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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TUESDAY,

NOVEMBER 14, 2000

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The Panel met at 9:00 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:

ALBERT PEACOCK, PH.D., Scientific

Reviewer Clinical Chemistry and Clinical Toxicology Branch

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:

DAVID BRILL, M.D., M.A., M.P.H

ROBERT DUPONT, M.D. (MRO),

DUPONT ASSOCIATES, P.A.

THOMAS CAIRNS, PH.D., D.SC., Senior

Scientist, Psychemedics

CARL SELAVKA, PH.D., Director,

Massachusetts State Crime Lab

RICHARD NEWEL, M.A., Professor of

Statistics, Research, Methodology and

Forensics, University of South Florida

WILLIAM THISTLE, ESQ., Vice President

of General Counsel, Psychemedics

I-N-D-E-X

[AGENDA]{.underline} [PAGE]{.underline}

Call to Order 26

Opening Remarks, Introductions, Conflict of 26

Interest Statement

Open Public Hearing

David Brill, M.D., M.A., M.P.H. 31

Robert DuPont, M.D. (MRO),

DuPont Associates, P.A.

Sponsor Presentation

Thomas Cairns, Ph.D., D.Sc., Senior 68

Scientist, Psychemedics

Carl Selavka, Ph.D., Director, 103

Massachusetts State Crime Lab

Richard Newel, M.A., Professor of 53

Statistics, Research, Methodology and

Forensics, University of South Florida

William Thistle, Esq., Vice President 159

of General Counsel, Psychemedics

FDA Presentation

Albert Peacock, Ph.D., Scientific 178

Reviewer Clinical Chemistry and Clinical Toxicology Branch, Division of
Clinical Laboratory Devices

Open Committee Discussion 130

Open Public Hearing 242

Closing Remarks 254

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

9:12 a.m.

DR. KROLL: I am Martin Kroll, and I am a Chairperson for this session.
I\'d like to call the meeting to order.

And first we have some opening remarks from our Executive Secretary,
Veronica Calvin.

MS. CALVIN: Good morning and welcome to this meeting. Today the
Committee will discuss and make recommendations on a pre-market
notification 510K for a first of a kind prescription use screening
device in human hair.

When yesterday the Committee discussed prescription use and OTC use
guidance documents for drugs of abuse, and information where you can
obtain transcripts or summaries from the meeting is on a salmon colored
sheet outside on the table, and that also goes for today.

Also, we had indicated persons may submit comments in writing. And where
you can send that is on a green sheet outside on the table.

At this time, I would like to ask the panel members to introduce
themselves starting with Dr. Lasky.

DR. LASKY: Fred Lasky, Director of Regulatory Affairs, Ortho Clinical
Diagnostics. I\'m the Industry Representative.

DR. REYNOLDS: Stanley Reynolds, Supervisor at the Immunology and
Virology Pennsylvania Public Health Laboratory. I\'m the Consumer
Representative.

DR. EVERETT: James Everett. I\'m the Director at Madison Memorial Health
Care and member of the panel.

DR. WILKINS: Diana Wilkins, Assistant Director of the Center for Human
Toxicology and Research Associate Professor of Pharmacology and
Toxicology at the University of Utah.

DR. KURT: Tom Kurt, Medical Toxicologist and MRO, who is a founder at
the Certified North Texas Poison Center at Parker Memorial Hospital in
Dallas, and a Clinical Professor of Internal Medicine at that
Institution.

DR. KROLL: Martin Kroll. I am the Director of Clinical Chemistry at the
Dallas VA Medical Center, and I\'m an Associate Professor of Pathology
at the University of Texas Southwestern Medical Center in Dallas.

DR. MANNO: I\'m Barbara Manno. I\'m a Professor of Psychiatry at the
Louisiana State University Health Sciences Center in Shreveport,
Louisiana.

DR. LEWIS: I\'m Sherwood Louis, Director of Toxicology at the Office of
the Chief Medical Examiner in the state of Connecticut, and faculty
member in the Department of Laboratory Medicine at the University of
Connecticut Health Center, consultant to the Committee.

DR. CLEMENT: Steve Clement, Associate Professor in Washington, D.C. at
Georgetown University and practicing Endocrinologist.

DR. ROSENBLOOM: Arlan Rosenbloom, Distinguished Service Professor of
Emeritus at the University of Florida of Pediatrics, and Director of
Children\'s Medical Services in Gainesville. I\'m a regular voting
member of the panel.

DR. GUTMAN: I\'m Steve Gutman. I\'m Director of the Division.

MS. CALVIN: I will now read the conflict of interest statement. The
following announcement addresses conflict of interest issues associated
with this meeting and is made part of the record to preclude even an
appearance of an impropriety.

To determine if any conflict 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 interest.

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 interest of the
government. We would like to note for the record that the Agency took
into consideration certain matters regarding Drs. Martin Kroll, Arlan
Rosenbloom, and Diana Wilkins.

Drs. Kroll and Rosenbloom reported unrelated interests with firms at
issue. Since the interests are unrelated to the issue before the panel,
the Agency has determined that they may participate fully in today\'s
deliberations.

Dr. Wilkins reported an imputed interest with a firm at issue. Since the
interest is imputed through her employer, and is not her personal direct
interest, the Agency has determined that she 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 excuse him or herself from such
involvement, and exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firm whose
products they may wish to comment upon.

Thank you, and I\'ll turn the meeting back over to Dr. Kroll.

DR. KROLL: All right. Thank you.

At this part of the meeting, we have our open public hearing. And as you
can see in the agenda, public attendees who have contacted the Executive
Secretary prior to the meeting, will address the panel and for that
information relevant to the agenda.

I\'m urging the speakers to state their name, where they\'re from, and
whether or not they have any financial involvement with the manufacturer
of the product being discussed, or with their competitors.

The first speaker we have on the agenda is David Brill.

DR. BRILL: Good morning. I\'m Dr. David Brill. I\'m Boarded in Internal
Medicine and Occupational and Environmental Medicine. Until June, I was
the Corporate Medical Director at Michelin of North America. That\'s the
tire company without the recall.

And I was also a representative on the hair testing work group for Donna
Bush, who I see isn\'t here today, which was evaluating hair drug
testing for the Drug Testing Advisory Board, SAMSHA. I represent an
industry interest in that group.

I have a conflict of interest. I do have shares of diagnostic laboratory
companies. I do not have any interest whatsoever in the laboratory here
today.

What I want to tell you today is that hair is critical \-- absolutely
critical component of the employer\'s tool box. And I\'ll share a couple
of anecdotes as to why.

So that you understand, hair testing for drugs tests long term use. When
you clip a hair from the head, an inch an a half tests about three
months worth of drug use. It cannot test acute use. It takes time for
the blood, or any involvement of drug with hair, to come into the hair.

It simply cannot test for acuteness. It can only test for chronic use.
Obviously, it can also not test for immediate impairment. Again, because
it takes days to move from the blood to the hair.

However, for employers who want to use effective tools in the workplace,
hair is critical because of its effectiveness and especially its
transparence. And what do I mean by transparence? You\'ll see in a few
minutes.

My past to this position right here in front of you today began shortly
after I began at my former employer. We used urine testing, and I\'ve
been taught that you don\'t use hair testing in MRO training because
it\'s a new technology which is not method tests and so on.

Shortly after I came, we had a 26 year old young man who passed his
screening urine test. He was a contractor. Again, he passed his
scheduled screening urine test. He passed his scheduled screening urine
test, and then two days later, died on the floor of a cocaine overdose
in the plant.

I repeated that three times. After we put in hair testing for new hires,
after investigating it thoroughly, both on scientific, legal, and other
basis. After we put in hair testing, suddenly our positive rates with no
other changes in the program tripled the same number of times that I
just repeated that statement.

Every time that we were doing the urine test, two other \-- and finding
one positive \-- two other people who were using drugs were entering the
company routinely.

Two years after that, we had implemented a random hair testing program
where we had the CEO of the company giving the first sample with a video
tape of that event distributed to all employees, and required to be
viewed by all employees so that they could see that everybody was in
this together.

And it starts with the top, with the CEO actually giving the sample with
one of my nurses taking the collection. Try that with urine. In fact, at
the time in Oklahoma, we had a plant where we couldn\'t use drug
testing.

The Oklahoma Board of Health has now changed that. We can use hair
testing in Oklahoma. But at the time, we had to put in a urine random
testing program. And there the plant manager, when coming to the same
moment, had to discreetly turn around and walk away toward the lab where
he would give his urine collection.

But you get the point. Hair testing doesn\'t involve genitals. It also
can\'t be adulterated. It also can\'t be substituted because it\'s a
witness collection.

In urine testing, the person is alone with the sample 95 percent of the
time. And of course, you know what wonderful creative things are on the
Internet. Many of you may or may not, but for instance, 30 miles away
from where our headquarters were, there was a creative young gentleman
who was marketing his own urine on the internet.

And further, he had developed a device which would strap the urine to
the leg, warm it to body temperature so that it could pass SAMHSA
temperature requirements. And then move along the genitals, so that even
if it were a witness collection, you couldn\'t see the tube.

I was asked to comment on this. And frankly, I said it\'s essentially
irrelevant to us because we\'ve used a hair testing program.

Now, let me help you understand workplace drug testing if you\'re not
familiar with it already.

There are essentially two critters here. Scheduled tests and unscheduled
tests.

The unscheduled tests tend to be reactive. That\'s if there\'s an
accident in the workplace and you have a trigger for a drug test after
that accident. That\'s catching \-- or perhaps catching something after
the damage has been done.

And 40 percent of the time, that\'s involving harm to someone not using
the drugs. It\'s not the person who\'s driving the forklift who gets
hurt.

Reasonable suspicion testing is another one. If someone is tottering in
the plant, and you have a drug test, that\'s a reactive.

Now, the scheduled tests are proactive, or can be viewed as proactive.
That would be an applicant drug test, and let me again repeat, as an
applicant drug test, that\'s not a new hire drug test.

Because Congress expressed its will very clearly in the Americans With
Disabilities Act saying that a drug test is not a medical test. In fact,
they went so far as to say that it can be done before an offer is made.
Whereas, every medical test has to be done after the offer is made to
the applicant.

So you say applicant drug testing, not new hire drug testing, because
you can do the drug testing before as per the will of Congress.

The second scheduled type of test is random or periodic testing where an
employer either periodically says, \"We\'ll test at such and such a
time,\" or, \"We will have random testing.\"

Let me describe to you what the difference is for an employer between
random urine testing and random hair testing. I ran five random urine
testing programs under the DOT airline \-- you know, aircraft pilots \--
everybody who puts a tire or who makes a tire for an airplane is
covered. Anyone who puts a tire on a bus is covered, and so on.

If I\'m an employer, or if I\'m the Medical Director of the company, and
I\'m running a random urine testing program, I am immediately going to
be a secret son of a gun. I\'m playing the keystone cops, because I have
to keep that darn list secret.

Because if anybody knows that they are going to be either giving a
random urine test, they can tip the person off. Or, if they\'re going to
be receiving the random urine test, obviously they have a thousand and
one ways to adulterate and substitute and so on.

So, we have to be secret, which is a pain. You don\'t want to be secret
with your employees and your staff. So, the list has to be really,
really secret.

Second, everything has to be incredibly abrupt. Once it goes down to the
nurse that there is going to be a urine test, they have to go out on the
floor, grab the person off the floor.

Usually there\'s two people off the floor. The person whose coming off
of the job, and another person to accompany them back to the laboratory
and make sure they don\'t stop at their locker, don\'t stop at the
drinking fountain, da da da da da.

So, you have two people off the floor and the Supervisor, who is a
little PO\'d that he suddenly lost somebody and he has to scramble to
get somebody to get on that machine. It\'s very abrupt. It\'s really not
fun. A lot of workplace disruption.

So, you\'ve got these two people off the floor. They come back. You have
to have it in a place with a laboratory because genitals are involved.
You have to have security in the laboratory as witnessed every time,
except for the moment when the person is alone with the sample, of
course.

And then the sample is put in a Fed Ex box or whatever \-- three samples
typically, and you send the biohazards through the mail. If it happens
to be the CEO on the other hand, if you want to have a fair program, and
the CEO is just about to fly off to General Motors to clinch that
contract and his number or her number comes up, you have to say, \"I\'m
sorry. You really can\'t fly on that plane right now. You really in all
fairness to all the other employees, you have to give the sample now
just like anybody else. Oh, you just peed? Well, here\'s eight ounces.
Drink this and we\'ll wait. We\'ll just keep the pilots waiting.\"

That\'s urine testing in a random person. That\'s the reality. Now, look
ahead. I don\'t have to keep it a secret. If anybody gets that list,
three weeks in advance, I don\'t care. We just took the list, put it on
an Excel spreadsheet, send it out, anybody can know who\'s on that list
a couple weeks in advance.

In fact, there\'s some preferences to do that because then they can
schedule their vacations or whatever else is going on. If somebody comes
back, the Supervisors have no trouble with people off the floor.

They schedule it in advance. You don\'t need two people off the floor at
any time. You don\'t need a laboratory. You don\'t send biohazards
through the mail.

And if somebody says, \"Oh, I\'m on vacation that day.\" Or the CEO is
heading off to Detroit, just say, \"Sure. Schedule it to come back at
your convenience any time in the next couple of weeks.\" No big deal.

You can\'t substitute the sample. You can\'t adulterate the sample, and
it\'s a long window of testing. So, it\'s wonderfully transparent. It\'s
beautiful for an employer, because you can be really up front with
employees.

That\'s what I wanted to tell you. Along with short window tests, which
are wonderful. For instance, saliva, urine, breath for unscheduled
tests, reactive tests. Hair is great for scheduled tests.

In fact, if you do have a scheduled test, everybody knows how to beat it
with urine. If you\'re going to have a scheduled test, really employers
have very little choice but to use something like hair.

In fact, hair is the only choice available. The long range winners in
the new media will probably be hair, saliva, followed by urine \-- or
breath, urine, and blood. Each one with a descending level of ability to
substitute the sample or difficulty in attaining the sample.

So, what I wanted to tell you today is that hair is a critical component
of an employer\'s tool box. Again, it has wonderful uses. It\'s
effective as opposed to the others. And it\'s transparent. It lets you
be a human being with your employees.

Thank you very much.

DR. KROLL: Thank you.

The next speaker is Dr. Robert Dupont.

DR. DUPONT: Thank you, Mr. Chairman. I apologize for the voice. I got
all prepared except for one problem for this, and that was I got
laryngitis last night, so I apologize for any difficulty you have
hearing. And please put up a hand and I will say it again. It\'s
distressing but not painful, so I\'m happy to mostly to listen.

Let me say about the conflict of interest issue that came up that I do
own stock in the Psychemedics Company and many other companies, and I
also serve as the Scientific Chairman of the Scientific Advisory Board
for the Psychemedics Company.

I have been a strong advocate for drug testing in general, including
hair testing. And I\'m also active in supporting all the other companies
that promote or develop hair testing. And I don\'t think of myself as an
employee or an advocate particularly for Psychemedics, but for drug
testing generally. And not even just hair testing.

Now, my background \-- I began in this field more than 30 years ago
working for the District of Columbia government, and drug testing was
central to what we did. We did a study in D.C. jail using urine testing
that identified heroin use as a major factor in the crime problem in the
District at that time.

That was published in the New England Journal of Medicine, and was one
of the central pieces of evidence in the identification of the heroin
epidemic in the early 1970\'s and the late 1960\'s in this country.

And I have been active in the drug testing field generally since that
time. I was the first Director of the National Institute on Drug Abuse,
the second White House drug czar, then called the Special Action Office
for Drug Abuse Prevention.

And since 1982, I\'ve been Vice President of Benzinger Dupont and
Associates, a national consulting firm advising workplace programs
dealing with drug and alcohol abuse. And in that role, I\'ve been a
Medical Review Officer, and have been active as a Medical Review Officer
not only supervising other physicians, but also doing medical reviews
myself.

And I speak primarily as a Medical Review Officer to you today. I came
to the Psychemedics Company into hair testing from working in my own
practice with my own patients who were addicted. And to send off samples
of their hair to be tested when I knew what their drug use was,
including sending samples of people who I knew were not users.

And I was impressed by the fact that the hair testing got the
information right. As Dr. Brill said, the phenomena of a long
surveillance window of 90 days as opposed to three days \-- one to three
days for urine testing \-- was very attractive from a clinical point of
view in my work.

But also the resistance to cheating. I want to emphasize that that also
is a very important factor. And it was on the basis of that personal
experience as a physician with my patients that I contacted the
Psychemedics Company and asked them what I could do to help encourage
wider use of hair testing in this country.

Now, I wanted to say two things by way of background with respect to the
opiate testing, which is our subject today.

First of all, drug testing is extremely important to demand reduction in
this country. It is absolutely central to the national effort to reduce
the demand for drugs. This is the most important part because a central
element of the drug experience is dishonesty \-- is lying about it.

And the .8 million current illegal drug users in the country are
spending 63 billion dollars a year on drugs. And the central technique
for being able to reduce that demand is drug testing linked to
consequences in all areas of our life including workplace, which is what
we\'re talking about primarily today. But the criminal justice system is
another very important area.

The second point of background that is going to come up in a moment that
may not be obvious is that heroin is a relatively new product. It was
introduced in 1898 by the Bayer Company, by the simple manipulation of
adding two acetyl groups to morphine.

And the addition of those acetyl groups was very important in terms of
what we\'re going to talk about in terms of the identification of heroin
use through hair testing because of the identification of 6-MAM in that.

That was introduced by the Bayer Company at the same time they added one
acetyl group to salicylic acid to create aspirin. And that\'s why the
two names heroin and aspirin are so similar. Because they were
introduced at the same time by the Bayer Company.

With respect to the opiate testing, as an MRO, the practical matter is
\-- and practical reality is that all opiate positive are reversed on
MRO review of the opiate positive. The only exceptions are if a heroin
user admits use freely. I have never had that happen as an MRO.

And the other possibility is that you identify 6-MAM in the urine
result. I have rarely seen that happen. Almost all opiate testing using
urine is reversed by the Medical Review Officer which means urine
testing is almost completely ineffective at identifying heroin use in
workplace drug testing.

That\'s very important to understand that that is the reality that is
faced today by anyone who\'s using urine testing to identify heroin in
workplace or other testing.

And that is because of the poppy seed problem. Poppy seeds contain
morphine. And they will trigger a positive test on a urine test. And
because of the way the testing is done, if there is any possibility that
the testing could be innocent, even if the person does not claim to have
eaten poppy seeds in the prior three days, the MRO is duty bound to
declare that test a negative test.

Now, hair testing is very different in two regards with respect to this
problem with the poppy seeds. First of all, poppy seeds do not produce a
positive hair test even when large amounts of poppy seeds are consumed.
They do not produce a positive test at the cut off levels that are
traditionally used.

And sencon, 6-MAM rather than being rarely identified, is routinely
identified on hair testing. That means that hair testing can identify
heroin use very efficiently. And urine testing cannot identify. That is
very important in terms of this particular application of this
technology.

Now, I want to mention three areas of \-- let me call it concern about
hair testing. The first has to do with the concern about external
contamination as an explanation for a positive result. And in thinking
about this, I call your attention to the fact that heroin is not a
common contaminant in the environment. It is not easy to get heroin on
your hair or anywhere else. So, that\'s probably the most important
point.

Second of all, should one get heroin on his or her hair, the wash
techniques that are used by Psychemedics of a minimum of three hours and
45 minutes of wash are sufficient to exclude external contamination as a
source of a positive test.

I think that that\'s very important about the external contamination \--
that the wash is very important to exclude that rare possibility. An
example being a police officer working in a narcotics unit where heroin
is an environmental contamination. That is important as a protection.
So, the external contamination issue is dealt with by the washing.

The second issue has to do with bias with respect to hair color. This is
very important that you understand this. First of all, there is no
possibility of a person who does not use having a positive test as a
result of hair color, or race, or any other factor.

So, non-use is zero for everyone. The only argument exists about if a
person has used the drug heroin, is the concentration in the hair the
same or different depending on the hair color. So, this only relates to
people who have used heroin. And I want to emphasize that point.

Now, with respect to the question of whether there is a \"bias\" based
on hair color, I call your attention to other drug testing, which is
very extensive including the most striking example to me, is alcohol
testing.

In alcohol testing, we make no effort to level the playing field in the
sense that each alcohol drinker can drink the same amount to get the
same blood level. We know that gender is a major factor in the
relationship between blood level of alcohol and alcohol consumption.

But we also know that weight is a major factor. And there are dozens of
other factors. And there is no attempt to normalize or equal the amount
of alcohol consumed in terms of declaring a positive test.

The same thing is true with urine testing. The biggest determinant of
whether a person is going to reach that cut off, or at a close call
which is only what we\'re talking about by the way for hair either \--
at a close call, near the cut off level, is how much fluid the person
has consumed.

We don\'t make any attempt at urine testing to normalize for fluid
consumption. The cut off is the cut off regardless of how much you\'ve
consumed. And the other determinant for urine testing is how many hours
it\'s been since you\'ve used.

We don\'t make any attempt to try to normalize that, to say a person who
has used six hours ago is going to be judged equal for someone who used
one hour ago. None of that is done as we use a per se standard for both
urine testing for all drugs, and for breath testing and blood testing
for alcohol.

No attempt is made to level that playing field based on the amount that
the person has consumed. And that\'s very important because I think this
whole argument is without precedent in the drug field, and throws a
curve ball into the equation that is very harmful to the process, and
bears no relationship to some sense of equity.

Now, in addition to that, the \-- and you will hear more about this \--
the tests that have been done looking at hair tests around the question
of racial bias that is now among the people who have used the drugs, is
there a difference in positive rates between urine self report and hair
have shown that there is not.

Whatever the laboratories studies show, this is the result of a real
world study. And it shows no difference in the ratio between hair, and
urine, and self report. That\'s very important data to take into
consideration about this.

Now, my third concern has to do with cheating. And that is \-- I think
those of you who are not expert in the drug testing area \-- Dr. Brill
did a wonderful job of explaining the fact that most drug testing in the
workplace is pre-employment testing, as he called it applicant testing.

That is a scheduled test. That is more a test of intelligence than it is
a test of drug use. The window for a urine test is one to three days.
That\'s very important.

That means that the major testing that is done in the workplace is
ineffective in a scheduled test with a one to three day window. All the
user has to do is not use for one to three days, and the test is
negative.

It is also very easy on a scheduled test to consume extra fluids. Never
mind the complicated kinds of problems as he was talking about a sample
substitution. The problem of cheating in urine testing is an enormous
problem.

And it is particularly a problem for the most serious drug users. The
ones who are most important to identify are least identified by urine
testing because of the ease of cheating on the test.

Hair testing cannot be cheated on as you heard. There is no possibility
of sample substitution. No issue of additional hydration, for example,
or using an adulterant. These are not relevant matters. This is
extremely important in terms of the integrity of the test and the
effectiveness of the test in being able to identify drug use.

Now, for these reasons, I believe that hair testing deserves a place
along with urine testing and other testing. Because I think saliva
testing is particularly important in an application like highway
testing, which as you may or may not know, there is no testing now for
drugs in the highway which is a terrible national problem right now. And
saliva is the obvious means of doing that.

But hair testing does belong in there with urine testing. And of the
hair testing, the opiate test is particularly important for the
identification of use. In fact, I think that one of the things that
would be a very practical thing for somebody who has a positive opiate
urine test where there is any concern whatsoever, is to require a hair
test.

Because as Dr. Brill said, you\'ve got 90 days. And the fact that you
get a positive urine test makes it fairly easy because you can\'t
substitute anything. You\'ve got 90 days to look at it.

So, I think hair testing does add substantially to the ability to detect
drug use. And it should be approved in the national interest to be able
to reduce the demand for drugs. And it is in that spirit that I address
you.

Thank you very much.

DR. KROLL: Thank you.

Now we proceed to the sponsor presentation from Psychemedics
Corporation. The first speaker is Dr. Thomas Cairns.

MR. THISTLE: Actually, the first speaker will be me. I\'m Bill Thistle.
I\'m Vice President and General Counsel for Psychemedics.

And before we start the presentation, I\'d actually like to go through
and introduce the people that we have that will not necessarily be
presenting. You should have a list of presenters there. But we brought
people who are available to answer questions, and I\'ll just go over
them briefly so you know who is here.

And the people here, just acknowledge who you are. We\'ll get that out
of the way first.

We have Werner Baumgartner, who is a Scientific Director of Psychemedics
Corporation. He is a founder of Psychemedics and a pioneered hair
analysis for illicit drugs over 20 years ago. Additionally, along with
working with Psychemedics, he has served until recently for the last 24
years as Director of the Clinical Radioimmunoassay lab in Los Angeles
for the VA Medical Center.

We have Thomas Cairns, Senior Scientist at Psychemedics, an adjunct
Professor at Pharmaceutical Sciences at USC. He served 20 years with the
FDA. Part of that time was as Director of the FDA National Center for
Toxicological Research. He continues to be a Senior Science Advisor to
the FDA, and he was at one point the recipient of the FDA Office of
Regulatory Affairs Regulatory Scientist of the Year Award.

We have Michael Schaffer, Vice President of Lab Operations at
Psychemedics. He\'s a licensed NIDA Inspector. He was formerly Director
of Toxicology at the Smith Klein Lab, and formerly Chief Toxicologist
for the Office of the Medical Examiner in Cook County, Illinois, where
he made the determination several years ago that the Tylenol scare we
had of tampering occurred post manufacturer.

We have John Irving, Deputy Director of Laboratory Operations at
Psychemedics. Again, a licensed NIDA Inspector. John Irving was a member
of the first drug testing Advisory Board for NIDA, now SAMHSA. He
participated in drafting the initial federal drug testing guidelines and
he was formerly Director of several Navy drug testing laboratories.

We have Virginia Hill, a Research Scientist with Psychemedics
Corporation who worked directly with Werner Baumgartner on hair analysis
at the VA Medical Center.

We have Carl Selavka, who\'s not with Psychemedics, but is Director of
Massachusetts State Crime Lab. He is co-chair of a hair testing working
group created by the drug testing Advisory Board to advise SAMHSA on
inclusion of hair testing. He has published one of the seminal studies
on poppy seed ingestion and the issues that that creates, and to serve
as a consultant in that regard to HHS.

He was formerly Director of Forensic Services for New York\'s 25 public
forensic science labs. Formerly Operations Officer for the U.S. Army
Toxicology Drug Testing Lab in Hawaii. And has testifies as an expert
witness in over a dozen military cases involving hair analysis.

We also have Richard Newel. He\'s a Professor of Statistics Research and
Methodology in Forensics at the University of South Florida. Along with
Dr. Mieczkowski, Mr. Newel has amassed one of the largest databases of
its kind regarding race, drug testing, and drug prevalence.

We have Jonathan Ma, Manager of Biostatistics at Engine X Pharmaceutical
Sciences, formerly a Mathematical Statistician with the FDA.

And myself, I\'m General Counsel with Psychemedics.

We \-- is there technical difficulties with this? Is that why it keeps
flipping?

As we approached this, we found it difficult to condense two decades of
research and over a decade of use into a one hour presentation. We tend
to provide a background on hair analysis as done by Psychemedics, and
then get into the submission specifics.

And already we\'re out of sequence here. But our Corporation \-- is that
legible at all?

Our Corporation was founded in 1987 to analyze specifically drugs of
abuse in hair following years of research by Dr. Baumgartner. We test
for the NIDA five drugs, opiates, cocaine, methamphetamine, including
MDMA, ecstacy, which should be part of the covered guidelines in the
future, just for marijuana and PCP.

We are licensed as a \-- you should have this incidentally in front of
you, so follow along as we go through this. The audience can pretend
they\'re watching this.

I think it would work better if we could get somebody clicking up there.
Is there a problem with the length of the cable? Why don\'t we do that?
Why don\'t we have someone clicking up there. We\'re going to take a
couple minute break and just set it up.

(Whereupon, the foregoing matter went off

the record at 10:52 a.m. and went back on

the record at 10:56 a.m.)

MR. THISTLE: We are a licensed high complexity clinical lab under
federal CLIA standards. We are CAP certified with the limited urine
testing that we do. We are licensed and certified by numerous states,
including states that have specific criteria for hair analysis labs,
Florida, Maryland, New York, Oklahoma.

We have three U.S. patents on aspects of the methodology unique to
Psychemedics. We have European, Japanese, and Canadian patents as well.
And we have over 1,800 corporate accounts from a wide variety and cross
section of U.S. businesses.

And by corporate accounts, I\'m not talking about doing one or two
tests. For instance, for General Motors, we do all their pre-employment
at a 104 North American plants, all the North American operations.

We do Anheuser Busch, testing for Anheuser Busch, FIC, Rubbermaid,
Toyota, BMW, Michelin, Goodyear, Whirlpool, Gillette, Steelcase, U.S.
Steel, Federal Reserve Banks. In addition to the major corporations, we
also \-- I know you thought it was going to be all 1,800, but in
addition to those major corporations, we\'re also utilized by law
enforcement agencies, including some of the nation\'s largest, NYPD,
Chicago PD, Boston PD.

We\'re used in prisons in several states. We\'re utilized by court
systems in diversionary and first offender and probationary programs.
These are programs designed to keep people out of jail through hair
testing.

We\'re utilized by state use and family service agencies, in child
custody issues, chemically abused children. We\'re utilized by schools.
We have over 100 schools in 26 states utilizing hair testing.

We\'ve been upheld in federal courts. This is a June 2000 decision. The
court agreed there was no scientific support for the claim that the
plaintiff could have tested positive due to her race.

Over ten years ago, we were upheld in federal court where the court
recognized that RA hair testing \-- they\'re recognized through
liability and acceptance in the field of forensic toxicology when used
to determine cocaine use.

We\'ve been upheld in state courts. We have a number of police officer
cases where there\'s a tremendous impact on society. These are people
involved in drugs and protecting the public.

We\'ve been upheld in state appellate courts, where the courts have
found that the radioimmunoassay analysis of human hair to determine
cocaine use is generally accepted in the scientific community.

We\'ve been upheld by state supreme courts. This Nevada case concluded
that hair testing, especially when coupled with a confirmatory GC/MS
test was an acceptable and reliable scientific methodology for detecting
illicit drug use.

We\'ve been upheld by administrative agencies, unemployment boards,
unemployment appellate boards. We\'ve been upheld in union arbitration
decisions, including Teamsters, United Steel Workers, Operating
Engineers, fairly tough unions.

Every issue that can be brought regarding a hair test has been brought
and is brought, and we get decisions similar to this where they find
Psychemedics\' wash procedures are effective in removing environmental
contamination.

The cut off level for cocaine is appropriate in the field studies. There
was no bias here on the basis of race or hair color. The chain of
custody was unbroken.

Many of these companies use hair analysis because of the advantages. The
hair analysis \-- and you\'ve heard some of them earlier today. There\'s
a wider window of detection.

Approximately three months for morphine, and six for acetylmorphine in
hair. Urine is 24 to 72 hours for morphine, several hours for 6
acetylmorphine. Six acetylmorphine, or other clinical evidence of use is
necessary to confirm heroin use.

We have significantly increased detection rates, because you\'re looking
at several hours. You\'re comparing several hours to several months. In
real life, the purpose of testing is for a third party to determine the
likelihood of future use based on approximate past behavior.

It\'s certainly more effective and safer to the general public to make
that decision based on a long period of time as opposed to a shorter
period of time.

There are many reasons to use tests with a shorter period of time, but
certainly in pre-employment, there\'s a reason to use a test with a
longer period of time. Many of our clients have done side by side hair
and urine tests, and have found tremendous differences in the detection
rates.

We are also a less intrusive collection. It\'s a small snip of hair, the
thickness of a shoelace tip. People regularly will get their hair cut in
public, at least with a barber present. Sometimes in front of a plate
glass window at the mall. It is not likely you\'ll find people urinating
in front of the plate glass windows at the mall.

In fact, the U.S. Supreme Court has long held that the collection of
urine was a search, and found that there are few activities in our
society more personal or private than the passing of urine.

In contrast, again the U.S. Circuit Court of Appeals Federal Court,
concluded that the collection of hair in 1982 was akin to obtaining
fingerprints and did not rise to the level of a search. We are also, as
mentioned earlier, an observed collection.

One of the biggest threats to urine testing is adulteration and
substitution. That can\'t be done at the collection site. And these are
just two companies off of hundreds that we\'ve pulled off the internet.

The one on the left is the gentleman that provides the clean urine and
heater pack. And the tubing guarantees 100 percent satisfaction, because
obviously a lab cannot tell the difference between if you submit clean
human urine that\'s of the proper temperature when it\'s collected. A
lab cannot identify that.

The second on the right is an adulterant, Spectrum Laboratories. The
gentleman that runs Spectrum Laboratories has been interviewed on
television, and he says, \"I get the same publications as the urine
labs. Obviously when they begin to test for my products, I change my
products.\"

We have the ability to repeat the collection. And this is a huge, huge
advantage for the employee or the donor. You can collect a wholly new
sample that can encompass the original time frame after the original
result is known.

This eliminates concerns over sample error or lab error, or sample mix
up. It\'s not possible with liquid matrices as the original window of
detection has passed by the time the result is obtained.

Getting a second urine sample four days later, or five days later, or
three days later \-- even two days later \-- is worthless in terms of
seeing what happened during that original time frame.

This provides unprecedented fairness to the donor. We have repeatability
with a new sample, with a new collection, with the union representative
present. Unprecedented fairness to the donor.

We identify 6 acetylmorphine, establishing heroin use. Hair testing
eliminates the poppy seed issue. Our studies that have been submitted
with this submission have shown that even massive ingestion of poppy
seed products will not cause a positive hair result.

In contrast, in \'95, HHS reported that 87 percent of confirmed urine
opiate positive were overturned largely due to the inability to
distinguish that use from poppy seed use. That was at the cut off level
of 300, which does not, as it turns out, protect the individual because
it could be a poppy seed positive.

The level has been raised to 2000, which at this point may not protect
the public, because now you\'ve raised it to the point where you may be
eliminating heroin users.

We also have ease of shipping and storage. It\'s not a biohazard. They
have much more safety \-- increased safety in shipping and handling the
specimen.

There are several unique aspects to our submission. It may be somewhat
different than what you\'re used to seeing. For one, it\'s been used in
millions of tests over 13 years. We have a track record of safety and
effectiveness.

It is an in house assay, a home brew. It\'s not sold to other labs. And
this is a test where the donor knows the results before taking the test.
The donor knows clearer than everybody what the results should be.

You\'re not advising the donor that they have cancer. You\'re letting
them know that they engage in activities that they know certainly well
that they engaged in.

It\'s a forensic test that provides a third party with information on
past illegal activity. Heroin is a Schedule one drug. This test does not
show intoxication, under the influence, or addiction. It\'s a forensic
test.

At this point, I\'m going to turn it over to Dr. Cairns who will get
into more of the laboratory operations and the science.

Thank you.

DR. CAIRNS: Good morning, Mr. Chairman, members of the panel. I welcome
this opportunity to do a presentation before you, not only on an
overview of our hair test procedures, but also on the seven important
questions that have been posed by the panel.

I need to go open my own presentation. Apologize. We used to get along
so better with these slides in the old days, and I wonder whether
technology should take a back seat and go back to slides.

However, what I wanted to do for you just for a few moments is to place
into a proper perspective setting where the RA assay for morphine sits
in our strategy of hair testing.

Now, the next slide will show basically that there are three major
platforms here. The first platform is in fact the primary stringing via
RA to identify presumptive positive based on morphine.

If at that point, the assay \-- the screen is negative, the sample is
reported negative. If however, that primary screen \-- and by the way,
that primary screen involves only eight milligrams of hair digested or
liquified for the analysis.

And that\'s a five drug analysis panel, similar to NIDA. The next step,
if a presumptive positive is triggered by the screening assay, then we
go into a second sample weighing from the original envelope that
contains the hair and the chain of custody.

Except in this case, this second weight of hair is in fact extensively
washed, washed to remove external contamination. Once the hair is washed
\-- and I\'ll be going into the exact details of the wash later \-- that
hair is then liquified, it\'s digested, and sent on for structural
confirmation.

Now Psychemedics has developed mass spectrometry that goes back to in
fact just the simple gas chromatography mass spectrometry, but more
recently has elevated the specificity by looking at these compounds,
meaning morphine, 6-MAM, and codeine, by a liquid chromatography mass
spectrometry, mass spectrometry.

So, what are we looking for? We\'re looking for morphine and the heroin
metabolite. And in that process, we\'re looking at the analysis of the
last wash in our review of the data before we release a positive.

Now, let me just go over the criteria for properly conducted hair
testing. We want the sample under chain of custody. We want the
digestion procedure, that is the process of dissolving the hair to
release the drugs from the matrix to allow the screening.

But it\'s important to stress at this point, that you must use rigorous
forensic standards that is both quality control and quality assurance.
Now, by that I mean that in the RA assay, we have in fact the standard
at the cut off.

We have a high control at 25 percent above. We have a low control at 25
percent below.

We have a negative and several blind samples in each batch. Now if in
fact that is then satisfied, the next step is the re-weigh and the
washing procedure.

And that is an extensive wash lasting three and three quarter hours plus
an analytical extrapolation to have five additional hours. Then we move
into structural confirmation.

Depending on the result, we will review the wash criteria. And then the
final review by a certifying scientist before the issuance of a positive
result.

Looking at all of the QA/QC blanks and blinds that go into the batches,
whether it\'s the RA batch or whether it\'s the GCMS batch.

Now, let me give you just one last slide on our overview. We accessioned
the hair. That\'s the process of weighing the hair, giving it a bar
code. At that point, the paperwork is checked for valids and invalids,
and fatals. Maybe that the seal \-- the integrity seal was not
initialized by the donor.

Weigh the eight milligrams, liquify the hair, go to radioimmunoassay.
Five panel drug, marijuana, cocaine group, amphetamine group, opiates,
and PCP.

The negatives are released, the presumptive positive move forward by a
new sample being re-weighed and washed, then digested, and moving into
structural confirmation by mass spectrometry, whether it is GCMS, or the
more sophisticated tandem mass spectrometry associated with either gas
chromatography or liquid chromatography.

Once that data is forwarded, the wash data is also reviewed in
conjunction with the mass spectrometry result, and the certifying
scientist reviews the positive before release.

Now, with that little background, let me move into the next part of the
presentation. And this is to focus basically on the issue before us
today. That is regarding the safety and effectiveness of an RA screening
assay for morphine using a cut off of two nanograms or ten milligrams of
hair.

Now, question one revolved around clinical studies. If you were to use
the traditional perspective clinical controlled study, there would be
two major impediments, and one is an ethical problem. That is, can you
ethically administer multiple and or chronic doses of heroin for a
period of 30 to 90 days to mimic drug abuse?

The second one is an analytical problem involved in the time frames
between urine and hair. And we\'ve heard that\'s a few days, and the
hair is 90 days. The administration of a single low dose would not
challenge the cut off of the sensitivity of the assay.

Therefore, the design of the clinical trials in Volume 3, which is a
response to FDA, was that the study hypothesis was to demonstrate
substantial equivalence to a urine predicate device.

Number two. The positive clinical gold standard was a positive urine and
a positive self report. A negative clinical gold standard is a negative
history of hair analysis and a negative urine.

And the inclusion exclusion criteria were the same for all the studies
we submitted in this area of the application. Now, from the statistical
point of view, the standard error of clinical sensitivity and
specificity has been determined and submitted.

The next slide will show you the five independent studies that were
submitted to support the performance of the assay. These are five heroin
user field studies, and they are involving Study A involves 22
individuals, Study B, 93, Study C, 94, Study D, 20, and Study E, 16.

Now, I\'d like to go through each of these in turn to explain perhaps a
few more details on each of these clinical studies. The first one was
published in Journal of Forensic Science in 1989. The hair testing cut
off was two nanograms per ten milligrams.

Again, 22 subjects. The use by self report was somewhere between 6.4 and
288 milligrams per day. The morphine range found in hair was from the
two nanogram level to 130 nanograms per ten milligrams of hair.

This permitted a mean detectable heroin dose use resulting in the value
of 173 milligrams of heroin per month. And the clinical sensitivity
derived from the data using 17 true positive, and five false negatives,
with 77.2 percent.

Study B, from the National Development and Research Institute to Mount
Sinai Hospital and various clinics surrounding the New York area, once
again, 93 subjects self report heroin.

The morphine levels found in hair by RA assay ranged from zero all the
way up to 605 nanograms per ten milligrams of hair. Cutting through the
calculations, the clinical sensitivity reported with 90.3 percent.

Study C, a NIDA Research Monograph Publication in 1997 from the Center
for Substance Abuse. Here again, 94 subjects. The clinical sensitivity
calculated from the study is 90.4.

Study D, published in the International Journal of Addictions. The study
conducted at the Van Etten Hospital Drug Treatment Program in the New
York area. Only 20 subjects, a sizable number, morphine range two
nanograms to 98 nanograms per ten milligrams of hair. Again, the
clinical sensitivity calculated from the study results, 80.0 percent.

Study E, by Baer et al U.S. Probation in Santa Ana Southern California,
in conjunction with the Veterans Administration Hospital in Los Angeles,
California. Sixteen subjects in the study. The morphine range found in
here, two nanograms to 130 nanograms per ten. The clinical sensitivity
calculated 75 percent.

Now, taking all five studies as submitted in the application, and doing
a combined approach to the calculation of clinical sensitivity from such
five independent sources resulted in a clinical sensitivity calculation
of 87 percent.

However, that clinical sensitivity really does not in fact address the
issue of the effectiveness of using hair versus urine. In Attachment 22
in our submission, we list the following data.

We looked at two matrices, urine and hair, and the number of tests
performed within a large population. Seventeen hundred and eighty-three
urine tests performed, eleven positive were identified yielding a
positive rate for morphine and for heroin use of 0.6 percent.

In the cases of hair samples taken from the same population, only 187
hair samples were taken. But the number of positive were 15, a dramatic
shift. Looking at the hair results, hair is more effective than urine in
this environment.

Next slide.

Now, looking at analytical sensitivity and specificity for the assay
admitted most of the data. The detailed data is in our Volume 3
response, but essentially, analytical specificity is 96.6 and the
analytical sensitivity is 100 percent.

Now, the negative portion of the clinical study, we used a group of
Psychemedics\' employees, 81 employees. And the clinical specificity is
100 percent.

Now, the questions the panel had regarding the clinical sensitivity and
specificity was in the inclusion criteria. And the cross question was
negative urine plus negative self report.

Psychemedics did not simply use those two criteria. We did not simply
use a negative urine and a negative self report. We used an employee
group with a history of negative hair tests and a contemporary negative
urine test.

So, the features of our negative controlled study where yes, they were
volunteer employees. They were required before entering employment to
have a negative hair test for Psychemedics. And the company policy is
that we conduct randomly monitored hair tests.

The urine samples were also monitored for any immunoassay response as
compared to the negative control. We did not apply a cut off there. If
the drug was present, even below cut off, it was pursued by mass
spectrometry for identification.

The next question asked, \"Was positive urine not always confirmed plus
a positive self report?\" And here again, we also went beyond those two
criteria by looking at clinical evidence of drug use. Hence, heroin
treatment programs basically for the controlled studies.

There is a limited ability in urine to confirm the heroin metabolite,
6-monoacetyl morphine, or 6-MAM for short. And this tends to make the
urine test the weakest piece of information.

Hair, on the other hand, does provide for storage of 6-monoacetyl
morphine, which can define heroin use. Therefore, in urine, 6-MAM will
clear in less than eight hours.

Now, if we look at the recent history with morphine at the old cut off
of urine of 300 nanograms, it took 24 to 72 hours to clear. When we
moved to the higher cut off of 2,000 nanograms, 24 hours to clear. And
6-MAM, that unique descriptor of heroin use, less than eight hours to
clear.

Now, the minimum dose issues. The estimated mean minimal detectable
heroin dose from the field studies, that is A through E as outlined to
you, results in a value of 173 milligrams per month. And that\'s in
Volume 3.

This translates to a choice for use of a cut off of two nanograms of
morphine. Heroin addicts, in a paper by Kintz, used 900 to 24,000
milligrams per month. So, you can see already that the average heroin
addict is way above the mean minimal detectable heroin dose, and i.e.,
well above the cut off.

Now, the poppy seed controversy. Psychemedics has presented data on the
poppy seed issue. And by feeding 150 grams of poppy seed, the morphine
level in hair was only 0.17 nanograms per ten, well below the cut off of
two nanograms. And of course, no 6-monoacetyl morphine.

Pharmacokinetic considerations. Again, I go back to the impediment to
controlled clinical trials is that it is not ethical to conduct single,
multiple, or chronic dose levels studies with heroin. The minimal
detectable dose information is all that should be really necessary due
to the proven accumulation and stability of both morphine and
6-monoacetyl morphine in hair.

That is, the ability for hair to act as a trapping device, not only for
the metabolite directly from heroin, but also for morphine. The RA assay
using hair can detect heroin use via the mass spectrometry confirmation
of any presumptive positive above the two nanogram level by detecting
the metabolyte, 6-MAM.

So clearly, the combination of morphine and 6-MAM is found in the hair
of heroin users. The combination of morphine and 6-MAM is not found in
the hair of non-users.

The bias issues. I\'m merely going to summarize some of the bias issues.
We have submitted a hair color and curvature study, meaning curly hair
versus straight hair, in Volume 3.

The large multiple statistical studies, that is those studies involving
large populations and a statistical analysis, are not significant. In
other words, no bias.

And these studies are the Pinellas County Probation Study, the Pinellas
Cleveland Juvenile Study, the New Orleans Diversion Data, the National
Institute of Justice Study, the Pinella County Drug Use Forecast
Emulation.

Eighteen hundred participated. And finally, a large metropolitan police
department. Again, very large study of 1,800.

Methological differences within research reports can create variances in
results that appear to be color related, but are not. By that I mean
that the study protocol may have used inefficient extraction procedures,
failure to remove melanin and sweat, ineffectual wash procedures. These
are all part and parcel of methological differences.

The bias studies have previously not been required for submitted
applications with immunoassay applications for urine to correct for
either diet, gender, muscle mass, creatinine level, body weight.

And finally, individual biochemical variability. That issue of the
bioavailability within the individual within any population can create
large variances.

Now, at this point I\'d like to introduce Professor Newel to discuss in
detail the statistical evaluation of these large populations as well as
the small.

Professor Newel has the largest database on hair to look at statistical
profiles with color versus hair.

Professor Newell.

MR. NEWELL: Thank you and good morning.

I do not have any conflict of interest or financial ties to the
Psychemedics Corporation, nor any other laboratory.

May I have the next slide.

I work at the University of South Florida. I\'ve been doing research
involved in hair testing with funds primarily from the Department of
Justice, National Institute of Justice for about ten years. So, I
appreciate the opportunity of being able to come before you and share
with you some of the work that we\'ve done.

First I\'m going to start with a kind of conceptual transition slide.
The question that was posed by the panel regarded racial bias.
Originally, racial bias evolved from some initial concerns that there
were associations between type of hair and its ability to record
exposure to drugs.

People wondered if racial bias would be part of that problem. And I
think, probably first that was because there was an erroneous perception
on the basis of the general public that there are biochemical racial
differences.

In fact, I think over time this has evolved further, and that now racial
bias issues are handled primarily as issues in the type of hair, that is
color of hair, or curvature of hair, other descriptors of the hair
itself.

Also, there have been some ethical limitations. Research has generally
relied on an epidemiological approach to this issue. That typically has
involved taking hair analysis results and comparing them to self report
drug use and urinalysis results.

For studies that have proceeded that way, no such race effects have been
confirmed for either of these drugs, cocaine or heroin. And more
recently, this issue has been addressed I would say more scientifically
than calling it racial bias, by calling it differences due to hair color
or hair type.

Can I have the next slide?

I want to share with you very briefly a secondary analysis, a
statistical analysis, that was conducted on five data sets that have
appeared in the literature. All five of these were characterized with
small-n.

Could we have the next slide? Thank you.

Small-n is just basically the number of people that participated in the
study. The basic question is, is there a statistical relationship
between hair color and assay concentration value?

In these five small-n studies, we had anywhere from nine to 20 subjects.
Analysis is done for studies recording analyte concentration along with
color. Now, that\'s important.

A lot of studies may have reported only the analyte concentration, and
we can\'t analyze for color unless the authors either initially reported
it or we were able to recover that data from the authors subsequent to a
paper\'s publication.

There are three methods of analysis that we used. These are statistical
techniques that we used through the analysis. I\'ll go through these in
a minute. But they include things like analysis of variance, when we had
two comparison groups and two piece procedures when we had three or
more.

And a linear regression, we had independent and dependent variables are
both continuous in a racial level data.

Next slide, please.

This is a one slide summary of these five small-n studies. You see
they\'ve started in the early 90\'s and up through the Kronstrand study
at the bottom, published recently in 1999. The n\'s refer to the number
of subjects, 20, ten, 15, nine subjects.

And the analytes refer to the kinds of drugs that were being examined in
the hair by these respective authors. What we did is a secondary data
analysis, taking those original articles and those original data points,
and subjecting them to additional tests to see if there were any
associations in those early works with hair color and with drug
concentrations.

Those statistical tests included analysis of variance, Tukey\'s HSD, and
some linear regression. Significant question mark as the column total
there refers to after the test, did we find any significant effect?

And you see for four of the five, we did not. The fifth one, the
Kronstrand study actually does show a strong significant effect. The
significance ranges are on there. We use an a priori alpha of .05. Most
of those are nowhere close. The Kronstrand study is a departure from
that.

Can we have the next slide, please.

This is just the summary of basically what I just said, four of the five
reviewed small-n studies do not show a statistically significant effect
associated with color for either cocaine or heroin.

Now, why is this a likely result? Why would we expect to see this? Well,
we have small-n studies, very small-n studies. And initially, I think
the authors, when they reported their studies, looked at mean values and
just reported, \"Well, the mean is bigger here than it is here.\"

The use of mean values is typically a very poor measure of central
tendencies since these scores are very sensitive to extreme scores. High
values for dispersion mitigate all the systematic mean differences,
especially in these small-n studies.

And of course, not all influencing variables can be controlled or even
enumerated in a laboratory design study, and hence the need for
epidemiological research.

The Kronstrand\'s study has significant results may indeed be due to
unique features of codeine. We don\'t know yet. Tommy, just a moment
ago, suggested some alternatives that included some important analytical
differences of what the lab does that may account entirely for this
particular effect.

May I have the next slide, please.

I\'m going to spend just a few minutes reviewing what are characterized
as large-n studies. We have five data sets here, each of which has 70 or
more cases.

Next slide.

These studies contain approximately 2,900 data points. Currently, we
have about 100,000 cases right now in our database, and I don\'t have
all of that analyzed. But we have substantially more than the small-n
studies.

The advantage of this is that generally larger-n studies provide a more
stable database, and they reduce the likelihood of a beta error. Large-n
studies are also more likely to find significant effects. They have
higher statistical power, and they allow a measurement of their
strength.

Here\'s basically a list of the five studies. One from Glasgow on MDMA
and analogs. One from Pinellas County, Florida on cocaine. One from Las
Vegas, Nevada, cocaine and cocaethylene amphetamine. Another from Los
Angeles, cocaine and so on. University of South Florida, morphine study
that we recently concluded and I\'ll report on last.

All of these statistical analysis utilized analysis of variance into
these procedures.

The first study, the Glasgow study, collected hair samples from
volunteers who attended rave parties. Hair samples were analyzed for the
presence of amphetamine, methamphetamine, and so on. There were 232
subjects who donated the hair samples. And the specimens were analyzed
at two laboratories, 139 at the University of Glasgow and 93 at
Tricho-Tech in London.

However, and unfortunately, hair color was only recorded for the 139
specimens that were tested at the University of Glasgow. Nevertheless,
there were no statistically significant relationships between hair color
and drug concentration.

The Pinellas County, Florida study. We had specimens collected from
adult probationers who were asked to voluntarily participate in a six
month project. For each volunteer, at least monthly urine and hair
specimens were collected. Psychemedics Corporation did do the hair
analysis with RA, GC/MS, and tandem MS confirmation.

We had a total of 589 hair samples, but only about 95 were testing
positive for cocaine. Hair \-- brown hair was the most prevalent color.
And when we looked at these 95 cases again, we found no significant
associations relating color to cocaine concentration.

The data from 500 randomly selected cocaine positive, and 500
amphetamine positive subjects were collected and analyzed by the same
techniques. Hair assays were performed for the parent cocaine, and
cocaethylene, and amphetamine by hair color.

Hair color was arrayed over seven categories, red, grey, blonde, light
brown, medium brown, dark brown, black. When you have this many people
involved, basically you have enough people in each one of those
categories for a sufficient statistical power.

The hair specimens at extracts were screened by radioimmunoassay,
cocaine metabolites, hair specimen extracts were confirmed by GC/MS. And
again, there were no significant relationships uncovered for these
analyzed drugs.

Out of these 998 people from the Psychemedics Laboratory \-- again
analysis was done by RA, confirmed with GC/MS, or GC/MS/MS. Samples were
taken as a consequence of employment, those people who were applicants
to employment.

Because this is an applicant test, only 72 tested drug positive. That\'s
typical for pre-employment screening procedures. Among these 72 people,
we had no statistically significant associations between color and
concentrations.

And finally, the last study \-- one we just concluded \-- random study
of 95 morphine positive clients. Hair color was arrayed in five
dimensions, and curvature in two, curly and straight.

Statistical associations were tested by my colleague, Tom Mieczkowski.
He has an article in the present Journal of Analytical Toxicology, and
myself presented here using a variety of statistical techniques.

Analysis that I ran included non-parametric Kruskal-Wallis one way
analysis of variance. It\'s actually a more powerful technique when we
can\'t make assumptions about the standard normal distribution in the
parent data set for a population.

And even with this, we\'ve again found no statistically significant
results either between hair and \-- hair color, rather, and morphine
concentrations, or curvature and morphine concentrations.

This is a one slide summary of each of these five studies. You see in
the first column, the original place where the data was gathered. The n
refers to the number of people. This would be drug positive that were
analyzed. Analytes were the drugs that we were looking for.

The test is a statistical test run on these data to look for
associations between color and curvature, and drug concentrations and
significance. Again, question mark. They all were non-significant.

The significance ranges, as you see up there, are way different from our
priority cut off of .05. Nowhere close.

Next slide.

So, as a summary, all of the large-n studies in most of the small
n-studies reviewed, do not demonstrate a statistically significant
effect between hair color or curvature and drug concentration.

Small-n studies were often initially reported showing differences
between mean concentrations, but mean value comparisons can be
deceptive. Significance cannot be determined by visual inspection. That
means they\'re sensitive to extreme scores, and that mean differences
cannot be evaluated without consideration of deviation values.

And finally, codeine concentration may be uniquely related to melanin,
but effects are probably small. In fact, in the Kronstrand study, I
believe, the most extreme effect showed that the difference was less
than one half of one nanogram.

Next slide.

I guess before I get into this slide, I just want to make one additional
comment. There was another study that I did not summarize on here by Ben
Hoffman, who also had 1,800 people, and again found no significant
difference, no significant association between hair color and drug
concentration.

DR. HENDERSON: Where was that study from?

MR. NEWEL: I\'ll have to get the records. I have the citation with me.

This is something completely different. This is a little study that we
have done outside of this bias issue that I wanted to share with you.

It has to do with external contamination, and I think Tommy made some
initial comments about studies that they\'ve done with external
contamination. We did this one with 110 undercover police officers who
logged their every day exposure to cocaine and other drugs over a 60 day
period.

The hair samples were analyzed for both cocaine and benzolecgoning by
Psychemedics. In our study, no officers were found to have drug
contaminated hair despite their frequent contact with cocaine, drug
paraphernalia, drug users, and their environments.

That\'s all I have for you today. Thank you for your attention.

DR. CAIRNS: Thank you, Richard.

If we can return to ‑‑ we just had done the biased issues, the two
slides on the biased issue.

Now, getting back to another theme and that theme is the removal, the
effective removal of external contamination. Now, let me begin by just
outlining the analytical procedure whereby we do washing of the hair.

The first wash is an isopropanol wash, and that wash is conducted mainly
to remove any cosmetic preparations that may reside on the external
surface of the hairs, such as gels, mousses, hair sprays.

The isopropanol is removed. The hair is then placed in a phosphate
buffer with agitation, and there are three such phosphate buffer washes
at 30 minutes each. After those, the hair is put into a phosphate buffer
for one hour again with agitation and again for another hour. At that
point, the hair is dried and then sent for liquefaction or digestion.

However, I want to put on an additional safeguard here on the washing
procedure, and that is that we also add a mathematical extrapolation as
if we were mimicing an additional five hours of washing.

Now, let me explain that. I\'m going to show you a graph. I understand
where you\'re coming from. I\'m going to show you a typical wash profile
for an opiate user. Now, you\'ll see the yellow bar diagram. The IPA
wash is not analyzed in this particular case. But the first buffer wash,
which was the half hour wash, contained 4.65 morphine. Removal from that
buffer and placement in the next buffer for 30 minutes resulted in a
wash value of 1.3 nanograms. Then into the third wash buffer for another
half hour, 0.54. Then buffer 4 is a one-hour wash with agitation, and
buffer 5 is another one-hour wash.

Now, I think you can see that the washing sequence is such that each
wash contains a diminishing amount of morphine. And we\'re rapidly
approaching a plateau in buffer number 3, 4, and 5. To add an element, a
strong element of conservatism, we take the fifth wash value, which is
0.52, and multiply that by five. What we\'re saying here is that if we
were to wash five more hours, the drug concentration would certainly not
be greater than 0.5. It would probably be less than 0.5. So, we multiply
the 0.52 by five. The hair is then dried, moves into digest and
confirmation, and has a value of 31 nanograms of morphine.

Now, if you look under the heading profile, what I\'m going to do is the
digest is 31. I\'m going to subtract from that five times the value of
buffer 5, which was 0.52. And, so the level after the extensive wash and
the mathematical extrapolation is 28.4.

So, what we\'ve done is to add a highly conservative buffer zone as if
we were washing five more times. Now, that\'s important, because when I
show you the profile for a soaked hair, a deliberately contaminated
hair, you will see the fundamental differences in profile.

Now, here\'s the soaking experiment. We took 33 different hair samples.
We soaked them for one hour at room temperature in an aqueous solution
containing 1,000 nanograms of morphine per milliliter. We applied the
wash procedure, that is the 3.75 hours of washing, and applied the
mathematical extrapolation of five more hours, and all samples were
negative. But let me show you a typical profile.

This is the decontamination profile for a deliberately contaminated
soaked hair one hour in aqueous morphine. Now, in this case, we analyzed
the isopropanol wash for this experiment, and you\'ll see that the
isopropanol wash, the wash was only 1.2. However, the first buffer, that
is the half-hour washing, 480 nanograms; the second buffer half-hour
washing, 98.1 nanograms morphine; the third buffer, 30.9; the fourth
buffer, 12.9; the fifth buffer, 7.2. This sample, externally, contains a
lot of morphine.

Then we digest ‑‑ dry and digest the sample, we find we have 20
nanograms in the digest. So, if we perform our routine wash criteria,
you have the digested 20 minus five times the last wash, which is 7.2,
would actually result in a value of minus 16.3, showing you how
conservative the analytical extrapolation procedure is. We\'ve
overcompensated.

But if you look at the profile here, the washes contain basically a lot
more than the digest. This is a typical contamination profile. The
previous profile was a typical user profile. So, we are able, clearly,
to use the wash procedure to distinguish or differentiate a user from a
contaminated hair.

Now, the sweat study. We were asked to respond with this type of study,
and it\'s in volume 3. Here we took three groups of 13 different hair
specimens and we soaked at room temperature for 15 minutes in a
chloroform solution containing this time 10,000 nanograms of morphine
and 10,000 nanograms of the metabolite 6-MAM.

The specimens were dried, they were then put in contact with synthetic
sweat for time periods one, three, and six. So, 13 samples in each of
these time zones. The Psychemedics wash procedure applied as I\'ve
outlined, 3.75 hours of washing and an analytical extrapolation of five
additional hours. The results were that all 39 samples were negative.

Now, we were also asked to comment on the cosmetic treatment; that is,
can you affect the hair testing result. Data would show that certainly
perming, relaxing, and to a lesser extent dyeing of the hair, could
reduce the amount. However, the samples at risk if such procedures were
performed would only be those samples that are existing between two
nanograms and 2.6, because such treatment would take them below the
cutoff.

So, a calculation of the morphine positives that we have in our
database, it would only affect about three percent of all positive
heroin tests. And you compare that with a urine test where adulteration,
substitution, and hydration, all samples could be at risk. In here the
only samples at risk are those residing approximately 30 percent above
the cutoff, meaning from two nanograms to 2.6.

Now, conclusions. To summarize, in the application, we have given you
five user field studies that we consider have provided more reliable
data from multiple sources than a single controlled clinical study may
have provided if it were ethical possible.

Secondly, the establishment of a dose-response curve strictly not
necessary for an assay where the decision is are you above the cutoff or
are you below the cutoff.

On the pharmacokinetic issues, yes, the key issue is to detect morphine
via the screening method application to identify heroin users. As with
urine testing dose-response was not required. Regarding the minimal
detectable dose, all the information that is necessary is contained in
the hair, because it has the ability not only to store, to trap, but to
stabilize over long periods of time.

And finally, urine testing for drugs of abuse did not provide such
detailed information as part of any FDA submission. The ratio and hair
color bias you\'ve heard from Professor Newel. With valid techniques,
meaning the analytical assays in conjunction with statistical
populations, there is no race or color bias. Statistical treatment and
review of small and large population revealed no evidence, as you\'ve
seen from the previous presenter. There are no conflicting large
population studies in the literature. The small studies may have
conflicting conclusions that result from different methodologies, and
these are influenced, as we\'ve said, extraction, efficiency of wash,
non-ingestion. And these results are not unexpected.

And, finally, with valid techniques such as the washing procedure we\'ve
outlined, there is no external contamination issue. In fact, the
research presented in our application has demonstrated that the
exhaustive level of washing effectively removes externally the positive
drug and can ensure with confidence the differentiation between a heroin
user and a non-user. There are no conflicts in the literature regarding
external contamination provided the correct techniques are applied.

Finally, research models without adequate washing procedures do not
remove contamination.

I think that\'s my last one.

Oh, hair treatment. Again, cosmetic applications, we\'ve seen it can
reduce the amount near the cutoff, and that would only affect three
percent of the samples. And this is a far less effect than that created
by simple hydration of adulteration.

And for the last comments, I\'m going to invite Professor Selavka to the
podium. We\'ve saved a little treat for last. Professor Selavka is in
fact co-chair of the Small Working Group for Hair Analysis under SAMHSA,
and he\'s going to share with you his views on hair testing and the
poppy seed controversy.

Professor Selavka.

DR. KROLL: Hi. Before we begin, I would remind you it\'s about 10:45,
which is getting into our scheduled break, so use your time wisely.

DR. SELAVKA: Say again how long I have. So, I\'m between you and food.

(Laughter.)

You probably thought I was here just to run the projector. My name is
Karl Selavka. I\'m the Director of the Massachusetts State Police Crime
Laboratory, which has nothing to do with hair drug testing. So, since
you wanted to see somebody outstanding in their field, there you go.

I do have to disclaim I\'m not here representing the state or the
executive office or any laboratories per se. I am hopefully representing
some insight into the operating process of the Hair Testing Working
Group that was sponsored by the Drug Testing Advisory Board of HHS, as
well as poppy seed studiers. Some day after my wife\'s vet bills are
paid off I hope to have a conflict of interest. Of course this is the
land of disclaimers.

Anyway, I was one of the co-chairs along with Dr. Donald Kippinberger of
the Hair Testing Working Group to DTAB. We\'re asked by them to review
the field, and there really are a world of different samples other than
those currently being applied in workplace testing that could allow for
some insight into a drug use history for a person being tested. Of
those, urine drug testing, sweat, oral fluid, and hair predominate the
matrices that are being studied currently for applications in the
workplace.

They all are providing complimentary information. The complimentariness
may be related to time periods and sensitivity to different substances
and graphically speaking some look into the past, and one can look into
the future. If you were to use all of the complimentary matrices for
each of the applications in a workplace, a business setting, forensic
examinations, and even post-mortem work, you\'ll find that all of them
have unique specialties that they can offer to the particular
investigation.

But the federal government is now looking outside the box. They are not
feeling that they have to use a single-matrix approach anymore, and
because of that, they also recognize that the old approach is the larger
approach, and it\'s going to take some time to demonstrate adequately to
everybody\'s satisfaction what needs to be demonstrated.

The Hair Testing Working Group was made up of a number of different
kinds of people. Those actively working in hair drug testing
laboratories as well as interested outside scientists and medical review
officers. A number of federal and non-federal observers and ghosts and
some people that were providing specific insight into issues since it
was federally funded, we were fueled mostly by doughnuts. The federal
government graciously paid for travel, but otherwise we were basically
on our own. But they did well for us.

We had three meetings, most of which were attended by volunteers. We put
out to the hundreds of people that have expressed interest in the past
about hair drug testing, a notice that we were going to have these
meetings, an invitations for them to come. We also had a number of
contrarians, people who had published in contravention to other people
in the field of hair drug testing to try to get their insight into the
process and to try to get their consensus with us.

But after the third of these meetings, I was invited to also give this
to the international perspective. It\'s important to recognize that
America is not the only place where hair drug testing occurs. In fact,
in Germany there\'s routine use, as well as France.

The substances that are listed are those that are routinely reported in
the literature, early in the literature that comes from those countries.
Canada has presented results in the literature, Japan, the United
States\' copious data, and the laboratory where I used to work, National
Medical Services, is actively involved in esoteric drug and other
analyte testing in hair.

This summarizes the drug classes that have been detected in hair. It\'s
virtually all of them that can be ingested. But we formed consensus on
all of the components for the most part that we were asked to by the
federal government ‑‑ how much hair to collect, what type of hair to
collect, the length to collect, stability of drugs, collection
integrity, screening cutoffs, which screening precisions and accuracies
were necessary.

One of the elements asked us to define the immunoassay cutoffs and what
the analytes should be. Those are listed here for you. We also formed
consensus on the confirmation cutoffs that should be chosen to limit any
claim of external contamination. These were chosen much higher than the
analytical sensitivities of the assays, but building in factors
recognizing that this particular matrix had not been used routinely in
federal workplace testing, and therefore we should be overly cautious,
using specific metabolites for amphetamines, opiates, cocaine, and THC
to rule out the presence of external contamination as the only source of
drug being determined.

We helped design what we thought would be adequate blind PT programs and
sources for open quality control materials. The confirmation cutoffs for
opiates are shown here. The difference between what you\'ve seen the
rest of the day and these is that you have to multiply this times ten,
because this is nanograms per milligram as opposed to nanograms per ten
milligrams. I\'m not a mathematician so I always have to do this for
myself.

These are the other confirmation cutoffs in case you care. I know today
we\'re here to talk about opiates.

We were able to reach consensus on interpretative guidelines, and that
is a positive finding in hair represents chronic and repetitive
exposures and uses during the time period represented by that hair.
It\'s not a single dose giving rise to these findings; it\'s repetitive
uses.

We talked about what alternative medical explanations you might have for
a heroin-finding hair. Well, there shouldn\'t be any. There are no
alternative medical explanations for that. We discussed dose-response
relationships, helped design what we thought would be a comprehensive PT
program, and for the first time for workplace drug testing defined what
we thought were adequate standards for tandem mass spectrometry for
confirmation.

About dose-response relationships, I think it\'s important to recognize
heroin is an illegal drug, there\'s no therapeutic drug monitoring
requirement here. It\'s sort of counterintuitive to deterrence to expect
there to be a dose-response relationship. In effect, we haven\'t held
any of the other matrices to that equivalent standard, and therefore
detection is appropriate, but cautious application of cutoffs is also
appropriate.

More consensus. You\'ve heard this well from Dr. DuPont so I won\'t
repeat it, but bias is a normal component of all biometric testing. We
recognize that. We also believe that it\'s important to have discretion
for MROs in order to take into account different factors of a person\'s
history when relating drug positive results.

Animal models do not generally correlate well with human use, and
low-dose studies should not be used dispositive of the issue. We know
very well that there\'s wide differences between the hair on animals and
the hair on humans. Therefore, animal-use studies have certain
application, but they\'re not dispositive in any way on the overall
studies in the field.

The other reasons I\'m here is because I\'ve done one of the studies on
poppy seeds that\'s been referred to by some, and also I\'ve recently
updated this and presented at the American Academy of Forensic
Scientists Meeting earlier this year. As part of the presentation,
basically, I\'ll go over what foods are out there, the toxicology
involved, the fluctuating policy we\'ve seen, and that there is help.

I was the Operations Officer for the Army\'s drug testing lab in Hawaii
for four years. I asked for Ft. Meade, Maryland, but they gave me
Hawaii.

(Laughter.)

In this laboratory, we were at that moment in time, in the mid-80s, we
were bringing opiate testing on board, and we had to recognize that
there were some issues. One of the issues we got inspected too often. I
did learn the official military vegetables for urine testing ‑‑ leeks
and peas. If you don\'t get it, I\'ll explain it later. And you should
never eat anything with the word \"whiz\" in it.

But anyway, opium poppies can give rise when ingested to morphine
findings in urine. There was some literature at that time, but we
recognized that we might have a problem. We didn\'t want to ignore the
problem; we wanted to use reasonable cutoffs in order to define the
difference between poppy seed ingesters and the contributions those
might have to positive findings and those that were using heroin.

When it comes to poppy seeds there\'s quite wide variability in
worldwide production and the amounts of opiates that are found in those
seeds. This lists those for you, and you see the word \"thebaine\"
there. It\'s one of the opiates that\'s found in poppy seeds that at one
point was thought to be maybe that\'s the magic bullet. We can use
thebaine detection to differentiate poppy seed eaters from heroin users.

There\'s also wide variability in how much you eat when you\'re eating a
poppy seed food product. You don\'t know whether the seeds were washed
or not washed, the latex on the outside of the seeds may or may not,
depending on the literature you read, contain the opiates that are in
question. You don\'t know what the difference might be from cooked and
uncooked foods. The problem is you don\'t really know where these things
come from when you\'re eating them.

But poppy seeds follow toxicological rules ‑‑ whatever goes in one end
comes out the other end. Those ends could be of course on the top of
your head or various other places. And the concentrations in urine are
generally described here: Less than 4,000 nanograms per mil of morphine,
less than 200 nanograms per mil for codeine, thebaine, generally below
150 nanograms per mil. All in urine and all peaking around four hours
after ingestion.

It can be extended if you have a lot of butter or rum in some of the
products that you\'re eating. Hopefully you do when you\'re eating poppy
seeds, because otherwise they\'re not that delicious. There is a good
deal of high subject intervariability.

In order to rule out poppy seeds, in the late \'80s, Mahmood ElSohly and
Skip Jones in Mississippi, described in a paper that there may be a
strategy using toxicologically placed analytical cutoffs on the
confirmation. If morphine was greater than 5,000, codeine greater than
300, and morphine to codeine ratio less than two, they described that
that should not be from poppy seed eating. This was around the time the
military laboratory system was putting in place opiate testing. They
also said 6-acetylmorphine, if you find it, it\'s heroin.

Well, we went in our laboratory. We wanted to study the effects. We
thought, well, if there\'s an analytical approach, we may also be able
to join them in the toxicological ingenuity and come up with this good
plan for the military. What we found is that the reasonable
toxicological ingenuity does not spell good policy.

The reason for that is in my own study with poppy seed ingestion, we
found levels of morphine 11,500 nanograms per mil at peak concentration
in one individual; codeine greater than 4,000 nanograms per mil. The
ratios usually work but the cutoffs that were being applied at 5,000 and
200 were not working.

There is very rapid 6-acetylmorphine clearance. Generally, within three
to four hours, you\'re not going to have 6-acetylmorphine in urine at
detectable levels. Thebaine is not ubiquitous among those that eat poppy
seeds, and there\'s always your idiosyncratic ingester. So, you may have
all the components of a positive, but MROs are routinely not reporting
it as a positive. That\'s the problem.

There have been bouncing cutoffs. The military, we started with 300
nanograms per mil for codeine and morphine. We went to 4,000 morphine,
2,000 codeine. It\'s now back down to 2,000 morphine and codeine, the
Medical Review Office making the majority of calls in this.

HHS\' cutoff changes are shown. DOT\'s cutoff changes are shown. In
their Notice of Proposed Rulemaking under new part 40, going in for DOT
testing, their cutoffs suggest that at 15,000 nanograms per mil for
morphine, there is no possibility of seeds. It\'s another hand wasted
toxicological ingenuity. I\'m sure we can eat enough ‑‑ if there\'s
enough rum and butter, I\'m sure we can get enough in our body with the
right seeds to clear that 15,000 hurdle. That\'s not the point. Let\'s
detect 6-acetylmorphine.

Now, taking the pieces apart and designing a good program, part one is
even the federal government when it was reviewing this issue and looking
at changing cutoffs recognized ‑‑ this is Dr. Autry\'s testimony in
front of subcommittee of the House in 1998. Essentially, among 1.1
million tests for drug use, opiate positives at 0.66 percent. That\'s
7,294 samples. Eighty-one percent of them were positive for morphine at
a level less than 2,000.

So, only 19 percent of the 0.66 percent had positives greater than 2,000
nanogram per mil cutoff. And of those, only two percent of the 0.66
percent were positive for 6-acetylmorphine. So, essentially, if you use
6-acetylmorphine or a cutoff of 2,000, you\'re going to miss the
predominance of positives in this population of 1.1 million people who
might be using heroin.

But the policy problem is really twofold. For one point, if labs are
doing lots of work and spending lots of money and time to find
morphine-positive results in urine and MROs are routinely not reporting
them to the company, well, we\'ve wasted a lot of time and money, and
that\'s not right. So, if you raise the cutoff, you lower the laboratory
burden and the cost to the system.

Unfortunately, higher cutoffs also reduce your likelihood of deterring
heroin use, and that ultimately is the problem we\'re after. We\'re
trying to differentiate poppy seeds from heroin abuse. Heroin on the
street has hydrochloride, or tar heroin, in a smokable form. We want to
distinguish, in effect, in this model, here\'s your heroin abuser. You
want to a program that has reasonable detection of heroin abuse that
will build a good deterrence. Without good detection you don\'t have
deterrence.

The other policy consensus that should be mentioned is cutoffs should
reflect drug use while minimizing potential endogenous, exogenous, and
chemical and electronic interferences. We all recognize that when you
find a piece of a tiger, you still have to differentiate the tiger.

(Laughter.)

Another piece of consensus to leave you with is positive opiate results
are conceded by all toxicologists poppy seeds can lead to positive
urinalysis findings at 300, at 2,000, maybe not at 15,000. You\'ll find
some consensus at levels below that.

So, heroin abuse is definitely increasing. My crime laboratory continues
to receive advancing numbers of submissions of heroin on a yearly basis.
Poppy seeds creates an evidentiary false positive in urinalysis;
therefore, urine tests are not effective in approaching the heroin
problem. Safety is compromised, because if you can\'t detect a heroin
problem, then the safety of the workplace or other tested population is
not good and with basically elevated cutoffs, lowering deterrence at the
very time that heroin abuse is increasing.

When you hear hoofbeats, you think horses. Well, the good thing is only
6-acetylmorphine proves heroin ingestion. One piece of bad news is ‑‑ or
good news, depending on how you take it ‑‑ urine does not routinely
accumulate 6-acetylmorphine in levels that are detectable, but hair
does. Six-acetylmorphine readily accumulates at detectable levels of
hair. You\'ve seen a lot of demonstration of that in the data provided
today.

The last part of this is what the Hair Testing Working Group provided to
DTAB was we suggested good reporting guidelines and maintaining MRO
discretion in the review of findings from hair. We believe hair provides
the complimentary matrix that is really needed in the program of
deterring heroin abuse. We should choose unique analytes, like
6-acetylmorphine, and use the lowest cutoffs we can while maintaining
reasonable safety.

This is the information that the workplace, the employer, and all of us
deserve. This is the information that urine provides. We need to do a
better job, and hair can do that for us. Thinking outside the box it was
nice to know that the Drug Testing Advisory Board has taken our advice.
The guidelines that will end up in a Notice of Proposed Rulemaking are
under development now. The second draft is already up; they\'re working
actively on the third. We\'re proud to have been a part of that process.
It\'s a very important time for hair drug testing and for heroin abuse.

I appreciate the opportunity to be here today. I\'ll slide out of the
way now and let you get to a break. Thanks very much.

DR. CAIRNS: Mr. Chairman, thank you for the extension of time. That now
concludes our formal presentation.

DR. KROLL: All right. Thank you very much.

We\'re going to take a short break now and report back to give the FDA
presentation in 15 minutes.

(Whereupon, the foregoing matter went off

the record at 11:12 a.m. and went back on

the record at 11:26 a.m.)

DR. KROLL: If the panel will take their seats, please.

Okay, at this time, we are going to continue with the FDA presentations.
And the next speaker is Dr. Albert Peacock.

DR. PEACOCK: Let me see if I can get some of your panel back.

DR. KROLL: All right.

DR. PEACOCK: I didn\'t want to make a presentation without my Division
Director here.

Good morning. I\'m Al Peacock, a scientific reviewer in the Chemistry
and Toxicology Branch of the Division of Clinical Laboratory Devices and
a member of the team reviewing this device today.

The Psychemedics RIA assay for opiates and hair that is presented here
today is a first-of-a-kind submission for the FDA for drug abuse testing
in hair. Currently, there are a number of review issues that we are
working with Psychemedics to resolve.

Today, I will be presenting to you several new matrix-related issues
that we would like your input on.

I\'ll summarize for you the study submitted by Psychemedics that
correspond to these new matrix review issues, and I\'ll ask you if these
studies are appropriate.

This device is a radioimmunoassay intended for use in the detection of
heroin in human hair. This device produces qualitative as well as
semi-quantitative results for morphine. For a positive report, two
nanograms of morphine per ten milligrams of hair are required. All
positive results must be confirmed by a more specific method, such as
GC, mass spec, or tandem mass spec or LC/MS/MS.

Now, heroin is metabolized in the body, obviously, to morphine at
6-acetylmorphine, or MAM, 6-MAM. Consequently, in order to report a
positive heroin result, this device has to identify morphine at a
concentration of two nanograms per ten milligrams of hair as well as
identifying 6-MAM in the mass spectrometry confirmation.

This is an assay flow chart for the analytical process. There are two
pathways that Psychemedics has presented to us for processing
presumptive positives after the initial digest and RIA screen.

The blue pathway here has an RIA assay who emits ‑‑ get a negative
report and the positives go through the mass spectrometry confirmation.
The red pathway emits the second RIA procedure and goes directly to the
mass spectrometry confirmation. One of our concerns with this approach
is that we don\'t think it\'s been fully demonstrated that these two
assay pathways will produce identical results when assaying the same
sample.

A total of 11 field studies were submitted by Psychemedics. Most of
these field studies were government funded and were designed by
independent scientists not associated with Psychemedics. Psychemedics
was contracted by these independent scientists to perform hair analysis
for their studies.

The following study design features are common to all of the clinical
field studies submitted by Psychemedics. The hair cutoff used was two
nanograms of morphine per ten milligrams of hair. The urine cutoff for
the opiates assay was 300 nanograms per mil. Of course, you\'ll note
that currently the opiate cutoff recommended by Sampson is 2,000. And
clinical truth was defined by Psychemedics as self-reporting in the
amount of drug ingested, self-reporting of the time of ingestion, and
verification of positive drug screen results, urine drug screen results
‑‑ excuse me, I\'m sorry, verification by a positive drug screen, urine
drug screen. And these were not confirmed.

There were two field studies which were used to determine the minimum
detectable dose. Biofield studies were used to determine clinical
sensitivity or positive percent agreement, one field study was used to
determine the clinical specificity or negative percent agreement, and
three field studies were used to determine the clinical usefulness of
hair testing.

The clinical data from research reports and data was collected ‑‑ other
data was collected from other diverse sources. The self-report and
urinalysis data from these studies were seen by Psychemedics only upon
receiving prepublication copies of the papers for the final peer review
copies of these papers.

We have the following concerns related to the field studies. These field
studies were uncontrolled, unmonitored, and not validated by
Psychemedics. They had no control of the hair sample collection process.
Psychemedics did not approve any of the study protocols used. There was
no demographic data submitted for these studies, so we couldn\'t
evaluate or make any kinds of conclusions of the potential of race, age,
sex, hair color or other individual differences and what their effects
could have been on the results.

The field studies lacked the gold standard method of determining true
drug use status. Therefore, we feel that in place of sensitivity and
specificity, clinical performance should be estimated in terms of
percent agreement with the available or chosen method of determining
drug use status.

We also have a concern that the positive percent agreement has been
determined primarily in clinical studies of heroin users, while the
primary use of this assay will be in a workplace setting.

Additionally, self-reporting has several deficiencies that can influence
clinical study results. These deficiencies include inaccuracy in
remembering amount of drug used and remembering the time of ingestion,
the truthfulness of reporting, unknown drug purity, varying efficiencies
of drug administrations, such as by injection or by smoking or by
inhalation. Validity of self-reporting may differ by the drug being
used, and the validity of self-reports of recent drug use may be less at
follow-up than at intake.

The environmental studies submitted by Psychemedics utilized ten hair
specimens. The studies were based on their three-domain properties of
hair, which are the accessible region, semi-accessible region, and
inaccessible domain. Excessive washing, perming, dyeing, and relaxing
hair treatments were evaluated.

The contamination studies consisted of three separate studies:
decontamination of drug pre-hair specimens that have been surface
contaminated with morphine, decontamination of hair specimens from
heroin users with morphine concentrations above the cutoff of two
nanograms of morphine per ten milligrams of hair, and potential of
contamination of hair ‑‑ drug-free hair by simulation of sweating of
hair that has been treated ‑‑ surface treated with drug.

One of the problems we have in evaluating this information is there\'s
conflicting evidence in the literature regarding some of these issues,
especially the potential for bias of testing results due to hair color.
Several human and animal studies have shown differences in drug
accumulation between pigmented and non-pigmented hair. Other studies
have found that hair pigmentation contributed negligibly to variations
in drug concentration values.

However, most studies found in the literature melanin concentrations in
the hair are not generally determined and correlated to the amount of
drug incorporated in the hair, making the evaluation of some of these
studies very difficult.

Psychemedics states that their procedure spins out the melanin fraction
from the dissolved hair digest. Consequently, any melanin-bound drugs
are excluded from the analytical procedure, and therefore no hair color
bias can be present if the Psychemedic methodology is used.

Now, I\'ll proceed to the questions. Lunch is approaching.

Okay. Due to the conflicting literature concerning these new
matrix-related issues, we need input from the panel to help us resolve
the following concerns. Question 1 for the panel: The clinical data in
this application is from research reports and data collected from
diverse sources and not from perspective controlled clinical trials that
evaluate heroin use. Therefore, a steady hypothesis inclusion/exclusion
criteria associated endpoints and a plan of statistical analysis were
not provided. First part of this question: Can assay performance be
established with these types of data? Why or why not?

DR. PEACOCK: And I\'ll go ahead and finish the question: Do the data
presented provide adequate characterization of assay performance?

PARTICIPANT: Read them all.

DR. PEACOCK: Okay, sorry. Question 2: With respect to making claims for
clinical sensitivity and specificity, is a single negative urine
analysis plus a negative self-reported drug use a sufficient, unbiased
standard for establishing true drug-free status?

Is a positive urinalysis that is not confirmed plus a positive
self-report of drug use a sufficient, unbiased standard for establishing
true drug-free status?

Question 3: Should the minimum dose required to produce a positive
result be determined?

Question 4: Should the relationship of the pharmacokinetics of drug use
and the incorporation of drug into the hair, that is single dose,
multiple dose, and chronic use be determined?

Question 5: Should the potential for bias by race, age, sex, hair color
or other individual differences in the incorporation and retention of
drug in the hair be evaluated? If yes, what additional studies should be
requested?

Question 6: Is the information provided by the sponsor adequate to
address the issue of retention of drug in the hair from environmental
exposure? If not, what additional information should be requested?

Seven, Question 7: Has the sponsor adequately demonstrated the effects
of various washing or hair treatment procedures on the internally
incorporated bound drug? If not, what additional studies should be
requested?

DR. KROLL: All right. Thank you.

At this time, I\'d like the panel members, if they have any questions,
to ask Dr. Peacock.

DR. KURT: Tom Kurt. I\'m asking about the precedence within the FDA of a
unique extraction method, which apparently is unique here ‑‑ not the RIA
technique itself, but an extraction method ‑‑ and comparing it to a few
years ago when Dr. Ostrea, that\'s O-S-T-R-E-A, came to FDA with a
unique extraction method for extracting meconium, or newborn infant
stools, for drugs of abuse in a PMA, and was that approved, and under
what precedence does that set for this?

DR. PEACOCK: I might have to refer to Dr. Gutman, that was before my
time.

DR. GUTMAN: There has been ‑‑ actually, I think it was clear ‑‑ but
there has been a meconium assay that was cleared, and the precedent is
whether there\'s reasonable science to support the submission. It\'s not
anything unique or special. It\'s a question of having the right science
to make you comfortable that this works in the way it\'s intended.

DR. EVERETT: James Everett. Is the data clear as it relates to race and
incorporation of drugs into hair? The sponsors suggest that there is no
difference. Is that true for the literature?

DR. PEACOCK: No, it\'s not. Hold on one sec. There are several studies
that ‑‑ Cone, et al. in 1996 found that cocaine concentrations in hair
of African-American subjects were significantly higher than those found
in Caucasian subjects.

Glyxner, in 1996, observed that drug residues for clembuturol were lower
in light hair, blond and gray, than dark hair, black or brown.

Henderson, in 1998, demonstrated that non-Caucasian subjects incorporate
approximately 2.9 times more duterated cocaine in their hair than did
Caucasian subjects in equivalent experimental conditions.

Kronstrand, in 1999, observed after a single oral administration of 100
milligrams of codeine to non-subjects, the incorporation of codeine into
hair is affected by its melanin content, and that relationship is
exponential.

As Psychemedics has mentioned, it\'s very difficult sometimes to compare
some of this data, because people use different methods, different
treatment methods, pre-treatment methods before analysis, and makes
comparing some of these results very difficult. But that\'s one of the
reasons we brought this question to the panel today to get your input,
because there\'s such conflicting information out there from
Psychemedics as well as some of the articles in the literature. We were
sort of at an impasse on what to believe, and that\'s why we wanted your
input.

DR. KROLL: Yes, Dr. Lasky.

DR. LASKY: So, based on what you just said, the uncertainty deals with
the drug that was measured and the extraction technique. Is that a
correct interpretation?

DR. PEACOCK: Well, it\'s the point and counterpoint. Psychemedics\'
position is that their enzymatic digestion process is much better and
especially since they spin the melanin out that they don\'t have an
issue with this. Whereas some of these solvent extraction processes
might lead to a problem.

DR. LASKY: All right. So, then that\'s really the issue, the fact that
in the literature it says that since that\'s variable if there is a
better technique, then demonstrate that that technique is better. And I
guess that\'s the question that in fact that we\'re addressing right
now, not what\'s in the literature but the data that has been submitted,
whether or not that\'s valid.

MS. PINKOS: This is Arleen Pinkos. I\'m also a member on the review
team. I think part of our dilemma is that the studies provided to us did
not have any demographic information associated with it. So, it was not
possible for us to, in an objective manner, evaluate whether there was a
bias or not. And the information that we do have is the anecdotal from
other people\'s studies or literature. So, we\'re just asking you is the
information that is available adequate?

DR. PEACOCK: One of the problems is that the studies that were submitted
to us came to Psychemedics from their contacts of people doing studies
that were independent of them setting up a study to answer some of these
analytical questions. And, so some of this demographic information is
not available and will never be available.

DR. KURT: Tom Kurt, another question.

MS. FLANNERY: A procedural point: Can Psychemedics address these
questions as they come or are they going to have a chance afterward?

DR. KROLL: Right now we\'re discussing these things with the FDA panel.

MS. FLANNERY: All right. So, they can address each of these issues
afterwards.

DR. KROLL: We can allow that. There is a time for open public hearing
scheduled at three o\'clock. We\'ll provide you some time to go ahead
and try to answer some of the questions. Why don\'t you write them down
and we can do it in an organized fashion?

DR. CLEMENT: I have a question. You mentioned the lack of a perspective
controlled study that\'s appropriately monitored by the Company,
particularly there\'s no controlled studies of actually ingestion of
heroin. That\'s a real problem. How would you, in a perfect world,
ethically do a study or how would you envision it be designed to
actually look at some of those issues?

DR. PEACOCK: No, I agree with you that it would be a very difficult
study to do, but people are given morphine and codeine under controlled
conditions all the time in hospital settings. And you could set up
something. People take morphine and codeine under controlled conditions
for pain management and they take constant chronic doses, and you know
what those doses are. You don\'t have self-reporting. I mean those can
be administered quantitatively with clinical drugs as well as monitoring
the time.

One of the problems we have with some of these studies is that because
Psychemedics did not design any of these protocols, even though they
were done monitoring people in criminal justice populations and parole,
some of the questions they could have answered if they had ‑‑ if they
were going to do it this way could have been asked but they weren\'t,
because they didn\'t have control over the studies. This is data coming
to them after the fact, and they didn\'t ‑‑ yes?

DR. CLEMENT: From looking at the results of the data, they cited four or
five studies where the sensitivity of people that they categorized
self-reported or urine positive testers sensitivities in the range of
like 70 at the low end. It was as high as 85 percent. I would think if
there\'s an error that occurred, it would err on the side of less
sensitivity. But from the data that\'s presented, they did their own
in-house study that showed zero false positives in their own workers.

DR. PEACOCK: Yes. It\'s not that I\'m arguing with what they did. I\'m
just asking your input, because this is the first hair study that\'s
coming in, and if you\'re giving the advice that this is acceptable to
you, it will become less of an issue for us. And we understand that
controlled perspective clinical trials on drugs like heroin, obviously,
would be very problematic. But there are ways to address some of these
issues, we feel, at least for morphine for sure.

DR. CLEMENT: So, if I can rephrase what you\'re trying to get an opinion
to us what is the minimum standard acceptable for an approval of this
type of product?

DR. GUTMAN: We\'re actually bringing this to panel so that you can in
fact provide us some perspective and advice, and I would remind the
panel, since Phil Phillips wasn\'t here to remind you this morning, that
we are under an obligation to seek a least burdensome threshold. So,
we\'re not looking to sell the product short, but we want to do what\'s
reasonable, and we want to make sure we aren\'t putting either incorrect
or artificial hurdles up. On the other hand, we want to have an honest
product with honest performance and honest labeling.

DR. PEACOCK: In other words, if you would agree or you feel comfortable
with the fact that a negative self-report, a negative urine, and a
negative hair test is good enough for a gold standard for a negative,
and a positive urine and a positive self-report and a positive hair test
is good enough gold standard for a positive, well, that question is
answered. But that\'s why we\'re asking it, to find out if you feel
that\'s true.

And if you feel that the data submitted to us from studies that they had
no control over, as far as I know, if data that came in secondarily is
good enough to answer some questions that we feel that could have been
answered with a little more of a controlled study that they designed
versus somebody else designing. Is that sort of where we\'re going?

DR. CLEMENT: Yes, yes, helpful.

DR. KROLL: Dr. Manno.

DR. MANNO: Barbara Manno. You said that, and I read in the materials
sent to us, that they are claiming they spin the melanin out. Have there
been ‑‑ is there adequate data comparing one or the other extraction
methods simultaneously against their procedure?

DR. PEACOCK: If there is, I\'m not aware of it.

DR. MANNO: What I\'m getting at is melanin-based or lack of melanin
specifically, is the data there for that comparison?

DR. PEACOCK: Not that I know of. Psychemedics might be aware of it. They
might be able to answer that question better than myself.

DR. KROLL: Dr. Henderson.

DR. HENDERSON: I asked Dr. Newel and perhaps in the break someone from
Psychemedics, along with Dr. Newel may be able to find some of the
answers. The data that he presented from Glasgow and London, to use that
as indicating that there was no effect on hair color ‑‑ by hair color
and hair type, I think that those are fairly homogenous populations, and
it\'s unclear what groups were analyzed in those populations. How were
they different? Were their hair textures, hair colors different?

I think there are enough populations that we are fairly confident
regularly used drugs ‑‑ incarcerated populations, patients in substance
abuse programs ‑‑ where if there was some interest in looking at whether
the test was different in different populations, that could be done.

I\'m concerned that the specificities and negativities are reported in
populations that have minimal or ‑‑ well, they\'re identified as
admitting to drug use, and since we\'re looking at using this in a
general population, I\'ve not seen and I\'m unaware of what the
predictive negative and positives are for general populations that I
would assume may have one and two percent prevalence of substance
abuses.

So, some of that information I would like if you could find some of
that.

DR. KROLL: I wanted to ask a question now to try to clarify for me and
maybe for the rest of the panel, it appears that Psychemedics has a
method that\'s pretty inclusive. If someone sends them a sample, they do
the sample preparation that uses RIA procedure, and then they have a
bunch of confirmatory procedures.

Now, what I\'d like to clarify for us exactly what is it that is
presented to the FDA for approval, what portions of that? Because
there\'s like three major sections, each of which are fairly extensive.

DR. PEACOCK: Right. The submission itself is for the RIA assay,
radioimmunoassay for opiates. But it\'s sort of like a package. I mean
the up front processing of the hair is critical to the assay as well as
the downstream processing, which is the washing as well as the mass
spec. And especially for heroin, I mean, you have to see 6-MAM in the
mass spectrometry. So, the application itself for the RIA assay, but
it\'s such an integrated system that we can\'t really exclude any piece.

DR. KROLL: All right.

DR. GUTMAN: And we would recognize that, I mean, for most drugs of the
assay we would recognize some reference methodology as an acceptable
framework for reference. So, this isn\'t ‑‑ the matrix is unusual, but
the idea of using a reference method to try and characterize performance
is not.

DR. KROLL: That\'s fine. I mean, I just wanted to clarify that, because
it\'s a rather ‑‑ I mean there\'s the whole back-end, which is the
confirmatory portion, isn\'t really part of the submission. And it
appears like the front end, the sample preparation, is that part of the
submission or not?

DR. PEACOCK: Yes.

DR. KROLL: That is part of the submission, okay.

MS. PINKOS: Yes, but the confirmatory ‑‑ this is Arleen Pinkos ‑‑ the
confirmatory method for a urine test would also not be part of our
review either.

DR. KROLL: Right, okay.

Okay, and just my intent, what we\'re going to do eventually is go
through each question, and everybody speak. So, this is to ask Dr.
Peacock. Do you have any other questions, just to clarify issues in what
he presented?

DR. KURT: Were any attempts made to go to a detox unit in combination
with a methadone clinic to take samples in that kind of a situation
where you actually have patients in that flow path as opposed to giving
them drugs as test subjects?

DR. PEACOCK: Psychemedics would have to answer that question.

DR. KROLL: Okay. That\'s a question we may actually ask the Company, and
what we could probably do is when we come back after lunch is if the
Company can succinctly answer some of the questions as we get back into
the discussion so we can clarify those issues.

Any other questions from the panel?

Dr. Manno.

DR. MANNO: Manno again. You asked the question would we be satisfied
with a one negative urine, one negative hair, I believe it was, and a
self-report. Are you talking about hair and urine collection
simultaneously in time or are you separating them in time?

DR. PEACOCK: Psychemedics, their studies collected urine and I think
hair samples simultaneously.

DR. MANNO: Okay.

DR. LASKY: Okay. Any other questions from the Committee for Dr. ‑‑

MR. REYNOLDS: Stan Reynolds, consumer rep, and I have just one very
simple question: What is synthetic sweat? I mean is there a standard
formula for this?

DR. PEACOCK: I think you\'ll have to ask Psychemedics.

DR. KROLL: Okay, Dr. Rosenbloom.

DR. ROSENBLOOM: I was a bit confused by the data that seemed to show
that there was a lot of false negatives among expected drug users. The
percentages were, as indicated, 75 to 90 percent, but that still leaves
a lot of false negatives. And I wondered maybe that needs to be reviewed
by the Company, those slides, because they\'re not ‑‑ those tables
didn\'t come through in the published ‑‑ in the handouts. And I\'m not
sure what that represents. Maybe you can clarify it and whether if we
know how many RIA negative individuals are subsequently positive by the
GCMS or LCMS testing; in other words, what the false negativity rate is
with just the RIA. Do we have that data? Did I miss it?

DR. PEACOCK: I don\'t think I have that data, no.

DR. ROSENBLOOM: Well, we need that.

DR. KROLL: Dr. Everett?

DR. EVERETT: James Everett. The studies that they used to support the
approval of this device, are the methodologies the same or are they
different?

DR. PEACOCK: The testing methodologies? Each individual study was
designed independently by ‑‑

DR. EVERETT: I know they didn\'t have control over how they were done,
but are the methodologies the same or are they different?

DR. PEACOCK: You mean testing.

DR. EVERETT: Right.

DR. PEACOCK: As far as I know, they\'re the same.

DR. EVERETT: Okay.

DR. PEACOCK: The testing. And once the hair sample came in to
Psychemedics, they were all treated identically.

DR. EVERETT: But from the different studies or the different groups that
analyzed the hair samples, initially, are those the same methodologies
or are those different methodologies?

DR. PEACOCK: I guess I\'m not hearing what your question is.

DR. WILKINS: I might be able to clarify his question for you. I think
what Dr. Everett\'s referring to is in the published statistical
evaluation that was in the Forensic Science International 2000 paper
that looked at a series of eight studies that were termed small-scale
studies and that were retrospectively analyzed, the data that were
presented were analyzed and that paper obtained using the same
methodologies employed by the company or by the sponsor.

DR. PEACOCK: I think some of these statistical studies were done on
existing Psychemedics data. They were pulled out of the Psychemedics
database is my understanding. Like I say, it\'s not totally clear to us
either, so maybe Psychemedics can give us a little clearer answer on
that.

It\'s my understanding, when I was reading I think the same article you
were, is that it\'s sort of like Psychemedics has a database of hair
sample results, and then ‑‑

DR. EVERETT: But these are secondary data sets, right?

DR. PEACOCK: Say it again.

DR. EVERETT: These are secondary data sets.

DR. PEACOCK: Yes.

DR. HENDERSON: May I just ask one question?

DR. KROLL: Yes.

DR. HENDERSON: Is the FDA aware of any false positives that have been
reported for heroin using this methodology?

DR. PEACOCK: I\'m not, no.

DR. KROLL: Okay. Does the panel have any other questions for Dr.
Peacock?

DR. WILKINS: I do have one more, and I may have missed it in the
material, so I apologize if I did. But has the sponsor proposed a
monitoring program or a follow-up to track reports of either ‑‑ or
inconsistencies between perhaps what the MRO might perceive to be this
is a drug user, and I keep getting negative results or this is someone
who will never in a million years I would have predicted to be positive,
and yet I\'m getting positive hair tests. Is there some type of
monitoring proposed to kind of assess for that once it were to be
introduced?

MS. PINKOS: We have not discussed that with the ‑‑ this is Arleen Pinkos
‑‑ we have not discussed that with the sponsor, but that certainly is
something you can give us input on.

DR. LASKY: Can I ‑‑

DR. KROLL: Yes, Dr. Lasky.

DR. LASKY: Fred Lasky. I\'d like to comment on that. Presuming that this
device will be cleared for market, the device is subject to quality
system regulations, good manufacturing practices. Part of that
requirement is to monitor all complaints and to address all complaints
and investigate what the source of those complaints ‑‑ what the source
is. So, your question is a requirement once a medical device hits the
market. I\'m a little surprised that this device, which will be used
only within this laboratory is in fact going through this process, but
that\'s the sponsor\'s option.

And I think also, based on Dr. Kroll\'s question that I think is part of
what I\'m having also some difficulty in segmenting but the
clarification was helpful, in that we\'re looking at a collection
device, which has not really been questioned from what I\'ve heard or
seen in any of the data. An internal RIA method that in every case will
be confirmed with an accepted, definitive method. And to me that seems
like almost like the device is the whole package, and the reference
method, the confirmatory test, I guess, has met other standards that
everybody is comfortable with.

So, from my standpoint, the only real question is not the presumptive
positives of the RIA tests, because they will be verified by the
definitive method, but the potential for a false negative and how that
might be addressed and whether or not the data support that. That\'s
what I\'m waiting to get some clarify on.

I had the mike, so I just went on and on. I\'m sorry.

(Laughter.)

DR. KROLL: Any other questions from the panel?

Okay, it\'s about 12 o\'clock now. What I\'d like to do is we\'ll take a
break for lunch. We\'ll come back exactly at one o\'clock. At that time,
I think Psychemedics has written down some of the questions that the
panel had. We\'ll give them ten minutes to try to clarify those issues,
and then the panel will go in and start trying to address each question.

We\'ll adjourn till then.

(Whereupon, the foregoing matter went off

the record at 12:06 p.m. and went back on

the record at 1:07 p.m.)

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

(1:07 p.m.)

DR. KROLL: I\'d like the rest of the panel members to take their seats,
please.

All right. I\'d like to resume after lunch.

And now I believe Psychemedics was going to answer some of the questions
that were queried before and any other additional questions that the
panel may have. And what we can do is we go and discuss the questions.
If other issues arise, we then can ‑‑ we\'ll ask Psychemedics to clarify
those issues as they occur.

DR. CAIRNS: Thank you, Mr. Chairman.

Ten minutes, or whatever time we\'ve been allotted, is a little short,
so we\'re going to try and make our answers as scientifically brief as
possible.

Let\'s deal with the studies that were submitted, in other words, the
clinical studies from the methadone or heroin user clinics. We find that
more appropriate than trying to use a hospital study with critically ill
people just on morphine sulfate. The ingestion of heroin is a different
issue from in fact the deliberate giving of morphine sulfate to a
chronically ill patient. So, we would reject that suggestion.

However, let me emphasize that the five studies, A through E, that were
presented to you all used the same RIA assay method as is being applied
for approval. And we use the same hair test and the same cutoffs. So, in
essence, the five studies, while independent of Psychemedics, used all
the same methodology.

Secondly, there is demographic data, and I\'m sorry the panel member who
asked the question is absent, but if you look at some of the attachments
where in fact the results of studies A through E were published, you
will demographic information on ethnicity, race, gender, color. Those
are all embedded in those publications.

The next thing that came up, basically, was the issue of bias. And you
heard me say in my presentation there are no conflicting studies. It\'s
the issue of using different methodologies. But let me turn this over
for a more succinct analysis by Professor Newel.

MR. NEWEL: Thank you. First of all, I\'d just like to reiterate a couple
of major points. First, on all of the large-n studies that we looked at,
there were no ‑‑ there was no evidence of any conflict between them. We
all had the same results. And what\'s important in the large-n studies
is that with the exceptions of the data from Glasgow and Las Vegas were
basically run under different methodologies. All the other studies, the
large-n studies, were run under the Psychemedics methodology. That\'s
actually a plus, because what we\'ve seen as independent evaluators in
this issue is that we can\'t find any bias even with other methodologies
used.

In regards to the small-n studies, Dr. Peacock referred to a number of
them as saying that there seemed to be some conflict in the literature,
and actually referred to most of the studies that I originally showed.
I\'m glad that he did that, because this allows me to emphasize an
important point.

First of all, none of those small-n studies used the Psychemedics
methodology. All of these original authors only showed mean
concentrations. In one study, they had three African-Americans, and they
reported a mean concentration for African-Americans and for the four or
five, I can\'t remember, Caucasians.

Well, it would be nice if the world were as simple as simply looking at
the averages of two small means like that and being able to draw a
conclusion that would have any validity in a population. It would be
nice. As Dr. Peacock correctly pointed out, one author actually did use
the word \"significant.\" He said that there is a significant difference
in African-American populations.

Unfortunately, that was probably a misuse of the term. What we\'re
concerned with is statistical significance. And, so small-n studies
simply don\'t have the statistical power to be able to show those kinds
of differences when we ran the appropriate and standard statistical test
on their data, on the data that was originally published by all the same
authors that Dr. Peacock referred to. None of those studies showed
statistical significance except for the Kronstrand study.

The Kronstrand study had nine people. When we look carefully at that
data with a linear regression, one data point is considered an outlier.
In other words, one person seemed to throw the results into a
significant result. Now, we can\'t say at this moment whether or not
that\'s an indicator that there is a problem with codeine or not. I
think it\'s too early. But remember it\'s based on nine people and one
person in particular that had an extreme score.

Finally, make a comment about the racial diversity in some of the papers
that we talked about. I mentioned very briefly a paper by Ben Hoffman
that appeared in Journal of Clinical Occupational Medicine, I believe.
It\'s a recent paper; he had 1,800 people. And I gave the reference to
the one member who hasn\'t joined us yet over the break. That had a very
large and diverse population. It was a group of police officers. So, it
was workplace testing. It was not a user population. Drug use was found
in only a small percentage of these people, yet again he found no
significant hair color, race or ethnic bias.

And also I want to point out that of all the studies that we reported
you have copies, I believe, in the journals that you have. And our
experiences with this have included criminal justice populations,
probationers, and arrestee populations. I spent a lot of time in jail
cutting hair. A very ethnic and racial diverse group. So, we certainly
have a lot of diversity in our data.

I think that\'s it.

DR. CAIRNS: Thank you, Richard.

We\'ve heard some panel questions concerning false negatives, and I\'d
like to turn this over for a compare and contrast of the false negative
issue, urine versus hair.

Dr. Selavka.

DR. SELAVKA: Thank you. I\'d like to say for the record I was never in
prison cutting hair.

(Laughter.)

I think on the issue of false negative it requires review of the nature
of determining the true value of use history for a person who\'s having
their hair collected. There\'s been no question, and the question was
actually posed and answered correctly, of a false positive with hair
testing. Hair tests accurately identify heroin users. They have for 13
years with this particular sponsor. Frankly, there are many other
laboratories that routinely detect the presence of 6-mono acetylmorphine
and morphine in the hair of heroin users.

The predictive value for the test therefore demonstrates that you\'ll
have a significantly higher positive rate among tested individuals for
heroin when you use hair compared to urine ‑‑ eight percent versus 0.6
percent in one of the tables that\'s provided for you.

If you were to turn this question on its head and say that if the
question for false negatives was let\'s use the gold standard of
self-reported use of heroin and a positive hair test, urine would have a
very low analytical sensitivity, because the false negative rate is so
high.

So, I think if we do look at the clinically significant, the
procedurally significant, and the programmatic significant question,
which is false negatives, you actually have a much better program with
hair than you would with urine. I think we need to remember that.

If you add to that the fact that there\'s a medical review officer at
the receiving point of a laboratory\'s output and that they\'re
routinely not going to forward or verify those results from a urine test
to a company, therefore no action will be taken on a positive, on the
other hand you\'ll have a much more effective and far greater safety
measure with hair testing for opiate positives, because MROs will
forward hair positive results.

So, I wanted to put the false negatives into context that way. Thank
you.

DR. KROLL: All right, thank you.

Any other questions from the panel, from the group right now? We can ask
some questions later on too.

Dr. Lasky?

DR. WILKINS: Can I ask a question?

DR. KROLL: Well, Dr. Lasky is first.

DR. WILKINS: Oh, I\'m sorry, Dr. Lasky.

DR. LASKY: Okay. I have a general question about your history with the
use of this particular test. And as we discussed earlier, there were
issues about the complaints in handling and how you resolve them. And
with 13 years experience, can you just summarize for us any issues that
you have received from people who use your facilities and how you\'ve
resolved them with regard, of course, to the accuracy of the tests?

MR. THISTLE: Regarding heroin-positive results, in 13 years of testing,
with several million samples being submitted, I had looked for an opiate
or a heroin claim that I could have showed you when I showed you the
cases when I was speaking. I couldn\'t find any court cases on heroin.

I looked back to see if we had claims in that regard, and I couldn\'t
find any until I was reminded that we do have one in several million
tests of a high user that\'s claiming as part of a union issue, first of
all, the right of the company to test but also challenging his result.
And, so I have one claim in several million tests.

DR. KROLL: Okay. Dr. Wilkins?

DR. WILKINS: Yes. I have just one other question. And I guess I may have
missed this, and I want to make sure I understand. But is the intent of
the submission to determine heroin use only, because that\'s what I keep
hearing for determining heroin users, heroine users, and ‑‑ let me
finish my question.

The reason I ask that is because reading through the documents that I
have, which may not be perhaps everything that\'s necessarily been
submitted, it appears that the product would be used for \"opiates in
general\" is how it\'s termed. And, so therefore morphine due to codeine
ingestion, morphine due to morphine ingestion, morphine due to heroin
ingestion.

And I just want to make sure that I clearly understand the intent that
you ‑‑ the setting or the specific application you want to use it for,
just so that I comment later appropriately. Thanks.

MR. THISTLE: The intended use has been narrowed to opiates due to heroin
use.

DR. WILKINS: Okay. So, it\'s only heroin use.

DR. KROLL: Dr. Manno?

DR. MANNO: Could we go back to the negative bias again? I just want to
ask a simple question: Is it safe for me to make the conclusion that the
bias in the negative direction ‑‑ let me state that again ‑‑ the bias is
towards the negative side when it comes to hair color? The less hair
color the more chance you\'re going to have of having a negative.

MR. THISTLE: I\'m not sure I can answer that.

DR. MANNO: I think what I\'m doing is trying to look at the other side
of the coin. I\'m thinking if you have a very blonde person, a White
person, you\'d have less of a chance with a low concentration of picking
up a negative or more of a chance of getting a negative than a positive.

DR. CAIRNS: I think the bottom line answer is there is no bias, first of
all, even on the negative side, because, remember, the melanin is spun
out of the assay for the confirmation step.

DR. MANNO: Okay.

DR. CAIRNS: And for the RIA step.

DR. MANNO: Did you present studies in here, I may have missed them,
where at some point to show the difference between having the melanin
present and the melanin absent?

MR. THISTLE: Yes. As part of the studies that were submitted, there were
results from Psychemedics where the melanin is spun out, but there were
also evaluations of laboratories that don\'t do that. And you\'re not
seeing statistically significant deviations in any of those studies.

DR. MANNO: Okay.

DR. WILKINS: I\'m going to ask another one, just because it\'s following
up on the same issue. Can I do that or should we wait and come around?

DR. KROLL: Well, Dr. Clement wondered if he could ask one.

DR. WILKINS: Okay, go ahead.

DR. CLEMENT: Well, I can defer to that.

DR. WILKINS: Okay. We\'ll bounce back and forth.

The one question I have and perhaps ‑‑ and I\'m not a statistician, so
I\'m going to refer this one just for the statisticians in the room. But
when you do a retrospective examination of literature, peer-reviewed
literature to support a particular hypothesis or to test a specific
statistical hypothesis, it seems to me that there are several really
important things that you need to look at.

One is which you\'ve already pointed out, the small size of the studies,
is whether or not these studies have adequate numbers of subjects. Well,
you can\'t have it both ways. Either they have too small of a subject to
be able to rely on the data and use it or it does. So, it seems to me
like if these are very small studies and have low statistical power,
they couldn\'t have determined a difference anyway.

So, they were not capable of answering that question, plus were the
studies originally designed to look at that issue? And I think
restricting it only to the opiate papers, not to cocaine, not to MDMA,
not to MDE or any other assay, because to me, just as a reviewer, those,
in my mind, are not pertinent to your application per se, because you
want to do this for opiates. So, I\'m going to restrict it just to the
opiates.

And if you go back and look at those studies that were not originally
designed to do that, the population that was selected for the two
studies in particular weren\'t selected for this purpose. So, I don\'t
know if additional ‑‑ there may be some additional variables coupled
with a low sample size that we don\'t even know. So, relying on two
negative studies seems to me be as doubtful or inclusive as the one or
two human subject, controlled dose subjects that are.

So, for example, the other ‑‑ one more issue, is that, again for the
statisticians, if you go back and retrospectively examine data that was
not originally designed to look at this question at all, does not use
the same analytical techniques ‑‑ one of the two papers I\'m referring
to just was a methanol wash, I wouldn\'t expect it to agree with your
data anyway ‑‑ and then do a one-way ANOVA only looking at hair color
and a single time point, I might not expect to see a difference either.

I mean I\'m not ‑‑ as I say, I\'m not a statistician. If you had that
data and you were doing a multiway ANOVA with dose, for example, or age
or hair color or gender, whatever, it doesn\'t really matter to me what
the issue was. But it seems like you sort of need to control for that in
some way, whether it\'s analysis of covariance if you\'re looking at
dose and hair color or something.

And I\'m just trying to understand how you can use it to support the
fact that there\'s no hair color bias if you don\'t know all those
things. And maybe I\'m too simplistic, and that\'s a statistician
question. I just don\'t know.

MR. NEWEL: I would agree with you, everything that you\'ve said. I think
one of the third or fourth slides that I had up said why is this likely
that we see four of the five studies when we reanalyze these data using
appropriate statistical techniques? Why do those initial ‑‑

DR. WILKINS: Is that for codeine studies or opiate studies? I\'m just
referring to just the opiate studies, because I\'m trying to define. I
don\'t want to confuse the issue in my mind, because you haven\'t asked
me to look at cocaine.

MR. NEWEL: Okay. With whatever studies we reviewed there the essential
points were that these are small-n studies. They do not have the
sufficient statistical power to be able to show us that there are or are
not racial bias issues.

The point that I was trying to make is to draw your attention to the
fact that the original authors on papers that said there may be some
relation to melanin content or hair and drug incorporation, those
original authors did not use statistics. What they said was, \"Here\'s a
big mean, here\'s a little smaller mean, and therefore, maybe, who
knows, there\'s some relationship.\" What we do is take their same data
‑‑

DR. WILKINS: So, those two opiate publications did that? I wasn\'t aware
that that\'s what they were trying to say. My understanding was is the
first one was used to evaluate a method development. And the second one
was to develop whether or not you could even detect heroin and that kind
of a thing in hair, which is a different question. That\'s why I\'m
asking it.

MR. NEWEL: Right.

DR. WILKINS: I want to really understand this.

MR. NEWEL: That\'s the second part of the question, is how do you go
back and use what are basically secondary data analysis for these
issues? Because in some cases, even with the large-n studies, we don\'t
have the original authors. On some of the articles, like the Glasgow
study, were never intended to collect data for the purpose of comparing
hair color or melanin content and drug concentrations. That just
happened to be in their data set. We became aware of that and utilized
that data on a secondary data analysis.

Now, that\'s not an illegitimate statistical technique. It\'s done ‑‑
secondary data analysis is done all the time. That is not the associated
with their A priority hypothesis testing at all. We\'re basically using
an existing data set and reanalyzing it, not with any particular
hypothesis test in mind, other than to say is there some association
between these two variables?

DR. WILKINS: Okay.

DR. CAIRNS: In some cases, I believe it\'s a mischaracterization of a
piece of research work that was put together to answer an entirely
different question. So, I think the data we presented is we\'ve got one
Psychemedics opiate, statistically valid study. The others really ought
to be removed from the table, because they don\'t even measure up to it
as regards. And the study design originally intended to address the
issue whereas the other studies are mischaracterized as conflicting but
small-n and other experimental difficulties.

MR. THISTLE: Some of the studies that were provided to you on other
drugs were actually provided because you were given studies originally
on other drugs. We would agree that perhaps a cocaine study has no
relevance here, and if you were to not ‑‑

DR. WILKINS: I didn\'t mean to imply that. I just meant I was trying to
narrowly focus my examination to not bring up irrelevant issues. I
didn\'t mean to imply that it wasn\'t good to have looked at that
material.

MR. THISTLE: But I agree. For the purposes of this application, for
looking at an opiate assay submitted by Psychemedics, the important
studies would be the results obtained by Psychemedics with their opiate
assay and not necessarily the results obtained by someone else with
another methodology for another drug. And that\'s what I think you
should be focusing on.

DR. KROLL: Okay. Other questions?

Dr. Clement?

DR. CLEMENT: I have one question. I guess it\'s more of a comment on one
the slides on the assay performance for the clinical specificity on the
handouts we have. It\'s on page 8. This is regarding panel question 1.
It was also on the Powerpoint presentation as well. Would you like to
comment? Did you actually mean to put results true positives or is that
‑‑ I mean ‑‑

DR. CAIRNS: Is this the slide saying, effectiveness of urine versus ‑‑
of hair versus urine?

DR. CLEMENT: No, no. This is the clinical specificity test that was done
on the in-house employees. N equals 81 ‑‑

DR. CAIRNS: Oh, yes, I have it now.

DR. CLEMENT: You had at least written on here, and you may want to look
at it, it says the results are true positives for N equal 81s. Does that
mean all your patients were positive for heroin use?

DR. CAIRNS: No, no. I\'m sure we meant that they were all negative. I
apologize.

DR. CLEMENT: Okay. I just wanted to verify that. That would be very
happy employment.

DR. SELAVKA: This wasn\'t PCP. This was a ‑‑

DR. CLEMENT: Okay. I just wanted to clarify that. So, if we swap those,
the correct numbers ‑‑ those true negatives were 81; false positives
were zero. Is that correct?

DR. CAIRNS: That\'s correct.

DR. CLEMENT: And then your formula obviously is correct. So, your
specificity is 100 percent.

DR. CAIRNS: That\'s correct, sir.

DR. CLEMENT: Thank you.

DR. KROLL: Dr. Rosenbloom, did you have a question?

DR. ROSENBLOOM: Well, I\'m back to my confusion about negatives. Do we
know how many in those who you expect to have ‑‑ those who are in
treatment programs and so forth, how many negatives are obtained in that
population and how many negatives in the RIA are retested and found
positives in the definitive test? Does that make sense?

DR. CAIRNS: I think you\'re asking the question is were all of the
positives via the RIA morphine assay, were they confirmed as positive
heroin users?

DR. ROSENBLOOM: Yes.

DR. CAIRNS: The answer would be yes.

DR. ROSENBLOOM: Okay. So, there would be then no reason to look for
false negatives in the RIA.

DR. CAIRNS: The cutoff level is determined so, a, the poppy seed
ingestion is not detected as a false positive.

DR. ROSENBLOOM: Right.

DR. CAIRNS: So, the cutoff is a protection mechanism so that the poppy
syndrome does not enter into the equation in the determination of false
positives. The two nanogram cutoff is still there to be able to detect a
minimal detectable dose of 173 milligrams per month, which is very
little concern with the consumption of the average heroin addict on a
monthly basis.

DR. KROLL: Dr. Kurt has a question.

DR. KURT: Dr. Cairns, I\'d still like to clarify, because you\'ve
explained to us how in separate scientific articles the extraction
method has shown so many results as positive. And then in other articles
not using the extraction methods there are so many positives. If you\'d
explain to me in the same scientific article that samples were divided,
some were extracted and some weren\'t, were the same number of positives
above the two nanogram level received or is the extractor group fewer
than past the two nanogram bar for positive?

DR. CAIRNS: Yes. Let me go back to a fundamental procedure again. That
first RIA sample is an unwashed sample. The second sample, should it be
presumptive positive, is washed. So, the question came up was the
comparison of the two different flow charts within the lab. And, yes,
we\'ve done comparisons. They\'re in the submission, volume 3, page 1
through 23. And there was no significant results between the two
mechanisms.

DR. KROLL: Okay. Thank you. Are there any other questions before we
proceed to try to answer the questions.

Okay, Dr. Everett?

DR. EVERETT: Most of my questions have been answered, but I\'m still
unsure about the issue of the FDA indicating that the literature says
one thing and then you guys are saying something different; that is,
whether or not the literature supports the differences between the
biases where you say there is no difference, and race is only one of
those. In your opinion, is it the same or is it different?

MR. THISTLE: The differences don\'t exist in the large population
studies regarding bias. And the differences don\'t exist in any study
utilizing the technology that we\'re putting forward here. There\'s no
study that utilizes this technology that is in conflict at all.

With regards to the other issue of external contamination, there is no
conflict in the studies. We do a wash of three hours and 45 minutes and
analytically extend it another five hours. Some of the literature that
you have has a wash mechanism of 30 seconds. There\'s no conflict there.
We know the 30-second wash will not remove external contamination if
it\'s present. That\'s not a conflict, that\'s just the differentiation
in procedures.

DR. EVERETT: Then you\'re sure that when you say it\'s removing
contamination from the external surface it truly isn\'t leaching from
the internal surface.

DR. CAIRNS: Yes, I think we demonstrated that on the wash profile for a
typical heroin user where you saw the third, fourth, and fifth wash
approach a plateau value. So, you could imagine the external being
removed and then reaching a plateau. If you continued to wash, that
would diminish, diminish, diminish, and then suddenly you have this 30
nanograms of morphine as a skyscraper against the profile of the wash.
So, there\'s a clear way visually to distinguish a user from someone
who\'s environmentally contaminated.

DR. EVERETT: Well, the reason I mention that, because in perm and
bleaching hairs, frequently there is damage. And in looking at the
studies as retrospective studies, as a prospective study, that doesn\'t
seem to bear out.

DR. CAIRNS: Yes. Obviously, when we quoted to you that certain cosmetic
treatments would in fact reduce the levels, that is because some of the
outer regions of the hair are in fact structurally affected. But please
remember that what goes in easily comes back out easily on the wash
kinetic profile that we use. So, there\'s the level playing field. What
goes in easily comes back out easily if in fact you\'re dealing with
treated hair.

DR. EVERETT: It doesn\'t appear the playing field is really level,
because the retrospective studies were not ‑‑ many of them, as I look at
them, weren\'t designed to do that.

MR. THISTLE: I know what you\'re saying.

DR. EVERETT: But the data is presented by using that fashion, but they
really were never set out to do that.

MR. THISTLE: I know what you\'re saying, but the element of consistency
between studies A through E and the large population studies that were
deliberately designed to look at biases, there\'s a consistency thread
in the methodology running through these. So, you can do direct
comparisons. Our problem is comparisons where methodologies such as
30-second wash with methanol, that is no way can be compared to a result
from an extensive wash procedures that\'s previously demonstrated to
show the differentiation. You must first of all differentiate external
from ingested before you make any statements as regards bias.

DR. KROLL: Can I suggest we continue now? We can try to clarify these
issues as we proceed.

DR. EVERETT: I have one other question, and that deals with the essence
of deciding to do this as a retrospective study, and I think many of
these questions could have been most appropriately addressed as a
prospective study. I\'m interested in your reason for choosing
retrospective data as opposed to prospective data.

MR. THISTLE: The contamination studies that ‑‑ the question I think
started out with contamination issues and leaching of drug out of hair.
The contamination studies weren\'t done with retrospective data. We
submitted data on hair that we contaminated.

And I think we\'re confusing two different issues here. The
retrospective data was done for the sensitivity and specificity. And
there\'s some retrospective data on studies that look at hair color and
race and denoted those features. And I\'m not sure what the difference
between ‑‑ those features don\'t really change, whether you\'re looking
at the data retrospectively or prospectively. Those are standard
features that you can look at regardless of when you get that data.

But I think we\'re mixing two things. We\'re mixing contamination
studies with ‑‑ actually, I think we\'re mixing three things here.
We\'re mixing contamination with bias studies, which were separate from
the retrospective, clinical sensitivity/specificity studies.

DR. KROLL: Okay. Why don\'t we proceed now, and thank you very much.

DR. CAIRNS: Thank you, Dr. Kroll.

DR. KROLL: Does Dr. Peacock want to come back up and ask the first
question for us? Is he here?

DR. PEACOCK: Can I just make one statement before we put the questions
up?

One of the reasons we\'re here today asking these questions is for the
very reason you\'re asking the questions of Psychemedics. The literature
is conflicted, and we had trouble deciding what is correct and what is
not. Psychemedics has their position. People in literature have
different positions with different methods, and that\'s one of the
reasons we\'re asking these questions of you today, to help us get a
feel from the experts that aren\'t directly involved in the review.

I\'m just supposed to read the questions now.

(Laughter.)

Sorry.

Question 1: The clinical data in this application is from research
reports and data collected from diverse sources and not from perspective
controlled clinical trials that evaluated heroin. Therefore a study
hypothesis, inclusion/exclusion criteria, associated end points, and a
plan of statistical analysis were not provided.

A, can assay performance be established with these types of data? Why or
why not? And, b, do the data presented provide adequate characterization
of assay performance?

DR. KROLL: Okay. What I\'d like to do is start with Dr. Everett, and
then we\'ll work our way around counterclockwise.

DR. EVERETT: Okay. For question 1, can the assay performance be
established with these types of data? Certainly they can, but the
question would be whether they were reliable or not, and I don\'t think
they really would be reliable considering the data that we\'ve already
looked at.

And then the second part: Do the data presented provide adequate
characterization of the assay performance? Clearly not, and that\'s
because the intent in the studies are different than what I\'ve seen at
this point. So, I just tend to disagree with this.

DR. WILKINS: I agree with Dr. Everett\'s comments, and I think for me I
do agree that in some cases, again, that certainly this type of data
analysis can be very useful and helpful. However, I think that
especially for a new or first-time application or first time it\'s been
seen, we don\'t have a lot to compare to, to go on. That unless we\'ve
controlled for some other ‑‑ for some critical factors, and I\'m not
necessarily intimating that means hair color, for example, or anything
like that, but unless the study is, in my mind, adequately controlled
for those potential variables that might have impacted on the
quantitative data that\'s being used to support the application, I just
don\'t feel like it\'s sufficient to go and try and pull that out
retrospectively from someone else\'s data in some cases.

The reason I think that\'s important is not so much related to the
specific techniques used but rather to the package insert and
interpretive guidelines that are going to be provided for the consumer.
And for me that\'s the bottom line in my mind is do the studies that are
incorporated to make the particular points, are they adequate to support
whatever we\'re going to tell the consumer for interpretation. And I do
not feel comfortable in doing that unless the study has additional
controls. And right now I don\'t feel that that\'s there.

DR. KURT: Tom Kurt. As a Medical Toxicologist, I would like to say that
I\'m quite enthusiastic about the prospects of hair testing versus the
problematic existence of easy cheating that has arisen under the urine
drug testing. However, I cannot say that my enthusiasm buoys me over the
problematic issues that both Dr. Everett and Dr. Wilkins have explained,
with which I agree.

DR. KROLL: Martin Kroll. I tend to be in agreement with what previously
has been said. I mean I tend to see that retrospective studies can be
used if they all are basically in agreement and they sort of cover most
of the possibilities. And from the data I\'ve seen submitted I\'m not
seeing that here. It\'s not there, and it can\'t be collected, but it\'s
not necessarily apparent that it\'s all here. Even a small prospective
study with very clear hypotheses and set goals perhaps can clarify some
of the issues. I think the fact that so many people here on the panel
are confused about what information is presented and where things stand
points out one of the problems.

There\'s also other issues that we keep coming back to hair and hair
color. I guess I get concerned with hair treatments. There\'s a lot of
variation. Certainly, there could be some small studies there where you
take an equivalent amount of hair and treat it many different ways so
that you can look at all the many different types of treatments. I think
those are things that at least I feel are real important for the FDA to
consider. And I would like to see that in a submission.

DR. MANNO: I can\'t add anything more to what\'s already been said. I
agree with all that\'s come before.

DR. LEWIS: Sherwood Lewis. I, likewise, am in agreement with the
foregone statements by the panel.

DR. CLEMENT: Steve Clement. Well, I never have troubles disagreeing with
my colleagues on some issues, and I think on this one, looking at the
practical issues of prospectively doing a prospective study of
challenging folks with heroin, which is the actual agent to be analyzed,
is very problematic, not only in this country but anywhere in the world
in terms of inducing tolerance, inducing addicts, inducing all kinds of
dependency. The studies are never going to get done.

And the sponsor did submit these four or five studies that did user
assay. Actually, I think there\'s some benefit of not having the sponsor
involved in the data analysis, because clearly that alleviates some of
the bias that could be done in-house by the sponsor, and the studies
were pretty uniform.

So, I think even though it\'s imperfect data in terms of looking at
sensitivity, it\'s the best there is, and I don\'t think I could come up
with any recommendations to improve on that based on the difficulties of
treating this disease.

And the issues on specificity look like we cleared up. It looked like
most of the employees are very happy but not on drugs, so it makes it
100 percent specific, which is fine with me.

DR. HENDERSON: Well, I actually gave my comments earlier, I think,
inappropriately. I certainly agree that there\'s problems with
retrospective data. But I too agree that I don\'t quite know how else
you could do that. But I do think that there are opportunities to obtain
retrospective data or perhaps even prospective data in diverse
populations.

I mean the data that we were submitted from the studies I think without
seeing the demographics, because I gather that\'s not available, but
just from the location of the studies, I think they\'re probably fairly
homogenous populations, and that concerns me.

Again, I think most all of these were in populations that were known to
use substances illicitly, and some of my concern in the workplace is
what are the predicted values for groups of people who do not have a
history of using substances?

DR. ROSENBLOOM: Yes. I agree that it would be nice to have populations
defined prospectively and with the ability to answer all these questions
without rejecting the retrospective data, which is convincing. But I
think that there are more studies that need to be done. So, I guess I\'m
halfway between what\'s been said by everybody else.

DR. KROLL: Okay, thank you, Dr. Rosenbloom.

DR. LASKY: Fred Lasky. First, I think that the small studies should just
be dismissed, and I think that was the intent of the presentation; that
they\'re not statistically valid, no conclusions can be brought from
them, so we should just forget about them. We should consider the larger
studies that were done to demonstrate the effectiveness or
ineffectiveness of the method that\'s under consideration. And I think
that\'s what we need to concentrate on.

I think that retrospective data is okay, but you have to be very careful
with it. So, I wouldn\'t dismiss the fact that this is retrospective
data. And it also brings to light the fact that there\'s over a dozen
years of experience that has been had with this assay and the fact that
hair testing is based on what we\'ve heard earlier in the day is really
an important matrix to look at.

And with that in mind, I think there are two issues, at least, that I\'m
trying to pull apart in my mind. One is, is hair as good as people who
are using the test believe it is? And I think that\'s one of the issues
that is in question. But I think that is true regardless of which test
is being done. So, I don\'t think that the test ‑‑ that the submission
before us is in a position to either answer that question one way or
another if it\'s going to be an accepted practice.

I believe that the sponsor has done studies that demonstrate in
reasonable studies that in fact hair is a reasonable matrix, that
they\'ve done adequate studies to demonstrate that they\'ve taken the
precaution to exclude as much as possible any contamination that may
occur from the outside. The washing steps I think are ‑‑ and the data
are convincing in my mind. And the way they handle those data
demonstrate to me that they are making an effort to reduce the
possibility of a false positive.

So, I think if there is an issue to be had here it\'s whether or not the
sample that is collected provides useful information with all of the
steps that is in the submission. And I believe that the sponsor has
demonstrated that the sample mix and based on what\'s in the literature
demonstrates hair is a reasonably effective sample, and that they do a
good job in trying to measure what\'s actually ingested through hair
analysis. So, I think it\'s reasonably convincing.

MR. REYNOLDS: Stan Reynolds. I agree with the point that Dr. Clement
made that there\'s really no way you\'re going to set up a controlled,
clinical study for hair. You\'re just not going to do that. But at the
same time, as Dr. Henderson and some others pointed out, that doesn\'t
preclude the possibility of gathering the demographic information that
you want.

I mean there\'s no reason that you can\'t go to methadone clinics and
treatment groups and get samples from people who are known heroin
addicts and at the same time have all the demographic information that
you need: race, age, ethnicity, hair type. All that information would be
available.

So, at the same time, you can design a study that would give you all the
demographic information to have and have the confirmation of the
standard urine test, confirmation by GC/mass spec or anything else that
you need to show a positive is a positive and a negative is a negative,
at the same time getting all the demographic data.

And we just don\'t have the demographic data here. You know, we\'re
comparing apples and oranges. You have study done one way, one study
done another way. I believe the data that they have presented for the
test is compelling. It shows that the test does work. But we don\'t know
about the population demographics. That\'s just the information we
don\'t have at this point.

DR. KROLL: All right. Thank you.

Why don\'t we go now to question 2.

DR. PEACOCK: Question 2: With respect to making claims for clinical
sensitivity and specificity, is a single negative urinalysis plus a
negative self-report of drug use a sufficient, unbiased standard for the
establishment ‑‑ for establishing true drug-free status?

And part B: Is a positive urinalysis that is not confirmed plus a
positive self-report of drug use a sufficient, unbiased standard for
establishing true drug-free status?

DR. KROLL: All right, thank you. And this time we\'ll start with Dr.
Clement, and we\'ll work around clockwise.

DR. CLEMENT: The first question, I think it may be the best we have, a
single urine analysis, although we know the inherent problems with that.
And particularly with self-reporting, there\'s incredible problems with
that. It\'s not the gold standard, but it\'s the best we have. But I
think in this case it\'s really not applicable, because in the data that
was presented by the company it was 100 percent negative, and they\'re
showing not only data of a single urinalysis but multiple urinalyses as
well in a fairly contained population. I think that\'s probably the best
that can be potentially done in any type of situation.

So, I think it may not be the best standard, but it\'s probably the best
that we can ever hope for.

And on the second question, I was trying to think in my own mind why
would someone self-report positive taking drugs for some other reason
besides he\'s really taking drugs, unless it\'s to try to get room and
board in some rehab center, and he\'s not taking drugs.

So, clearly, there could be some underestimation on that. But even if
that\'s the case, that would underestimate the performance of the assay
as opposed to overestimating the performance of the assay. And in the
numbers that are shown here, the performance is in the range of 70 to 80
to 90 percent. So, even given that problem, if anything, because it
would potentially underestimate the performance, it\'s still not bad at
numbers of 80, 85 percent.

So, I say, yes, it\'s probably true, but it\'s probably too true and
unrelated in this case.

DR. KROLL: Dr. Lewis.

DR. LEWIS: I\'m of the school with regard to A and B, which says you
don\'t believe anything you hear and only half of what you see. And as
far as self-reporting, I put it in that first category of what is it you
hear from the individual as far as claiming use or non-use. So, I have
to sort of reject both of those on that basis.

DR. MANNO: Manno. I\'m a little bit with Dr. Lewis in terms of
dependability of self-reporting. My experience has been that the
percentage of people that are honest in these situations is not too
great, so I have a problem there.

But, again, we don\'t have too much more to go on here. So, I guess a
negative urinalysis and a self-report if you\'re going to be able to do
‑‑ and I\'m taking this to mean in the ‑‑ at the end of the overall
scheme of things to make an interpretation that you may perhaps see this
person back later. I guess I can go along kind of tentatively with A.

I\'ve never been one to rest easy not confirming a positive urinalysis,
so I\'m not too comfortable with that. I would much rather see it linked
up with a hair sample confirmation, but then again there\'s a problem
with when is it going to be seen in the hair. We haven\'t even discussed
that here today. What is the delay from use to the first time you can
detect it in hair? So, I\'m just uncomfortable with both A and B, as the
way it\'s presented. I\'ll just leave it at that.

DR. KROLL: Martin Kroll. I tend to agree with Dr. Manno. I\'m looking at
this, and from the data that was presented a single negative urinalysis
will a lot of times ‑‑ there could be a lot of false negatives there.
So, I think you probably need something a little bit more than that to
establish a negative.

DR. KURT: Tom Kurt. A single negative urinalysis is too easy, as we
know, to cheat on nowadays, and so it\'s not necessarily a reliable
test, but that\'s what we rely upon under the DOT standards.
Nonetheless, we know the self-reported histories are totally unreliable,
and I\'ll cite the Australia study, the same Australia that I referred
to earlier in pediatrics in 1993 who studied the meconium stools of
3,000 infants in Detroit and found that 44 percent of them were
positives for opiates, cocaine or marijuana, and questioned the same
mothers and found that 11 percent, or one out of four, of the mothers
admitted they were using drugs of abuse during pregnancy. So, one out of
four admitted.

A similar Fendrich study reported in the American Journal of
Epidemiology last year on 320 samples of hair found only one out of our
told the truth about their drug abuse that was verified by hair
sampling.

So, self-reported history is generally markedly underestimates or is
reasonably wrong. And it\'s much more reasonably under two, or B. The B
portion is if the positive urinalysis is reviewed by a reliable medical
review officer in questioning the person to find out whether or not
they\'ve been using other drugs that could possibly render a test
positive under the circumstances.

I would say that a secondary sample, such as the hair sampling test once
it becomes more accepted into the Department of Transportation review,
should be acceptable in a medical review officer\'s situation also. But
I can\'t rely upon the self-reported history. I reliable upon a reliable
laboratory test.

DR. WILKINS: This is Dr. Wilkins again. I just want to comment. I don\'t
have anything in addition to add to the previous speakers. I agree with
actually aspects of all of the previous comments. And my significant
reservation is the issue of relying on self-report and the issue of a
single urinalysis result coupled with the timing issue of collection.
And I\'m not ‑‑ I\'m using that simply for ‑‑ the study design is where
I\'m concerned about that. So, that\'s it.

DR. EVERETT: James Everett. My concern here is that the initial test is
considered to be a screening test. It\'s not a guarantee that you\'re
going to be drug-free. But given the limits of science and the
sociological impacts, part A where it indicates that the negative
urinalysis plus a negative report is okay with me. That part is okay.
You can\'t retest everything.

But when you develop a positive test at this point, the general rules
for screening tests is to select out those people who most likely have
what you\'re looking for, and they are cheaper, they\'re easier to
perform, and the idea is that you will follow-up on a positive screening
test to determine if it is a true positive or if it\'s a false positive.

So, in reality, performing a screening test without some method for
determining if it\'s truly positive is almost irresponsible. It\'s like
why would you screen somebody for a disease and then you find the
disease on a screening test but you don\'t look to make sure that it\'s
there. So, it\'s not reasonable to perform this test, then get a
positive test, and then rely on the person\'s report now to determine if
you\'re going to do the confirmatory test.

The rules have to be consistent with any scientific test. If this is how
you\'re going to do it, then it can\'t be based on what the person says.
It has to be based on the results of the screening test, not necessarily
the report of the person, because if you do, it opens up again this ram
for abuse where perhaps the screening test was tampered with. And now
you induce a false situation where a person admits to something they
really weren\'t doing or they did but it wasn\'t in that time frame.

So, in reality, you must be consistent with the rules. If the screening
is positive, then the confirmatory test must be done regardless of what
the person\'s history.

MR. REYNOLDS: Stan Reynolds. And I pretty much agree with everything the
folks in the Committee have already said. I don\'t have any additional
comments.

DR. LASKY: Fred Lasky. I\'m not completely comfortable with the use of
these methods, but as Dr. Clement mentioned, I don\'t know what else to
do, quite frankly.

I have two comments with regard to what other people have said and also
just an editorial note, that many years ago, probably about 15 years
ago, Ray Gambino reported in his lab report to physicians that he had
done a study, actually he was looking at sensitivity of lab methods for
alcoholism, and he determined that in fact a self-report was more
sensitive than a serum alcohol level for determining alcoholism. And it
seemed to me, that was quite enlightening for me as a laboratorian, that
just asking a patient would provide more information than I could
provide from the laboratory was a tremendous blow to my ego.

But it seems that these sort of patients or subjects would not want to
self-report unless there was ‑‑ I would think there would be bias to say
that they weren\'t drug users and they were. And the intent of these
samples is to provide a challenge to the method that\'s being evaluated
to have a high probability that indeed these samples did have drugs in
them and that that is the only reason that these samples were selected.

If in fact the subject did lie, it seems to me that that would be a
greater challenge to the method that is being evaluated because of the
reliance of being truthful on this, quote, unquote, \"gold standard\" as
tarnished as it is.

So, my bottom line assessment is it\'s far from perfect, but I don\'t
know how else to do this.

DR. ROSENBLOOM: Rosenbloom. Yes, I have with looking at either A or B as
a gold standard, because we\'re talking about evaluating a test that is
measuring something quite different than what a urine test measures. And
we\'re talking about true drug-free status if looking at B a positive
urinalysis not confirmed, that\'s not confirmed on a repeat urine I take
it, not on the same urine ‑‑ on the same urine, okay. But a positive
self-report could relate to drug use in the past but not in the past few
days and why that would establish a true drug-free status I can\'t
imagine. So, I have trouble with these, because I have trouble with the
concept of a gold standard for sensitivity and specificity for a test
that could be itself the gold standard that\'s replacing or saying
something else about drug-free status. But I don\'t like either A or B.
I guess that\'s what I\'m saying.

DR. HENDERSON: Well, I certainly, as others have mentioned, and there
are problems with both of those, but having taken care of a lot of
pregnant drug users in my special population, I think the self-reporting
is a good edition, although new mothers may not confess to having used
drugs that their babies are obviously suffering the exposure. But
certainly pregnant women are very likely to admit it primarily because
they\'re afraid that not admitting it will jeopardize the health of
their fetus. So, I tend to believe women when they tell me that.

So, it may just be a special population, but I don\'t really have
objections to either of these, although obviously they\'re not perfect.

DR. ROSENBLOOM: I think we have to be careful about interpreting
admission data for alcohol as people will readily admit that they\'ve
had a few drinks, particularly if they know that they\'re going to be
tested, and they know the reliability of the testing, and it\'s a legal
drug. So, people will admit to smoking too, but I don\'t think that
relates at all to illegal drug use.

DR. KROLL: Okay. Good. Thank you.

Why don\'t we proceed and go to question 3.

DR. PEACOCK: Question 3: Should the minimum does required to produce a
positive result be determined?

DR. KROLL: Thank you. And this time I\'d like to start with Dr. Wilkins,
and we\'ll go counterclockwise.

DR. WILKINS: Thank you. I think my answer to this is truthfully it
depends in that if the intent of the product is to say that heroin use,
understanding that it\'s specifically for heroin, heroin use can be
detected within the last 90 days, then I think you do have to answer
this question, because you need to know whether or not you really would
have been able to detect heroin use if it\'s a single use within the
last 90 days. I mean I\'m fairly open on this issue. To me it depends on
what do you want to do with that result and what are you going to say
about that result?

So, again, to me, it\'s an interpretation issue or an ability to provide
adequate interpretation issue for a positive or a negative result,
whichever way it goes. Was there ‑‑ you know, if they use a lot, will
you be able to detect it? If they use only once, will you be able to
detect it? I\'m not even suggesting that you, and I\'m certainly not
suggesting that we, go out and administer heroin to non-drug using
volunteers and give them heroin or even drug-using volunteers and give
them heroin.

I think that they\'re perhaps getting back to our ‑‑ this directly
relates for me to the other question that you can design a perspective
study that is well enough statistically controlled, I think, in the data
analysis to do this without having to administer necessarily controlled
doses to non-using drug volunteers to answer this question.

So, if the intent is to be able to make statements about your ability to
detect individuals as positive or negative, and I think you need to know
the minimum dose required to product a positive result.

DR. KURT: Tom Kurt. I agree in part with that, but I think this is best
left up to an advisory board that reviews on this particular topic, such
as the DOT cutoffs were set by an advisory board specifically set for
such and Dr. Selavka who was here earlier with his Hair Testing Working
Group could very easily set up a kind of a working group in that kind of
a situation to review this exact topic based upon the existing
scientific studies, taking into account what would be considered a
rather substantial use, which I think in part has been explained in the
sponsor\'s application.

DR. KROLL: Martin Kroll. I have a tendency to like to see that the
minimum dose and detection of any system is determined sort of
independent of the matrix. Now, I understand there\'s a lot of ethical
issues; you don\'t want to give heroin to people. But you do appear to
have information that can relate the amount of morphine. That way you
could detect versus the amount of the MAM in hair.

And there are certainly plenty of people who take morphine for medicinal
purposes where it could actually be fairly well controlled. You know
what the exact dosage would be. So, it might be appropriate to use
something like that as a surrogate to get at least an idea so that if
somebody was interested in what the minimum dose was, that there would
be some reliable information.

DR. MANNO: Barbara Manno. I think I heard something earlier today
concerning the fact that this test is really a test to detect chronic
use of heroin versus it\'s not so great for acute use. And looking at
the pharmacokinetics, assuming that this is ‑‑ this is a big assumption,
I know ‑‑ but that the first test, the RIA test, as proposed here, would
be confirmed knowing that you have such a short window of detection of
6-MAM in urine, I\'m wondering if we don\'t need to know when that\'s
going to show up in hair, which then reflexes back. \>From that
standpoint, we\'re going to need to know when an approximate minimum
dose to give us a positive.

There\'s a second issue that I don\'t see ‑‑ I did not remember seeing,
but here again is addressing just the assay itself, and that is what\'s
the LOD and the LOQ of the procedure itself, both within day and between
day? So, there\'s really two issues to determine whether ‑‑ you don\'t
know what you\'re looking for to start with without those two things.
And ‑‑ yes, that\'s all I have to say.

DR. LEWIS: Sherwood Lewis. I don\'t think that it\'s at all reasonable
to even talk about minimal doses when we\'re dealing with heroin. This
is not like conducting a controlled clinical trial where you give the
particular drug or medication under known conditions, quantitatively,
and then look for whatever the results might be, if their analytical
results, by drawing blood samples, what have you.

So, to me, it doesn\'t have any meaning. Knowing the notorious nature of
the material itself and the roots of administration with regard to
heroin, I don\'t know how you could even begin to talk about minimal
doses or any other doses in that respect.

DR. CLEMENT: I concur with Dr. Lewis. I think the sponsor showed a
negative threshold between their sensitivity of doing the test, the two
nanograms, to pick up chronic heroin users, but still is high enough so
it does not pick up poppy seed users.

I guess my ignorance of not being familiar with the toxicology is
whether or not cough syrup and codeine and cough syrup and other forms
of codeine can counteract particularly on a MAM test, but I\'ll be
interested in the sponsor\'s comments or any of the other panel\'s
comments on medicinal amounts of codeine can be found positive both on
the urine test and the confirmatory.

DR. KROLL: We can try to clarify that now.

MR. IRVING: Hi, I\'m John Irving. Codeine does not produce 6-MAM in
either hair or urine. It\'s a specific metabolic product from the use of
heroin. There\'s no way the body can produce 6-MAM other than that.

DR. CLEMENT: Okay. Thank you. Well, in that case, I think the sponsor\'s
done a sufficient job on clarifying the sensitivity based on the studies
available and it\'s within a sufficient range.

DR. HENDERSON: Cassandra Henderson. From the materials submitted, it was
clear that MAM was only produced if a person ingested or used heroin in
some manner. So, as a clinician, I don\'t really care what the minimum
dosage is. If it\'s there, it\'s there, and that\'s all I need to know.

DR. ROSENBLOOM: Yes, I agree. This is an illegal drug. If it\'s there,
it\'s there. I don\'t think ‑‑ a minimum dose required to get a positive
result might be interesting and someone might want to do a study in
legally administered morphine, but I don\'t think ‑‑ oh, it\'s just in
heroin, yes, so there is no legal heroin. So, I don\'t know how it could
be done or why it would need to be done.

DR. LASKY: I agree. It\'s the obligation of the sponsor to demonstrate
that their cutoff point is analytical supportable, and that\'s the limit
of what this test is designed to do, and which that also addresses
question number 4, in my opinion. Trying to move ahead.

(Laughter.)

MR. REYNOLDS: And I agree with Dr. Rosenbloom and Dr. Henderson that
this is an illegal drug. There\'s no level that\'s acceptable. It
doesn\'t really matter whether you\'re talking about a low dosage over a
period of days or weeks or a large dosage over the course of a weekend.
If it gives you a positive, it gives you a positive, and it doesn\'t
matter how the positive got there. Whether it was chronic low dosage or
short-term high dosage, a positive is a positive. So, I don\'t think
it\'s really that critical. I think that they\'ve established their
detection limit, and that\'s the only thing that\'s really pertinent in
this area.

DR. EVERETT: James Everett. Certainly, I think the minimum dose should
be detected or determined, which they have. And that\'s very important
for any test that you do. You must know what the detection limits of
that test really is. Because this is test performance we\'re talking
about, and this is the real reason for detecting things that might
cross-react with your test.

It\'s when your lab results fall outside of that range, you have to
question whether the test is accurate or not. And without those
detection limits, you have no real recourse for knowing whether you\'re
dealing truly with an instrument failure, procedure failure, a
technician failure or in this particular case something the patient or
the client may have done to their hair.

And in a real-world situation ‑‑ I am family practice, and I see tests
all the time that are incorrect. They don\'t necessarily agree with what
the patient says. but in essence the question becomes who do I believe
the test or the patient? And the first thing I look at is the parameters
of the test. What did the manufacturer say the test is capable of doing,
and then I move on to evaluate whether or not the test truly is positive
or whether it\'s a false positive.

But, in essence, without looking at the patients, if you\'re going to
have a test, that test must have performance parameters, and you must
know what that test is capable of doing, if for no other reason than to
determine if the test is capable of doing what the manufacturer says it
can do.

DR. KROLL: All right, thank you. Let\'s go to question 4.

DR. PEACOCK: Question 4: Should the relationship of the pharmacokinetics
of drug use and the incorporation of drug into the hair, that is single
dose, multiple doses, and chronic use, be determined?

DR. KROLL: Okay. Let\'s start with Dr. Lewis, and we\'ll go ‑‑

DR. LEWIS: Yes, I\'m still mulling over my response to question 3. I
read that as meaning minimum dose, literally dose, not detection limits,
as Dr. Everett was speaking. I certainly agree with him on that.

And I would say that for question 4, to get on with it, it would be
nice, but I don\'t think that it\'s necessary this purpose to have that
pharmacokinetics information.

DR. KROLL: Okay, and let\'s move clockwise. Dr. Manno.

DR. HENDERSON: Should we move back just briefly to 3 to comment on Dr.
Everett\'s interpretation of 3 that it\'s the parameter of the test? And
I think Dr. Lewis and certainly I thought that it was how much drug does
a patient have to take in order to get a positive result. And I don\'t
care. I mean whatever they take is ‑‑ but Dr. Everett\'s point is that
the parameters of the test need to be identified and specific that you
can go to the packet insert and everybody knows what the test measures
and what the cutoffs are.

DR. KROLL: Okay. Maybe Dr. Peacock can clarify this question and whether
we\'ve answered it adequately.

DR. PEACOCK: We were thinking about the dose required, especially with
the 6-MAM and the morphine. You know, you might ‑‑ it goes back to the
variation, you know, we were worried about for hair, bias to hair color
as well, that it was related to the dose of drug being taken, not the
performance of LOD.

DR. ROSENBLOOM: I think that\'s the way most of us read it.

DR. KROLL: Dr. Manno?

DR. MANNO: Barbara Manno. Like the physicians, I don\'t care if a person
took a single dose, multiple dose or they\'re chronic users, but what I
do concern myself with from the laboratory standpoint is did the sample
get collected in the right time frame relative to drug use, and that
gives me ‑‑ I\'m more concerned about that aspect of the
pharmacokinetics at this point than I am anything else. So, a full
pharmacokinetic profile I don\'t think is necessary in order to say
whether the test is working or not.

DR. KROLL: I tend to agree with Dr. Manno. I think if there\'s
information in literature or other studies, if they can be put together
in a very nice review and they can be modeled some sense to show how
different types of patterns or drug use over different periods of time
how that would get incorporated in here and what you expect to see, that
that would be adequate.

DR. KURT: Tom Kurt. Because this is a testing for chronic drug use, I
think the pharmacokinetics is somewhat of a moot point, except as Dr.
Manno pointed out, the sample needs to be collected proximate in time.
It\'s nice to know that there are other metabolites that are captured by
the hair, such as the 6-MAM and are there, but I think it\'s important
to rate this as a chronic test, and perhaps in the future it could be
used in companion with the an acute test, such as a saliva test.

DR. WILKINS: I agree with the previous speakers, Dr. Kroll and Dr. Manno
and Dr. Kurt, what they just said. And I\'d like to say that I don\'t
think full-scale pharmacokinetic studies are necessary for chronic use.
However, again, to me, to my mind, just as a panel member, it\'s going
to totally depend on what the claims are that are going to be made. And
in my mind, if the claims for the consumer or the clinician is going to
rely on this test to assist them in making a determination of drug use
or whether, a treatment intervention is necessary or whatever.

And as it\'s been pointed out by the panel member, what they really want
to know is, is this ‑‑ if I\'ve got a positive, I\'m fine. Well, great.
So, are you always going to find if somebody takes heroin, how is the
test going to be reliable enough to determine that this person took
heroin and I can detect it? And am I going to pick up every positive,
and am I going to accurately determine the negatives?

And I think to some degree you can\'t really ‑‑ I don\'t think that the
data that I\'ve seen has really answered that question for me, that if
you get a negative result, for example, that that means the person has
not used heroin, okay, totally. And I realize that\'s an issue of false
negatives and false positives, but for most products you\'re looking at
sensitivity and specificity, and I need more information for that, I
think.

The other issue that hasn\'t come up yet, but really to me relates
directly to questions 3 and 4 in a way, is that the one thing that I
haven\'t seen yet, and again the sponsors may have the information, is
for 6-MAM, if this test is intended to be used for heroin use.

Just a simple question: If you have a hair sample or hair from a donor
and you analyze that hair sample 20 times from the same donor, do you
always get the same ‑‑ how does that relate to your cutoff and the
positive result, not standards or controls but a donor whose hair
contains drug, and you analyze that over and over again? Can I rely on
the fact that if I get a positive result this time, I\'m going to get a
positive result the next time and the next time?

That\'s the reproducibility of the test system that I don\'t think
we\'ve talked about at all, and I may have missed that. But to me that
relates to questions 3 and 4 and the ability to interpret a positive
result of the test.

MR. IRVING: My name is John Irving again. Let me put this in
perspective. If I\'m a drug user, a heroin user, and I get collected now
and I\'m positive, I get collected four hours from now, I\'m negative.

DR. WILKINS: That wasn\'t the question.

MR. IRVING: I know. If I take a hair sample now and I repeat the sample
numerous times, I\'m going to get a positive. If I collect the sample
tomorrow and an individual was right off the cutoff, I\'m going to
continue to get a positive. So, we are going to get a much more ‑‑ I\'m
not sure exactly what your question is.

DR. WILKINS: I don\'t think that that answers ‑‑ I\'m just saying if I
take a heroin user\'s hair sample and take a sufficient sample that I
can analyze that same pool of their hair or specimen that is received by
the laboratory multiple times ‑‑

MR. IRVING: I think that that is in the submission.

DR. WILKINS: ‑‑ on the same sample ‑‑ well, I haven\'t seen any data.
That\'s why I\'m asking the question, on hair, not ‑‑

MR. IRVING: It\'s in the submission we passed on to the FDA.

DR. WILKINS: Okay. Because that was one of the questions I had is for
6-MAM how reproducible is that? And if you have a sample that\'s around
your cutoff ‑‑ it\'s defining the issue of positive.

MR. IRVING: We had data in there that provided that information, and ‑‑

DR. KROLL: Excuse me, Dr. Gutman wants to make a comment.

DR. GUTMAN: Yes, that\'s not a review issue. We have that information
and didn\'t think it was a problem.

DR. WILKINS: It may not, but for me to answer these questions I felt
that that was something I needed to know.

DR. GUTMAN: Diana, it\'s in the submission under physician data. We went
even as far as taking the sample, testing it a year later, the same
sample, and got comparable results. That\'s in the submission. We took
the sample and ‑‑

DR. WILKINS: No, I thought some of those decreased over time, didn\'t
they? But that\'s a different issue.

DR. GUTMAN: A slight decrease.

DR. WILKINS: Okay.

DR. GUTMAN: It\'s within experimental range, but that was also part of
that submission.

DR. WILKINS: Okay.

DR. GUTMAN: So, yes, we will continue to get a positive on that sample.

DR. EVERETT: James Everett. I don\'t think the pharmacokinetics under
these conditions is truly necessary. But I didn\'t read anything in the
papers that we got that described whether the hair was incorporated ‑‑
whether the drug, rather, was incorporated into the hair uniformly in
its distribution. And that is did they have a particular site where they
thought the hair sample should be taken from; that is, is it
incorporated in the back of the head the same rate as it is in the front
or the side? I didn\'t really see that.

DR. HENDERSON: It\'s there.

DR. EVERETT: It\'s there?

DR. HENDERSON: It\'s there.

DR. EVERETT: Okay.

DR. KROLL: Stan Reynolds?

MR. REYNOLDS: Stan Reynolds. And I pretty much agree with the rest of
the panel that basically I don\'t think you need to do pharmacokinetics.
Again, there\'s the problem with how would you do it if you wanted to
unless you could compare it to morphine or something else.

Basically, what I need to know and what people using this need to know
is if an addict took heroin yesterday, can I pick it up today? It\'s
that simple. Or can I pick it up tomorrow. What\'s the time frame from
the time of use that you can pick it up? I think that\'s what we all
need to know. It goes back to the sample collection. When I can be sure
that the sample from a user actually is going to become a positive? Is
six hours too soon? Is eight hours enough? I think that\'s the basic
information that you want.

DR. HENDERSON: That\'s in the submission about it depends on the rate of
hair growth. It\'s in the submission, and it depends on the rate of hair
growth, that I think it was 0.6 millimeters to, I think, four
millimeters was the length that I read, and from 14 days to 90 days. So,
that\'s in there. And the reproducibility I think is in there where they
stored it for a year and then tested it again, and that was similar.

DR. LASKY: Fred Lasky. This is not necessary for the submission, in my
opinion.

DR. ROSENBLOOM: Arlan Rosenbloom. I would like to know ‑‑ I think it
would be interesting to know if a single-dose exposure ‑‑ say a kid goes
to a rave and two months later if it\'s in his hair or her hair. I think
that would be interesting. I\'m not sure how important it is for
workplace testing and all the other applications.

It would seem to me that ‑‑ and this is not a pharmacokinetic issue as
much as how much exposure you need to get a positive test ‑‑ I would
think that the differences in usage would be worked out by the MRO
who\'s reviewing this data with the user and if they say, \"Well, I\'m
not using it anymore\" or \"That happened six months ago,\" is there a
possibility of looking at the hair segmentally to get them by the short
hairs, as it were, and determine whether they\'ve had drug use in the
last month or so? Perhaps the Company can comment on that.

DR. CAIRNS: I regretted, perhaps, to educate you to the science of hair
testing. Yes, hair grows half an inch per month. And as regards the
ingestion to the hair appearing at the surface of the scalp for cutting,
that would take between five and seven days to grow from base of
follicle to surface of skin for cutting. So, your question is that if
someone took heroin today, yes, it would take seven or perhaps a few
days longer for that section of the hair that the heroin is incorporated
in to be cut from the scalp and tested.

For the issue of segmental analysis, that is correct, you can in fact
look at, say, that first half-inch of growth from the scalp which will
detect the drug use within that 30-day approximate time window. The
minimum detectable dose, we\'ve outlined in the submission as a mean
detectable dose of 173 milligrams per month. And that\'s an
infinitesimally small amount compared with, say, a chronic user up at
800 milligrams per month.

DR. ROSENBLOOM: These doses mean nothing to me. That\'s not a ‑‑

DR. CAIRNS: But you\'re correct, it can be detected in a shorter length
of hair.

DR. ROSENBLOOM: Does a dose like that, as a single dose, I mean does
that make sense as a single dose, number one? Number two, if it does
make sense as a single dose, then it would appear, I presume, in a
segment.

DR. CAIRNS: Well, a single dose, Dr. Rosenbloom, may well be only
somewhere of the order of 16 or 20 milligrams, if you\'re talking street
dose. In that case, the individual may have to consume several little
doses to go just above the cutoff.

DR. ROSENBLOOM: So, the problem of picking up a single dose is you
likely wouldn\'t.

DR. CAIRNS: Yes. We stress the fact that the reason for not doing the
single-dose study was an analytical problem, that a single dose would
not challenge the assay or the cutoff.

DR. ROSENBLOOM: Okay.

DR. HENDERSON: I have nothing to add. Cassandra Henderson.

DR. CLEMENT: I have nothing to add.

DR. KROLL: Okay. Thank you. Let\'s go to question 5.

DR. PEACOCK: Question 5: Should the potential for bias by race, age,
sex, hair color or other individual differences in the incorporation or
retention of drug in the hair be evaluated? If yes, what additional
studies should be requested?

DR. KROLL: Let\'s start with Dr. Kurt. Then we\'ll move
counterclockwise.

DR. KURT: I think that it should to avoid discrimination problems under
the Americans with Disabilities Act and other factors in the federal
legislation. And I think that a point could be made in the hair testing
that has been presented in the larger-n groups that there was no
division by sex. As we know in the male population, most of us don\'t do
anything to lighten our hair except when it gets gray. Women tend to
lighten their hair, which, in general, I think probably removes some of
their melanin, so that population might be somewhat skewed if included
in the population as a whole. So, I think further studies need to be
done in this regard.

DR. KROLL: I tend to agree with Dr. Kurt. I don\'t think they have to be
tremendously thorough studies, but there are a lot of women who dye
their hair or change their hair color or do other things to it.

And as with respect to hair color, maybe do enough studies or put
together the studies in such a way so that things related to the amount
of melanin that\'s in the hair since that seems to be the main culprit.
But even though I think that you probably have some evidence that the
melanin\'s removed, but to make certain that that\'s very clearly stated
what\'s going on and how that works.

DR. MANNO: I agree with Dr. Kroll. Nothing else to say.

DR. LEWIS: Sherwood Lewis. I have nothing to add.

DR. CLEMENT: Steve Clement. I think some of these should be done but
possibly as post-marketing. From looking at it as best I can it looks
like, if anything, any of these variables would, if anything, decrease
the sensitivity of the assay, so the bias would be against picking it up
instead of for picking it up.

So, from that standpoint, if you still get a positive test, the person
took heroin, period. There\'s no questions about it. It\'s just a matter
of whether it picked me up or it picked up someone else. But if it is
positive, I didn\'t see anything in the materials presented that showed
that there would be a bias on causing a false positive, which is the
biggest concern I had.

DR. HENDERSON: I think there\'s no question that studies need to be done
to assess the influence of any of these demographic factors. And my
concern is that it would discriminate against populations where perhaps
the test was more sensitive; that is, that it\'s not that they didn\'t
take it, it\'s just that their friends who did take it may be at an
advantage of being able to treat their hair, wash their hair, do things,
because their level was lower than when they started than other
populations. And, so I think there\'s no question it has to be studied.

I agree with Dr. Clement, it certainly could be post-marketing, perhaps,
but definitely that data needs to be gathered.

To Mr. Reynolds\' suggestion a couple of questions ago, there are
populations that could easily be accessed to collect populations to look
at these issues.

DR. ROSENBLOOM: I have nothing to add.

DR. LASKY: Fred Lasky. I agree that these are important studies that
have sociological impact. I believe that the sponsor has shown, at least
with reasonable assurance, that this is not a major issue, but I don\'t
think that the specific questions which are important here have been
addressed to the specifics. I would think that these studies would be
done because of liability issues, and that would probably be the primary
incentive. But I think it would be an important thing to do post-market.

MR. REYNOLDS: I pretty much agree with what everyone else has said, that
the dyeing and treating and things of this nature seem to, if anything,
decrease the sensitivity, and you\'re not going to get false positives
as a result. The demographic data should be collected. Once again, it
can be collected post-market. This can be done fairly simply, and I
don\'t think it would be too burdensome for the manufacturer to do that.

DR. EVERETT: James Everett. Certainly these items are necessary to be
done, if for nothing other than to help prevent fraud and abuse. This is
a test that stands at high potential for fraud and abuse as well as
general accusations about who\'s used a drug, who hasn\'t used a drug.

Without doing these tests you will not know who the test is not suited
for. If the test is suitable for young kids, the only way you\'re going
to know is you have to check. If it\'s suitable or not suitable for
elderly people because their chemistry changes quite a bit, and if you
don\'t do the test, then you won\'t know. And these are just the
fundamentals of all tests that should be done.

DR. WILKINS: Diana Wilkins again. I agree with the comments of Dr.
Everett just a moment ago. I think that the studies do need to be done.
And the thing that I\'m focusing in on, I think, is the individual
differences in retention of drug in hair. And I think ‑‑ because I\'m
thinking of this as a potential application in a clinical setting.

The average hair growth rate, at least of what I\'ve seen reported in
the literature, is a huge range. And we\'ve talked about earlier with
the problems of using a mean data, a mean data point or a mean value.
That can be problematic at times. I\'ve seen anywhere in the literature
from 0.6 to 1.3 centimeters per month. I don\'t know which number is
valid, to tell you the truth, because it\'s from a wide range of
studies. So, hair growth rate is important.

So, my question then is, well, if I\'m going to rely on this to
determine whether someone has stopped using heroin in a clinic or
something like that, when am I going to be able to determine this? I
would think hair growth rate would be somewhat important in that issue.
When will a formally positive user become negative? Or if I keep testing
them for six months, are they going to be positive for six months
whether they continue to use or not? I can\'t answer that question. I\'m
not saying that this test isn\'t sensitive enough to do that, but I
don\'t know that I have the data to convince me that we can answer that
type of question.

DR. KROLL: Okay. Let\'s go to question 6.

DR. PEACOCK: Question 6: Is the information provided by the sponsor
adequate to address the issue of retention of drug in the hair from
environmental exposure? If not, what additional information should be
requested?

DR. KROLL: Let\'s start with Dr. Manno and move clockwise.

DR. MANNO: Barbara Manno. May I ask the sponsor a question ‑‑

DR. KROLL: Sure.

DR. MANNO: ‑‑ before I answer this? In your procedure, in processing the
hair prior to the ‑‑ during the wash process, who determines or what
determines what you\'re calling the short process and the long process?
That wasn\'t exactly clear to me.

MR. IRVING: Right now, our standard process is for all the samples to go
through the entire wash procedure. We don\'t do a retest of the sample.
We do an initial screening test. We do the extensive wash, digest our
sample, do a confirmation, and apply the wash kinetics. And that\'s
across the board for all our samples right now.

DR. MANNO: Then why do you have ‑‑ well, never mind.

MR. IRVING: Part of the reason that\'s in there is because some of the
initial studies had some of that data in there also.

DR. MANNO: Oh, okay. But you are proposing it with that long process.

MR. IRVING: We\'re proposing that the single immunoassay followed by the
extensive wash and the confirmation.

DR. MANNO: Okay, thank you.

DR. KROLL: Can you just give us your name, so we can ‑‑

MR. IRVING: Oh, John Irving, I\'m sorry.

DR. MANNO: Barbara Manno again. I think that I\'m satisfied with that
wash procedure that they\'ve presented.

DR. KROLL: Martin Kroll. I\'m basically satisfied. I would like to see
when they do the analysis, the short analysis, against what they
consider typical drug users, it would be nice to manipulate the data and
show it against somebody who\'s right near the cutoff and what the
effect is. I mean, again, when you\'re working with real problems, it\'s
not the typical user. Where you get in trouble is somebody who\'s right
close to a cutoff or whatever, and that presents issues and problems.

DR. KURT: Tom Kurt. I agree with both Dr. Manno and Dr. Kroll, and yes.

DR. WILKINS: Dr. Wilkins. I\'m going to say in general yes with one
exception. The only thing, and I\'m not necessarily ‑‑ I\'m just saying
this as a possibility to be considered ‑‑ is that the effectiveness of
the wash procedure and retention of drug in hair, the data looks very
good what presented for ‑‑ the data that was in the submission looked
very convincing.

But from my perspective is that most users or heroin users it was soaked
drug, and most heroin users are not soaking their hair in heroin
solutions. And that\'s always been brought up as a limitation in the
past for doing these type of studies is that that\'s not a really good
‑‑ it\'s not a realistic model for assessing environmental exposure.

Having said that, I think, if anything, it probably sort of pushes it to
the one extreme where you would probably, if anything, be getting a lot
of drug in there and challenging your system. But in reality and
practice, I think people are being exposed to smoke and exposed to
powder on hair, and I think that\'s a very different ‑‑ I think it\'s a
different route or a different means of environmental contamination that
the wash procedure would need to be addressed.

So, while the data that is submitted here using the soaked procedure
does suggest to me that the washing procedure is quite effective, it
would have been significantly enhanced in my mind and very convincing
had there also been some data with hair that had been exposed to smoke
or perhaps powder or what have you. That would have really clinched it
for me.

DR. EVERETT: James Everett. I particularly like the washing data, and
that\'s kind of rare. But in reality, it does demonstrate that you can
remove a consistent amount of drug from the hair before the actual
specific test is performed at the end. And I think, again, it\'s very
difficult to go through all of the possible environmental exposures that
a person\'s hair could go through, particularly one who\'s using heroin.
So, I\'m satisfied with the data that they\'ve already presented.

MR. REYNOLDS: Stan Reynolds. In addition to the experimental soaking,
they also had the group of police officer, undercover police officers,
who did have exposure to the environment in the testing that they did on
them.

DR. WILKINS: That was a different drug. Wasn\'t that cocaine? That was a
different drug. That\'s why ‑‑ I think that last study that the
presenter showed this morning ‑‑

MR. THISTLE: Yes, Bill Thistle. That study with the undercover narcotics
officers was with cocaine, because that, in the literature, has always
been the drug of issue. There really has been no literature expressing
the fact that heroin is floating around or that people are soaking their
heads in heroin. We did those as extreme contamination scenarios.

The real contamination scenario that has been brought has been brought
with regards to cocaine, and that\'s why ‑‑ in fact, the articles that
you\'ve gotten about removal external contamination, both from the FDA
and from Psychemedics, deal primarily with cocaine. The exception is the
study that we did specifically for this assay where we soaked the hair
and where we did the sweat contamination experiment.

DR. KROLL: Let\'s move on. Anymore comments?

MR. REYNOLDS: But just to finish up that point, in my limited experience
in this area, if you\'re talking about environmental exposure, people
who tend to spend a lot of time in shooting galleries, generally are not
there as observers. So, I think exterior contamination of hair is really
not going to be a major issue.

DR. LASKY: Fred Lasky. I thought the data, as presented, were
convincing, but there were a couple of things that I think are worth
looking at with the data that\'s probably in the submission. And that is
we saw the washing steps, and it was based on average data, based on my
understanding of what I saw.

And I was intrigued by this extrapolation technique, which I thought was
also very convincing. But the question that I would have is whether or
not that extraction technique ‑‑ sorry, extrapolation technique
compensates for the wash-to-wash variability that might be seen from
sample to sample. I think the data probably contained in the submission.

And my suggestion would be that if it doesn\'t, that perhaps they extend
the extrapolation technique out a little bit further if that is how to
deal with that problem. But based on what I saw and the way it was
presented, I thought the data were convincing.

DR. ROSENBLOOM: I agree.

DR. HENDERSON: I\'d also agree.

DR. CLEMENT: I think the study was adequate. We hear all kinds of
stories of people saying they use something they\'re caught with for
various reasons. I remember in Newsweek, they said after the Olympics in
Australia, the coaches found, what, 20 vials of growth hormone and they
asked him what he was doing with it, and he said he uses it for his bald
spot on his head, and he rubs it in his hair. So, I guess you never can
be completely immune from what people will creatively come up with. So,
I think it was a good study, and it proved a point, and there\'s no
other further studies that need to be done.

DR. KROLL: Dr. Lewis.

DR. LEWIS: I\'m sorry. I have nothing to add.

DR. KROLL: Okay. Let\'s go to question 7.

DR. PEACOCK: Question 7: Has the sponsor adequately demonstrated the
effect of various washing or hair treatment procedures on the internally
incorporated or bound drug? If not, what additional studies should be
requested?

DR. KROLL: Okay, I\'d like to start with Dr. Henderson, and then we\'ll
go counterclockwise.

DR. HENDERSON: I was very impressed with the washing. And as a
clinician, I think that I would be hard pressed to argue that there\'s
an environmental risk to claiming someone\'s positive.

DR. ROSENBLOOM: Yes, I think that\'s probably true. There may be hair
treatment modalities of which we are unaware, and I would expect some
post-marketing further studies on whether one might be able to get a
wash-out from very badly damaged hair. But I wonder if that kind of
thing couldn\'t even be done in the laboratory without having to do it
from a person\'s head.

DR. LASKY: Fred Lasky. I agree with Dr. Rosenbloom\'s comment that if
this does become an issue, and I\'m not convinced it will, but if it
does, it could be easily handled in a post-market situation.

MR. REYNOLDS: Stan Reynolds. I have nothing further to add.

DR. EVERETT: James Everett. I agree. That\'s probably one of the better
parts of the entire study, I thought.

DR. WILKINS: I agree.

DR. KURT: Tom Kurt. I agree, in general. I would like to point out an
issue that this is a kind of an ongoing process that makes this washing
technique unique. The RIA technique is not necessarily unique, because
it\'s been used in the drug testing industry, the laboratory testing
industry for decades at this point. So, that\'s not the unique part of
this process that\'s being reviewed.

I would like to point out as a footnote one of my concerns that I
didn\'t mention this morning is the sodium azide reagent, which is 20
percent sodium azide, which is metabolized as cyanide in the body. It\'s
quite a dangerous substance, and I\'ve seen it used in our institution
once by a pharmacologists on the faculty for suicide. And familiar with
reports of it in the literature. It cannot be treated with a cyanide
antidote kit, so it\'s a very dangerous substance and should be
appropriately labeled.

DR. KROLL: Martin Kroll. I have no other additional comments.

DR. MANNO: Barbara Manno. I have no additional comments, but I have an
additional question. I just happened to notice, as I was looking at the
presentation of the wash on the ‑‑ it was question 6 in your
presentation. I was looking at the numbers for your deriving the 28.4
milligrams. It\'s page ‑‑ I can\'t make out which page it is. It looks
like page 11. As you\'ve derived this final answer of 28.4 nanograms per
ten milligrams of hair, I noticed that the test reports out on ten
milligrams of hair, but you\'re weighing in eight. Do you do a massaging
of the data there?

DR. CAIRNS: No. Again ‑‑

DR. KROLL: Please identify yourself.

DR. CAIRNS: Dr. Cairns again. The original screen is eight milligrams.
Then if it is screened positive, it would move forward for washing and
then digesting and confirmation. We do that on a weight basis.

DR. MANNO: So, how do you report it then?

DR. CAIRNS: Per ten milligrams.

DR. MANNO: But you started with eight milligrams of hair in the
analysis.

DR. CAIRNS: No. The first screen is eight. That\'s gone.

DR. MANNO: Okay.

DR. CAIRNS: Then we go back to the envelope and weight out a new amount,
and then it\'s prorated per weight.

DR. MANNO: Gotcha. Thank you. That wasn\'t clear to me. Thank you.

DR. KROLL: Any comments? Dr. Lewis?

DR. LEWIS: Yes, to answer the question, I think that there has been an
adequate demonstration of the effect of the washings.

DR. CLEMENT: I agree.

DR. KROLL: Okay, good.

Now, let me ask the FDA, do they think that we\'ve commented
sufficiently on these questions?

DR. GUTMAN: Yes.

DR. KROLL: Okay. Good.

DR. CAIRNS: Mr. Chairman, may I have your indulgence just for one
moment?

DR. KROLL: Well, right before that, I just want to ask if anybody else
in the panel had any other short comments they wanted to make, and then
we\'ll let you speak.

DR. WILKINS: Comments or questions?

DR. KROLL: Comments or questions but please keep them brief.

DR. WILKINS: A short one?

DR. KROLL: Yes.

DR. WILKINS: Just another clarification, just so I understand. On the
wash procedure, I\'m just a little confused. Again, this is all for me
determining a positive or a negative and how that\'s occurring. Is the
results of the final wash buffer subtracted from the quantitative mass
spec result to determine a value that is then compared to your cutoff?
And if so, is the wash analyzed by the semi-quantitative RIA or by the
MS? I\'m just not clear on it, and it doesn\'t really matter. I just
wanted to make sure I understood.

MR. IRVING: When we do ‑‑ this is John Irving again ‑‑ when we do the
wash, we do it by radioimmunoassay; however, we do a full curve on that
wash, and we do multiply that final value times five, subtracted from
the digest, and compare it against the cutoff.

DR. KROLL: Okay. Any other additional comments?

You wanted to make a few additional statements?

DR. CAIRNS: It\'s very short.

DR. KROLL: At three o\'clock, we do need to do the open public forum

DR. CAIRNS: It\'s Dr. Cairns again. For the record, I just feel it
necessary to address a few points made during the discussion of the
panel.

First of all, as regards additional information, such as regarding bias,
et cetera, that\'s holding hair to a different standard than urine has
been held traditionally.

And as regards to the demographics, I was sorry you had left the room
when we addressed the issue, but it is in the attachment 21, 22, 23, as
regards the individual studies A through E. There is demographic
information contained in there.

And as regards the clinical standards for exclusion/inclusion, I repeat
that Psychemedics just did not use that two parameter. We also used the
fact that there was a negative urine and a negative hair test in some of
those inclusion/exclusion criteria. So, we went beyond the standard as
presented in the questions. Thank you.

DR. KROLL: All right. Thank you, everybody, very much.

We need to do the open public hearing at three o\'clock, and now it\'s
about five minutes to three. I suggest we forego the break and do the
open public hearing now.

Okay, so we\'re going to hear from Rosemary Mumm.

MR. MUMM: Yes, thank you for inviting me and letting myself be invited.

I\'m presenting the practioners\' point of view for hair testing, and
we\'ve had some experience, obviously, with heroin. I\'d like to also,
in general, though, address my comments to technology.

I see there\'s a note here that if we have any financial obligations or
indebtedness to Psychemedics that they need to be stated. We do not. As
the DA\'s office, we in fact have a high accounts payable with them, and
we feel it\'s well worth it.

I\'m the Director of the Diversionary Programs, and I have been for
eight years with the New Orleans District Attorney\'s Office. The
Diversion Program is an alternative to prosecution program for new
offenders. These are both juvenile and adult folks who\'ve been arrested
on both narcotics and non-narcotics charges. They\'re all non-violent
offenders.

I\'ve been using hair testing for eight years to monitor the people in
our program to determine whether they need to be in a counseling track
for substance abuse or a counseling track for some other mental health
or clinical issue.

We assess them, if they are in a drug-free track, to become ‑‑ in a drug
counseling track, to become drug-free. That is our intent and our
motive. I\'m not trying to find reasons to put people in prison. I\'m
trying to find reasons to assist them to deal with their drug problem so
that they don\'t repeat their criminal offenses. Now, we are very
effective, by the way, in reducing criminal recidivism.

Our population ‑‑ I know that\'s been a big issue today ‑‑ ranges from
the ages of 12 to 66. We are primarily an African-American city by about
65 percent, and the population in our program reflects that demographics
data for the city. Primarily two-thirds of the people are male, and
complimentary, a third are female.

My background has been 20 years in the field of substance abuse
treatment. In the last ten years, that has been the context of criminal
justice. Someone asked what the BCSAC is behind my name, and that\'s
Louisiana credential, a Board-Certified Substance Abuse Counselor.

In addition to the Diversionary Program role that I have, I\'ve been
assisting with my boss, Harry Connick, the District Attorney, in helping
to implement high school drug testing programs, and I\'ll talk a little
bit about that.

We began our program eight years ago through funding from the Department
of Justice, specifically to look at hair testing to monitor offenders in
a supervisory program. Was it effective? Did it work? How did we feel
about it? We\'ve used Psychemedics technology during that whole time.

I believe that the program is so ‑‑ the technology, hair testing, is so
vital in our success that should I go to another program and continue in
substance abuse treatment, I cannot imagine myself doing treatment
anymore without hair testing. For us, a piece of hard evidence or as
hard of evidence as one can get in an imperfect world about whether
someone is using drugs or not.

We also used urinalysis. We want the benefits of both technologies ‑‑
the longer-term window of detection as well as determining whether
someone has recently used drugs. We use hair testing when someone is
first assessed when they get into our program to determine, as I said
before, what kind of counseling track they go into.

We have a lot of people who are arrested on non-narcotics charges who
deny drug use. And perhaps about half of those, when we administer a
hair test, come back with a positive result. Now, had we not done that
and only used urine, I would predict that that would be much lower,
because we have scheduled appointments with people. They know when
they\'re coming in, and they would know then that if they were to be
drug tested that many of those could refrain from use for a day or two.

Again, we also use the hair testing to monitor their three to 15 months
in our program. It allows us to decrease the number of urine tests that
we do and thus the cost of urine testing. We really are monitoring
whether someone is remaining drug-free as a part of their treatment
program. We would have to be urine testing maybe three times a week,
which would get enormously expensive for us.

With the kind of 24-hour tape recording that the hair offers for us, we
can reduce that frequency and still periodically do a hair test to see
if they\'re remaining drug-free. But I wouldn\'t abandon urine testing.
It\'s really important to know whether someone has used today or
yesterday or some recent ‑‑ had some recent use.

In addition, we like the advantages of the collectionees. Certainly, my
staff dislike collecting urine samples. They don\'t mind doing hair
sample collections. We like the retest capabilities when a result is
challenged. And again for other reasons, observing urine collections,
the frequency of being able to do a hair test rather than the high
volume manual labor-wise of doing random urines is greatly beneficial to
our program.

We have a very high level of confidence in its detection abilities. Our
staff rates heroin detection in hair as excellent, in light of the
self-report of the person being tested, their arrest history, and their
urinalysis results. Fortunately, in our 12 to 16 age population, which
is our juvenile program, we have had no self-reported heroine users nor
any positive hair tests, nor positive urine tests, I might add. In my
experience, though, beginning with some of our arrestees at age 17,
we\'ve seen some very, very serious heroin users who apparently just
hadn\'t been arrested before their 17th birthday.

For us, and this is not related to heroin use as this hearing has
directed, but the recent addition of MDMA in the panel has been very
welcome because of the expensive urine testing for MDMA, which we would
not be able to afford otherwise. And in New Orleans there\'s been quite
a number of young people who have either died or have had medical
emergencies, severe medical emergencies for which we now feel we have a
tool to assist with that intervention.

As far as the high school drug testing goes in New Orleans, there are
now ten schools in New Orleans that have adopted drug testing programs
using hair. A number of other principals, because of the success of
these schools, have stepped forward and are looking for money so that
they can adopt similar programs.

The principals have said, those who\'ve used hair testing in their
schools, that they\'ve seen disciplinary and behavioral problems drop.
The school milieu has changed, the student attitudes have changed, and
they feel that this has been a real positive addition to what\'s
happening in the schools.

Last week, one of the principals who\'s been doing testing for over
three years now, reported that they had tried urine testing. They knew
they had a big drug problem in their school ‑‑ I don\'t think she\'d
mind if I mentioned the school, called De La Salle High School, known in
the community as De La Drug High School prior to beginning hair testing
‑‑ and found that urine testing was not effective in turning their
school around with their drug use problems.

They gave a 90-day warning to their students and the parents. This is a
private school, so they had the constitutional right to test all their
students. The first year they had a 3.4 percent positive rate. The
second year went to 2.1. And year three was less than one percent. I
think their population is about 850 students.

They feel it has a very strong deterrent effect in not only discouraging
kids from using drugs but also in identifying those few kids who did
have a positive detection to get them into counseling and treatment.

All these high school programs are intended as student assistant
programs and not punitive programs.

And last week, finally, my boss and I testified before the ‑‑ well,
spoke before the mayor\'s Subcommittee on Violence in the Schools. We
had a shooting, like many other high schools in the country. As a result
of that, this Subcommittee was formed. And the Subcommittee agreed that
it would propose to the mayor and city council to seek advocacy from the
top administration to look to the public schools to adopt more testing
in the programs and endorsing hair testing as the method.

All I can say in summary is that as a clinician and someone whose
motivation is to get people into the proper services to turn their lives
around, I can\'t say enough about hair testing. It\'s not a perfect
technology. Certainly, we\'ve had people who have challenged the results
in our program, people who care not to admit that they\'re using but
when confronted with results 90 percent of the time or higher admit to
doing that.

We have power over the situation, unlike a pregnant mother who would
want to come forward with acknowledgement of drug use as a step and
where the DA\'s office ‑‑ these are people who are not motivated to
reveal their drug use, knowing full well that if they did it may
jeopardize their court case and potentially land them in jail.

That\'s all I have.

DR. KROLL: All right. Thank you.

All right. What did you want to do now? Do you think it\'s pertinent,
Dr. Gutman, to ask her questions from the panel?

DR. GUTMAN: Certainly. There\'s no reason you couldn\'t.

DR. KROLL: Okay.

DR. LEWIS: Sherwood Lewis. I had one quick question for you. And I\'d
like to know what the rationale and the ramifications for doing drug
testing in those individuals who are arrested or apprehended for
non-drug related offenses?

MR. MUMM: Well, it\'s my belief that if someone is arrested on a theft
charge, for example, there may in fact be an underlying substance abuse
disorder. We know that people who are needing money for drugs resort to
thefts and other criminal activities to get money for their drugs.

We want to screen ‑‑ when we put someone in an appropriate counseling
program, the priority is first to get them drug-free if they are abusing
drugs. Then if there are other family issues, mental health issues, that
can be worked in accordance with the drug treatment program. But unless
we serve to help that person get off of drugs, I personally would expect
that that criminal activity would continue.

DR. LEWIS: I guess my question goes to the point of whether an
individual voluntarily subjects himself or herself to that ‑‑

MR. MUMM: Yes, it\'s a voluntary program, yes.

DR. LEWIS: ‑‑ testing, even though they\'ve been arrested for something
not connected with the crime.

MR. MUMM: Right.

DR. LEWIS: So, the volunteer to ‑‑

MR. MUMM: Yes.

DR. LEWIS: ‑‑ do this.

MR. MUMM: Yes, they can enter the program or they can go to court and
face the charges there. So, it has some coercive elements to it.

DR. LEWIS: They enter the program, but they enter the program subsequent
to their having been tested positive.

MR. MUMM: No, they enter the program whether they\'re using drugs or
not, if they choose to, do so. Once they sign in and we take a hair
test, then that determines what type of program we would ask them to
participate in.

DR. LEWIS: So, they sign on to the program, then you folks do the
testing.

MR. MUMM: Right, and we tell them, though, when they sign in they know
that they will be hair tested.

DR. LEWIS: Thank you.

DR. KURT: Could I ask a quick question? Is there a consent form that
they sign when they give the specimen or is it an order from the court
that they give a specimen?

MR. MUMM: No, it\'s a consent form. There\'s no court order involved.

DR. KROLL: All right. Does anybody else from the public wish to speak?
Okay.

Dr. Gutman, do you have any questions or concerns or any comments you
want to make?

DR. GUTMAN: No, I don\'t.

DR. KROLL: All right. I was talking to our executive secretary, and she
said, well, I could summarize what our comments were. I think it\'s
rather difficult to summarize them, because for many of the questions I
think you heard divergent opinions. And some of them you heard a lot of
agreement. But I\'d certainly open it up to the panel if anybody wants
to make a closing comment or something else pertinent to the questions
that they have to ask.

DR. HENDERSON: I think in summary we all are excited about the
technology and would certainly urge that it be marketed soon, although
we do have reservations and perhaps many of those, if not all of those,
could be addressed in post-market study.

DR. KURT: As a medical review officer, I\'m certainly looking forward to
hair testing that can be performed under direct observation rather than
having urine testing performed, for it\'s so easy to cheat. However, I
think that the problematic areas that we pointed out today should be
remedied, and some of it can be done on a post-marketing basis.

DR. KROLL: Anybody else have any other comments?

MS. CALVIN: I just wanted to make some closing remarks. Thank you,
Psychemedics, FDA staff, and the panel, of course, for all of your
recommendations. And the next tentative meeting for the Clinical
Chemistry and Clinical Toxicology ‑‑ how could I forget Toxicology ‑‑
Devices Panel will January 17, 2001.

DR. KROLL: I\'d like to also thank the members of the panel, the FDA
staff, both from Psychemedics and other people who have made comments
for today.

Did you want to make any closing comments, Dr. Gutman?

DR. GUTMAN: No. I\'ll add my thanks to yours.

DR. KROLL: Okay. So, we now can adjourn the meeting.

(Whereupon, the FDA Meeting was concluded at 3:18 p.m.)