we all
forget about. But the bottom line is that there is some definition about
that is really needed. Also, I think that I was getting some mixed \--
at least I was hearing what appeared to be some mixed messages about
this plus or minus 50 percent.

That is related to the concentration, and is compared to the cutoff, and
is pretty typical of the sort of things that are used and looked at for
qualitative tests. So you have a cutoff and you go down 50 percent, and
you go up 50 percent, and you see how robust the test is at those
points.

In the guidance document it says that essentially all samples should
give the correct result, and again here essentially is a very
problematic word and needs some definition.

And I don\'t think that we are the group right here to make that
decision, but I think it is the sort of thing that if a guidance is
going to be helpful, it has to provide some guidance, and I think that
is what is needed.

And another comment is that when you are dealing with qualitative tests,
often times you are not dealing with linear relationships. So those
statistics often times don\'t help.

But there was a guidance that was produced by ECCLS, the European
Committee for Clinical Lab Standards, which is no longer in existence,
but fortunately the document still exists, that I think is excellent to
consider for determining the characteristics of a qualitative test, in
general, and not just the drugs-of-abuse.

And obviously with drugs it is going to get a lot hairier because of the
impact of metabolites on positive reports and negative reports if a
testis not quite sensitive enough.

With regard to number eight, I also agree that the question needs some
clarification, but as Mr. Reynolds mentioned, often times the
manufacturer will have data certainly to support the claim.

The FDA requires that and if there is any hope of getting a test cleared
or approved, we have to have data in order to support a claim. But also
a manufacturer often times may make a claim that is not quite as good,
whatever that means, as what has been submitted in order to make the
test more robust for the way it is intended.

So when I look at that question, I am not sure as I think Mr. Reynolds
mentioned, if that limitation is good for the user, or if it is bad for
the user, in terms of providing some confusion or clarity.

And I think that is really what has to be looked at, and how the numbers
are going to be used, and whether or not it is really going to help the
end user interpret what the test kit is supposed to tell him.

So I guess more guidance and definition is really what I am looking for.

DR. KROLL: All right. Thank you. Then we can go to the next group of
questions.

DR. COOPER: These are related to study design questions for
drugs-of-abuse. Is the study design as described in the guidance
appropriate for demonstrating performance of the device in the hands of
the lay user. Please consider sample size, use of spiked samples,
concentration range, and distribution of samples, and size of consumer
study.

And the second question is the FDA is suggesting that the sponsors
conduct only the consumer studies described in the OTC document when the
device has already obtained prescription clearance, and are there any
other studies warranted other than what was described in the previous
question.

DR. KROLL: Okay. Thank you. Why don\'t we start with you, Dr. Lasky.

DR. LASKY: Okay. This is sort of a quick think mode. For
over-the-counter labeling, I think there has been a lot of very helpful
and substantial guidance on how labeling should be divided for
over-the-counter use.

And I think that has been very helpful and I don\'t mean to presume that
the FDA is going to throw all of that out, because I know that is not
the case.

In my experience, which is not vast with OTC, but is

\-- I do have some experience with it, when you hit numbers with OTC
devices, you really are getting into a very sticky area.

I think the instructions for what to do with the result, and how in
simple lay terms it can be interpreted, including follow-up information,
I think is really the key here.

If too much is \-- the critical issue of too much is provided and most
of it is useless, the important things are not going to be seen, and I
think that is the key.

In terms of \-- and so I don\'t advocate the use of performance data for
OTC as a general guide. With regard to the study designs, I think the
study designs, in terms of in the hands of the user, I think are general
are fine from an overall perspective.

I do have some concerns about the very strict, I would say, requirements
or guidances, in terms of the distribution of samples, because it may
not really suit the need of the particular device, depending upon the
full range and capability of the device.

And also as we talked about a little bit before, sometimes it is just
\-- it is virtually impossible to get a large number of samples at all
different kinds and ends of the scale, and many times it is more
important to get many samples so that you see a variety of matrix,
versus the full concentration in the sort of sample distribution that
has been suggested.

That is not to say that challenging the test is unimportant. It is. But
there needs to be a bit more flexibility on how that mix is actually
obtained.

MR. REYNOLDS: Insofar as the study design in the sample size and things
of that nature, I tend to defer to the chemists and statisticians as to
what is appropriate for the actual design in the study. To me it seems
reasonable, but again I would defer that.

DR. BUSH: Donna Bush. The study design question, I concur with what was
presented by Dr. Cooper earlier, in terms of the structure of that study
design.

And I concur with question number six, and that\'s when the device has
already obtained prescription clearance, and I concur with that.

DR. EVERETT: James Everett. I tend to agree with number five, in the
sense that this kind of guidance should certainly be provided from
previous devices that we looked at.

There have been instances where the manufacturer only reviewed less than
five consumer individuals in the study and that was disastrous. So I
think up front providing a potential manufacturer with some idea of how
many consumers must be involved in the study, the sample size, as well
as this information we use to determine whether or not the instrument
actually works, is a very good idea, because frequently the
biostatisticans again come to the forefront, and then they reorganize
the data.

And it says though the manufacturer had no idea how many individuals to
include, what the sample size should be, and again it is like they took
the data and then matched it to some statistical calculation, and that
is backwards. It shouldn\'t really be done that way.

So I think up front that providing that information is a very good idea;
and then the other one, I think that is pretty clear that it is just
necessary.

DR. WILKINS: In answer to the first question, I think that the model
proposed for the consumer studies is a very fair and reasonable place to
start for this type of testing. The only additional comment that I have
is that in terms of the distribution of the samples \-- well, that\'s
probably not quite what I mean, but the populations, or sort of
subgroups in which this is tested, that that needs to be representative
of the groups in which the test kit will be used.

And I am not sure with this question when you say the distribution of
the samples, if you mean the distribution of the number of samples in
each of the individual categories, plus or minus 50 percent, or if you
meant distribution of the samples, in terms of the types of subgroups
that might be looked at.

For example, different education levels, or reading abilities, or
whatever that might be. I wasn\'t sure what the intent of that was for
that question. But I am assuming there that that means that many
different groups in which the kit might be used would be included in the
study or represented.

And with number six, I agree. I don\'t have anything to add to that,
except that I think it is reasonable to conduct only the consumer
studies when it already has prescription clearance.

DR. KURT: I agree with what has been said, and I agree with the
guidelines as presented by Dr. Cooper earlier today, from the standpoint
of performance.

I am concerned that the spiked samples and the definition be carefully
defined to be sure how those are really spiked. And in question six
concerning the consumer use, I think it would be helpful to the
manufacturer to trial it through a small sampling of consumers before it
actually gets out there to be better prepared for problems that might
potentially occur, although you might not have the full 200 consumer
sampling size at that point.

DR. KROLL: Looking at question five, that appears to be adequate. I
think there needs to be some care taken with spiked samples. Depending
on what the drug is, metabolites might be very important.

And in those cases probably it would be better off using real samples,
and if they can dilute them with other samples that are of the same
approximate matrix, and then to get the appropriate concentrations of
drug that way. And that could be determined by looking or using your
reference method.

You might also want to consider adding in the spiked samples as well.
One thing we really have not looked at is that in some cases you have to
make certain the spiked samples aren\'t the actual drug that you are
trying to measure, and that there is no problem with being right or left
oriented. That\'s all.

DR. MANNO: On question number five, I think everything is okay as it is
presented. Dr. Wilkins brought up a point on concentration and range,
and distribution of samples.

I originally thought of that as perhaps knowing what the concentration
of the sample being tested is against whether you get a positive or a
negative result on it, and doing your statistics on it that way. I
appreciate the comments of the sponsors about the difficulty in getting
a large sized sample to test at a given concentration.

So I think that you could go about that several different ways, but I
think that generally question five is okay. Question six, I agree with
that question, and I don\'t have any problems with going ahead and just
doing the consumer study on an already approved product.

DR. LEWIS: Sherwood Lewis. All of the good points have already been made
by the previous persons addressing these two questions and so I will
pass.

DR. HENDERSON: Cassandra Henderson. I agree and have nothing to add
other than just to point out that certainly the post-marketing surveys
should be budgeted into all of the financial plans for the sponsors.

DR. ROSENBLOOM: Rosenbloom. I agree with the design as presented
relative to question five, and that consumer studies are all that would
be needed if the device has already been approved for prescription use.

DR. KROLL: All right. Dr. Gutman, are there any other points that you
want to clarify on these?

(No audible response.)

DR. KROLL: All right. Let\'s go to the next set of questions.

DR. COOPER: Okay. I believe that this is the last one. Oh, there is one
more. The FDA does not encourage inclusion of performance data in OTC
labeling. Do you feel such information should be included?

If so, what types of studies should be done to characterize performance
well enough so that it would be meaningful to the consumer? How should
performance be related to consumers in the labeling?

DR. KROLL: All right. Why don\'t we start with Dr. Rosenbloom.

DR. ROSENBLOOM: Why don\'t we. I can think of several reasons, but that
is not the question. I guess we are talking about OTC labeling for all
the various environments that we have been discussing \-- school, home,
sports, and so on.

I think under the circumstances, given the variety of environments, that
performance data should be included. In some settings, you are going to
be dealing with rather sophisticated users, and actually in all settings
you may be dealing with sophisticated users who want that information
and others who won\'t.

The alternative is to give them a website to find it on, which the
sophisticated users will use. They will probably find more information
than you have got in the labeling anyhow if they are really interested.

But I don\'t see any downside to including that information. What types
of studies should be done to characterize performance well enough so
that it would be meaningful to the consumer? I think the kinds of
statements that relate not so much to sensitivity and specificity, and
those kinds of things, which a small range of consumers would be able to
understand.

But things like at such and such a level, there is an X possibility,
percent possibility, that the test is truly negative and that you need
to get confirmation, and those kinds of statements relative to the
linear performance.

And again you can\'t say what that will be without having the data in
front of you, but I think people need to know what a specific result
means in very specific terms, and I think that could encourage
compliance with confirmatory testing.

DR. HENDERSON: I think there is no question that study information
should be included and provided to consumers, and I certainly think that
the vast majority of consumers are capable of understanding that, and I
base that on trying to discuss alpha fetal protein screening with women;
inner-city women in New York City, and middle class, and very educated
women, and they all have difficulty understanding it.

But when given examples of false positives and false negatives, and what
they may mean, they understand it, and they can make sense out of it,
and make an informed decision.

DR. LEWIS: Sherwood Lewis. I certainly think that that information
should be included in the labeling, and I am just curious to know why
FDA does not encourage the inclusion of this sort of information, just
for my own understanding.

DR. GUTMAN: Yes. There are at least two reasons and we have obviously
had internal discussions and are interested in seeking outside input on
this issue. There are at least two reasons.

One is that it is very hard sometimes to couch performance in a term
that actually makes sense to patients. It is easier said than done.

And the second is that our data threshold for these submissions is
clearly based on analytical studies. I wish we did know the predictive
value of a negative or a positive in the actual intended use setting,
but we actually don\'t know that.

And so there has been in the internal discussion about the pros and cons
of putting the performance in concerns that if the performance was not
carefully couched, that it could in fact misrepresent the device.

I actually think that Dr. Rosenbloom\'s suggestion of indicating at
certain cutoffs what positive and negative rates might be seen, and if
you were to try something like that, you might create understandable
labeling.

But actually I think it would be challenging, and I would be curious as
to what the rest of the group says.

DR. MANNO: Manno. I have nothing to add to what has already been said.

DR. KROLL: Martin Kroll. Actually, I agree especially with the comments
of Dr. Rosenbloom and the way that he stated them.

DR. KURT: Tom Kurt. I agree with merging some of the good ideas of Dr.
Rosenbloom and Dr. Henderson, and to saying that in a simple sentence
the false positive rate, or the false negative rate is, and for further
information see our website at.

So you could have some performance data in a simple nature there, but
the more elaborate information could be available and found at a website
for the more sophisticated person who probably would have a computer to
look it up.

DR. WILKINS: I would just state that I agree with Dr. Rosenbloom\'s
comments earlier and don\'t have anything additional to add.

DR. EVERETT: James Everett. Certainly some information about performance
should be included. Obviously you would not put the raw data in there,
but once a responsible manufacturer develops a kit, they should stratify
the data so that if there are obviously certain circumstances where the
kit does not perform well, then that information should be there, and
almost anybody can understand that.

For instance, if you are going to do the test on the North Pole, it is
freezing and it is outside, and you do the test and it doesn\'t work.
Most people can understand that, and once the data is evaluated, those
kinds of things will usually surface without a lot of effort.

And at the same time, they do affect performance, and in a sense some of
that kind of performance information should be included. I don\'t think
we should just assume that they wouldn\'t understand anything, but
perhaps they don\'t have to understand everything.

DR. BUSH: I concur with Dr. Rosenbloom and Dr. Henderson on their
approach. Thanks.

MR. REYNOLDS: Stan Reynolds, and I also agree with Dr. Rosenbloom and
Dr. Henderson, and the idea of a website or 800 number, where people
could call and get additional information and clarification, and where
if they did have a question that they could just get a simple
clarification from someone over the telephone.

DR. LASKY: Fred Lasky. Under the stressful situation of the last round,
I can answer this question partially. I would like to comment on what
Dr. Gutman said. We also have found that it is like threading the eye of
a needle to put in just the right amount of information from a labeling
standpoint.

In general, I believe we need to be very clear on how a kit should be
used, the procedures and under what conditions, as Dr. Everett
mentioned. What the results actually mean in terms that are
understandable to the lay user, so that we don\'t confuse the user with
a lot of information that he or she might have to go to a professional
to help clarify.

And thirdly I agree that if additional information is requested that it
should be available, and I think of the kind of information that we
currently put in inserts, and instructions for us, as we do with 510K
products; and that being available if requested I think is very, very
appropriate, because these sort of tests, over-the-counter tests, are
used often times \-- and if you will excuse the expression

\-- very sophisticated users, because they are easy to use and often
times very cost effective because of things like time and through-put
and all the other things that we are all aware of.

DR. KROLL: Thank you. We have one more question and that is question
number seven.

DR. COOPER: Should only those devices with SAMHSA cutoffs be eligible to
be cleared for OTC use and that is the last question.

DR. LASKY: Can I get a clarification from Dr. Bush on what are SAMHSA\'s
objectives? I am familiar with some of the requirements, but I don\'t
frankly know why they are there, and I think that would be helpful in
our discussion.

DR. BUSH: SAMHSA\'s objectives for including the drugs that are on our
testing panel?

DR. LASKY: Yes, and the mission also.

DR. BUSH: The mission, simply stated, in the form of then President
Reagan\'s executive order in September of 1986, when he said there will
be a drug free Federal workplace. We are the largest employer in the
world, and we can make this happen and offer employees a helping hand.

With that broad brush statement said, then everybody had to interpret
what does a drug free Federal workplace mean. So the focus was placed on
illegal drugs of abuse, hence the classes of drugs that were established
then that remain today, and that is marijuana, cocaine, PCP, opiates,
and a focus on heroin, and Tylenol with codeine compounds, and refocused
our efforts on heroin, the illegal drug-of-abuse.

And amphetamines, and now we are looking to broaden our horizon to
include MDMA, MDA, MDEA, in that broad brush, illegal drugs of abuse.
And so when asked, well, why not include benzodiazapines, and
barbiturates, and we have been asked this multiple times.

We interpret our mission as not to look at diversion or misuse of
prescription drugs, and so we focus only on illegal drugs of abuse. So
the classes are marijuana, cocaine, PCP, opiates, morphine, codeine, and
then amphetamines.

DR. KROLL: Dr. Lasky, do you have any comments on question seven?

DR. LASKY: Yes. Actually, thanks, Dr. Bush. That was really very
helpful. Based on that and comparing that to the mission of the FDA, I
don\'t think that these guidances should be restricted to those drugs
because of the fact that there might be other uses and reasons that
over-the-counter testing would be helpful for other classifications of
drugs.

MR. REYNOLDS: Stan Reynolds, and I pretty much agree with Dr. Lasky
sitting here. There could be other drugs, such as LSD, and things like
that, that a parent might want to be able to test their child for, and
someone may have a very good kit for that. So we should have the ability
to look at some of these other things.

DR. BUSH: Donna Bush. We would love to find that marvelous LSD kit.
Bring it on, please. The short answer is please expand the panel. There
is multiple need out there for plenty more than just the SAMHSA-5. Thank
you.

DR. EVERETT: I agree.

DR. WILKINS: I agree.

DR. KURT: I agree that the panel should be expanded, but I think those
that are not the SAMHSA drugs, the cutoffs as they are stated for kits,
should be stated how they were arrived at by, say, an academic panel, et
cetera, et cetera.

DR. KROLL: Martin Kroll. I agree. Also, I think that it should be very
clear if you are looking at a drug that is not an examined a lot with
other methods that there are good reference methods for it.

DR. MANNO: I agree with Dr. Kroll, and I agree with Dr. Bush. I might
suggest that on the more obvious, the next five, that we have any
database on, that you could refer to the College of American Pathology,
and the American Association of Clinical Chemistry has a database that
could provide us a good starting point for establishing cutoffs, because
they have had an accreditation program for a while.

I don\'t know whether I totally agree with all of them or not, but at
least it is a point to start at.

MR. LEWIS: Sherwood Lewis. I have nothing.

DR. HENDERSON: I certainly think that this panel should be expanded to
those other than what is included in SAMHSA.

DR. ROSENBLOOM: Yes. I mean, yes, I agree with everybody.

DR. KROLL: Very good. Dr. Gutman, do you have any more questions that
need to be clarified on this issue?

(No audible response.)

DR. KROLL: I would like to thank the panel for going through this
succinctly, and is there any issue that any panel member would like to
clarify in any of their comments? Now is a good time to do it.

DR. WILKINS: Actually, I want to clarify a comment that I made before
the break, and that was the issue of distinguishing between the labeling
guidelines on home-use kits, versus insurance and sports testing. And
the issue of confirmation testing.

It was my intent to say that I thought it should be clearly labeled
whether the intent of the kit was \-- what the intended use was by the
manufacturer is what I meant there.

I did not mean to imply that confirmation testing should not be done in
any of those settings. It was my position that I felt that confirmation
testing should occur in all of those settings.

However, I think that the kit insert or package insert should clearly
state what the intended purpose of the kit is, or the setting in which
it should be applied, because I think there may be interpretation issues
associated with that that the consumer might need to be aware of.

DR. KROLL: All right. Any other panel members have comments? If not, at
this time, since we have some time left, if there is some people among
the public observers, if they would like to make a very short, brief
comment, limited to about maybe 3 or 4 minutes, they can make it at this
time.

MR. AROMANDO: Bob Aromando. As I mentioned earlier, I am an independent
consultant. I just wanted to address 1 or 2 points that were mentioned
this afternoon. Just as an example, if we went back to question eight,
where it is stated that visually read devices frequently render positive
results well below claimed cutoff.

Well, this also occurs in instrument based tests, and Donna Bush, of all
people, would know that this does occur, since these instruments rely
daily on calibration curves that tend to drift from one hour to the
next. So this is fact.

Secondly, if a visual test calls samples positive below the cutoff, the
confirmation test will usually agree, and I use cocaine as an example,
which has a 300 nanogram cutoff value, and if some of these visual tests
are picking up positives at 200 nanogram, the cutoff value for
confirmation tests is 150 nanogram. So it will pick it up, and there is
no question about it that it will confirm the result.

The other issue that I wanted to make was that I don\'t think \-- and
unless I heard something differently here, nobody is disagreeing that
confirmation tests should or should not occur. We all agree that they
are absolutely extremely important in every single case.

But I also heard some comment about confirming negative results, which
is probably physically impossible in this country considering that 90
percent or more of drug test results are negatives. I don\'t think any
lab in this country is equipped to confirm every negative result that
potentially could be out there.

There also seems to be concerns specifically about confirming screen
results in the workplace and it must be known that just about every
State in this country requires drug testing results to be confirmed
before any action takes place.

So there are State laws already in place to protect employees, and there
are also union contracts that require confirmation testing as well. So
there is no disagreement here.

The other thing that I would like to just go back to, is that early on
in the day there was some statement about on-site testing being more
expensive, and I think it was Donna Bush who may have said that.

Well, perhaps that may be the case, but a lab based test is extremely,
and I go back to my statement earlier where when labs are allowed to
dilute or water down reagents for the sake of economic purposes,
certainly they are going to be less expensive.

But at the end of the day, if you look at the total cost of ownership on
on-site drug tests, it is less expensive, because the results are
immediately available, especially in a workplace testing environment,
where a candidate can be hired immediately upon a negative result,
versus several days for a negative result from a laboratory. Thank you.

DR. KANG: Thank you, Dr. Kroll and panelists. I am Jemo Kang from
Princeton BioMeditech Corporation. We make about 42 products,
FDA-cleared products, all point-of-care direct assay.

And we are more acutely aware of the problems with assays, and first I
would like to make some comments on confirmation. If we package products
and make consumers aware of the content, my question is what are they
buying.

Those test kits may cost under \$20, and if you include confirmation
requirements, it may go into \$30 to \$50. What are the customers paying
for? And these issues about benefits and harm issues, can the FDA make
this available to customers.

The clear intent is to make this program widely available at a
reasonable cost. To me perhaps the national goal of deterring drug use.
If the test unnecessarily, because of confirmation requirements, cost
twice or three times \-- and if they have to pay \$40 or \$50 for tests,
many of the customers may have to think about whether they want to buy
test kits to test their children, or they would like to buy a bag of
groceries to prepare for supper.

It is a difficult issue and decision, and I think the one object to make
this test widely available, readily available to customers, is we are
not meeting that goal somehow.

And also from the point of the manufacturer, there is a tendency of
misusing the confirmation issue, and currently I am hearing from many
other people that if they put over-the-counter drug tests requiring
confirmation, they are expecting perhaps below 50 percent of the tests
will come back for confirmation.

That means that another 50 percent may never send for confirmation.
Those people who do not send in for confirmation, they are also paying
for this confirmation test.

In case the test results are negative, they are also penalized to pay
for this confirmation test. So my proposal is whether it would be
possible to make this over-the-counter product available a different
way. One way is packaging it as a purely drug test, and then make
confirmation tests available on the shelf to make it optional.

If that doesn\'t meet FDA\'s requirements to ensure safe and
effectiveness of this test, perhaps co-sharing, sharing the costs or
sharing the bottom with the manufacturer may be one option.

If a confirmation test requirement may cost \$30, perhaps the
manufacturers could share half-and-half. Therefore, it may be possible
to use the test price lower to customers, and that might actually help
to make this test more widely available.

If the packaging says we are detecting the presence of drug rather than
\-- what was the language again \-- well, rather than the impairment of
the individuals. That says two things. We are concerned about
concentration or presence of drugs in the sample.

That to me is more of a legal issue, which later part addresses medical
use. That may bring jurisdiction issues. If you are talking about simple
presence or non-presence of drug, which does not apply any medical
implications, why are you talking about that.

And also as a manufacturer, I know some panel members raised the issue
of whether we can make approximations about 50 percent, and whether we
can tighten further. In principle, it is a very good idea to make the
test highly accurate.

But we have to think about what is possible in the hands of a lay
person. It is very, very difficult to distinguish at 50 percent cutoff
level, a positive or negative issue in the eyes of many customers. It is
not easy. I think tightening further is not really adding more benefit
to the customers. Thank you very much.

DR. KROLL: Thank you. Dr. Lewis, did you want to make a comment?

DR. LEWIS: Sherwood Lewis.

DR. KANG: If I could add one more thing. The last question was about
whether we should follow SAMHSA guidelines cutoff rather then if we want
to include only SAMHSA or NIDA-5 drugs. I noticed that most of the
panelists was talking about adding more drugs rather than talking about
whether we should stick to the cutoff level of SAMHSA.

DR. KROLL: Dr. Lewis.

DR. LEWIS: Sherwood Lewis. I just wanted to respond to the statement
that was made regarding the testing of all negative results. I did not
suggest that all negative results be confirmed. I was saying what would
happen should an individual want as part of the package as purchased to
have a negative result sent out for confirmation. I certainly appreciate
that you can\'t confirm all negatives.

MR. AROMANDO: I\'m sorry, but maybe it was not you, Dr. Lewis, but there
was \-- and I am sure that we have transcripts here, but it was almost
verbatim that it was suggested that all negatives be confirmed.

And again that was my response, was that that is physically and
logistically impossible to confirm all negative results.

DR. LEWIS: I thought you were referring to my comment.

MR. AROMANDO: What was the intent of the document.

DR. GUTMAN: The intent of the document was to look only at positives.

MR. AROMANDO: We are in agreement with that. And before I just give this
to Dave, there was just one other last comment, and there was another
comment made earlier that wet chemistry DATs are more accurate than
on-site drug review tests.

So, first, I\'m curious to know how many studies are we drawing our
conclusion from, and in what peer review publications have these studies
been reviewed.

And secondly there are currently several dozen studies, including one
that was commissioned by SAMHSA that have beyond a doubt established a
level of performance of these on-site drug tests comparable to lab-based
wet chemistry drug tests.

In another study conducted by the Administrator of the U.S. Court, about
3 or 4 years ago, in fact the lab test for the amphetamines used in the
study showed a 27 percent false positive rate, versus a zero percent
false positive rate for some of the on-site amphetamine tests.

DR. KROLL: Thank you. Can we keep our comments down to about 3 minutes.

MR. EVANS: I promise not to talk about legal issues. I flunked chemistry
in high school, and that is the reason that I did not become a doctor. I
come from a long line of doctors, but I learned enough to know about the
scientific method.

And you are about to make a decision that is going to affect thousands
of businesses and a lot of people, and I am asking you to slow the
process down a little bit, and just ask if you have gotten the evidence
that you all need.

I would urge you to have more hearings, and get more evidence, talk to
the users of the on-site tests, especially DOT people that have been
using them for years. I urge you to talk to the people from the United
States Postal Service that are doing hundreds-of-thousands of these
tests.

That may alter some of your decisions. Again, look at the evidence and
see what is really going on. Talk to people from all different
categories \-- industry, workplace, insurance, sports, and schools.

We went through this process with SAMHSA over the last 2 or 3 years, and
they kept an open mind. Many of the members of the drug testing advisor
board had a mindset against on-site testing when we started.

I think we worked out something that is acceptable to us and acceptable
to them, and that guarantees a good reliable test that will be used in a
good reliable way. I would ask you to look at their studies and hear
some of the same evidence that they heard before you make up your mind.

I am a little concerned that you are rushing to judgment. This guidance
could come out within about 90 days and you may be making a mistake. I
am a former bureaucrat, and I once exceeded my authority, and I got
slapped by a court, and I never forgot it, and they were absolutely
right. I had done the wrong thing.

I had not looked at the evidence when I made a decision as a bureaucrat.
It is embarrassing and it made the front page of the legal newspaper in
New Jersey with my photograph on it. So I am acutely sensitive to this,
and I learned a great lesson from it.

And I would urge you to look at the consumer protections that are
already built in. I don\'t think you have gotten enough evidence about
that. I don\'t think you have gotten enough evidence about the intent of
Congress.

Congress recently passed a law probating \$10 million for drug free
workplace programs, and a Congressional committee specifically said they
wanted on-site testing included in that.

So I would ask you to keep an open mind, and walk through the process
with us like SAMHSA did, and I really think they came up with something
that is really going to protect everybody. Thanks.

MS. HOGAN: I promise to be very brief.

DR. KROLL: Could you state your name, please.

MS. HOGAN: Absolutely. My name is Lorraine Hogan, and I am a California
licensed clinical toxicologist scientist. I have a seven year history in
working in the SAMHSA laboratory. I am not a product manager.

Historically, I worked for Phamatech, which was the first
over-the-counter cleared drug test. I have moved on to another in-vitro
diagnostic manufacturer, but I probably have more direct experience
talking to the end-user from these products than anybody, because I
wrote the training manual for the support representatives that handle
the toll-free number for Pharmatech.

I can tell you that my recommendation would be that we look at the
package insert and maybe back up a little bit and explain why
confirmation tests are needed. I think that the principle of immunoassay
is something that escapes most consumers and lay people.

If you couch it in the manner that they understand why chemically
similar compounds will react and that it is not necessarily \-- it is a
limitation of the assay, but it does not make the assay a bad assay.

I think that right now that things are couched in a manner that people
think that the test is not good. I know originally the term inconclusive
was used for a presumptive positive result.

Also, I think that it is important that toll free numbers in any
over-the-counter product, particularly medical devices, are built and
that they are administrated well in consumer feedback, particularly on a
high stress level product like this, is extremely \-- there are a lot of
people that call and ask questions that are clearly stated in the
package inserts, but that they just did not seem to understand.

And, Dr. Lewis, I can assure you that with Phamatech\'s product, the
fact that the confirmation cost is built into it, there are numerous
people that send their negative results in because they want that extra
feeling of comfort.

So people do send negative results in. We have to explain to them why
the intensity of the line was light, for example, and this is built into
the assay.

We have to explain why light intensity was light, and sometimes it gets
into a technical dissertation about cross-reactivities. But I think that
confirmation is relevant.

I think it is relevant to have a mechanism built in for confirmation
testing to be done, but not necessarily to include the cost of it. I
don\'t think people truly understand the two step process of a drug test
when you get to a consumer individual.

DR. KROLL: Thank you very much. Dr. Gutman, are there any other issues
that we should address? Well, I think maybe you could submit those in
writing.

DR. KANG: I forgot to mention one comment about Dr. Gutman discussed;
including more information about the product. My suggestion is pregnancy
and ovulation tests on the market as an over-the-counter product, and
our company has that product on the market. Clinical guidelines do not
require performance data in OTC product packaging, sir, and that has
worked quite well.

And from my experience, even if we give more information, there will
always be a lot of questions, and we have an 800 number for customers.
We receive a lot of telephone calls about the implications, and it seems
to be working fine.

But adding more information, more confirmation, more customer data in
the packaging insert, is not necessarily helpful, and would probably
have to be made very, very small because of the limited space in the
packaging.

DR. KROLL: All right. Thank you for your comments. Dr. Gutman, do you
have any questions or comments that you would like to make?

DR. GUTMAN: No, I would like to thank you all for bearing with us, and
giving us this input.

DR. KROLL: All right. Are there any other comments from the panel
members?

DR. KURT: Tom Kurt. I would like to comment that outside of the realm of
the DOT, some people used the word confirmation in a more broader
context, and tried to confirm by FPIA and other methods, which are
really not state-of-the-art confirmations.

So I would like to point out how confirmation is really defined in your
documents and labeling.

DR. KROLL: Well, thank you very much. I would like to thank all the
panel members for all their efforts today and thoughtful comments. And I
would also like to thank all the staff members and especially Veronica
Calvin, our executive secretary, who has been writing here like crazy,
and all the other people involved with the FDA staff, Dr. Gutman, and
everyone else. Thank you.

DR. ROSENBLOOM: I would like to request a change in the seating
arrangement tomorrow.

MS. CALVIN: I have just a couple of comments to make before we leave. I
just want to echo my thanks, and as Dr. Kroll indicated, to all the
panel, FDA staff in particular, and the public speakers.

And if anyone was shy or has additional comments, as I think Mr. Evans
alluded to, the comment period is open for 90 days after the notice of
announcement in the Federal Register, which was around the beginning of
November. So I guess that brings you to probably late January or early
February.

Also, if you found today\'s discussion to be very interesting, we invite
you back tomorrow. The panel will be discussing a device application
that detects drugs-of-abuse in hair. Thank you.

(Whereupon, the panel adjourned at 4:40 p.m.)