U.S. FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

**U.S. FOOD AND DRUG ADMINISTRATION**

**AND NATIONAL TRANSPORTATION SAFETY BOARD**

**JOINT PUBLIC MEETING**

**TRANSPORTATION SAFETY AND POTENTIALLY SEDATING**

**OR IMPAIRING MEDICATIONS**

National Transportation Safety Board Headquarters

429 L\'Enfant Plaza

Washington, D.C.

Wednesday, November 14, 2001

8:00 a.m.

BERNARD A. SCHWETZ, D.V.M., Ph.D.

Acting Principal Deputy Commissioner

Food and Drug Administration

CAROL CARMODY

Vice Chairman

National Transportation Safety Board

[Chairmen]{.underline}

STEVE GALSON, M.D., M.P.H.

Deputy Director

Center for Drug Evaluation and Research

Food and Drug Administration

DR. VERNON ELLINGSTAD

Director

Office of Research and Engineering

National Transportation Safety Board

[Technical Panels]{.underline}

[Food and Drug Administration]{.underline}

DR. ROBERT TEMPLE, Director

Office of Medical Policy and

Office of Drug Evaluation I

[Food and Drug Administration]{.underline}

DR. CHARLES GANLEY, Director

Division of Over-the-Counter Drug Products

DR. THOMAS LAUGHREN

Supervisory Medical Officer

> Division of Neuropharmacological Drug Products

DR. ROBERT MEYER, Director

Division of Pulmonary and Allergy

Drug Products

DR. RUSSELL KATZ, Director

Division of Neuropharmacological Drug

Products

DR. PAUL ANDREASON, Medical Officer

Division of Neuropharmacological Drug

Products

[National Transportation Safety Board]{.underline}

DR. MITCHELL GARBER, Medical Officer

Office of Research and Engineering

PETE KOTOWSKI, Motor Carrier Specialist

Office of Highway Safety

DR. MARGARET SWEENEY

Transportation Research Analyst

Safety Studies Division

Office of Research and Engineering

RAFAEL MARSHALL, Project Manager

Office of Highway Safety

[Witnesses]{.underline}

[Measuring Impairment]{.underline}

JAMES F. O\'HANLON, Ph.D.

Santa Barbara, California

GARY KAY, Ph.D.

Washington Neuropsychological Institute

Washington, D.C.

[Measuring Impairment]{.underline}

R. WILLIAM SOLLER, Ph.D.

Senior Vice President and Director

Science and Technology

Consumer Healthcare Products Association

Washington, D.C.

DR. JOHN WEILER

University of Iowa

Iowa City, Iowa

DR. BERT SPILKER, M.D., Vice President

Pharmaceutical Research and Manufacturers

of America

Washington, D.C.

[Epidemiology]{.underline}

JUDY A. STEVENS, M.S., M.P.H.

National Center for Injury Prevention

and Control

Division of Unintentional Injury Prevention

Centers for Disease Control

Atlanta, Georgia

WAYNE K. JEFFERY, B.Sc., M.Sc.

Toxicology Services

RCMP Forensic Laboratory

Vancouver, British Columbia

DOUGLAS LAMAR ALLEN

Alcohol and Drug Program Management

Federal Rail Administration

Washington, D.C.

FIONA J. COUPER, Ph.D.

Washington State Toxicological Laboratory

Washington State Patrol

Seattle, Washington

[State and Local Government]{.underline}

JON R. MAY, Ph.D., RPh

Consultant Pharmacist

National Association of Boards of Pharmacy

Gaithersburg, Maryland

[State and Local Government]{.underline}

WILLIAM GEORGE

Deputy Attorney General

Wilmington, Delaware

[Military]{.underline}

COLONEL ARLEEN SAENGER, USAF, MC, CFS

U.S. Air Force

Washington, D.C.

CAPTAIN DWIGHT C. FULTON, MC, USN, FS

U.S. Navy

Washington, D.C.

[Education]{.underline}

NATALIE HARTENBAUM, M.D., MPH

Occumedix

Maple Glen, Pennsylvani

KENNETH EDGELL

Office of the Secretary of Transportation

Washington, D.C.

ALLEN PARMET, M.D., MPH

Midwest Occupational Therapy

Kansas City, Missouri

[International]{.underline}

ASBJORG S. CHRISTOPHERSEN, PH.D.

Associate Director

National Institute of Forensic Toxicology

Pharmacy

Norway

DR. JOHANN J. deGIER

Ultrecht Institute for Pharmaceutical Science

The Netherlands

JENNIFER BERGIN, Bpharm, MBA

Pharmacy Consultant

Pharmacy Guild of Australia

# Warning Labels

R. WILLIAM SOLLER, Ph.D.

Senior Vice President and Director

Science and Technology

Consumer Healthcare Products Association

Washington, D.C.

DR. BERT SPILKER, Ph.D., Vice President

Pharmaceutical Research and Manufacturers

of America

Washington, D.C.

MICHAEL WOGALTER, Ph.D.

North Carolina State Unversity

Raleigh, North Carolina

RUTH DAY, Ph.D.

Duke Unversity

Durham, North Carolina

[Advocacy Group]{.underline}

KAREN TARNEY

Citizens Against Drug Impaired Drivers

Milwaukee, Wisconsin

[Advocacy Group]{.underline}

DAVID WILLIS, President

AAA Foundation for Traffic Safety

Washington, D.C.

NANCY SANDER, President

Allergy and Asthma Network/Mothers of

Asthmatics, Inc.

Fairfax, Virginia

DR. JOHANN J. de GIER

International Council on Alcohol, Drugs,

and Traffic Safety (ICADTS)

Tucson, Arizona

[Industry Group]{.underline}

R. WILLIAM SOLLER

Senior Vice President and Director

Science and Technology

Washington, D.C.

STEVE LISTER

LAURA TAUBIN

BILL BRADLEY

Consumer Healthcare Products Association

Washington, D.C.

NEAL THOMAS

American Trucking Association

Alexandria, Virginia

DR. TOM FAULKNER

Air Transport Association

Washington, D.C.

TODD SPENCER

Owner-Operator Independent Drivers Assc.

Grain Valley, Missouri

CAPTAIN JOHN DeLEONARDIS

Liberian International Ship and Corporate

Registry, LLC

Vienna, Virginia

WILLIAM MAHORNEY

American Bus Association

Washington, D.C.

[Industry Group]{.underline}

NORM LITTLER

United Motorcoach Association

Alexandria, Virginia

[Operator Union Group]{.underline}

KAREN HEAD

Legislative Council

Teamsters

Washington, D.C.

CAPTAIN RANDY POPIEL

Allied Pilots Association

Fort Worth, Texas

# Government Group

ROBERT M. CLARKE

> U.S. Department of Transportation Washington, D.C.

[Professional Group]{.underline}

RICHARD GELULA

Executive Director

National Sleep Foundation

Washington, D.C.

DARREL DROBNICH

Senior Director of Government and

Transportation Affairs

Washington, D.C.

[Also Present]{.underline}

DR. FRED TILTON

Deputy Federal Air Surgeon

Federal Aviation Administration

NANCY LaMONICA

Office of the Secretary

Department of Transportation

A G E N D A

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

Administrative Announcements 9

Dr. Vernon S. Ellingstad

Opening Remarks 11

Dr. Bernard Schwetz

Food and Drug Administration

Carol Carmody 16

National Transportation Safety Board

Introductions 22

Dr. Vernon S. Ellingstad

Witness Panel I - Measuring Impairment 27

Questions from Technical Panel/Parties 55

and Discussion

Audience Discussion 151

[Afternoon Session]{.underline}

Witness Panel II - Epidemiology 157

Questions from Technical Panel/Parties 183

and Discussion

Witness Panel III - State and Local Government 221

Questions from Technical Panel/Parties 229

and Discussion

Witness Panel IV - Military 278

Questions from Technical Panel/Parties 289

and Discussion

Adjournment 322

P R O C E E D I N G S

8:00 a.m.

Administrative Announcements

DR. ELLINGSTAD: Good morning.

I think we will begin. We have given people a little extra time to get
here and our apologies for the confusion that led some people to the
freight elevator and apparently a considerable wait.

Welcome to an unusual meeting that\'s a joint effort of the U.S. Food
and Drug Administration and the National Transportation Safety Board on
Transportation Safety and Potentially Sedating or Impairing Medications.

I\'m Vern Ellingstad from the National Transportation Safety Board. With
me is Dr. Steven Galson from the Food and Drug Administration, and we
will try to facilitate the efforts here today and tomorrow.

Before we begin the substance of the meeting, there are a few procedural
announcements that we need to make. In the event of an emergency, such
as fire, the building alarm system will activate and a voice message
will instruct persons to vacate the building. You should proceed to the
nearest exit. There are emergency exits up front to the left and to the
right of the platform and also at the back of the room.

Also for your convenience, restrooms and telephones are located in the
foyer on the left as you exit the room.

To provide an appropriate meeting environment, I\'d request that you set
your pagers and cell phones to alert you silently to avoid interrupting
the meeting. If this is not possible, please turn your device off. If
you must use a cell phone, please do it outside of the meeting room.

To begin the meeting, I\'d like to introduce Dr. Galson, who will
introduce our first greeting from the Food and Drug Administration.

Steve?

DR. GALSON: Thanks very much.

I\'m really extremely pleased today to welcome all of you, and I want to
start by introducing our Principal Deputy Commissioner for Food and
Drug, Dr. Bernard Schwetz.

Dr. Schwetz was from 1999, in September, until January 2001, Acting
Deputy Commissioner of Food and Drug, and he served as a senior advisor
for Science from September 1999 till June 2000. He was Director of
FDA\'s National Center for Toxicological Research in Jefferson,
Arkansas, from 1993 to 1999.

He\'s a Diplomat of the American Board of Toxicology and an Honorary
Diplomat of the American Veterinary Epidemiological Society.

Dr. Schwetz was the Acting Director of the Environmental Toxicology
Program at the National Institute for Environmental Health Sciences in
Research Triangle Park before coming to FDA in 1993.

Dr. Schwetz is a Member of the National Academy of Science\'s Institute
of Medicine. In addition to numerous other professional awards during
his career, Dr. Schwetz received the U.S. Government\'s 1998 Meritorious
Executive Presidential Rank Award.

It\'s truly a pleasure for me to welcome Dr. Schwetz here today to open
up the meeting for the Food and Drug Administration.

Thanks, Vern.

Opening Remarks

DR. SCHWETZ: Thank you, Steven.

Good morning to all of you. First, I\'d like to acknowledge the
important role that the NTSB plays in our nation\'s transportation
safety and particularly over the past few days with the heroic efforts
you\'re making to investigate the tragic plane crash in New York City on
Monday.

As devastating as that accident was, your quick work to investigate the
cause has helped to calm Americans\' immediate fears. Although the
precise cause of the crash is not yet known, it helps to know that it
doesn\'t appear to be another terrorist activity. We certainly wish you
every success in that on-going investigation.

From the FDA, we\'re happy to co-sponsor this first-ever FDA/NTSB Joint
Public Meeting. I\'m glad to see that our two organizations take this
opportunity to work together, to look at the role of sedating or
impairing medications in accidents and related injuries.

I\'d like to thank Mary Ann Blakey, the recently-appointed Chairman of
the National Transportation Safety Board, and Carol Carmody, the Vice
Chairman, and Dr. Vernon Ellingstad and his staff at the NTSB for
assisting FDA in putting this meeting together, and I would also thank
Dr. Ellingstad and Dr. Steven Galson from the FDA for co-chairing the
meeting today and tomorrow.

I\'m pleased to see the level and range of expertise that is assembled
here today on our panels and as witnesses as we consider the issues in
front of us. So, thank you all very much for being here.

The FDA is certainly very supportive of NTSB\'s efforts to improve the
safety of our nation\'s transportation operators, and we look forward to
being part of this effort. Our former FDA Commissioner, Dr. Jane Henney,
indicated last year that we would take this issue very seriously, and we
continue to have this as a high priority.

Today\'s workshop demonstrates our commitment to consider all
perspectives, including those of the transportation industry, other
government agencies, and the public. We will also work with the
pharmaceutical industry when considering recommendations that relate to
labeling changes.

Well, what are the issues that we hope to address in these two days?

First. How can we increase awareness of the public about the possible
impairment caused by prescription and over-the-counter drug products?

Second. How can we identify those products that cause impairment?

Third. How can we help the public avoid taking products that will cause
impairment while they\'re driving?

And fourth. Would relabeling those prescription and over-the-counter
products help the issue?

By looking at the data available today, we hope to define the magnitude
of the public health issue, both for transportation operators and for
those with whom they share the roads, rails, skies and the waterways.

We\'d like to look at possible mechanisms to screen for effects of time
on driving, perhaps by looking at well-established assessment methods to
see if they could be used to evaluate operators taking potentially
problematic medications.

We want to identify the best ways to communicate the potential risks to
the public. If we decide that labeling modifications are one effective
way to accomplish this, what changes should be made so that labeling
will be more informative to the user?

In closing, let me say that to the extent that drugs we approve are
contributing to errors made by vehicle operators, we are very concerned.
I assure you that we will take seriously any comments related to this
issue, whether the comments come out of this meeting today and tomorrow
or whether they are submitted to the docket.

The issues are complex, but they\'re not insurmountable. So, we want to
work together to help find solutions.

Thanks to all of you for participating in this meeting and for
contributing your time, expertise and creativity. I\'m looking forward
to a productive session.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. Schwetz.

I\'m pleased now to introduce our Vice Chairman, Ms. Carol Carmody. Ms.
Carmody worked for the Federal Aviation Administration from 1977 to
1988, including a tour as Deputy Director of Congressional Services.
From 1988 to \'94, she was an Aviation Staff Member of the Senate
Commerce Committee. From 1994 to 1999, she was the U.S. Representative
to the Council of the International Civil Aviation Organization, ICAO,
in Montreal.

She was sworn in as the 30th Member of the National Transportation
Safety Board in June of 2000 and appointed Vice Chairman on January 19th
of 2001. She served a stint this year as Acting Chairman, and she brings
a considerable amount of experience to the transportation area.

Carol?

Opening Remarks

MS. CARMODY: Thank you, Vern.

Good morning. I\'m Carol Carmody, as Vern said. Mary Ann Blakey was very
sorry not to be here this morning. She had looked forward to this. I
spoke with her yesterday evening, and, of course, she\'s occupied in New
York but wanted me to send her regards and her wishes for a successful
conference.

Before I get started this morning, I wanted to recognize the
contributions of a couple of former government servants. Former NTSB
Chairman Jim Hall and former FDA Commissioner Dr. Jane Henney. Those two
really initiated this concept some time ago, and they deserve credit. I
don\'t know if either is here today, but I did want to mention their
names.

Also, the planning has been ably executed by Dr. Vern Ellingstad of our
staff and by Dr. Steve Galson of the FDA, who are co-chairs of this
conference.

I also appreciate the attendance and the remarks very much of Dr.
Schwetz. I appreciate what you said about the NTSB and about our
efforts. We all feel that way, too.

Those of us gathered here today come from different sectors of society,
from different agencies, and in some cases from different countries, but
we all have the same goal, and that\'s to ensure safe travel for our
citizens. Just as in the past, when faced with a problem, we have come
together to work towards a unified solution.

Today, we\'re looking at an issue that we\'ve known about for years: the
fact that over-the-counter medicines and prescription drugs contribute
to transportation accidents. We\'ve made some recommendations to address
certain aspects of this issue. Even so, we\'ve not yet solved it, and
it\'s clear that we need to learn a lot more.

Many medicines have long been known to cause drowsiness. Others may
impair an individual\'s ability to fly an airplane, drive a car, steer a
ship or operate a train. In fact, recent studies have shown that several
over-the-counter medicines and prescription drugs can adversely affect
an individual\'s performance without him or her being aware of it.

Since 1987, the NTSB has investigated over a 150 accidents in all modes
of transportation in which over-the-counter medicines or prescription
drugs caused or contributed to the accident. In aviation alone,
over-the-counter medicines and prescription drugs played a part in 72
fatal accidents between 1987 and 1995. Since 1995, the numbers have been
on the rise.

We at the Safety Board believe that the numbers may be even higher than
we realize. Only a small percentage of people are ever tested for such
drugs following an accident. So, we believe that they may contribute to
more accidents than we\'re aware of.

So, we\'re faced with a tough question. How do we reduce the number of
accidents caused by such medications when the extent of the problem is
unknown? The answer is not simple. We must work together to expand
testing programs to educate the public.

Last year, the Board made a number of recommendations, including
expanding current toxicological testing requirements to get appropriate
samples from fatal transportation accidents, so we could determine what
effect these prescriptions and over-the-counter medicines are having.

The Board proposes expanding educational programs and providing better
warning labels on the medicines.

All of us here today understand that when education can prevent
accidents, it\'s our responsibility to provide that education to the
public. To all of the people operating planes, trains, cars, buses and
ships, they deserve to know what effect drugs will have on their
performance.

We should also recognize the efforts to date, and there have been many.
The Department of Transportation and its many modal administrations as
well as many other organizations here today have taken steps to reduce
the number of accidents caused by over-the-counter medicines and
prescription drugs.

The NTSB commends these efforts. As always, we want more. We recognize
that more needs to be done, and we must do it together. Certainly none
of us would be here today if we didn\'t think there was more room for
work.

Both the NTSB and the FDA appreciate the attendance of everyone today,
the experts, the participants, and those of you in the audience, and I
think we\'re one step closer to a common solution.

Thank you.

DR. ELLINGSTAD: Thank you, Vice Chairman Carmody.

Before we begin, we\'ll kind of outline the sort of procedures that we
will follow today and tomorrow in this public meeting. I\'d like to sort
of make it as clear as we can what this meeting is and is not.

It is not an adversarial proceedings. It is not a hearing. It is a
public meeting designed to elicit information and to provide information
that will inform both the FDA and the NTSB with respect to our interests
in this particular topic.

The way that the meeting will proceed is through a series of witness
panels. The panels, the members of the panels will each make a short
presentation and then respond to questions. The questions will be
directed by a technical panel composed of staff members from the FDA and
the NTSB, and questions will also be solicited from a number of

\-- those who are familiar with NTSB proceedings, referred to as
parties, and we will in a moment introduce who these parties are.

But each of the party groups representing various constituencies
affected by the issues of drugs in transportation safety will have an
opportunity to pose questions to the witnesses.

When we have completed that round, and we will try to do that as
equitably and fairly as we can, we will pass the questioning back to the
Technical Panel. Dr. Galson and I reserve the right to butt in and ask
questions, if we desire.

We will also solicit from the audience questions in writing that will be
forwarded up here to the podium and whichever of us is not moderating a
particular panel will sort those out, and we will pose those questions
also to the panel.

Time is of something of an essence, and we will try to maintain a
schedule better than our starting time was maintained this morning. So,
we would appreciate that all of the presentations as well as the
questions be kept concise.

The staff will circulate among the audience and hand out cards that will
contain the questions that will be brought up here. So, if you see staff
with cards, if you have a question, draw their attention to that and
send them up.

Another thing that is a little bit unusual in terms of proceedings that
the Board has been involved in is the provision for audience
presentations, and there will be two of those. One this morning at
approximately 11:15.

Anyone desiring to make a short five-minute presentation should contact
the desk in the lobby area, and we will only recognize individuals who
have registered to do that, and they will be called on to make those
short presentations today at 11:15, and there\'s also another session
that\'s set aside for that tomorrow.

What I\'d like to do, I believe that Dr. Galson has a couple of
administrative announcements with respect to the opening of a docket of
this meeting, and then I\'ll ask him to also introduce the FDA members
of the Technical Panel. When he\'s done with that, I\'ll catch the NTSB
members of the panel.

Introductions

DR. GALSON: Great. Thanks.

FDA, in our regulatory capacity, is required to have a copy of all of
the presentations in writing and filed to the FDA docket, and the docket
number for this meeting is 01N0397. Please make sure you file the copy
of your presentation, and if you\'ve not, give a copy to the FDA
representatives out at the table.

Also, any special requests for copies of the presentation from this
meeting should be asked for at the Registration Table if people in the
audience want copies, and they\'ll be mailed to you at a later date.

We\'ll put a transcript of the meeting on our FDA website by the middle
of December.

I\'d like to quickly introduce our Technical Panel that are here from
the agency. We\'ve really got an all-star cast of experts sitting up at
the table over here, and folks, if you\'d just raise your hand, so folks
know who you are.

Leading the team is Dr. Robert Temple, who\'s the Director of two
offices in the Drug Center, the Office of Medical Policy and the Office
of Drug Evaluation I.

Dr. Robert Meyer is the Director of Pulmonary and Allergy Drug Products.
Charlie Ganley is the Director of our Over-the-Counter Drug Products
Division. Russell Katz is the Director of our Division of
Neuropharmacological Drug Products. Tom Laughren is the Supervisory
Medical Officer in the same division, and Paul Andreason is a Medical
Officer in the division as well.

So, thank you, FDA experts, for being here, and we look forward to your
active participation.

DR. ELLINGSTAD: I\'d like to introduce the NTSB\'s staff who are serving
on the Tech Panel and will make themselves known with questions
throughout the course of today and tomorrow.

First, Dr. Mitch Garber is the Board Medical Officer, and I\'d like to
give a special acknowledgement for his very extensive effort in
coordinating this whole activity.

Next, Mr. Pete Kotowski, a Motor Carrier Specialist and Accident
Investigator with the Board\'s Office of Highway Safety. Dr. Rafael
Marshall, Project Manager and Investigator, also in the Office of
Highway Safety, at the NTSB, and Dr. Meg Sweeney, the Transportation
Research Analyst in our Safety Studies Division, here at the Safety
Board.

I\'d like also to acknowledge the participation of the various parties,
and what I\'d like to do very quickly is go around, and we\'ll do this
in an orderly sort of way to begin with at least, and I\'ll ask \--
we\'ll go to each of the tables and ask each participant at the various
tables to introduce themselves.

I\'d like to also mention that in the interest of expediency, what we
will ask each of the tables to do is to designate a spokesperson for the
purpose of questioning of our witness panels. We aren\'t going to have
an opportunity to go and have everybody at every table ask questions,
but if you will provide designated spokesman \-- provide your questions
to that spokesman, and we can handle the questioning in that particular
way. We certainly can rotate that spokesman duty during the course of
the two days.

Okay. Let me start over on my right with the Union table. Push the
button.

CAPTAIN POPIEL: Randy Popiel, Allied Pilots Association.

DR. ELLINGSTAD: Thank you.

And the Industry Table. Try it again.

MS. TAUBIN: Lorna Taubin, representing the Consumer Healthcare Products
Association.

DR. ELLINGSTAD: Okay. And we have another Industry Table, a
Transportation Industry Table.

CAPTAIN DeLEONARDIS: Captain John DeLeonardis, representing the Liberian
International Ship and Corporate Registry.

MR. SPENCER: Todd Spencer with the Owner Operator Independent Drivers
Association.

MR. LITTLER: Norm Littler with the United Motorcoach Association.

MR. MAHORNEY: Bill Mahorney with the American Bus Association.

MR. THOMAS: Neal Thomas with the American Trucking Association.

DR. FAULKNER: Tom Faulkner with the Air Transport Association.

DR. ELLINGSTAD: Thank you.

And the Advocacy Group Table.

MS. TARNEY: Karen Tarney, Citizens Against Drug Impaired Drivers.

MS. CHRISTOPHERSEN: Asbjorg Christophersen from the National Institute
of Forensic Toxicology in Norway.

DR. de GIER: Johann de Gier, International Council on Alcohol, Drugs and
Traffic Safety.

MS. SANDER: Nancy Sander, Allergy and Asthma Network, Mothers of
Asthmatics.

MR. WILLIS: David Willis, AAA Foundation for Traffic Safety.

DR. ELLINGSTAD: Okay. And the Government Table? Why don\'t we start \--
go ahead.

MR. CLARKE: Bob Clarke, U.S. Department of Transportation, Office of the
Secretary.

MS. LAMONICA: Nancy Lamonica, Department of Transportation, Office of
the Secretary.

MS. STEVENS: Judy Stevens, Centers for Disease Control and Prevention.

DR. ELLINGSTAD: Okay. Thank you.

Okay. Without further ado, we\'ll go to the Witness Panel, the first
Witness Panel dealing with the topic of Measuring Impairment, and what
we will do with this panel is kind of go right down from my right to
left.

Let me just very quickly introduce and kind of give the rules of
engagement for this group. We\'ll ask you each to confine your set of
opening remarks to five minutes, and we\'ll trust the Technical Panel
and the parties to elicit the additional information that you have
brought along.

We\'ll start with Dr. John Weiler from the University of Iowa.

Witness Panel I - Measuring Impairment

DR. WEILER: Are we ready with the slides?

Thank you for the opportunity to be here and talk about the use of
driving simulators to measure impairment in driving.

Next slide. There are a variety of medications that may impair
performance, and I\'ve listed some of them on this slide, including
anabolic steroids, anesthetic agents, anti-anxiety drugs,
anti-depressants, caffeine and stimulants, and the remainder of the
drugs, one that\'s very concerning to us and to me as an allergist would
be those drugs we use to treat respiratory disease.

We also are concerned about drugs given to the elderly and combinations
of drugs and, of course, drugs that may be abused.

Next slide. Now, sedation is the issue, but sedation can be broken into
drowsiness and impairment. It\'s easy to measure drowsiness. It\'s a
subjective feeling, and we record the numbers. It\'s much more difficult
to measure performance impairment, and that is an interference with the
ability to perform a task or tasks measured objectively.

If the patient experiences drowsiness only, that\'s a subjective feeling
that\'s not pleasant, but performance impairment only is a very serious
problem because the patient doesn\'t have the idea that the person is
impaired. If the person has both, then hopefully the drowsiness will be
a cue not to do the task.

Next slide. We can ask a variety of sample experimental questions, and
these are some of the ones that we\'ve asked, such as do
first-generation sedating antihistamines cause performance impairment as
compared with non-sedating antihistamines, when measured, using a
high-fidelity driving simulator, and if yes, can the subjects predict
impairment based upon drowsiness or upon their feeling of being
impaired?

Next slide. What I would like to show you is a very small video clip of
the new National Advanced Driving Simulator that will allow us to do
some studies that were not possible before this facility was completed.
Let\'s put the video in.

(Videotape shown)

DR. WEILER: We\'ll just keep going on with the slides, and hopefully we
can come back to that at some time later.

Next slide. Next slide. Unfortunately, that shows you the ability to do
some of the tasks that are described on this slide as end points. The
fidelity with that simulator will be something that will be unmatched in
the future, the ability to look at all of these many end points,
including lane tracking, lane excursion. Obviously, it\'s very important
that we keep within our lanes. Steering instability, ability to follow a
car. We can measure a variety of end points for that. Curve trajectory,
staying within the lane, speed control measures.

Eye tracking is a very important and a very interesting end point that
we\'re looking at with a variety of different new pieces of equipment.
The percent of closure of eyes and things that would tell us that
someone is impaired and is about to nod off. Head tracking.

Next slide. We can look at responses to events, subtle events, repeated
events, and events that are potentially life-threatening, and we can do
that in a simulator that we couldn\'t do on on-the-road driving.

We look at subjective drowsiness, and we correlate that with objective
measures, and we correlate subjective feelings of being impaired with
subjective drowsiness. Then we look on the other side of subjective
feeling of being impaired, and does it correlate with objective
measures, and does it correlate with drowsiness?

Next slide. There are a lot of advantages of the use of the National
Advanced Driving Simulator and perhaps we can show you actually a
picture of it later. We can use realistic crash scenarios, put people in
harm\'s way that we couldn\'t in on-the-road driving. The tasks are
realistic. We can control traffic both in lane and in the oncoming lane
and with high-density traffic with people who are impaired. We can look
at a variety of weather conditions.

We have a high-fidelity image generator that is a 20/20 image in the
center, something that has never been possible before. High-fidelity
motion, so the motion is what you would feel in on-the-road driving, and
we have tremendous flexibility in designing the scenarios, both rapidly,
and they\'re very realistic, and finally is the fully immersive
environment.

Next slide. So, in conclusion, driving simulator studies have been
accepted as demonstrating performance impairment. They may be more
expensive than other kinds of studies, but the rewards may justify the
cost if lives are saved.

The National Advanced Driving Simulator will indeed be a unique facility
to study human performance in a variety of settings that have not been
possible in the past. It will offer us an opportunity to cross-validate
lower-fidelity simulators and other tests.

The bottom line is that driving is a real world task. It\'s very
important to many of us.

DR. ELLINGSTAD: Thank you, Dr. Weiler.

Our next panelist is Dr. James O\'Hanlon from Santa Barbara, California.

DR. O\'HANLON: Good morning.

Can you hear me? Fine. I have two points to make today; that is, that we
have the technology for screening drugs in the registration process.
We\'ve had it for nearly 20 years, and this procedure will lead to a
labeling system, an example of which that I will show today.

May I have the first \-- actually, the second slide. That just says
who\'s talking.

We, beginning in 1981, began developing an over-the-road driving test
for assessing the effects of medicinal and recreational drugs. We
standardized that test two years later, in 1984, and essentially it has
been applied in more than 45 major studies, unchanged ever since.

We\'ve used it with psychiatric patients, depressed and anxious. We\'ve
used it with cognitively impaired elderly and mostly with healthy
volunteers. The test is recognized by the EMEA, which is the FDA\'s
equivalent in Europe, as valid for assessing the effects of certain
drugs, specifically hypnotics and anxiolytics.

May I have the next one, please? I haven\'t brought pictures of this
test because we\'ve done everything we can to make it appear completely
naturalistic, both to the subjects of the test and also to the other
people in the driving environment with whom they interact.

The safety is supervised in this test by an on-board licensed driving
instructor. The test begins with the test subject or patient entering a
primary highway into normal traffic and proceeding 50 kilometers, 30
miles, in one direction, exiting and returning and returning 50
kilometers to the origin.

During this time, speed and lateral position of the vehicle are measured
by automatic means. The standard deviation of lateral position measured
over the entire test is the primary outcome variable. It is a measure of
\-- combined measure of swerving and weaving, and we call that SDLP from
now on.

I\'m using one example of the work that we did together in the
Netherlands until my leaving in \'98. I must add that it continues today
under other direction.

The example I\'ve chosen is an example of hypnotic drugs. We have
studied nearly every hypnotic drug available in Europe and the United
States, and the way we do it is administer the drug to the patient or
the volunteer and allow them to sleep. We test \-- we have tested
patients and volunteers five to 17 hours after drug ingestion.

The experiments. There have been about a dozen in number. They have all
followed double-blind placebo and active control designs in a number of
different experiments, with an exceptional case of 12, usually 18 to 24.
The power for detecting a significant effect of the drug has always been
better than 90 percent.

May I have the next one, please? The next one. Now, the reason that
we\'re interested in the residual effects of hypnotic drugs is because
we have a little epidemiological information to indicate that that
problem is most severe.

Flurazepam or Dalmane, as it\'s called in the United States, was the
first benzodiazepine registered in this country. It has been shown in
epidemiological research to increase the risk of an injurious accident
more than five times normal, which is the equivalent to driving with a
blood alcohol concentration of .95 milligram per milliliter or in the
United States term, .09 gram per deciliter.

So, I\'m going to be talking in the European units, but if you\'d like,
just put a zero in front of that 9, and you will have the units here.

In the old dose, Triazolam or Halcion raised the relative risk of
injurious accidents more than three times. There is a drug available in
Europe but not here. It\'s supposed to be a slow-acting drug and very
safe, according to the manufacturer, but it was shown in England to
raise their risk of injurious accident four times, which is the
equivalent of a blood alcohol concentration of 0.8.

Next slide, please. I have too much data to discuss in detail. I would
just like you to concentrate on the three bars to the right. This is
average standard deviation of lateral position SDLP over a one-hour
ride, 10 hours in the blue bar after taking the drug, and the red bar,
16 to 17 hours.

These all are hypnotics with very long half life, but I would like to
focus on Flurazepam, a drug I already mentioned, Dalmane. We have
studied it three times, twice with patients, once with volunteers, and
we have measured a greater effect of that drug 10 hours after
administration than produced by a blood alcohol concentration of .10 or
drunk in every one of the American states. Even 16 to 17 hours after
administration, the effect is still greater than a blood alcohol
concentration of .05.

I would like to go quickly over the next slide, just actually look at
\-- glance at it briefly. These are intermediate-acting hypnotics. They
have less effect. These are not in the system so long but still, as you
see, some of them are impairing the next morning and even in the next
afternoon after ingestion.

The next slide, please. Modern hypnotics are very short-acting. The two
that are quite popular in the United States, one is Zaleplon or Sonata
is the trade name. The other is Zolpidem, ZPD up there, and it is called
Ambien in the stores.

When you look at either one of those drugs, the first three bars on the
left, 10 hours after ingestion, neither one of them has an effect, and
even Zaleplon in 20 milligram dose, which is twice recommended, still
has no effect. But how close to the time of awakening can you take it?

I skip over the nasal amitrazalem bars, and going now to where it says
in the top, \"Five to six hours after administration\", we\'ve measured
the effect of Zaleplon here and of both 10 and 20 milligram doses.
Again, they\'re not significant. We\'ll leave the Zoplicone bar. That\'s
a European drug.

Now, far over on the right, here is taking the drug only four hours
before the test, and here, you see Zaleplon 10 and 20 milligram have no
effect. Zolpidem 10 milligram, the registered dose, has an effect
greater than .05 blood alcohol concentration, almost .08, and if you
would take twice the dose four hours, you could see that the effect is
greater than .10 blood alcohol concentration.

Last slide. From these data, we are able to make pictograms which
precisely and informatively allow the user to know what to expect from a
hypnotic drug. These are only two categories. We\'ve actually published
a six-category system, and it could even be expanded, but in this, for
the two examples I\'ve just given of Zaleplon and Zolpidem, we don\'t
know how long it would be dangerous to drive after Zaleplon. We only
know that after four hours, it had no effect.

So, we say zero to four hours, you are forbidden to drive, according to
our recommendation. After that, you are free to drive for the next 24
hours. With Zolpidem, a very good drug, a very safe drug, still again we
haven\'t tested it before four hours, but we advise people not to drive.
We have tested it four to five hours. There was an effect, and so we say
all right, from that point until the next time we\'ve tested it and
found no effect, you drive with great caution because the effect we
anticipate is greater than the blood alcohol concentration of .05, and
after that, you\'re free.

We have done this for many drugs. The worst of them, Dalmane, as I
showed you, has red around the clock. You should never drive using that
hypnotic in 30 milligram doses. We think this is a reasonable way of
portraying crucial information to the patients who use this drug.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. O\'Hanlon.

Our next panelist is Dr. Gary Kay from the Washington Neuropsychological
Institute in Washington, D.C.

Dr. Kay?

DR. KAY: Good morning, and I appreciate the opportunity to speak to you.

If we can go to the first slide, my comments will be more general on how
we measure impairment, what the methodology is and extent to which we
have advances in this methodology currently.

I think one of the reasons why we\'re here, if you\'ll show the slide,
why we\'re here is that the public has little awareness of the risks
associated with taking especially sedating over-the-counter medications,
and often, there is a belief that if you don\'t feel drowsy, that in
fact you aren\'t sedated.

But as Dr. Weiler has shown, go on to the next slide, next slide after
that, please, in fact, a depressant medication\'s effects on the central
nervous system could be manifested different ways. In fact, you may feel
sleepy. You may feel drowsy. That\'s your personal experience. Often,
people have \-- they think the definition of sedation is drowsiness, but
it\'s more.

In fact, there could be changes physiologically in brain activity. There
may be a change in your ability to stay awake during the day. There may
be a detrimental effect on your performance. In fact, if we are going to
evaluate medications and give an honest appraisal about whether a
medication is sedating, we must use all of these methods. We must find
out do people feel drowsy or sleepy? Are there physiological changes?
Are there performance changes?

With respect to self-report measures, commonly we use diary cards.
Often, there\'s too much reliance on diary cards. There are rating
scales, visual analog scales. There are newer devices, such as the use
of personal data systems, like Palm Pilots, and there\'s also data we
can obtain from prescription event monitoring.

Taking a look at the new methodology of the use of these personal data
systems, these provide us with very high subject compliance. You
actually program them to inquire of the subject at different points
during the day about their current subjective level of sleepiness. You
get a time logging of these entries, and there\'s improved data
handling. They were recently demonstrated at the DIA Conference in
Denver to be superior to the paper diary.

The problem with self-report measures are that they are subjective.
There may be biased reporting. There is poor diary compliance, and as
Dr. Weiler pointed out, there\'s low agreement often with physiological
and performance measures.

Somebody may report no self-reported sleepiness, but in fact show
physiological impairment or cognitive impairment or in fact driving
impairment in the absence of any self-reported sleepiness. We do have
physiological measures. I\'ve listed some of them here for you. EEG.

At Georgetown, we\'ve been working with functional brain imaging. Sleep
latency testing has been around for awhile, and there\'s activity
monitoring as well.

Here is some data from one of our studies at Georgetown where we are
looking for the physiological and subjective. This is night-time, 10
p.m., dosing with Chlorpheniramine. The red is eight milligram, the
purple 12 milligram Chlorpheniramine at 10:00.

Looking at the next day, from 9 a.m. till 5 p.m., the number of \--
average number of minutes before people fell asleep during naps, and
what you\'re seeing here is that for placebo, we have a normal sleep
latency greater than 10 minutes, but for either the eight or 12
milligram Chlorpheniramine, taken 10:00 the night before, the next day,
the sleep latencies drop down to six minutes, both statistically
significant but clinically meaningful as an evidence of excessive
day-time somnolence, and looking to the right, it\'s indicating that on
the Stanford Sleepiness Scale, the subjects who received the eight
milligram dose of Chlorpheniramine are reporting no more sleepiness than
the patient who received placebo. They had no awareness of their
sleepiness.

This is looking at the results from our functional brain imaging. We\'re
looking at changes in brain activation with \-- while people are
performing a mental arithmetic test after they\'ve been dosed with again
eight and then 12 milligram Chlorpheniramine. The white is placebo. This
is showing you the brain imaging. The left side shows what activates
during training. The right side under retesting with placebo, there\'s
only one-quarter the amount of activation once you\'ve learned to
perform an activity in the FMRI.

If you know you\'re looking at another subject here on the left side
that\'s training, the right side, this is three days of dosing
Chlorpheniramine at night, looking at day-time performance in the FMRI,
and you\'re seeing actually five and a half to six times an increase in
the amount of brain activation.

Now, those are physiological. Lastly, we have performance measurements,
and performance measurements include tests of thinking or cognition,
tests of skilled motor activity, psychomotor, and as you\'ve heard from
the first two speakers/witnesses, simulation testing.

In terms of what we\'re doing currently to measure cognitive
functioning, we are using a lot of computer-based neuropsychological
tests, and these are tests that we initially developed largely to look
at early-on chemical defense and did a lot of this work in the
Department of Defense.

These methods provide us a number of advantages. There is standardized
instructions, standardized presentation of stimuli. There\'s enhanced
sensitivity over traditional paper and pencil-type testing, highly
accurate measures of speed and accuracy. They can be designed using
computer-based testing methodology with a lot of different sponsorship.
Department of Defense, Food and Drug Administration, and pharmaceutical
industry.

This is showing you basically a screen of somebody taking the cog screen
test. They are not going to use a keyboard. We basically keep them up on
the screen using a light pen. You may test a whole room full of people
all at one time. This is a test item for you to practice, memorize that,
which one\'s the same, left or right. Hopefully you choose right.

This would be a divided attention test that involves working memory at
the top. Remember the previous number being shown in that top square,
and then a tracking test where you maintain that blue square in the
center of the screen. You do both of these tasks at once. It\'s a very
good predictor, sensitive to changes and shift and that kind of thing.

The test which we find most sensitive to sedating impairing drugs are
tests of vigilance, the ability to sustain attention during a boring
activity. Divided attention. Your ability to perform simultaneous mental
activities, like perform the tracking at the same time that you\'re
doing some other type activity. Working memory, holding information
temporarily in your mind.

This is just showing you a very simple 12-minute test. We\'ve actually
recorded this on to a Palm Pilot, and looking here at Diphenhydramine in
yellow, 50 milligrams, versus placebo, basically you\'re looking at four
times the number of lapses of attention for a subject taking a common
over-the-counter sedating antihistamine.

This is a study we just did, sponsored by FDA, actually looking at very
low dose over-the-counter antihistamine, Chlorpheniramine at two
milligrams and four milligrams versus placebo, and this is looking seven
hours post-dosing. Nobody\'s reporting any sleepiness. Stanford
Sleepiness Scale scores all below two, yet there is impairment on our
dual task tracking test for the subjects at either dose in the absence
of feeling sleepy.

Summarizing for you. Sedating medications can cause impairment in the
absence of sleepiness. Sedating effects may carry over to the following
day, even when the medications are taken the night before, and the
functions which we believe are most vulnerable to sedating medications,
which we\'ve demonstrated, are in fact vigilance, very important in
transportation safety.

Psychomotor skills under divided attention obviously involved in
transportation and working memory. We have, we can provide reliable and
valid measures. They are available. We\'re evaluating all of these
dimensions of sedation, self-report, physiological and performance.

Thank you very much.

DR. ELLINGSTAD: Thank you, Dr. Kay.

Our next panelist is Dr. Bert Spilker, Vice President of the
Pharmaceutical Research and Manufacturers of America here in Washington,
D.C.

Dr. Spilker?

DR. SPILKER: Good morning.

I\'m Dr. Bert Spilker, Senior Vice President of Scientific Regulatory
Affairs for the Pharmaceutical Research and Manufacturers of America.

PhRMA represents the country\'s leading research-based pharmaceutical
and biotechnology companies. In regard to the subject of this panel\'s
discussion, I wish to make seven points.

First. Every investigational drug is carefully and thoroughly evaluated
for adverse reactions it may cause.

Second. These evaluations are conducted in both artificial as well as
highly-controlled clinical trial settings during Phase I and II of
development of a drug, and, in addition, in close to real world clinical
settings during the Phase III development.

Three. Evaluations are made through adverse drug reporting via
spontaneously-volunteered verbal communication by patients in diaries
recorded by patients when they\'re kept as part of a trial and in
responses by patients to written questionnaires for quality-of-life and
for other tests.

Responses to verbal non-biased questioning, such as, have you had any
problems or noticed anything different since you were here last, are the
basis for collecting adverse drug reactions during each phase of drug
development.

Four. Any real world or real life events, such as traffic accidents
during a clinical trial, is collected as an adverse event, no matter how
mild, and every attempt is made to ascertain the cause, whether it be
drug-related or non-drug-related; i.e., the accident could be due to
drowsiness due to the drug or from an event due to the disease under
evaluation or from other non-drug-related causes prior to the accident.

Five. Adverse drug reactions for an investigational drug are compared
against placebo and often versus other approved drugs prescribed for the
same disease, either in head-to-head clinical trials or using data from
the respective package inserts.

A benefit-risk determination is eventually made by the sponsoring
company and by the FDA, and drugs are allowed on the market if their
benefits exceed their risks.

Six. After market approval, adverse drug events that a company learns
about through its post-marketing surveillance program or global safety
network, as described in the Code of Federal Regulations, are sent to
FDA on an expedited or periodic basis. The company\'s network captures
reported ADRs occurring anywhere in the world.

Seven. The relationship between drowsiness as an adverse drug reaction
and impairment of performance has not always been demonstrated to be
related or correlated. Drowsiness tends to be a subjective feeling,
whereas impairment is based on more objective testing.

Various methodologies have been utilized to evaluate performance
impairment in both real life and clinical trial situations when certain
adverse drug reactions, such as drowsiness, have been associated with
its use in some patients.

There are more than a dozen commonly-used tests that measure performance
impairment. However, there is no accepted universal standard approved by
FDA for testing impairment in a clinical trial setting, and a validated
reference for what may be a clinically meaningful threshold of
impairment is not presently agreed.

In conclusion, well-documented methodologies are currently being
utilized during the development phases of a drug for evaluating adverse
drug reactions and their potential relationship to performance
impairment.

Once a drug is approved for marketing, the drug\'s safety profile
continues to be monitored through post-marketing surveillance programs
with resultant relevant updating of prescribing information based on the
additional information.

Thank you for the opportunity to address this group, and copies of my
talk are available in the table outside.

DR. ELLINGSTAD: Thank you, Dr. Spilker.

Our final witness on this panel is Dr. William Soller, Vice President
and Director of Science and Technology for the Consumer Healthcare
Products Association.

Dr. Soller?

DR. SOLLER: Could I have the slide, please?

Thank you, Dr. Ellingstad, Dr. Galson. Good morning, and thank you for
the opportunity to be here.

I\'m Dr. Bill Soller with the Consumer Healthcare Products Association,
a 120-year-old trade organization representing the manufacturers and
distributors of non-prescription medicines and dietary supplements.

Do I ask you for the next slide? It didn\'t seem to be working. I think
I\'ll do it orally, if I may.

My remarks focus on OTC antihistamines, a class of OTCs with a
drowsiness side effect. OTC antihistamines are highly effective for
treating symptoms of allergies, runny noses and sneezing associated with
the common cold, for nausea, and for some ingredients as sleep aids.

OTC antihistamines have been thoroughly evaluated under the OTC review
by FDA and its expert advisory panels, including a detailed examination
of the chief side effect, drowsiness, the concern about driving and
operating machinery, and the creation of special warnings for this side
effect.

FDA and its panels concluded that there is a wide range of
susceptibility to the drowsiness effect with less than 10 percent to up
to 50 percent of users experiencing drowsiness, depending on the
antihistamine used, the dose and the underlying condition.

FDA and its panels also created specific carefully-worded drowsiness
warnings for different classes of antihistamines, depending on the
degree of drowsiness associated with their use. In so doing, they
created in detail or they considered in detail the potential for
machinery-related accidents and the potential exacerbating drug
interactions.

With this warning and other labeling, OTC antihistamines have been
determined to be generally recognized as safe and effective.

Next slide. Antihistamine containing OTC products bear a specific
drowsiness warning shown here. Though drowsiness may occur, it does not
always occur in all users. Alcohol and drug interactions are identified,
and there\'s a specific caution about motor vehicle and machinery
operation, and I might add, studies support the fact that consumers read
the label before using the product the first time, and CHPA has had a
very long involvement in educating consumers on the need to read and
heed the OTC label.

Next slide. We conducted a 10-year post-marketing surveillance analysis
for these OTC antihistamines in single and combination products, looking
at AERs with an accident-related term in persons 16 years or older. The
accident term was defined very broadly to include all forms of
transportation accidents and other possible related terms, including
falls, injured limbs, and so on.

Next slide. Over this 10-year period, there were a total of 23 serious
AERs with antihistamines as a primary or suspect \-- secondary suspect
drug with an accident term in any field of the AER. There were no more
than four AERs in any one year over this period.

About 850 million OTC units for adults alone were sold during this
10-year span, and I might add there are also RX uses for certain of the
drugs studied. These findings were supported by previous studies by the
National Highway Traffic Safety Administration, Ray et al., and
Turnbridge.

In a study in the early \'90s by the National Highway Traffic Safety
Administration, post-mortem blood samples were analyzed from over 1,800
drivers in seven states. NHTSA concluded this and other studies have
found that there are relatively few drugs which have prevalence large
enough to present a highway safety problem. These were mainly drugs of
abuse.

Ray et al. determined the risks for injurious crashes for drivers who
had received prescriptions for various drugs, including prescription and
crash records, for over 16,000 elderly drivers in Tennessee. However,
the relative risk for current users of only RX antihistamines was 1.2
with the confidence limits spanning one, and no dose effect was
demonstrable.

We therefore in these long-term larger-scale epidemiologic studies see
no signal for concern. We conclude that the OTC warning label and
educational programs are having an impact.

May I have the next slide, please? With the new drug facts label, there
will be even better communication with the consumer. On the left is the
old label. On the right is the drug facts label. Note the more
consumer-friendly format that allows a more prominent and more
consistent placement of the drowsiness label across the product
categories.

You may not be able to read it from the audience, but the warning
appears when using this product, marked drowsiness may occur and so on,
in the middle of the label.

May I have the next slide, please? In conclusion, OTC antihistamines
have a demonstrated history of safe and effective use when used
according to label directions. OTC antihistamines are appropriately and
adequately labeled. Drug facts label will make the warning label even
better.

CHPA believes that it\'s important to maintain an on-going program of
consumer education on the importance of reading the entire OTC label.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. Soller, and thank you to the panel.

What we\'ll do now is turn to our Technical Panel for a round of
questioning. I\'d again like to remind the people in the audience that
if they have questions that they would like asked of this panel, please
identify the staff that are roaming around and obtain from them a card,
write your question down and hand it to them, and they\'ll bring it up
here, and we will ask those questions.

I\'d also like to remind the party groups to think about their questions
and to identify their spokesperson here, and we will, after the Tech
Panel is done with their questioning, begin a round of questions from
the parties.

To lead off the Technical Panel questions, Dr. Garber will start.

Questions from Technical Panel/Parties and Discussion

DR. GARBER: Thank you. Thank you very much, Dr. Ellingstad, and thank
you very much to the panel. I really appreciate your presentations.

I do know that we had a little bit of audio-visual difficulty with Dr.
Weiler\'s presentation with his videotape. Has the video tape problem
been corrected? Can we show that video tape now? I just wanted to give
Dr. Weiler an opportunity to present that, if in fact that\'s \-- we
have that ability now.

DR. WEILER: I believe we can certainly show it. I believe we can show it
now. I guess it\'s coming from the booth as opposed to from down here.

(Video tape shown)

DR. WEILER: This is an animation of the National Advanced Driving
Simulator, and it demonstrates the X, Y, and you can\'t see the Z
access. You\'ll see that when we zoom in on it.

But it\'s a facility that exists in the Oakdale Campus at the University
of Iowa, and here we see zooming in on the facility itself. This is the
control room that runs the facility. You can see off in the bay the dome
structure that contains the cab.

We have currently four cabs that we can use in that dome structure, two
sedans, a tractor-trailer front end and an SUV.

This is all animation demonstrating driving maneuvers. There\'s 360
degree of visuals, something very unique. Here, we see the actuators,
and this is what gives us the feeling of motion. It\'s very realistic.
So, we can set crash scenarios that really wouldn\'t be possible with
on-the-road driving.

This is a demonstration of a spin-out. This is what the subject would
actually see while driving the car. Both the sound and the feel are very
realistic, and we can record all of the end points that I showed on the
slide. It can help us to understand what happens.

We have in-town driving. We can pick tiles to set these up very rapidly,
so that you can have a scenario that\'s in town and quickly goes to a
rural setting. We can repeat these drives with every individual. We have
triggers on the roads, so that when you drive over a trigger, it may
cause something to happen, such as somebody jumping out in front of the
car.

It\'s extremely easy to set this up, and we have data reduction tools
that allow us to collect the data and analyze them quite rapidly. It is
an \$80 million facility, so it\'s not something that we can do for
every drug and every test, but it does allow us some tremendous
flexibility in being able to run studies in ways that really weren\'t
possible in the past.

Thank you.

DR. GARBER: Thank you very much.

I just have actually just one question, a quick question, for the entire
panel, and I\'d like to get an answer from each of the participants, if
I may, so that we can quickly get this to the parties after our FDA
counterparts have also asked their questions.

But the only question I have, and this is for each of the members, is,
do we have the capability now, given the tests and the data that we have
available, do we have the capacity to identify drugs which we do know do
not impair vehicle operators?

In other words, can we reliably identify or compile a list of drugs
which we now know or which we can readily identify fairly shortly that
do not in fact impair vehicle operators that we can declare relatively
safe for their use?

I\'d like to pose that to each of the panelists.

DR. WEILER: There probably are a group of drugs that have been studied
to some extent. The problem is that I believe that the drugs that don\'t
cause drowsiness to any great measure probably haven\'t been studied
very well for their impairing capacity.

So, if we believe, as we\'ve shown with the antihistamine classes and
with other drugs, that drowsiness and the subjective feelings don\'t
predict impairment, the problem is the drugs that are either mildly or
not very sedating at all have really not been studied in any great way
for impairment.

So, we can make guesses, but I\'m not sure that it would be entirely
accepted by everyone.

DR. O\'HANLON: I disagree with my colleague. I think we know a number of
drugs which are not impairing, relatively, of course. There can always
be an impaired \-- one impaired person out of a thousand or whatever,
but in the \-- for the drugs that I would call non-impairing, they have
no significant effect at the recommended dose, no significant effect at
twice the recommended dose and sometimes higher, up to four times, and
there is no individual in a representative group of, say, 24 to 32 who
shows an anomalous untoward reaction.

Now, having said that, the caveat I have to add is that in our tests in
the Netherlands, we did not study every population of drivers, and what
I\'m saying now pertains to young either patients or volunteers and not
elderly patients or otherwise impaired drivers.

So, with those caveats, yes, we have a number of drugs in every
therapeutic class, that we have nearly every one that we\'ve defined as
safe.

DR. KAY: The only thing I would add would be that if we used as a
criteria lack of evidence of sedation meaning no findings on
self-reported sleepiness, no findings of problems or abnormalities on
physiological tests of sedation or performance measures, we have very
few drugs we\'ve tested across all those, you know, types of
measurement.

That was in fact a lot of the work being done in the Department of
Defense when we were doing work on chemical defense drugs and looking to
find out which drugs you could take and still fly a plane, which drugs
you could take and still drive a tank, and we did study certain
medications but very few have been studied across all of those domains
and dimensions of testing.

DR. SPILKER: It\'s well known that people react quite differently to any
drug, and it\'s difficult, if not impossible, to say that Drug X never
causes drowsiness.

If you look in the PDR, you will see that many, many drugs not
associated with sedation and impairment certainly also have drowsiness
listed as an adverse reaction.

So, I think it would be a disservice to say to any group these are drugs
that do not cause drowsiness or sedation. I think we\'d be sending the
wrong signal medically.

DR. GARBER: Just as a follow-up question to that then, you\'re
suggesting that all drugs may potentially cause sedation or drowsiness?
Is that my understanding?

DR. SPILKER: Yes.

DR. SOLLER: Thank you.

You know, I think it\'s important to think about how far we want to
tease out some of the laboratory values and how far we\'re going to look
at those laboratory studies.

Dr. Galson, Dr. Ellingstad, do we have anything we need to do now? I\'m
happy to return to my answer later, if I need to.

DR. ELLINGSTAD: This is Wednesday, and they do test the fire alarms.
I\'ll ask our staff to verify that that\'s what it is, and we\'ll \--

DR. SOLLER: Okay. We\'ll see how well we do on divided attention.

DR. ELLINGSTAD: \-- deal with it. Thank you.

DR. SOLLER: I think it\'s important that we think about how far we want
to tease out the laboratory values and particularly as we look at
simulator or other types of studies, where what we see are perhaps doses
that are not those that are necessarily used in an in-use situation.

I\'m speaking from an OTC context in certain cases. Our view is that the
broad term sedation as has been defined in the clinic and the clinical
studies has been appropriately looked at for OTC medications. This is
well studied through the OTC review.

There was a great discussion on the issue of drowsiness and the effect
on driving as well as operating machinery for certain of the products
and even beyond the antihistamines, and when you look at an RX/OTC
switch drug, again a very thorough clinical experience, and I think in
the end, when you match that against what we\'re seeing in the AER
profiles as well as the larger epidemiologic studies, I think we\'re on
track in focusing our efforts on the kinds of warnings that would direct
people about what products might cause drowsiness or impairment.

DR. GARBER: Then your colleague suggested that all those drugs might
cause impairment. Are you in agreement with that?

DR. SOLLER: No, I\'m not in agreement with that.

DR. GARBER: Okay. Thank you.

DR. SOLLER: Although I will say, you know, I\'m talking about
recommended dosages for OTCs in that context.

DR. GARBER: Understood. I\'d like to pass the questioning now to Dr.
Temple for the FDA.

DR. TEMPLE: Is this on? Yes. A number of you have been talking around
this.

Do we have enough information to think that any one of these kinds of
tests provides different information? For example, Dr. O\'Hanlon has
developed one specific test for driving based on lateral movement. Dr.
Weiler has shown a method for assessing a wide variety of functions, and
Dr. Kay has talked about a variety of things that tell how alert you are
and whether you fall asleep when you lie down during the day.

Are all these \-- do we have any way of knowing whether all of these
things tell us the same thing or whether they\'re actually different?
Are you just as informed if you know that a person is not alert on one
of the standard tests as you are if you have information about lateral
motion?

Is there any way to tease this out? Obviously my question goes to
whether we should be thinking of a standard battery of tests or whether,
as we have sort of concluded in the past, that once you know a drug is
sedating, it causes all of these problems, and you just already know
that and the rest doesn\'t add much.

Can any of you comment on that?

DR. KAY: From perspective neuropsychology, I would say that it\'s
important that we study not just one test as an indicator of whether
there is sedation because we look at medications. Some medications will
affect psychomotor functions, skilled motor activity and have very
little effect, if any, on cognition.

For example, if you look after days of dosing with some of these
medications, we cease to see the effects on measures of attention,
concentration, vigilance, but we can still detect significant effects in
psychomotor ability, especially under divided attention.

So that, I think it\'s important that we realize that different drugs
are going to affect the brain differently. We\'re talking about central
nervous system function and differential effects of different agents
depending upon what neurotransmitter systems are being disrupted by that
particular medication.

DR. O\'HANLON: An investigator uses the tools at his disposal. I don\'t
have an \$80 million simulator. On the other hand, I did work in a
country that allowed me to test drug effects in a real environment which
would be difficult in the United States, but it could be done. As a
matter of fact, it started here.

What you have, though, is a consensus across people who devote full time
to assessing the behavioral toxicity of drugs regarding some drugs, and
there is a gray area where various investigators will argue with each
other about whether this drug belongs in the next category or the next
category down, and then we go into a white area where nearly all
investigators agree that the drug is relatively safe.

In spite of the diversity of methods, experience with these drugs in
performance testing laboratories has led to a very broad and very strong
consensus about the worst and the best drugs. I don\'t think that the
diversity of methods is the issue.

Everybody uses what they have to, but the conclusion, the focusing, the
narrowing of opinion on certain drugs is inescapable. It was there 15
years or 17 years ago, Bob, when I visited. It\'s there, and it\'s
better today.

DR. TEMPLE: But that, in some ways, is what I\'m getting at. Should we
be content if any one of these methods, even if it\'s \-- whether it\'s
an actual driving method or it doesn\'t involve driving, shows
impairment, do we then more or less have our answer, assuming we\'ve got
data over time and data related to dose and all that, or do you actually
need a driving test?

DR. O\'HANLON: Impairment is not a real \-- something in itself. I mean,
drugs can be impairing. You can have such a sensitive test that you can
measure tiny impairments of minuscule amounts of dose of drugs relative
to therapeutic doses. That\'s not important.

You need an external standard. We\'ve tried to use the blood alcohol
concentrations as our external standard of safety. It may or may not be
the best. You need that, and if you have that, you can \-- impairment is
not the issue. It\'s impairment relative to a drug which is known to be
behaviorally toxic and known to kill people at a rate of 40,000 a year
in the United States. If you have that, you have a very good screening
test.

DR. WEILER: I\'d like to make one point. This raises a very \-- I think,
a very important issue, and that is, that it\'s very clear why
drowsiness has been something that we\'ve been able to quantify and put
into package labels, because we can measure it, and it\'s pretty clear
what we\'re measuring. It doesn\'t matter whether it\'s a visual analog
scale or collecting adverse events or whatever we\'re doing. We can
measure drowsiness.

We\'ve gotten into a very difficult area when we talk about measuring
impairment because there are so many different tests, and there are so
many different standards.

I mentioned that driving is a real world task, but it\'s not the only
real world task. The person who operates heavy machinery, the person who
works in a shop and has to operate equipment there, those are also very
real world tasks for those people, and the issue\'s going to come up in
developing some kind of a standard, some kind of a way that we can
quantify the impairment that people will accept.

I agree that it shouldn\'t be one test, but there should be a group of
tests or a group of standards by which we can determine impairment, and
it shouldn\'t just be drowsiness. We shouldn\'t just say that the lack
of drowsiness is okay, you\'re fine, or if you\'re drowsy, that we
don\'t have to go further in quantifying the level of impairment, and
that\'s going to be the difficult task.

I don\'t think we\'re going to come up with a single test today. I think
that\'s going to be a task that you folks are going to have to work with
and some time come down with a series of tests that will be acceptable,
that will work, that will allow investigators to be able to look at the
question and know what kind of guidance they need to determine where
they\'re going to go next in looking at the impairment of these various
drugs.

DR. SOLLER: Just a comment, if I could. Thank you, Dr. Temple.

I think you\'re on target when you restated the question, do we actually
need a driving test for every drug, and I don\'t know. Maybe the
investigators would say so, and I do find the results interesting, but
from the state of the knowledge that we have now, the questions about
extrapolating from laboratory to in use and whether these particular
studies are validated and which ones to pick, I think you\'re probably
on target, at least where I thought you were going, in terms once we
know that it\'s sedating, do we have enough at this particular time?

I think if you know a product produces drowsiness, then in some
individuals, potentially it will affect performance, and if you find
that you have ambiguous findings around that particular effect in a
battery of clinical trials that are done on a new chemical entity, then
maybe on a flexible case-by-case approach or perhaps that\'s the way to
do it, to look for further performance effects that might be seen to
better elucidate what\'s going on until we have, I think, more
information.

DR. TEMPLE: This isn\'t a question. It\'s really a comment on what
everybody said, but one of the things that was very striking to me was
the pretty precise ability to see how long impairment lasted with some
of these tests, which is obviously crucial, Bill.

You know, you can put watch out for drowsiness on your label, but that
doesn\'t tell you about dose. It doesn\'t tell you about duration. It\'s
really not enough information, given what we\'ve just seen. There are
big differences in how long the effect lasts, you know.

Sonata wipes you out for the first four hours and then nothing. That\'s
different from the other drugs. Those seem very important.

DR. SOLLER: Well, I haven\'t seen that one on the switch list, but if I
could comment, it\'s important to think about, and I\'m again talking
from an OTC standpoint, not for prescription products, but to think
about what does go on the label, and what is transferrable to the
consumer, and what they can act on, and at least from looking at the
information we have at hand, we\'re not seeing that signal that would
suggest that what has been done by FDA and what is now being done with
the new drug facts label, and I can say that most of the antihistamine
products are already in that label and all will be there by May 16th,
2002, the compliance date.

So, we\'re in the process of a very large change in information that\'s
going to be conveyed to the consumer on what is already apparently a
very good AER profile for these products.

DR. SPILKER: I wanted to clarify my response briefly to Dr. Garber\'s
question before.

I was saying that drowsiness or sedation is likely to be reported by at
least some patients for all drugs, not that this is considered or the
drug is considered as impairing or as clinically significant.

But when you do clinical trials or you collect adverse reactions, you
will always find reports that some patients are sedated or drowsy.

DR. GARBER: Thank you for that clarification. If I can follow up just
briefly again, as we\'ve heard other people state here, are you
suggesting that that subjective report of that adverse event may not be
a good indicator of whether the drug is impairing for the purposes that
we\'ve been discussing today?

DR. SPILKER: Yes, I would certainly feel that.

DR. GARBER: Okay. Thank you.

DR. TEMPLE: But, I mean, we know that all so-called non-sedating
antihistamines have reports of drowsiness, but they\'re equal to the
reports of drowsiness in the placebo group.

So, we conclude they\'re minimally impairing. You don\'t mean
everybody\'s going to report drowsiness from time to time? So, you
don\'t mean that has anything to do with the real effect? You wouldn\'t
really know that.

DR. SPILKER: Well, I agree with you. I\'m just commenting on the fact
that you will see these data, and then we interpret it the way you do.

DR. WEILER: Could I make one more comment? The issue about quantifying
the impairment is important or otherwise we\'d trivialize the warnings.
If we put a warning on every antihistamine that it\'s impairing, we then
send a message that it doesn\'t matter what you take, and so the really
impairing drugs are drugs that people are going to take just as commonly
as those that are either minimally or non-impairing at all. So, it is
important to quantify the risk in some way, if we can.

DR. SWEENEY: I have a question for Dr. Weiler. Have you used the driving
simulator to test the effects of any specific over-the-counter drugs,
and can you describe the results?

DR. WEILER: Well, we have used it in a study that we looked at
diphenhydramine, and we compared it to alcohol. I could review some of
those data, if you\'d like to, very briefly.

DR. SWEENEY: Please.

DR. WEILER: Okay. Do we have our AV person here to \--

DR. SWEENEY: Anyone for AV help up front, please.

DR. WEILER: Try to go through this very rapidly. We do have some data on
the point. We looked at the Iowa Driving Simulator which was slightly
different than the new National Advanced Driving Simulator in that it
doesn\'t have a track. It is a motion base, but it doesn\'t move on a
track.

This was a simulated driving. There were two phases. The first phase was
about 30 percent of the drive, and it\'s following a car. The second
phase is going through a variety of curves and driving as a free agent
as you typically would.

Next. We looked at coherence as the primary end point, and on this slide
is an example of the worst, the best and the median coherence. Is there
a pointer on this thing? The big button. You\'ll just have to read
worst, median and best, and the bottom one is the best. It shows really
close following, and it happens to be in somebody who was drunk.

Next slide. And the point is that someone who is drunk can follow very
closely, but that\'s the only test they can perform well, and in this
particular case, we found significant differences between fexophenidine
and diphenhydramine, alcohol and diphenhydramine, and placebo and
diphenhydramine, and in fact, in this particular end point, the
diphenhydramine group performed the worst.

This was a divided attention task. They did well. The alcohol group did
well at performing this task but nothing else very well, and the alcohol
was .1. They were dosed to .1. I\'m not moving this thing, am I? Oh,
okay.

This is minimum following distance, and it shows significant differences
between the fexophenadine and alcohol and placebo and alcohol. Now,
we\'re starting to see the alcohol group not perform very well.

Steering instability is something we can measure very easily in the
facility. We found differences between diphenhydramine and
fexophenadine, diphenhydramine and placebo. I won\'t go through the
other groups because I really think the issue here is the impairment
that we saw with the diphenhydramine.

Steering instability in the phase where they drove as a free agent, we
saw the same kind of results. Again diphenhydramine impaired and caused
steering instability. There were left lane excursions and that\'s
important obviously because you won\'t want to be driving in the lane
where oncoming traffic is coming, and this gave us an opportunity to
look at that, and again you can see the diphenhydramine group stands out
with differences between it and the fexophenadine and differences with
the placebo group.

We looked at self-reported drowsiness, and as expected, the
diphenhydramine group had the highest percent of self-reported
drowsiness, but, and I think this is probably one of the messages that
came through very loud and clear, is we\'ve got really nice P values
looking at the correlation between drowsiness and performance
impairment.

We\'ve got P values that are fine. Those are in the parentheses, but
when you start looking at the R values, which are really more important,
the correlation, we get very poor correlation. It\'s highly significant
for a very small percentage of the population. That\'s really a problem
because the people who thought they were drowsy and wouldn\'t drive, the
cues weren\'t there, and in fact, I don\'t know how well this projects,
but if you look at the very drowsy drivers, they aren\'t the ones that
had the accidents. The accidents are in red, and there\'s one in black
that are \-- I\'m sorry \-- the black is the median.

They\'re in red, and they demonstrate where the crashes were in a
scenario that we set up, and we didn\'t see crashes necessarily in the
most drowsy individuals. We did see crashes in those who had the high
crossing counts, so that those people who drove into the left lane were
more likely to have a crash in this last event. So, that\'s a really
concerning result.

I\'d be happy to show some video clips if you want. I\'ve got a
two-minute video. It\'s up to you, if you want to see it. Yes? Okay.
We\'ll do our best here. This is certainly multimedia time.

(Video tape shown)

DR. WEILER: We\'re showing the Iowa Driving Simulator. This is a control
room in that old facility. The way we take somebody up to the facility
is they walk up the ramp, and you can see the dome structure. This is
getting in the car. This is very similar to what NADS is, a regular car,
seatbelt, adjusting the mirror. Again, the control room controls the way
the car drives, and this is what you would see if you\'re sitting in the
driver\'s seat.

It doesn\'t \-- it isn\'t easy for me to see here. I hope you can see
where you all are sitting. Again, there\'s a side mirror rearview. We
had 270 degrees of visuals, and you can see the motion. It was very
realistic, again very similar to NADS, it just doesn\'t move on a track.

You\'ll see four panels, a driver right there. Let\'s see. You can see
steering instability. We can measure that, and we can view it. Here\'s
the center insert that shows the speed. We see where the foot is.
Acceleration and braking are recorded and that\'s a view of the bay
itself showing frame counts.

Here, we\'re looking at the ability of the car to follow. Individuals
who were on placebo were able to follow the car at a comfortable
distance. In this case again, a person showing steering stability.
She\'s able to drive real well and follow the car, does a nice job.

I don\'t know if this is going to demonstrate it, but we were able to
measure the distance, and the varying distance was tremendous in the
people who were on diphenhydramine. Here, we see an example of alcohol
driving over the center lane.

Now, this is the last event where I talked about crashes. It shows the
person crashing. These aren\'t things we\'d want to be doing in the real
world, and we can measure those. I mean, we can actually measure the
fact that that individual ran into that tractor-trailer coming at him,
and we were able to look at those.

This study wasn\'t powered for that, but it does allow us to do that in
future studies. We can do either frequent events or we can do infrequent
events to measure these kinds of things.

DR. TEMPLE: When he crashed, did he fall asleep briefly? Is that what
the assumption is?

DR. WEILER: Yes. In that particular individual, he was having a lot of
problems getting around, and he did hit the oncoming vehicle.

What was supposed to happen was that they had driven this scenario three
times previously. It\'s a 45-to 50-minute drive, and they\'re pretty
well lulled to sleep at the end of the drive. We\'re at the end of the
drive for the fourth time, and so it wasn\'t powered for this particular
event, but we wanted to throw it in and see what would happen if a car
pulled out that had been sitting in the driveway every one of the three
previous drives, and so it pulled out, and we measured the time, we can
measure reaction time, from the time it begins to move until the time
it\'s blocking the lane.

What\'s supposed to happen is the car blocks the lane, plus there\'s a
vehicle coming in the other lane. You\'ve got some choices here, and the
best one is to stop, and the people would stop generally, but some
people would go into the far lane.

We had one woman who was so drunk that she was in the far lane to begin
with and actually got able to get back to the right lane before the
tractor-trailer came. So, we have a variety of different things, but
that scenario is set up. It\'s an identical scenario for everybody. We
can run them through it. We can categorize the events.

It allows us to do some really tremendous things that are very well
controlled, like we would like to do in a science laboratory, where we
can actually look at events and control for everybody passing through
the study. It\'s wonderful the way we can look at these kind of things
in that setting.

DR. TEMPLE: This, I\'m sure, is going to seem like a naive question. Are
you trying to find out whether people are in a state where they\'re
likely to actually fall asleep and therefore run into something or is
their function impaired even if they\'re not asleep or both?

DR. WEILER: Well, our interest was really looking at the end points that
were important and not \-- sleepiness and drowsiness, if the person can
stay awake and drive well, is fine, and that was my contention on one of
the early slides, was that if you\'re drowsy, but you\'re driving okay,
it\'s not a pleasant feeling, but that\'s not really what this is about.

What this is about is the individual who\'s impaired. Our end points
that we\'re most interested in are those that reflect impairment,
inability to control the car, inability to keep yourself in your lane,
keeping the lateral position where it should be. You pick the lane of
best fit and stay there, so you\'re not over-controlling, a lot of
steering instability. We don\'t want that because we know that predicts
a bad event, a crash or some bad event occurring.

We looked at drowsiness. We looked at questions of do you feel impaired
to predict those kinds of things because we thought that was important.
We find a tremendous disconnect, as the literature demonstrates, but our
interest was in impairing. What was impairment?

DR. TEMPLE: But Dr. Kay showed data that people had way decreased sleep
latency, even if they did not feel impaired. So, whether you\'re going
to fall asleep or might not relate to whether you feel drowsy.

DR. WEILER: That\'s correct. That\'s why we feel it\'s important to
cross correlate, and you may say cross validate, these various tests
against each other. I believe that\'s very important, so that we
understand the consequences of changes in the mean sleep latency and
some of the other tests that would predict impairment.

But we have a real world task. We can either do it with on-the-road
driving, things that we\'ve done, or we can do it in a simulator. Again,
we think there\'s some advantages. In some cases, there are advantages
of real world driving in a real car, and in other cases for the
simulator, but the point is it\'s a real world task, to which we can
correlate some of those other tests, low fidelity, low in simulators,
and some of the other cognitive tests and some of the other tests that
were described, allow us to run the continuum from a facility that\'s
really the high end to the studies that are obviously a lot less
expensive to perform, but we can cross validate each other against the
other tests, so we can look at how they predict the impairment in a real
world task, driving.

DR. SOLLER: I\'d like to \-- can I make a comment just by way of putting
that in perspective? Because I think that study was, as I saw it
reported out, had dramatic headlines about the comparison of alcohol to
the OTC in question, and just by way of perspective, from the prevalence
studies, I\'m remembering that the fatal traffic accidents related to
alcohol were upwards of 50 percent or more, and I think one of the
questions you have to ask is that if it translates out from a simulator
study that alcohol is worse than a particular drug, you have to ask
where are the crashes, particularly given the very large usage profile
for some OTCs in this regard or other drugs.

It\'s possible that one of three things is happening. The in use
antihistamine drowsiness is not happening as much as we think. There\'s
individual variability, 10 to 15 percent, depending upon the dose, the
drug, the condition. When it does or if consumers think that it may
because they read the label, they can compensate. They might not choose
to drive. They might chose to stay home in bed with their particular
malady or third, the simulator studies may have some limits in terms of
how you extrapolate that out to real world.

The other comment I wanted to make is that just by way of putting this
in perspective, often the 50 milligram dose is the one that is chosen in
these particular studies, and from the standpoint of usage patterns,
only a minority of the number of different antihistamine-containing
products recommend only the maximum dose for this type of antihistamine,
the 50 milligram dose.

They\'re usually recommended in the context of a 25 to 50 milligram dose
for diphenhydramine, and many products only have the 25. The expert
advisory panel and FDA in the final monograph recognized that consumers
would choose these products based on labeling and based on their
experience.

The so-called PM products or the night-time products have 50 milligrams
as the recommended dose but with directions to take at bedtime, and I
think this is important as we think about the range of drowsiness, this
10 to 50 percent that we see for this class of drugs, the dose, the
underlying condition, the fact that concomitant medications are taken in
combination like a sympathomimetic, because there is extensive
variability.

So, in sum, I think you need to take into account usage patterns when
trying to understand the practical relevance of simulator studies and
also recognize that the consumer\'s being informed that a market, a very
significant effect, market drowsiness, may occur with the product, and
in a separate part of that warning, being warned to use caution about
driving a car or operating machinery.

That, with what has been very extensive publication \-- public education
on read the label, I think, can be supportive of what we\'re seeing in
the post-marketing surveillance studies and the other prevalence
studies.

DR. KATZ: I have a question about time course of effect. We\'ve seen
some information about the time course post-single dose, but what about
post-multiple dose or drugs to be given chronically? Is there an
accommodation to this effect over time?

DR. O\'HANLON: Russell, are you asking me?

DR. KATZ: Anyone who knows.

DR. O\'HANLON: Okay. Those figures that I showed were generally the
second night of use. We have done some chronic dosing with hypnotics as
well as with most other CNS active medication that we\'ve studied.

There generally is the phenomenon of tolerance, as you\'d recognize. On
the other hand, there is also the phenomenon of accumulation. Dalmane\'s
effects increase for a week as with accumulation and then begin to
decline afterwards with developing tolerance.

As another example, using Ativan, two milligram BID, which is a pretty
hefty clinical dose, with anxious patients, we found out that the
patients drove very badly the first day indeed and felt very \-- sedated
is not a good word. They just felt bad. They felt sleepy. They felt
ataxical, all kinds of things. By the end of a week, they were still
driving bad, but they felt much better.

There was a decline in impairment over the week. There was a greater
decline in subjective drowsiness, and the decline was about the same as
the accidents and the number of injured, including fatally-injured
drivers, in Saskatchewan as a function of time from the initial
prescription.

There is a drop in the relative risk, taking Lorazepam, from 13 times
normal in a first week all the way down to two times normal at the end
of a month. That\'s the kind of pattern we were seeing. Yes, tolerance
does occur. Yes, you are still in danger of a fatal accident at the end
of a month in spite of tolerance occurring.

DR. WEILER: I certainly agree that these studies need to be conducted
after first dose and at steady state, but one of the things that we
ought to recognize is compliance is a terrible issue with drugs that we
prescribe, and many of these antihistamines are really taken on a PRN
basis.

So, if we actually look at the use of the drugs, we tell somebody to
take the drug when they\'re supposed to take it, and they really don\'t
take it that way, they take it now, and then they don\'t take it
tomorrow or the next day, they take it the day after.

It makes it very difficult to look at impairment. So, I think you can\'t
just look at steady state. You really do have to look at the effects
after a first dose or acute intermittent use.

DR. KAY: When we\'ve looked at steady state, what we have found is that
you need to think again in terms of these different dimensions of
sedation.

With respect to self-report, we have found, for example, with
diphenhydramine, that 25 milligram QID dosing, people continued to show
significant fatigue with five days of that steady state dosing on
self-report measures. So, that would be looking at self-report. A recent
study looking at Citerazine, showing significant self-report sedation at
seven days of dosing. So, self-report seems to persist.

With respect to the physiological measures, we see tolerance, clearly,
in our sleep latency testing that we do. If we continue night-time
dosing with Chlorpheniramine for four nights, by the fourth night, the
eight milligram dose was pretty much close to the 10-minute mark. There
had been quite a reduction in the day-time sleepiness.

The higher dose, the 12 milligram, was still at about eight-minutes
sleep latency, which is clinically abnormal. So, there is evidence
physiologically of tolerance.

In terms of the cognitive tests, those seemed to develop some kind of
\-- I don\'t want to call it tolerance but more adaptation. You learned
to function under the influence, and we began to see the dropping out of
the cognitive effects after about three days of continued dosing, even,
you know, with several of these medications.

But with respect to psychomotor, that\'s why we can\'t just rely on any
one measure, we have shown, for example, at the 25 milligram
diphenhydramine dose on that tracking test I showed you, 15 percent of
the subjects on diphenhydramine crashed on Day 5 compared to zero
percent on placebo on that kind of measure.

So, psychomotor performance can persist, and I think John or Jim might
be aware of some research done in the Netherlands by the military
looking at three weeks of antihistamine dosing and again showing on
their dual tasking test a persistent psychomotor effect, but the
self-report effect was dropping down, and the other cognitive effects
had disappeared.

DR. ELLINGSTAD: I might interrupt. I think we\'ve reached a point where
we probably could use our first break of the conference. I\'d ask
everyone again to develop their questions and the audience to submit
them on the note cards, and the parties to be assembling theirs.

We will reconvene at 10:15.

(Whereupon, a recess was taken.)

DR. ELLINGSTAD: A couple of things before we begin. There\'s apparently
been some confusion about where to get cards. So, I\'d ask the staff who
have cards to distribute to collect questions to make themselves known
and wave your cards around.

DR. GALSON: The card ladies are back there waving the cards.

DR. ELLINGSTAD: So, anybody that needs those, you know, please summon
them and turn in your questions. We have at the moment one individual
who has indicated that they will be making an audience presentation.
That\'s in your agenda at 11:15.

Anybody else that falls into that category, please check at the desk
outside, and we would need to have them registered immediately before
that would happen.

Okay. We will resume, and before I turn it back to the Technical Panel,
let me exercise the prerogative of the chair and sneak in a question
here.

It was interesting, the discussion, I guess, that started with Dr.
O\'Hanlon, that referred indices of impairment to alcohol, and what I\'d
like to ask as sort of a general discussion of that as a calibration
standard for impairment, you know, from other kinds of agents, and my
assumption is that you\'re going on the basis of a long history of
epidemiological research that associates various levels of blood alcohol
with known probabilities of accident involvement, etc., and then makes
the logical extension that from that, we can use that as a calibrating
standard for impairment and other drugs.

Would you comment, if I\'ve mischaracterized that logic?

DR. O\'HANLON: Thank you, Mr. Chairman. I\'m glad to have this
opportunity to expand a little bit on my five-minute presentation.

I used alcohol as a standard in two ways. When I compared the
epidemiological data, the limited epidemiological data concerning three
hypnotics, I was comparing it to the Borgenstein, the famous Borgenstein
epidemiological relationship between blood alcohol concentration and the
risk of an injurious or actually in this case fatal accident.

When I was referring to the empirical data from our tests in the
Netherlands, I was making the comparison to data we had collected in a
special calibration study. Alcohol was probably the most dangerous drug
we ever studied, and we did not do that particular investigation on the
real road in traffic as we did subsequently with every medicinal drug.

Rather, with the help of the Dutch Province of Ronaken and the traffic
enforcement, the law enforcement personnel, we closed a 15-mile segment
of secondary highway, and we took a group of 24 social drinkers defined
by sociologists and psychiatrists as representative of social drinkers.
As close we could come to a really representative group were civil
servants, and we had 24 civil servants who undertook the test sober and
at .03 blood alcohol concentration, .06, .09, 1.12, and we were very
pleased to see that our primary outcome variable standard deviation of
lateral position increased exponentially with the blood alcohol
concentration.

The correlation between mean concentration and mean SDLP change was .99.
On the basis of that strong relationship, we developed an alcohol
calibration curve which allowed us ever thereafter to state the amount
of weaving and swerving that occurred after medicinal drugs relative to
the equivalent blood alcohol concentration.

I think that could be done for every test and should be done. Now,
alcohol is a most complex pharmacological entity. It is not the same as
any other drug. So, this comparison is limited but nonetheless, it\'s
the best we\'ve got with the most notorious hazard to traffic safety,
pharmacological hazard being alcohol.

DR. ELLINGSTAD: Okay. Thank you.

Dr. Soller?

DR. SOLLER: Just a comment, and I know we\'re going to be talking about
the labeling tomorrow. I would ask that you perhaps bear with me because
as we think about these kinds of standardizations, ultimately they
potentially can have a public health intervention impact in terms of
where you go, and that\'s where I\'m coming from in this particular
comment.

I think from the standpoint of looking at these kinds of relationships,
and I\'m not going to argue it from a scientific standpoint but that
stamp, they imply sort of an all or none standard, and I think that\'s
important in trying to think about what that might look like ultimately,
and that may be appropriate from a scientific standpoint, where you\'re
investigating these products and trying to look at comparisons in the
scientific framework in a laboratory of clinical setting and that kind
of framework, looking for those kinds of comparisons.

But I think from a labeling standpoint, it\'s totally inappropriate, and
the reason I say that is that for at least the products that we are
concerned with in the OTC market, there appears to be a considerable
amount of individual variability, that these are effects that may occur,
not necessarily occur all the time in all people, and two things can
ultimately happen, and that is, for those individuals who have a
pejorative view about alcohol, having something like that translated
into labeling would unfairly disparage the product, and for those who
are interested in abusing products might well lead them to think that
they\'re going to get alcohol-like effects.

So, just a comment as we think about how these things might ultimately
translate out.

DR. ELLINGSTAD: Okay. Thank you, and we will discuss labeling and get
into the actual interpretations of \--

DR. SOLLER: I understand.

DR. ELLINGSTAD: \-- that later. The point of my questions to Dr.
O\'Hanlon was principally from a psychometric point of view, of having a
reference against which \-- that has been reasonably well accepted and,
we presume, reasonably well empirically established as an impairing
substance.

DR. KAY: Just briefly, Dr. Ellingstad. Also, blood alcohol equivalents
have also been worked out for many of the cognitive and psychomotor
tests.

DR. ELLINGSTAD: Okay. Thank you.

DR. KAY: Expressing the amount of impairment in something like an
alcohol-type thing.

DR. ELLINGSTAD: Thank you.

Let me turn it back to the Technical Panel.

DR. GARBER: Just before we get into our last few questions, I did have a
couple of comments from the audience during the break that suggested
that while those of us here on the Technical Panel and the Witness Panel
are certainly well aware of all of the various names by which the
medications are described, some of the folks in the audience are not as
well versed in pharmacology.

If there is no objection to this on the industry\'s behalf, I would like
to ask if we can at least \-- and recognizing that the trade names of
these drugs are not the only names by which they are marketed, but if we
can perhaps indicate what some of the common trade names may be for
these medications, just so that our audience understands what we\'re
talking about when we are discussing some of these drugs.

Is there any objection to that on \--

DR. SOLLER: I thought we were here to talk about the ingredients. Very
purposely, we did not include the trade names in the AER analysis that
we presented because of the issues of causality and mentioning one trade
name and not mentioning all, that\'s a certain degree of unfairness as
well.

I would opt for dealing with the ingredient names.

DR. GARBER: Okay. Then I\'ll have to ask that if we can at least
describe what the drugs are commonly used for, unless there is an
objection to that on behalf of the industry.

DR. SOLLER: Oh, I think that\'s fine. In fact, I mentioned for
antihistamines, they are used in cough/cold preparations, for runny
nose, sneezing, for cough. They\'re used \-- some of them are used as
sleep aids. Some are used as anti-nausea medications and others for \--
and all of them for allergy symptoms, by way of examples.

DR. GARBER: Okay. And I\'d like to \-- if we can, when we do discuss a
drug or if it\'s something that we haven\'t mentioned in awhile, if we
can make that same \-- if the presenter can make that same comment, just
to note what we\'re talking about for those of us who are not all that
familiar with the medications and their uses.

Thank you. We have, I think, one or two more questions from the rest of
the Technical Panel.

DR. TEMPLE: Much of the data on impairment was presented as changing
meanings. Do any of these studies allow one to determine whether what
you\'re seeing is a fairly consistent change in the entire group or a
particular subset of a population that is driving?

In other words, how much individual data do you have versus group data?

DR. KAY: With the cognitive testing, obviously we\'re able to test
larger groups than we do in a driving situation. In fact, typically when
we have a hundred subjects, a third receiving a positive control, the
third receiving an agent under study, and a third receiving placebo.
We\'re trying to find out whether there\'s any difference between the
drug under study and placebo, and to demonstrate that we have
sensitivity to sedation, we include a positive control, and with the
size of the groups, we typically can look at specific groups.

For example, when studying diphenhydramine, this one we\'ve been talking
about, the cold, allergy and sleep medication, that we basically find
that only a third report feeling sleepy. Actually, that was a
recommendation by the FDA. Look and see what percentage of the people in
your study are reporting sleepiness. We did.

Then we looked specifically at the two-thirds that didn\'t feel sleepy,
and we found that those individuals were just as impaired on the
cognitive measures as people who felt sleepy, you know, that lacked
awareness.

So, yes, we could break it down. We have a large enough group. We can
find out within a group what\'s going on.

DR. TEMPLE: But it\'s not just the little subset that\'s driving the
mean; it\'s \--

DR. KAY: No.

DR. TEMPLE: \-- more than that?

DR. KAY: We analyze a study not just looking at mean but also
non-parametrically in terms of the percentage of people showing an
impairment. For example, on the psychomotor test I mentioned on Day 5 of
dosing, 15 percent crashing would be abnormal versus zero percent on
placebo.

DR. WEILER: Another issue would be to look at, as we do with the
effectiveness responder, looking at an analysis of responders. We could
be looking in this case at an analysis of those who have the adverse
event.

The other thing that\'s really important to mention again is that the
control groups that we use, if they\'re healthy people, are going to be
different than if we use people who have allergic rhinitis, for example,
in season, and it may be important to do the study in season rather than
out of season.

So, we may justify giving them the drug out of season, and it may not be
the same thing as coming in and driving when they\'re sick, they have a
runny nose, itching and all the symptoms and feel drowsy to begin with.

So, a lot of variables, not just the dose levels, not just the reaching
steady state, but the characteristics of those subjects in the study
group would be very important when we\'re looking at impairment.

DR. O\'HANLON: Our studies were typically done with 20 to 30
individuals, being patients or volunteers. That\'s too few, we agree.

As far as making an extrapolation of the population, we have two ways of
doing that. First, at least in the healthy volunteers, we\'d give twice
the recommended dose. If nobody has responded or very few to the
recommended dose, and they still don\'t respond to twice, we can be
pretty sure of the safety of that particular drug.

Regarding are we looking at a few outliers that inflate the mean, in the
case of seriously-impairing drugs, which antihistamines, by the way, are
not in our view, then the drugs which cause more change in driving
performance than the blood alcohol concentration .10 affect virtually
everybody. That means 19 out of 20, 28 out of 30. If the effect is that
strong, we are very confident that it is a consistent effect across our
subject sample.

DR. KATZ: I had a question for Dr. Kay. You had said that your results
on your \-- if I heard you correctly, your results on your cog screen
testing were predictive of real world situations.

I\'m wondering which real world situations and which subsections of the
\-- or which specific tests or measurement functions were correlated
with what those real world situations are, and that sort of raises the
larger question, which is, what do we know on the basis of evidence
about how these various test methodologies predict bad outcomes? Let\'s
say traffic accidents.

For example, what\'s the \-- Dr. O\'Hanlon talked a little bit about the
evidence for the lateral sway, but what about the various following
closely as a parameter? That\'s, you know, the various sorts of things
that people are looking at. What do we really know about how they
correlate with what we really care about?

DR. KAY: Well, cog screen was a test that was developed for the Federal
Aviation Administration as a measure to detect changes in brain
functioning which left undetected could interfere with operational
performance of an aircraft. It was based on a task analysis of the
mental abilities required to fly an airplane, the cognitive, perceptual
and psychomotor requirements.

It was later determined that it does predict performance of pilots. In a
study done by a major carrier, it was shown that measuring operational
performance of the person flying the plane, the commercial airplane,
that cog screen was the better predictor than some simulator
performance, whether or not the pilot had flown in the Air Force, his
knowledge-based test, his IQ test, personality test.

So, it\'s a major selection tool.

It\'s also shown in studies where \-- you couldn\'t do this in the U.S.
but overseas, when we get the flight data recorder and measure landing
performance, it was a good predictor of landing performance, and in
studies where we have looked at pilots who\'ve been referred for
aviation performance problems, again looking at the overlap between
those aviation performance problems, they have been rather striking.

The Navy has done studies in a different area, looking at landing
performance \-- rather, the landing craft that they used and found that
cog screens, just using three or four subtests, was a very good
predictor for them of who they could train to actually operate these
landing craft, which is a fairly complex vehicle, and so those are some
of the areas in which it\'s been studied, and we also looked at truck-
driving simulation.

DR. SOLLER: Dr. Katz, just a comment in terms of when we use the term
\"predict real world\" and then predict what\'s happening
post-marketing, if that\'s real world, and a comment on that in terms of
the drivers and machinery operators, the pilots.

There are compensatory strategies that might take place, avoidance
strategies that might take place as well. Flyers are supposed to
self-ground based on the condition, not necessarily the medication, but
also if taking a medication, self-ground by way of example.

I had mentioned usage patterns before in terms of the particular dose
and the variability, and with what we see as consumers reading the label
and the type of labeling we have and what might be important in terms of
added education, I think that provides at least a perspective in terms
of thinking about how we think about predicting real world.

DR. KATZ: Could I just \-- one quick follow up to Dr. Weiler.

What sorts of evidence is there linking the predictive power of the
various submeasures that you look at and traffic accidents? Is there
much

DR. WEILER: Well, I agree that what we really do need is real world
experience from crash data and from the use of these drugs, and we are
missing that link in many areas. We simply don\'t have a lot of good
epidemiologic data.

Unfortunately, that wasn\'t what our panel was charged with, but I agree
with the others who have said that that\'s the kind of information we
need, that we can correlate with what we\'re getting.

The problem is that it\'s very hard to understand how someone who gets
in a simulator or on-the-road driving has \-- who is really impaired
when you ask them to do tasks isn\'t going to have a problem when they
actually drive a car. Do they have ways of compensating? Probably. But
we really need data to look at this.

Many of the studies that have been done previously have problems. The
crash studies really don\'t answer the questions very well, but I
believe, and I\'ve seen some more recent data that should be coming out
soon that are helpful in this area and will provide us with this kind of
information.

I think we need to encourage the collection of that kind of information
to help us to correlate it because then we really are talking about the
real world. We\'re talking about situations in which we collect data and
look at impairment and not just laboratory experiments. I think we have
to correlate the two and that will give us what we need.

I wasn\'t prepared to respond to some of that. I just hope those data
come soon so that we can do that.

DR. ELLINGSTAD: We will be into that topic area this afternoon.

DR. TEMPLE: Anything, Dr. Kay, that you refer to, could you be sure that
we know where to find it or that you provide the tests? Of course, Dr.
Weiler, anything you can sneak us before publication.

DR. WEILER: Well, I\'ll see what I can do.

DR. TEMPLE: Actually, I had a question for Dr. Soller.

It seems likely that some people who are taking an antihistamine and are
made sleepy stay home, but most people\'s lives aren\'t adaptable easily
that way. If you have to drive to work, you drive to work, and I think
seasonal allergies, you don\'t want to use your sick leave up for
seasonal allergies.

Do you really think most people on those kinds of drugs, which are very
widely used, really stay home and don\'t drive?

DR. SOLLER: I think consumers choose.

DR. TEMPLE: That\'s sort of what we\'re worried about.

DR. SOLLER: Yeah. No. But I think that\'s what you ought to also have
confidence in, and the reason is that they have experience with these
particular products. These products have been around for a long time.

There are alternates that are available, if these are unacceptable to
consumers, and at least as we\'ve looked at this particular situation, I
won\'t repeat our position that we mentioned before, is that we\'re not
necessarily seeing the signal, and that what is being done or what has
been done by FDA and what will be done with the drug facts label will
allow the consumer to make the best choice.

DR. GARBER: I think that probably concludes our questioning from the
Technical Panel.

DR. ELLINGSTAD: Okay. We\'ll let the Tech Panel recharge their
batteries, and we can come back to them when we\'re done with the
parties.

What we\'ll do now is turn to the parties for questions. Again, our
operating procedure here will be to ask one individual from each of the
party tables to serve as the spokesperson. The rest of the folks, please
give their questions and communicate them as intelligibly as you can to
that spokesperson.

Let me also correct an oversight. At the beginning, I left off one \--
the introduction of one of the party tables, our Professional Group, and
what I\'d ask you to do before you begin is, if you two gentlemen will
introduce yourselves, and then we\'ll find out which of you is the
spokesperson.

MR. GELULA: I\'m Richard Gelula with the National Sleep Foundation.

MR. DROBNICH: I\'m Darrel Drobnich, Senior Director of Government and
Transportation Affairs.

DR. ELLINGSTAD: I think the mic\'s off there. Is the button \--

PARTICIPANT: If you leave the button up, that will leave the mic on.
It\'s up.

DR. ELLINGSTAD: Okay. Does this group have questions?

MR. GELULA: Yeah. I\'m aware that different types of people are taking
medications for different reasons. For instance, some people are taking
medications to help them sleep. Others are taking them for cold,
allergies, flu, or other medical reasons.

I\'m wondering if the studies have compared the impairment effects for
people, for instance, with chronic insomnia who would be taking the
medications for the purpose of helping them sleep at night versus the
impairing effects on the normal population.

DR. ELLINGSTAD: Go ahead, Dr. O\'Hanlon.

DR. O\'HANLON: Yes. We\'ve always tried to do that with different
patient populations, not only insomniacs, but with depressed patients
and anxious patients as well, and to study them first in a controlled
condition, not even with a placebo, to find out what their baseline
performance is, and we have not been able with insomniacs or depressed
or anxious patients to measure a baseline impairment. In other words,
the impairment occurred after the administration of drugs.

One other thing. We have tried with our tests to produce an insomniac
effect to limit people to only three hours of sleep before taking the
test. We measured slight impairment but nothing like the impairments
shown on \-- at least in the worst cases to you this morning.

So, yes, it would seem that the morbid condition is not in itself
responsible for driving impairment to any great extent as far as we\'ve
seen probably because the individuals have learned to compensate for
their impairment.

A drug effect is something new, and I\'d like to add to what\'s been
said already. Often drug effects are to reduce a person\'s
self-awareness, their insight and their judgment, and it\'s not fair to
say to patients, you are the final person that decides whether you are
fit to drive today or not. They\'re vulnerable, and drugs make them
vulnerable to the mistake of driving in the first place.

DR. ELLINGSTAD: Any other questions from the Professional Group?

MR. GELULA: No.

DR. ELLINGSTAD: Okay. We\'ll turn to the Pharmaceutical Industry Group,
and again as we go through, if the spokesperson will introduce
themselves and then ask any questions.

MS. TAUBIN: I\'m Lorna Taubin from the Consumer Healthcare Products
Association, and I have a question for Dr. Weiler.

I was wondering if the methodology used in the National Advanced Driving
Simulator, is that correct, is a unique facility?

DR. WEILER: So, the question is, is there a replication of what we do?

Actually, I should tell you that the facility isn\'t even on line yet.
It will soon, and I\'m not sure what soon is. In the next couple of
weeks, hopefully. But there isn\'t anywhere else in the world to do
exactly what\'s done in there.

The Daimler facility in Berlin has some similar attributes, but it\'s an
older facility, and it doesn\'t have the track and so on. We can cross
validate facilities like that with lower-end simulators, but there will
be the need to do that, and it\'s something we\'re very interested in
doing, correlating the end points that we\'ll look at with on-the-road
driving and with lower infidelity simulators as well as some of the
other cognitive tests. It\'s something we\'re very interested in doing.
It\'s obviously important to do in a new facility of this sort.

I would also like to mention that there are additional materials
available. I was made aware of this, that NHTSA has \-- if you would
like to have a much longer version of what I showed with more realistic
video, we can make it available to any of you who would like to have it.
It\'s not an advertising thing, but we can provide more background
information if you would like to have some more.

If you\'ll let me know, I\'ll make sure that we get it to you.

DR. ELLINGSTAD: Any other questions?

MS. TAUBIN: No. I just wanted to add on that even when the studies are
done there, that will be the only place that\'s using that methodology?

DR. WEILER: Well, in a sense, yes, but the idea is that we want to be
able to use that facility to do other studies. We have a fixed base
facility there, and the question is, when we look at this facility, when
we set up our tests, what else can we do along with those tests to show
that they correlate with each other? That will help us to understand
situations in which we really don\'t need to use a facility like that,
situations in which maybe we don\'t get the same data from two different
kinds of tests.

We believe that it\'s extremely realistic, and we should have a great
opportunity to be able to look at these kinds of questions in a
scientific way.

MS. TAUBIN: Thank you.

DR. ELLINGSTAD: Thank you.

We\'ll turn to the Union Group.

CAPTAIN POPIEL: Randy Popiel, Allied Pilots.

My question has to do with tests and performance levels in the airline
industry. Are there facilities, such as yours, Dr. Weiler, that are
measuring aircraft operations and pilot performance with the use of
drugs and sedatives?

DR. KAY: Well, there are studies that have been conducted, not too much
with commercial aviators but we\'ve conducted several tests with the
Navy down in Pensacola, looking at specific agents. Two of those studies
are now published.

One\'s currently in the current issue of Aerospace Medicine, looking at
cholesterol medications, again looking to see if there\'s a sedative
effect of these cholesterol-lowering medications, and this was done with
several hundred pilots, using a test which is a predictor of aviation
performance.

It was done using flight simulation, but there are studies that are
conducted elsewhere that use flight simulation, looking at specific
agents and comparing the active agent versus placebo to see if they
affect pilot performance in aircraft, but I think there\'s more study
going on now using cognitive and psychomotor tests which relate to
flying.

DR. WEILER: There is indeed a literature using simulators, flying
simulators. It should be said that it\'s easier to generate a flying
simulator than a driving simulator because it\'s okay to feel like
you\'re flying in a plane, but if you have a disconnect, you feel like
you\'re flying in a car, that\'s the kind of thing that gets you sick
and really invalidates what\'s going on because they may have simulator
sickness, and it shouldn\'t really occur if you\'re driving a car.

So, it is difficult to build these things. They\'re not trivial
developments.

DR. ELLINGSTAD: Any other questions?

(No response)

DR. ELLINGSTAD: Okay. We\'ll turn to the Transportation Industry Group,
and who is our spokesperson there?

DR. FAULKNER: They say because I\'m a doctor, I\'m the one that should
feel these things. I thought it was because I\'m better looking on the
megascreen up there, but we\'ve been talking among ourselves here \--
oh, God. Talking about some of the studies going on here.

As you\'re aware, in many of our industries, our employees are traveling
for long times, over multiple time zones. Have there been any studies
done not so much focused on maybe the medication but sleep- deprived
individual employees and their impairment?

DR. O\'HANLON: I mentioned one, and there have been others. I was not
prepared for that particular question today.

Certainly sleep deprivation and particularly that which occurs in jet
lag is responsible for impairment, but the psychomotor impairment which
is manifest in driving impairment is not the biggest thing. The biggest
thing is difficulty in sustaining attention, concentrating to a dull
task like people\'s every day jobs, and to respond quickly and hurriedly
like people would normally do.

There have been no tests that I know that show that people who fly over
to Europe and get whatever poor sleep they can and try to drive around
are in more danger or in greater hazard of an accident than normal,
except, of course, they have to be familiar with their territory.

It is a problem but apparently not a huge problem inasfar as traffic
safety is concerned. Work efficiency may be something else.

DR. ELLINGSTAD: I think we do need to restrict this \-- our discussion
here to the issue of illicit drugs. We can launch into a very large
symposium, if we get into this whole issue of fatigue and sleep and so
forth.

DR. GALSON: If the questioner would just identify himself for the
record?

DR. FAULKNER: Tom Cruise? No. Dr. Tom Faulkner with APA.

Can I ask then a question, if we\'re talking about drugs? And I agree,
employee fatigue is an extensive issue. Any studies you\'re aware of
using the new class of anti-depressants, the SSRIs?

DR. O\'HANLON: Which one? We\'ve studied most of them, and my colleagues
have as well.

The SSRIs have been extensively studied. Their propensity for producing
driving impairment is very low. That does not mean it doesn\'t happen in
an occasional individual, and it does not mean that impairment cannot
occur when you\'re taking an SSRI and something else.

Doctor, as you know, there\'s the potential for a pharmacokinetic
interaction with some SSRIs and other drugs, like example
benzodiazepines, and my group has measured an effect, impairing effect
of the SSRI or necessarily even the benzodiazepine but both in
combination due to a pharmacokinetic interaction.

But in general, they\'re very safe drugs. I have more question about the
mood stabilizers which are moving so heavily into psychiatry and even
general medicine these days.

DR. FAULKNER: Final question. Seeing, I guess, interest in terms of the
supplements, such as Ginseng, Ephedrine, St. John\'s Wort, Echinacea,
any studies that you\'re aware of here or abroad on the impact of those
used as a directed or in excess of directed?

DR. KAY: We have conducted several studies looking at NADH. We actually
used it in a study on jet lag. I guess we could answer your jet lag
question. We did find after flying people from the West Coast to the
East Coast of the United States on commercial aircraft, this was done
with, I think, all together 48 subjects in the study, that we found
people were actually having trouble with undivided attention, about
six-tenths of a second slower, which could have transportation impact.

We found if we gave them NADH, that we didn\'t find any deterioration in
cognitive performance. They were talking about impairment. It seemed to
have some protective effect, but we didn\'t see any side effects,
comparing it obviously to placebo, looking at various ways to mitigate
effects of jet lag, and we have studied supplements that way, and we
basically use the same methodology with the supplements that we\'ve used
with the other prescription or over-the-counter medications.

DR. FAULKNER: Thank you.

DR. ELLINGSTAD: Any questions from the Transportation Industry?

(No response)

DR. ELLINGSTAD: Let\'s turn to the Advocates, and who is the
spokesperson?

DR. de GIER: I\'m Johann de Gier from ICADTS.

I would like to ask three questions to Dr. O\'Hanlon. First of all, if
you talk to physicians about the impairing effects of drugs, they mostly
answer with the question that the ailment itself is also a problem for
drivers and thereby the drug might have some improvement of the
performance.

Did you, in your studies, ever look upon the placebo conditions with
people with anxiety disorders, people with depression, people with
sleeping disorders, to see how they behaved or performed under placebo
conditions compared to healthy volunteers in the placebo conditions in
order to see how this effect of the illness could be determined?

The second question is, how extensively have the effects of various
sedating drugs prescribing in the long term prescribing of prescription
drugs been studied with the so-called \"at-risk populations\"? For
example, elderly, people diagnosed with several diseases but also people
using multiple drugs or medicinal drugs, and then the issue you just
mentioned, drug interactions is just one issue.

Should I raise the third question as well now?

DR. O\'HANLON: Thank you. I\'ll try to remember.

I believe I mentioned that we did not see any particular impairment
associated with depression or anxiety. I\'ll say that a little bit
stronger. The anxious patients drove about as well as our healthy
volunteers.

The depressed patients in our test paradigm drove actually a little
better, and we measured them on two baseline days to see if they drove
reliably better, and the correlation between their Baseline 1 and
Baseline 2 was about .85, which is higher than we\'ve ever seen in a
healthy volunteer study.

It\'s difficult to get real depressed patients to drive a car in many
cases, but when they could do that with all the assurance of our very
nice driving instructors give them, they drove well in our test, and so
they took drugs, in which case, some of them didn\'t drive well after
that.

Now, as far as the at-risk population \-- in other words, let me answer
your question, as far as we know, patients unmedicated drive normally in
our test paradigm, and there\'s only a little bit of epidemiological
data to indicate that depressed patients in particular, when they\'re
unmedicated, have a higher-than-normal risk of accidents.

Going to studies with populations at risk, we have studied elderly
drivers, mildly cognitively-impaired drivers. They are worse. Unlike the
younger patient groups, the elderly are worse drivers. The drugs that we
were administering were not intended to make them still worse but make
them better, and the drugs failed. So, all we know for sure is that the
elderly are at more risk to any kind of insult, could be drugs or
anything else.

Polypharmacy. Nobody studies polypharmacy as it\'s practiced. Now that
I\'m out in the clinical sphere, I see that every day, and I\'ve seen
much more drastic impairments as a result of combinations of drugs which
extend in reality to 16 psycho-active drugs in a number of certain
patients. I\'ve usually just seen two or three or sometimes four.

We know nothing about that. We can suppose that this is an extremely
dangerous situation for patients who still drive.

DR. WEILER: Can I make one comment? We\'ve talked about a lot of
variables that can occur when we do studies. We\'ve talked about the
underlying condition, talked about whether the person is drowsy to begin
with, so they\'re sleep-deprived, and all of these other issues.

It\'s no wonder that it\'s a daunting task to answer the question, is
this drug impairing? There are so many different variables that have to
be considered to answer the question, and in some circumstances, they
may be quite impairing, whereas in other circumstances, when the tests
are run, we don\'t see a lot of impairment, and nonetheless, maybe it\'s
the tests we\'re running to look at the effect.

So, it is a difficult task for us to answer these questions.

DR. de GIER: I would like to make a comment on that one, because I think
it\'s always better to choose the least-impairing one, if you have a
choice within a therapeutic class.

I would like ask the final question to Dr. Soller. Have you conducted
any research or is there any data available to measure how patients make
decisions about which OTC products to purchase?

DR. SOLLER: The types of studies that have been undertaken to look at
individuals\' label comprehension and then actual use were \-- have
their roots in a particular OTC class of drugs many years ago in terms
of in-use effectiveness of a certain type of drug, and then in the early
\'90s, there was an interest, particularly in the RX/OTC switched
products, and I think a good reasonably predictive set of types of
studies, rather, developed, a label comprehension study and an actual
use study, and these have been used and over the years have gotten
increasing emphasis, particularly through the input from Dr. Ganley,
who\'s here today, in terms of selection and de-selection.

The OTC new drug facts format has, during the development of the final
rule for the drug facts format, there were studies that were undertaken
by FDA supporting how that particular labeling is set up to ensure that
you have a rationale flow of information from active ingredients to uses
to warnings, absolute contraindications, do not use, relative
contraindications, ask a physician before you use, in- use precautions,
and then other information.

So, a lot of thought has gone into how to present that information to
make it most successful and in a consumer-friendly way to the consumer.

DR. ELLINGSTAD: Thank you.

And the Government Group? Mr. Clarke?

MR. CLARKE: We have a couple of questions.

Dr. Kay, this question was asked somewhat similarly, but I\'ll ask it
again, if I may.

Have any specific studies been done on older populations as relates to
the effects of some of these medications, specifically focusing on the
\-- whether or not there would be greater differences in that
population?

DR. KAY: Not in the studies that we\'ve conducted with the cognitive
psychomotor testing at the current time. We\'ve not studied special
populations, older populations like that.

MR. CLARKE: Anybody else with any other specific study results?

(No response)

MR. CLARKE: An observation by way of a question. It\'s been interesting
to note over the past several years the increased tv ads for
prescription drugs, and at the end of those ads, the extensive list of
precautions and side effects and so forth.

Dr. Soller, by way of increasing the public\'s awareness of drugs and
drug side effects, are you seeing any carry-over effects of increased
public awareness of these kinds of concerns spilling over into the OTC
arena?

DR. SOLLER: I\'m not sure I know exactly what you mean by \"concerns\",
but could you maybe just amplify for a moment?

MR. CLARKE: The advertising is obviously geared towards highlighting the
beneficial effects of these various medications for different
conditions, but then they also at the end talk about the potential side
effects, which is the case with almost all medications.

Is it your sense that the public is reacting favorably to these ads in a
way that would indicate increased sensitivity to concerns about side
effects?

DR. SOLLER: I don\'t have any information specifically on that. Dr.
Spilker might. I think in looking at direct consumer advertising of
prescription products versus OTCs, it\'s important to recognize that
advertising is best used in terms of raising awareness about what a
product\'s for and where they might be able to get it.

In the terms of the learned intermediate that might be there for the
prescription product, and a consumer having information to engage in the
dialogue with the physician on that particular point and what DTC might
use be done in that area.

I think there have been some reports on that. I can\'t speak
specifically to them, but from an OTC standpoint, it\'s important to
think about the use pattern where the individual picks up the product,
has it in their hand, and how do you present the best information for
them so that they can read it, as I mentioned earlier, in that logical
flow of information, so they can get all of it in a consumer-friendly
manner with bulleted points that give it chunks of information that they
can take away with them?

So, I think, as I\'ve mentioned before, I think what we are about to do
in terms of the implementation dates for drug facts labeling, that
we\'re in a position to raise the level of awareness on some of these
warnings because they will be more prominent and more consistently
placed on the label.

DR. SPILKER: We know that the public and patients in general are very
pleased with the direct-to-consumer advertisements, based on a large
number of surveys done by a wide variety of consumer and other groups.

The patients are looking for information. They are going to their
physicians in many cases, and once there, one of these, if you will,
side effects of this type of advertising is diagnosing heretofore
undiagnosed problems.

There are large numbers of patients with diabetes, hypertension, and
other chronic diseases who have had this disease diagnosed and treatment
initiated based on their going to physicians for direct \-- as a result
of direct-to-consumer ads.

Vis a vis your specific question on the adverse reactions, I think that
that information that is presented both through the ad, both through
handouts at the pharmacy and through discussions with their physicians
and other health care professionals, is all to the good because it is
giving this \-- informing the patients and encouraging them to take more
responsibility for their own care.

I think that the \-- rather, we know that the objections of the
physicians to the directed consumer ads have been decreasing over the
last half dozen years, and the objections of the AMA also have
decreased. While there still are some, the physicians are recognizing
the benefits of the information which does include the adverse
reactions.

DR. O\'HANLON: I would like to say something about that.

Since old Merrill Dow began the directed consumer advertisements with
Terfenadine, extolling the drug\'s lack of behavioral toxicity, I have
heard very, very little in television advertisements concerning effects
of drugs that can impair skilled performance and even dangerously so in
the case of driving.

I wonder why you asked the question, because it seems that if the
manufacturer has any suspicion that there may be a behaviorally-toxic
effect of the drug, either directly or in interaction with another, we
do not hear about that on television.

MR. CLARKE: The question was a general one, whether or not the
advertising is increasing awareness on the part of users/consumers that
there are side effects that they need to be concerned about. I wasn\'t
focusing on any one particular type of side effect but rather just the
whole issue of side effects as a secondary effect of taking this thing
for positive reasons.

One other question. I think it was Dr. Soller made his comment about
this 18 primary and five secondary AERs in 10 years with 850 million
prescriptions. Can you elaborate a little bit on that study or \-- I
found that fascinating.

DR. SOLLER: Let me turn to a chart that I should have here, if I could.
Lorna, do you have the

\-- no. The attachments?

We had undertaken a review of the adverse experience reporting profile
for the antihistamines that were listed in the slides that I showed.
These were OTC monograph antihistamines. Some are covered under an MDA
for OTC use, and they\'re used for cough/ cold purposes, allergy,
antiemetic use as well as sleep aids, and they have both OTC and
prescription use.

We went to IRI to get an estimate for \-- I can\'t see you. There you
are. IRI to get an estimate of what the unit sales would be over this
particular period of time, and it was estimated in the subpopulation
that we looked at, the individuals who were 16 years and older \-- we
were figuring drivers licenses. We took that age break, that
approximately 850 million packages or what we call units were sold over
this period of time.

Reflecting the overall usage, I would expect that that is probably
higher because there\'s prescription use, too, that we did not go to IMS
to get the script information.

Then as we looked at this, the total serious AERs as they were defined
in the MedWatch System, that would include hospitalizations and so on,
were 23 in number. There were 18 serious AERs for individuals over 16 in
accident terms for the antihistamine listed or reported to be listed as
the primary suspect. There were five where they were listed as a
secondary suspect, and in about seven of those 18, there are probably
other reasons.

For example, there were two subarachnoid hemorraghes. There was a
cerebral infarction. These are rare events, and there were falls. So,
the point of this, though, I mean, you can get into all the details, and
I\'m not going to go any further, is that over that 10-year period,
there was nothing more than about four per year that were being
reported.

MR. CLARKE: That was my question. These are events that are reported
back to the manufacturers, is that it?

DR. SOLLER: These would have been reported to manufacturers and to FDA
by health professionals, by consumers, by people that may be monitoring
drug studies.

MR. CLARKE: Thank you. That\'s all.

DR. ELLINGSTAD: Okay. Thank you.

I\'ll ask the parties to consider one final question, if you have one,
but before we do that, Dr. Galson has got some questions that have been
submitted by the audience, and I\'ll ask him to pose those to the panel.

DR. GALSON: Thanks. We have received four questions. One is a multipart
question, and one of them is not really pertinent. It has to do with
effects of a specific medication, which is a medication for pain, and
we\'re not going to talk about it because we\'re not talking about pain
medications. We\'re also not talking about specific drugs.

So, I\'m going to put that one aside but just to acknowledge the
question, and I\'ll have to talk to you more about that at the break.

The first question I want to raise is to the whole panel. Can you please
comment on the use of PC-based virtual reality driving simulators to
evaluate impairment?

DR. WEILER: I\'ll try to address that one. There are some problems with
them. The problems that are faced sometimes with the lower-end
simulators has been sickness, simulator sickness, and that\'s been an
issue that\'s been raised.

So, many of \-- there are a wide range of simulators that are available.
We had a symposium last week, a meeting last week in Iowa City of people
who do simulation research, and I was struck by how many different kinds
of simulators there are. There are a lot of options for people to do
these kinds of studies, ranging from NADS to low-end simulators that are
PC-based or that use some kind of virtual reality, and each one of them
has their own special advantages.

Maybe on the low end, the advantage would be low cost. On the high end,
it would be the reality of the actual driving experience. So, there are
data on using those. I\'m really not prepared to address for each
product how it would be, but again, it\'s the level of complexity that
we\'re talking about here, and how we define what is an impairing drug.

DR. O\'HANLON: We all are to respond to this, is that correct?

DR. GALSON: Anyone who wants.

DR. O\'HANLON: Okay. I know of no investigator that engages in full-time
research on drugs and behavior who uses them. The reason why is because
an instrument is not a test. Tests have to be developed and embedded in
instruments, and it\'s usually easier to do, as my colleague Dr. Kay has
done, to use something that\'s easier to control. It\'s not as much fun
as a video game, but it is a lot more scientific and reliable.

The question with all simple devices, including PC-based simulators,
are, are the results they provide valid in predictive purposes for
showing a drug\'s behavioral toxicity? That has to be shown for the
test, not the device.

DR. KAY: We are currently engaged in research actually with the Centers
for Disease Control. We\'re doing some current work looking at the
relationship between low-cost PC, you know, desktop PC-based driving
simulation and how it relates to actual driving, to do that development
of it as a test, but we have conducted studies with pharmaceuticals
using the virtual reality-type driving simulation to look at dizziness
brought on by Floxins, certain antibiotics that people might take, and
we had a downtown driving task, and what happens is people who were
dizzy don\'t turn their heads as they would need to do to see
pedestrians in the crosswalk and were running over pedestrians.

So, it\'s quite an interesting demonstration of what was occurring with
a CNS side effect, but, you know, we are \-- there is a problem still in
terms of development with the simulator sickness, but that\'s being
responded to by improved kind of graphics which are very important.

DR. SPILKER: Your question, Dr. Galson, and all of the discussion this
morning really brings out the point that there is no gold standard and
no universal standard for measuring impairment which really is the
subject of this session.

DR. SOLLER: Just a brief comment, and with considerable respect to Dr.
Weiler for being involved in creating what is a very complex design,
must be fun to operate that design, and I was very much taken by your
comments, Dr. Weiler, at least as I interpreted them, that \-- and I may
be overstating this.

I apologize, but simulators do simulate and that doesn\'t take away from
the design that\'s created within that simulator setting, but it does
speak to what might be the missing link, and the need for, as I heard
Dr. Weiler speaking, and I would agree, correlating the information from
the simulator to the real world, looking for correlations across
simulators.

DR. GALSON: Okay. Great. The next question, again addressed to any and
all of the panel members, is, is there a relationship between an
individual\'s baseline level of cognitive function and the likelihood of
becoming impaired by a drug?

DR. KAY: If I can answer first, in our studies actually in order to
conduct good cognitive trials, good clinical trials, we generally will
screen out individuals who are at the lower ends of cognitive function.

If they can\'t actually take the test and provide reliable data, then we
actually don\'t include them in our trials. So, there would be a
screen-out, an exclusionary criteria for inclusion in the study. Whether
having high IQ or high cognitive performance might be a protectant
effect, we\'ve never really looked at or analyzed our data in that
regard.

DR. O\'HANLON: I was very fortunate when I retired from the drugs and
driving business about three years ago to find myself in an even more
challenging occupation, and that is, working with the developmentally
disabled who use drugs, and I can only tell you, whoever asked the
question, of my personal observation, that the drugs do have quite
different effects sometimes in people with borderline intelligence and
mild mental retardation.

How this relates to the topic of this conference, I\'m not sure, but it
is possible that the drug effects could be different in drivers at the
low end of the, call it for lack of a better word, intelligence spectrum
possibly but not shown.

DR. WEILER: And that may not be the only issue that we have to consider.
We may have folks with ADHD who may have an impact on their driving
performance that\'s unrelated to their underlying condition of allergic
rhinitis or whatever. That adds another level to the complexity in
trying to sort out the effects we might see with these drugs in those
people.

DR. GALSON: Any other responses to that question?

(No response)

DR. GALSON: Okay. The last one is the multipart one, and it\'s addressed
to Dr. O\'Hanlon, Dr. Spilker and the remainder of the panel. So, maybe
the two of you could speak first, if you have comments on this.

Do we have sufficient data to suggest a known period of impairment for
sedating drugs?

DR. O\'HANLON: For some, yes. I would like to make a general remark. We
know enough now to be sure that prescribed medicinal drugs and
presumably some OTC drugs kill people, and driving situations are the
primary cause of their driving accidents.

If we wait until there\'s complete consensus among all the investigators
who study these effects and a standard universal methodology, we wait
forever. Now, to go specifically to the question, yes, because of
epidemiological research and also some empirical research, we know that
the period of danger after certain drugs, specifically benzodiazepine
tranquilizers and hypnotics, which were once very popular and gave us a
good database, is maximum during the first week, but it is not gone for
a month.

In driving, the risk, as I mentioned earlier, the risk of an injurious
traffic accident, when you are taking a benzodiazepine tranquilizer
during the first week is about 13 times normal. By the end of a month,
it\'s about only two times normal, and there\'s a nice exponential
progression of relative risk from the 13 in the first week to two at the
end.

We see similar changes in empirically-measured driving impairment. It\'s
maximum right after the drug begins. It is not gone at the end of the
month. Okay. But whether and how this applies to all other drugs, we do
not know. Some drugs, we suspect, get worse over time due to
accumulation or late-emerging side effects. We have not shown that
empirically yet.

The second part of the question was?

DR. GALSON: I didn\'t read it, but why don\'t I go ahead and read the
three parts of the question, since they\'re all very closely related.

DR. O\'HANLON: My colleagues would also like to respond.

DR. GALSON: Let me read all three because they\'re related. I think it
will flow a little better.

The second one is, would it not be prudent to specify a time range that
driving performance might be impaired? The third part is, why not err on
the side of conservative and specific advice, that this drug may cause
drowsiness on a label seems to be non-specific and weak to guide most
people?

DR. SPILKER: I\'ll start with the first part of the first question. If a
drug is believed or is known to cause impairment, then obviously this
should be studied in terms of the time at which the impairment is going
to occur, both the onset, duration, range for different groups, if it\'s
found to be different, for example, for men than women, possibly for
different ages, different fat content, depending upon the distribution
of the drug in the body.

Basically, we\'re saying that you\'ve got to study this, and I\'m
confident the FDA would demand this of the companies that are
investigating this drug. The information on the range certainly should
be put in the label which really, I think, gets to the second part.

Certainly it\'s prudent to give this information out because just saying
a drug causes drowsiness or may cause impairment is not giving as much
information as for other adverse reactions or just given as a statement.

Now, I do believe that when a drug is known to cause impairment, that
this is studied by the companies. I obviously can\'t talk about all
drugs and all situations, but I do believe it is very relevant for
companies and FDA to agree on a mutually-agreed-on process by which they
will evaluate this consideration.

DR. SOLLER: I\'ll just make a comment, if I could, reacting to the
comment that we shouldn\'t wait forever, and I\'m not saying that
everything has been done for all drugs.

But I don\'t think we\'ve waited forever on OTC medications. By way of
example, we tracked the experience of our products. OTC labeling has
been very carefully devised over a very extensive public rulemaking
process. There are quite a number of different on-going educational
efforts, and we participate in them. We think we can do more here.

We look for ways to partner with other organizations to amplify the
message, and on the issue of the specific label language, I think it\'s
important to tell people what they most likely can look out for and that
was debated within the development of the final monograph for
antihistamines, for example, and there is a very specific statement, a
precautionary statement about driving motor vehicles and about operating
machinery.

I think in the end, in looking at this, in looking at what is done and
what will be done with drug facts label and understanding what we have
by way of experience, I think we\'re on the right track, at least for
this class of drugs. I\'m not speaking for others that have been brought
up today.

DR. KAY: First off, I\'ll comment on the duration, and I think it is
important that methods be used that look at the duration of effect when
sedation is likely to occur and for what period of time, and I\'m not
sure if that methodology is there and if those standards are there
because the methodology certainly isn\'t.

With Palm Pilot, for example, we could find out when people begin to
report feeling sleepy. A study done recently with Cisterazine, which is
an antihistamine, showing the sedation was delayed. It\'s not like what
we see with the over-the-counter antihistamine. It was like about four
hours later. The same thing on the SLT, the sleep latency test, looking
at the sleepiness isn\'t there an hour and a half. The first nap of the
day isn\'t until like, you know, 1:00 in the afternoon, 3:00, four to
seven hours after we dose.

So, it\'s important to know when sedation \-- when\'s the onset of
sedation going to occur, and how long is it going to occur for, and I
don\'t think the bottom line is, you know, how much driving is going to
be affected as how much impairment is going to occur.

In our studies, we\'ve looked at Chlorpheniramine, an over-the-counter
antihistamine, looking at duration of effect. We\'ve seen impairment of
about 15 percent of performance at seven hours after dosing, and so, you
know, you see an effect of this duration. We\'re not saying how much
that impairs driving, but if you\'re working, it\'s an impairment of
your ability to do your job. If you\'re a student, am I going to be
impaired, my ability to learn when I take this medication?

Just saying may cause drowsiness, I think the answer for some drugs is
this drug will probably not make you feel drowsy. It will just impair
you, and I think we need to let people know when that\'s likely to
occur.

DR. SOLLER: Two comments, if I could. Just by way of information, I
don\'t know. The study on Chlorpheniramine, was that the OTC dose of
four milligrams or at the eight and 12 that you described?

DR. KAY: That was actually a study that was done with two and four
milligrams.

DR. SOLLER: The other thing that I came across and had not thought we
would be getting into this, but there is at least one study I\'m aware
of that looked at antihistamines and the performance of children in
school and did not find an effect. So, there is some information. I
didn\'t find a lot of information.

DR. GALSON: We\'ll have the opportunity to discuss some of these issues
more later in the meeting. So, don\'t feel like we have to discuss it
around the table right now.

DR. WEILER: But this does bring up the issue of having a profile for
each medication that helps us to understand the onset of adverse events,
such as impairment, if it\'s going to occur, and how long it lasts.
Really, it\'s important that we have the profile for each drug. If we
really believe it\'s impairing, we need to know the degree of impairment
with each agent, and it\'s not a class-specific thing certainly.

There are really differences amongst these drugs, some which are really
mildly impairing and others which may cause a significant amount of
impairment and may last for a long period of time, just like the class
we consider non-drowsy, may have differences amongst them, if there\'s
dose-ranging differences and so on. Again, it makes it difficult to
answer the questions. It\'s not a simple yes or no answer often.

DR. ELLINGSTAD: I think we\'ll try to get ourselves somewhere close to
schedule, but I promised another quick round, and I\'d ask the groups,
the parties, to keep the questions focused specifically at individuals
on the Witness Panel and keep them reasonably concise.

First, with the Professional Group.

MR. GELULA: Thank you.

I\'m thinking about a particular class of people, those who are needing
to sleep but perhaps battling a circadian situation, like a pilot who
has flown overseas, has a lay-over time, has to sleep in that time, a
truck driver whose time is regulated and must sleep in a fixed period of
time, regardless of what time of day or night that is, a shift worker,
etc., and I\'m wondering, going back to Dr. Weiler\'s suggestion that
there is a need to differentially rate the impairment of sedating
medications, and Dr. O\'Hanlon summarized the data showing a great deal
of impairment variability among long-acting versus short-acting hypnotic
medications.

Given those two things, and this probably relates back to some of the
points that were just made, should not those particular cases where the
impairment effects are known be brought to the attention of those work
groups?

DR. WEILER: Yes.

DR. O\'HANLON: Yes.

MR. GELULA: Second question.

DR. KAY: I would say we\'ve tried even showing that information with the
aviation industry in terms of night-time use of over-the-counter
medications which they may assume isn\'t going to have an effect on them
the next day when they have to get up and fly the airplane. So, we\'ve
been trying to get that word out.

DR. WEILER: Again, we don\'t want to trivialize the warnings. There are
so many warnings on so many things, that you pick up everything, and it
has a warning on it. So, at a certain point, you say I guess I\'m not
going to worry anymore and that\'s not what we want to do here.

We want to tell people these warnings are serious, and we want them to
be concerned about these issues, and we may not be able to run every
last test to determine in every last circumstance the degree of
impairment. We have to make some assumptions, and I guess what we\'re
saying is the assumptions we make are the taking of the worst case or a
reasonable case that would suggest to people it\'s probably not a good
thing to take a drug such as diphenhydramine if you\'re drowsy to begin
with and making a long trip.

MR. GELULA: But if I read you correctly, it might be appropriate to take
a short-acting hypnotic in the situation where it\'s better than not
sleeping at all.

DR. WEILER: It might.

DR. O\'HANLON: Oh, I think it would in fact. There are drugs that I have
recommended for that purpose precisely, but I\'d like to go to my
colleague\'s remark about it not being a good idea to take 50 milligrams
of diphenhydramine or even 25 four times a day just before you\'re going
to drive from here to Sarasota.

There are alternatives. They might cost you a little bit more, but there
are alternatives that myself and my colleagues have shown to be much
safer.

MR. GELULA: Let me ask you another question. How effective is caffeine
as an antidote to the sedating effects since that\'s what people will
often do?

DR. O\'HANLON: Well, it\'s not a good antidote to alcohol\'s effects,
has virtually no physiological antagonistic activity against a
reasonable blood alcohol concentration.

I can\'t tell you how it would be for every single drug, but because the
pharmacology of caffeine is different than the pharmacologies, plural,
that cause sedation, they\'re not direct pharmacological antagonists. It
would be a guess on my part. I\'d rather not speculate. I wouldn\'t
count on it myself.

DR. ELLINGSTAD: I think we\'re getting a little bit beyond the scope of
this panel. If we can move to the Pharmaceutical Industry?

MS. TAUBIN: I don\'t have any questions at this time.

DR. ELLINGSTAD: Okay. The Union?

CAPTAIN POPIEL: No questions.

DR. ELLINGSTAD: And the Transportation Industry?

DR. FAULKNER: No questions.

DR. ELLINGSTAD: Advocacy?

DR. de GIER: First question is actually, are any of the driving tests,
whether real world or simulated, involve multitasking by the driver who
has taken drugs or are the drivers charged only with controlling their
vehicles?

DR. WEILER: Well, I can answer in the case of simulator studies that
we\'ve run. There are many end points. In fact, there can literally be
hundreds. In the one study that I talked about, I think there were 70
end points in the protocol we looked at, and in fact, that\'s an
important issue because when we look at drugs, such as alcohol, which is
a divided attention task-impairing activity, when we looked at the
primary end point, we saw that they did okay, and if we just let it go
at that, you could say oh, it\'s okay to drink and drive and that\'s not
a good conclusion by anybody\'s standards and that\'s a good point.

We really need to look at the multitude of end points that you look at
in order to define the kind of impairment that you see. So, it is
important we look at that and that\'s why comparing not only a driving
task itself but also some of the other activities we can look at, such
as subjective report of drowsiness and the subjective report of how
impaired you feel, plus other cognitive tests, may help us to define
really well the profile for each product.

DR. O\'HANLON: As far as the actual driving tests are concerned, I
described only the standard tests that we have used so long because
methodologically, it\'s a lovely test. It\'s very limited, however. It
measures only direct vehicular control in two dimensions.

My groups in the Netherlands have gone on, it began while I was there
but have gone on to develop a car-following test and also tests for
urban driving which involve the measurement of eye movements to catch
cross traffic at intersections. These are not standardized to the same
degree, and they have not been \-- they\'re evolving still, and they\'re
changing from study to study.

The point I would like to make is that these more complex, you call them
multitasking tests, they could possibly and probably be run in a
simulator, not necessarily the one I was conversant with, and at the
same time that the tests go on in the real world, and if they do agree
regarding the hazard potential of certain drugs, I think that this
complement is perfect.

I mean, it must understand that this is not an either or situation when
it regards methodology, use the best methodology for the purpose, but
you might have to combine the methodologies.

DR. WEILER: And I would agree with that. We looked at some technologies
last week at our meeting, and there were actually some vendors there
that had some equipment, and much of this has been implemented in real
cars and real drives, and we believe that\'s absolutely essential, that
we have to look at real driving.

We don\'t look at just one particular scenario, one particular
environment, but real cars, real simulators, added together to give us
information upon how these could be useful in detecting impairment, and
I mentioned some on the slides, such as glance, head movement and so on.
These are very important tests, and we\'re going to be studying these
obviously.

DR. ELLINGSTAD: We\'re going to have to go to your final question.

DR. de GIER: Yes, it\'s a very quick one, just for clarification,
because it\'s for Dr. Weiler. Has impairment or other negative reaction
important for driving been documented after using anabolic steroids? Is
that what you just gave in one of your lists?

DR. WEILER: I gave that as an example of the drug that could be studied.
I believe there\'s one paper somewhere. I don\'t have it with me to give
you the reference.

DR. de GIER: Okay. We would like to see that. Thank you.

DR. WEILER: There\'s been some work in the area. I don\'t have the
references with me. I know that we did a search on the list of drugs,
and it certainly popped up as one that had a number of hits.

DR. ELLINGSTAD: Thank you.

And the Government Group?

MR. CLARKE: We don\'t have any questions, Mr. Chairman. Thank you.

DR. ELLINGSTAD: Okay. We do have one presentation, but before we get to
that, I\'d like to ask a very brief question of each of the members of
the panel.

On the basis of the research that you\'re familiar with with respect to
impairment, is it feasible to develop a list of medications or classes
of medications that may safely be used when operating a vehicle? Dr.
Weiler?

DR. WEILER: Yes, I think we can certainly develop lists of drugs that
appear to be relatively safe and those that appear to be relatively
impairing on the extremes. We\'ll argue about some that are in the
middle perhaps, but I believe that we could come up with some lists that
we could be relatively comfortable with under general circumstances,
given all of the many variables that could be considered when we
generate such a list.

DR. ELLINGSTAD: Dr. O\'Hanlon?

DR. O\'HANLON: Dr. de Gier\'s already prepared such a list with his
colleagues, and it\'s widely accepted. It needs to be updated on, but
what you\'re asking has been done several years ago.

DR. ELLINGSTAD: Dr. Kay?

DR. KAY: I believe the answer would be yes to that.

DR. ELLINGSTAD: Dr. Spilker?

DR. SPILKER: Whether the answer is yes or no, I would question the
wisdom of developing that list and putting that out because I do believe
that there are patients, whether it\'s those cognitively-impaired,
whether it\'s those with certain psychological issues or those who just
react differently to drugs, given the large individual variation, and
even if in the clinical trial, you find a number of cases of drowsiness
or sedation to be the same in a control group and the drug group, when
you\'re in open label or you\'re just taking a drug, it\'s still a
hundred percent for you. So, I really would question the purpose of it.

DR. ELLINGSTAD: The question was, on the basis of the literature that
you\'re aware of and the research that we\'ve done, is it feasible to do
it?

DR. SPILKER: I\'d say it creates many problems to do that.

DR. ELLINGSTAD: Okay. Dr. Soller?

DR. SOLLER: Yes, I reflect the similar view. I think there\'s a caution
in looking at that kind of list because of the potential of overstating
what the particular effect might be, and the questions we\'ve heard
today in terms of which particular parameter you\'re going to look at.

From an OTC standpoint, I\'ve said it, I think, more than once this
morning, that the focus has been on what the warning label would look
like for the consumer, and so in that regard, focusing, I believe, from
a consumer standpoint, and I know there\'s a larger public health
perspective with patients here, but from a consumer standpoint, focusing
people on reading the label, the new drug facts label will get them into
the warnings and give them the information they need.

DR. ELLINGSTAD: Thank you, and I\'d like to thank the panel very much.
This has been a very useful information-gathering activity.

We have one presentation from Ms. Karen Tarney of the Citizens Against
Drug Impaired Drivers. If you would come up to the podium here, and
again I\'d remind you that we\'re confining these to a five-minute
presentation, and we will not have an opportunity for questions.

Open to Audience Discussion

MS. TARNEY: Thank you, and I would like to make just a general \--
couple of general remarks.

My organization, Citizens Against Drug Impaired Drivers, also known as
CADID, has been working in this area for 12 years, and part of our
mission is to reduce the number of crashes and fatalities due to
prescription and over-the-counter drug driving impairments.

I\'d just like to share a few observations with you of what we have
found. There\'s very often a not-me syndrome because people who look at
taking medications, whether be they over-the-counter or prescription,
are generally the average citizen we\'re talking about, not the person
who goes out to abuse drugs, not the person who drinks, but the average
every day citizen who says I\'m a good person. I don\'t take drugs. I\'m
just, for instance in prescription drugs, my physician\'s orders, and if
my physician has prescribed it, it\'s okay.

As far as over-the-counter drugs are concerned, if it\'s
over-the-counter, people often believe it\'s harmless. If you add to
that mix cold, flu, winter driving, certainly where I come from, or
spring with rain, snow, sleet and the allergy medications, we have
prescriptions for crashes, and if we take the two highest crash rate
groups of the elderly who mix many of these medications or the teens,
the young people, we then have a major, major problem.

I propose that people do often ignore the labels on the over-the-counter
drugs. They ignore labels on the prescription medications. Not everybody
is able to read. People vary in the combination of drugs that they take,
and different things during different times they\'re taking the
medications will impact whether or not they become impaired.

Physicians do not necessarily know all the drugs an individual takes,
and they don\'t necessarily want to always get involved in the arena of
counseling people on the drug and driving issue because they don\'t
necessarily know what the law in their state is.

I would like to see a very simple label that is very dramatic that comes
out of the FDA that will have universal meaning to everybody, even those
who can\'t read or who don\'t read.

I would also like to tell you that there are ways of arresting and
tracking and looking at the impairment from the legal side, and I don\'t
think we will ever solve this problem until we join hands with law
enforcement, and within the law enforcement community, there is a group
known as Drug Recognition Experts.

These people have been specifically trained to detect drug impaired
drivers. Thirty-four states and five countries have approximately 4 to
6,000 drug recognition experts that are trained. This is not well
publicized, and I think that this is \-- that we need to take our \--
join hands with these people because they\'ve done years and years and
years of research on simulators, not simulators, the driving tests, as
to what are the drugs that impair the driving? What are the laws, and
what will get people\'s attention?

I also think unless there\'s a deterrent for the public, as much warning
and education as we do do, I think that it will be mildly effective, and
I think it\'s very heavily needed. I don\'t think \-- I think what
really is the big deterrent is whether they will be arrested, especially
among the young people where they\'ve just gotten their licenses.

I propose that there are uniform standards in pharmaceutical products
that every state needs to follow, and a uniform reporting system for
prescriptions so that people don\'t go from pharmacy to pharmacy to fill
the prescriptions.

I\'d like to also see alternative dosing schedules. I\'d like to see the
physicians become educated in the role of counseling people with the
driving because they may be prescribing two or three drugs and then the
person goes to the next doc and the next doc and the next doc.

I think a lot of the work has already been done through the drug
recognition \-- the Drug Evaluation Classification Program which is the
name of the program that is run by NHTSA and the IACP, International
Association of Chiefs of Police, and the people that are trained are
called the drug recognition experts.

We have worked and talked with the public for 12 years in predominantly
what I see as a bunch of blank faces, and the biggest group that is
very, very worried about this is the elderly, but the elderly are not
necessarily always able to handle their own problems.

I propose that by the end of today and tomorrow, that we come out with
looking at a holistic approach and a much better solution in working
together. I think a lot of the information is already out there, and I
think \-- I\'m just thrilled to be here with this symposium because we
have done this for 12 years, and I\'m glad to see other people beginning
to recognize it.

Thank you.

DR. ELLINGSTAD: Thank you, Ms. Tarney.

We are very close to schedule. I realize we\'ve got an anxious Technical
Panel that hasn\'t had all of their questions answered, but we hope to
give them the opportunity to gather this information in other ways
throughout the rest of the day and also tomorrow.

We will resume at 12:50 promptly, and we have three panels this
afternoon. So, we\'re going to have to try to keep ourselves as close to
the schedule as we can.

Thank you.

(Whereupon, at 11:47 a.m., the meeting was recessed, to reconvene this
same day, Wednesday, November 14th, 2001, at 12:50 p.m.)

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

12:50 p.m.

DR. GALSON: Folks, could you take your seats, please?

I\'d like to kick off our afternoon session today with the second
Witness Panel, and the focus of this one is Epidemiology. We\'ve got
four witnesses here, and we\'ll start from the right side.

Again, a few reminders. People in the audience who may want to ask
questions should write them down on cards and take the cards up to the
women standing in the back from FDA, and they will bring the cards up to
us.

The speakers should try to limit themselves to five minutes, and again
the parties should appoint one of you to be the spokesperson. It can be
the same person or it can be a different person from last time.

So, I think with that, we\'ll go ahead with the first speaker, who is
Dr. Fiona Couper, and she is with the Washington State Toxicology
Laboratory, the Washington State Patrol, in Seattle.

Thank you.

Witness Panel II - Epidemiology

DR. COUPER: Thank you.

Good afternoon. Well, in this brief presentation, I\'d like to answer
the following question: how do we know that a person\'s use of
prescription or over-the-counter medications (a) may affect their
ability to safely operate a motor vehicle and (b) contribute to
accidents?

And as a forensic toxicologist, we\'re often asked to answer this
specific question in court after driving under the influence cases.

To answer this question, we rely basically on four different data
sources or information, and I\'d like to break these down into two
different groups. The first group is the perspective information and
that\'s the pharmacological information, usually from the drug
manufacturers, laboratory studies and driving studies, which in this
morning\'s presentation, they covered them a lot, but also we rely on
this fourth group of data sources, the epidemiological studies, and this
is more retrospective, and I\'ll go briefly through all of these.

Basically for the pharmacological information, primarily we look at the
nine pharmacological effects of the drug, the primary therapeutic
indications. If it\'s a sleep inducer, we know that it\'s a sedative or
hypnotic drug, so the primary effect will be to sedate the patient. The
known desired effects and also the adverse reactions.

The pharmacology. We like to get information on the peak time of
effects. So the peak effects, is it an hour after taking the dose, is it
two hours or is it four and five hours after the dose? The time of the
day the drugs are meant to be prescribed. If it\'s a night-time
medication, are the patients actually taking it before they go to sleep
or are they taking it in the morning?

Other things. Interesting to know whether the drugs have active
metabolites because after the parent drug passes through the body,
sometimes the active metabolite, as I said, is still active and that
produces a therapeutic or an effect in itself.

Also the age of the individual. We\'ve mentioned elderly people often
are more affected by some of these drugs. Gender, and a lot of the
patients will develop tolerance to some of the pharmacological effects
over time.

Also very important area is the known drug interactions, whether it\'s
alcohol or other central nervous system-acting drugs, and finally, drug
manufacturer recommendations. You often find these in the PDR.

Laboratory studies. This is \-- I\'ll just briefly go over these. It\'s
been mentioned this morning. These demonstrate whether a drug produces a
dose-related impairment of cognitive and/or psychomotor functions in a
laboratory setting, and these often don\'t simultaneously test for all
the psychomotor performance functions that are required for the safe
operation of the motor vehicle, but they\'re great studies to look at.

The actual driving studies, as mentioned before, like the driving
simulator or the actual on-the-road driving tests, these attempt to
duplicate real life situations. So, they go a step beyond the laboratory
studies.

Quite often in toxicology, it\'s the epidemiological studies that we
concentrate more on. Firstly, a lot of these studies will actually give
the incidents or the extent of drug use in a population, whether they be
actual driving fatalities or just driving under the influence cases. So,
epidemiology is after the fact, after someone has been pulled over for a
driving under the influence, after they have died, after they\'ve been
involved in an accident and taken to the hospital.

We also look at actual case reports, and this is a great source of
information, particularly for toxicologists, and it shows great evidence
of driving impairments, and as mentioned before, the DRE, the drug
recognition evaluation officers, toxicologists work closely with them.

The police actually or witnesses observe the erratic driving, observe
the car weaving all over the road or causing the accident. Often the DRE
officers will then perform field sobriety tests, so the driver will be
asked to walk a straight line, touch their nose and so on, and so they
can get an indicator of how impaired the driver is, and this is backed
up by the toxicological tests, where the toxicologist tests the blood
and urine specimens and confirms that the drug was present.

We also have responsibility analysis or culpability studies. Wayne
Jeffery will be talking a bit about this later. There was also a great
study by Olive Drummer in Australia that provide a risk assessment of
the role of the drug, and often they can account for \-- they usually
have controlled studies as well, so they can account for the accident
was caused by weather conditions, road conditions, car conditions,
medical conditions, fatigue or other drugs when present. So, if a drug
is involved, they can reasonably conclude that that drug may have caused
the impairment or may have caused the actual accident.

Just to give some examples now, I\'ve just given a brief overview of
what information we use. So, I\'ll give two examples. Firstly, the
benzodiazepines as a class of drug. So, we look at the drug information.
They are used as sedative hypnotics, anti-anxiety and muscle relaxants.
So, this is the primary effect that it has on the body.

You have both short and long duration of action with the
benzodiazepines. Their primary effects last for about six to eight
hours, and some will last longer, 12 hours or 24 hours later. They may
cause drowsiness, dizziness, confusion, lethargy. This is all in the
PDR, and some of them, like diazepam and lorazepam, they often cause
residual hangover effects. So, if you take them before bedtime, you
actually have some effects the morning after, and as I said before, some
patients can become tolerant of some of the effects of the
benzodiazepines.

Just down below, this is what it actually says in the PDR for the drug
Alprazolam, which is Xanax. The PDR, the manufacturer suggests patients
not operate dangerous machinery until they appreciate the effects of the
medications and warns the drug effects may be additive to those of
alcohol or other CNS depressants.

If you then go to laboratory studies, most of the laboratory studies
across all of the benzodiazepines state that single therapy doses are
capable of impairing cognitive and motor performance, again tolerance
may develop, but again the effects of alcohol and the CNS depressants
are additive.

Driving studies. Significant impairment of example tests that test for
lateral position control, visual perception, speed control and
anticipation of hazards.

Then going to epidemiology studies, again this is like the incidence of.
You take fatalities or DUI cases. How many of these cases, what
percentage have benzodiazepines present, and we\'ve found that
benzodiazepines are the most frequently-detected illicit drugs. So,
prescription drug or over-the-counter medication found in accidents and
fatalities.

Although the percentage is quite low, it is, as I said, the most
frequently-detected drug.

And from case reports from police studies and toxicology studies, the
police have found that these drivers are often uncoordinated,
disorientated, drunk-like, so they\'re stumbling. They just appear like
they\'re drunk.

The responsibility analysis. There\'s been some inconsistent results
with the responsibility analysis. This is mainly due to the wide range
of benzodiazepines studied. Different doses have been studied in
different studies. Some of them are short-acting, as I said. Some of
them are long-acting, and tolerance can develop. So, there has been some
inconsistency with the results, but overall, however, the
benzodiazepines approximately double the risk of an accident. Most of
the studies have found that these effects are dose-related and higher,
the risk is higher in the elderly population.

The second and last example that I\'ll give is the drug Zolpidem. The
trade name is Ambien. The drug information, it\'s to treat insomnia. So,
it induces sleep. That\'s the primary effect of it. It\'s a sedative
hypnotic. Peak concentrations occur at about one and a half hours after
dose. So, this is when you shouldn\'t be driving, between one and, say,
three or four hours after you actually dose.

In the PDR, it says it may cause drowsiness, dizziness, fatigue and so
on, and again it states \-- the manufacturer states cautions against
activities requiring complete mental or alertness or motor coordination
and again warnings against the combined use of other CNS depressants and
alcohol.

Laboratory studies. Single hypnotic doses of Zolpidem are likely to
cause significant impairment of psychomotor skills for the first four to
five hours. A lot of the laboratory studies and driving studies, a lot
of them dose the patients up just before bedtime, and the tests were
done 10 or 12 hours afterwards, so in the morning, and no residual
effects were documented, but still in those first few hours after
dosing, it\'s imperative that the patient does not drive.

And epidemiology studies. The incidence of Zolpidem in drivers is quite
low. It\'s usually one percent or lower, but in a study that I did a
couple of years ago, we had about 30 Zolpidem drivers, and consistently,
they were erratically driving, going over the center line. They had
slurred speech, slow movements, confusion, poor balance and
coordination. They performed very poorly on the field sobriety tests,
the walk and turn, the touch the nose and things like that.

And as a closing comment, I\'d like to say even though on the bottle or
the drug manufacturers may say that you should take Zolpidem before
going to bed, a lot of the driving cases that we looked at had actually
taken Zolpidem during the day, and they hadn\'t just taken one tablet,
they had taken two or three tablets. So, they\'re not following the
physician\'s recommendations, and then they\'re getting in their car and
causing accidents.

Thank you.

DR. GALSON: Thank you very much.

Our next speaker is Wayne Jeffery, who\'s with the Toxicology Services
at the Royal Community Mounted Police Forensic Laboratory in Vancouver,
Canada.

Welcome.

MR. JEFFERY: Thank you for being here.

The data that I\'m going to present today is data from all the forensic
labs in Canada, and the specific research project which was conducted in
the Province of British Columbia, where we looked at every fatal motor
vehicle accident for a cause; that is, we looked at the driver record,
the police record, and the weather record, and then we looked at the
drugs and determined if they were the actual cause of the accident.

It was mentioned this morning, the most common causes of drugs which can
cause impairment. We had a Toxicology Meeting in Seattle two years ago
with toxicologists, in which a lot of people got together, and we went
through the list of all the pharmacological classes of drugs and said
yes, we can come up with classes of drugs which are central nervous
system depressants which can cause impairment, and this is the list
which was presented.

We also went through the whole class of the DRE Categories Drugs, and
what we said with the DRE Program, if you\'re unaware of it, we can
break down impairment into seven different classes of drugs.

The other drugs that we said, cannabis, hallucinogenics, inhalants,
Gamma Hydroxy, Butyrate and disassociative anesthetics, I\'m going to
keep my comments down to the depressant drugs.

These are the drugs which we decided not to include. We said these are
the four things which Fiona has already said how do OTCs and RX drugs
cause impairment. It\'s the effect of the drug causes the impairment
sedation. Typically, what we\'ve seen in impairment cases, the drug is
taken in higher-than-recommended dosage. This causes the impairment. The
drug is taken with other medication, and this is also one of the other
factors for prescription labeling warning for the combined effects of
drugs.

Typically, also, the drug at therapeutic levels is combined with
alcohol, and the combined effect causes the impairment.

This is going to be talked about more tomorrow, and I just want to
mention it briefly. Europeans have got a classification of drug
impairment which goes on pharmaceutical labels, which I\'m recommending
that we use in Canada. It\'s a great idea to tell the public how to \--
whether this drug is impairing or not. You\'ll hear more about that
tomorrow.

Typically, what I want to do is talk about the drug occurrence in
Canadian cases. What we\'ve looked at, we\'ve broken this down into the
impaired drivers and the fatals. Typically, with pharmaceuticals, the
benzodiazepines are Number 2 in fatals, and I\'ve put these into the
groups of drugs, and then the narcotics. The main narcotic we see, of
course, is codeine, also causes CNS depression.

Typically, impaired drivers, the ones that we see most often right off
the top, are diazepam and nordiazepam, triazolam and lorazepam, with the
narcotics in there or the other two drugs. The fifth class of drugs is
all of the other classifications together. That\'s where the
antihistamines fit. As Fiona said, the incidence of this is very low.

Typically, the data which I wanted to state out of British Columbia as
the important data is looking at all of the fatal motor vehicle
accidents in one year. We came to the conclusion that nine percent of
all fatals were caused by drugs alone. Fifty percent of these were
illicit, 50 percent of these were pharmaceuticals. We had another 11
percent of all fatals were caused by the combined effect of low levels
of pharmaceutical drugs and low levels of alcohol. So that again, that
goes to the labeling. These are other drugs that we found. THC, other
drugs, cocaine.

The impact of sedating drugs. DOT says drowsiness contributes to so many
accidents per year and 10,000 fatals each year, Department of Transport.
That\'s Canadian. Canadian study showed that a driver who\'s killed and
has been the cause of the accident is 1.5 more times likely to have
taken an antihistamine. That\'s a Toronto study.

This report says five percent of all drivers may have used
antihistamines before driving. CNS depressant effects are common in many
OTCs and RX drugs. Typically in the antihistamines, we have three types
of antihistamines. The first generation, the sedating. The second
generation. Those are thought to be non-sedating at recommended
therapeutic doses. The third generation are experimental.

Typically, the conclusion for older generations, these are recognized as
sedative effects and are capable of impairing performance to a blood
alcohol level equal to about 50 milligram percent or higher. That was
mentioned this morning.

The second generation of antihistamines are clearly less sedating and
impairing than the predecessors. However, these may produce sedation at
two to three times higher than the recommended dosage. The adverse
effects of antihistamines may be minimized by time of ingestion, and the
risk of an MVA result is inconclusive to negative results.

Conclusion. Patients who took sedating and felt sedating had wore off
and was not affecting their driver performance were tested and found to
have impaired performance, even though there was no feeling of sedating
effects at all. Again, this was mentioned this morning.

Typically, as I mentioned, the benzodiazepines, the cause of
benzodiazepine impairment is in the first few days of treatment,
combined with alcohol, combined with other drugs, too high a blood level
and the type of benzodiazepines.

Typically, as Fiona has already mentioned, it\'s two to five times the
risk of accident in the first two weeks. That\'s after \-- for an
accident. The first two weeks of use, the risk is five to 10 times. It
was also mentioned this morning that risk drops down to about twice
after about a month.

Effects on driving performance and somnolescence and sedation, loss of
motor coordination, memory impairment, behavior disinhibition and
paradoxical agitation. This is the most solidly-documented evidence with
regards to impaired driving.

Typically, the barbiturates are not widely prescribed anymore, but
typically these are equivalent to a BAC of greater than a hundred
milligram percent. We deal with the properties of the antidepressants.
It\'s been broken down to the no sedation, minor sedation, moderate
sedation, and severe sedation. These are recommendations from the
toxicologists.

Stimulant drugs. We won\'t deal with opiates at all, as I said.
Typically, there\'s no significant impairment during methadone
maintenance therapy. However, in high doses, there is lots of abuse of
that, and also in Canada, we see lots of abuse of codeine because it is
legal, and we have lots of abuse of it, of the Tylenol 3s.

Effects on driving of sedation. Impairment of cognitive functions, mood
changes, impairment of psychomotor functions, and typically, these wear
off after some days or weeks.

Required medication. There are certain required medications,
specifically the anti-convulsants, that also may cause impairment.
Typically, I want to mention one thing. Being a pharmacist, also, the
important thing for prescription labeling \-- and I know this is for
tomorrow, but I won\'t be here tomorrow, so I want to get my two cents
worth in.

Specifically interaction with alcohol, specifically driving impairment,
drug interaction, and side effects, these should almost be mandatory
labeling for specific classes of drugs which we\'ve talked about which
cause impairment, and again those are the things I have to say.

DR. GALSON: Thank you very much.

Our next speaker is Judy Stevens from the National Center for Injury
Prevention and Control, the Division of Unintentional Injury Prevention,
at the Centers for Disease Control and Prevention, in Atlanta.

MS. STEVENS: Thank you, and I\'m glad to be here today.

What I\'ll be talking about briefly is what epidemiology can tell us
about medications and driving impairment. There\'s a longstanding
concern that commonly-used psychoactive medications, such as sedatives
and tranquilizers, may impair driving ability.

Today, I\'m going to be focusing on the evidence provided by a number of
population-based epidemiological studies that examined the association
between medications and traffic crashes.

Unlike small-scale clinical studies, these epidemiologic studies use
data from large populations and assess the public health effect of
medication use on driving safety. These studies estimate the relative
risk of motor vehicle crashes associated with certain types of
medications while adjusting to factors that might affect the
relationship between driving and medication use, such as age, previous
medical care, and health status.

Based on epidemiology, what do we currently know about this problem?
Between 1990 and 1998, there were six large population-based
epidemiologic studies published that examined the association between
medication and traffic crashes. The majority, four of six, only included
drivers aged 65 and older, while two included drivers of all ages. These
studies used databases that linked Medicare or other large health care
databases with emergency or hospital records, pharmacy and prescription
data, drivers license records and motor vehicle crash reports.

The studies looked at a limited number of psychoactive drugs. All six
studies included benzodiazepines. Three studies also included six
antidepressants, two included oral opiates, and one included selective
serotonin and reuptake inhibitor antidepressants.

Over time, the studies have defined medications more precisely. For
example, while five studies looked at benzodiazepines as a group, two
more recent studies also assessed long- and short-acting benzodiazepines
separately. Two studies divided benzodiazepines into sedative hypnotics
that are prescribed for insomnia, and anxiolytics that are prescribed to
alleve anxiety. Three studies included dose response effects. Two
compared risks for short- versus long-term use, and two compared crash
risk to long- and short-acting benzodiazepines.

To summarize the results of these studies, despite study limitations,
evidence from this research suggests that benzodiazepines do increase
crash risk as much as 50 percent, and this risk increases with
increasing dose or with taking more than one benzodiazepine.

Two studies suggest that this risk drops with continued use. The
majority of the risks may be with the long-acting drugs. With the
short-acting medications, crash risk seems to be highest during the
first week or two of therapy. Among the benzodiazepines, hypnotics that
are taken at night appear to pose less risk than the anxiolytics that
are usually taken during the day.

A limited number of studies provide less convincing evidence about other
drugs. Results from only two studies of older adults suggest that
different antidepressants may double crash risks while oral opiates and
antihistamines do not increase risk, but there\'s still a great deal we
need to know about this issue.

In order to accurately estimate risk, we need to precisely determine
exposure. Many psychoactive drugs are prescribed on an as-needed basis.
So, studies using records and dates of prescriptions may not accurately
reflect use. Other drugs, like antihistamines, are available
over-the-counter. So, it\'s difficult to get accurate information about
use.

Unlike alcohol, we cannot use blood levels of drugs that affect soluble
measures of impairment. We need better ways to ascertain what drug or
drugs are taken, at what time of day, at what dosage, and then to link
this information with data on motor vehicle crashes.

We need to conduct additional epidemiologic studies of benzodiazepines
to clarify the differences in risks for long- and short-acting
medications, to study the risks associated with hypnotic and anxiolytic
benzodiazepines and to look at risks for short- and long-term use of
these drugs.

We need further study of antidepressants among people of all ages, and
we need to study additional prescription and over-the-counter
medications that may impair drivers, such as codeine cough medicines and
antihistamines, and see if these medications also contribute to an
increased risk of motor vehicle crashes.

Studies need to be broad to include drivers of all ages and to assess
whether alcohol in combination with some medications is a significant
factor, and to take into account the metabolic effects of aging on drug
metabolism and on tolerance.

We need to know whether impairment differs by gender. We need to
understand whether long-term use of some medications increases or
decreases risks, and we need to learn more about conditions, such as
depression, that may influence the relationship between driving ability
and the likelihood of taking medications.

To answer these questions, we will need to develop more complete and
complex databases. We\'ll also need to develop new and creative
approaches to obtaining detailed information about the use of
prescription and non-prescription medications that may be impairing
drivers, and finally, this information needs to linked to comprehensive
data about motor vehicle crashes.

So, in summary, these population-based epidemiologic studies have
provided us with basic information about the risks of traffic crashes
associated with benzodiazepines. However, further research is needed to
provide clear and comprehensive answers about the impact of all types of
medications on transportation safety in the United States.

Thank you.

DR. GALSON: Thank you very much.

Our last speaker on this panel is Douglas Lamar Allen from the Alcohol
and Drug Program Management of the Federal Rail Administration.

Welcome.

MR. ALLEN: Thank you very much.

As mentioned, I am from the Federal Rail Administration, but since
we\'re one DOT, we\'re interchangeable. So, I\'m speaking from FRA for
the entire DOT about some of the data that we have available to us to
review this particular issue.

This first slide, even though it\'s pretty busy, I thought I would throw
it up here so that everybody could review it, reflects our post-accident
testing program since we started it in 1986 with the first data coming
in in 1987.

Everybody understands the years and that goes down through about two
weeks ago in 2001. The events mean \-- this, of course, is not all the
times that we put a wheel on the ground in the rail industry, but it
reflects essentially non-fender benders, most of the events that are
required to be tested for under our regulations.

The other column reflects the number of safety-sensitive employees
tested after one of these events per the regulation, and then the last
and most important column is the number of positives, and you can see
that it is descending the way we would want it to with the programs that
we have to address illegal and in many cases in our program legal drug
abuse.

Now, these are positives. I do need to caution you that these are
identified as drug or alcohol present. It does not indicate a causal
relationship, and, of course, the D stands for drugs and the A stands
for alcohol.

This particular data reflects 1,717 events in the last 14 years, where
we had almost 6,000 railroad employees tested for seven drugs and
alcohol. Specimens taken for analysis were urine, blood, tissues in
fatalities, and a review of the cases with positive drug test results
indicated to us the following: that from this six-year time frame that
we have here, that was the non-archived data that I had available to me
to review for this particular meeting, we had 460 qualifying events, and
believe it or not, it came out right on 1,200. I was hoping it would
come out a little different. I didn\'t fudge the figures. It\'s 1,200
personnel.

The results were 16 cases involving non-authorized drug use and 27 cases
involving authorized drug use. I\'ll discuss that further. Cases
involving unauthorized drug use, illegal drugs, if you would, marijuana,
eight cases. It was a total of 12 in this particular arena. Eight cases
with marijuana and four cases of cocaine.

Now, legal drugs, if you would. We had two cases that were identified
for amps and one for \-- excuse me \-- two for barbs. Now, these are
cases involving authorized drug use, authorized prescriptions used while
on duty. We had eight cases, broke down as follows, as you can see here,
four cases for benzos, two for amps, and two for codeine.

Now, in these particular review of the circumstances of why these
individuals were \-- had these in their system and whether or not they
were authorized per our regulations, in all cases, we found that they
had been authorized by a dispensing physician with the knowledge that
this person was doing a safety-sensitive duty in the rail industry. So,
that\'s why we call that an authorized use per the regulations.

The next bullet, medications administered after the event, of course,
this stands on its own here, that these medications that we found in our
post-accident tox testing really had nothing to do with the event
itself.

Now, I looked at a couple other studies from the FAA perspective. They
have been tracking crash autopsy results for general aviation, this is
not commercial specific, it\'s general aviation pilots for years.

In a study conducted by CAMI from \'94 to \'98 on all fatal crashes,
there was 1,683 pilots tested for at least 58 different drugs. We say 58
because that\'s what we identified, 58 different classes were found. I
don\'t know exactly how many they tested for.

Over-the-counter drugs present was in 301 cases, 18 percent,
prescription drugs presence, 240 or 14 percent. Dose levels in this
particular study was not reported, so therefore it could be
insignificant and/or non-impairing, and also the study did not identify
any linkage to the accident causal factors either.

Now, this data gives us some trend data to look at to establish for our
policies the risk, so that we can appropriately address the policies
that we have in the DOT, and in final conclusion, the rail data that
we\'ve looked at, there were only four cases or .33 percent involved
unauthorized use of over-the-counter or prescription drugs, and the
review of cases even on those indicated other factors were the principal
cause of the event. Even though they had these drugs in their system,
that drug did not cause that rail to break and so forth.

In general aviation, we surmised that the higher prevalence was due in
part to larger samples of drugs analyzed and also that the population
that was reviewed here was general aviation as opposed to commercial
operators, and they are under a different umbrella, if you would, of
deterrence and programs that applied to them.

That\'s all I have. Thank you.

DR. GALSON: Thank you very much.

We\'re now going to move to have questions of the panel, first from the
\-- questions of the witnesses from the Technical Panel, and we\'ll
start off with FDA, Mr. Meyer.

Questions from Technical Panel/Parties and Discussion

DR. MEYER: First of all, thank you all for your presentations.

One of the problems that we often have in assessing causality for
adverse events that we see is something called \"confounding by
indication\". Basically, the fact that the adverse event may be itself
related to the disease rather than the drug, and I\'m curious.

I know Dr. O\'Hanlon had mentioned some limited indications where he did
not find evidence of baseline driving impairment, but to use a very
perhaps hyperbolic example but one that\'s perhaps not wholly theoretic,
if you had a single car accident, for instance, the person drives into a
tree, no skid marks, he\'s on a tricyclic antidepressant, could be that
he fell asleep due to sedating properties of the drug. It could be a
suicide, and that\'s again a hyperbolic example, but there are a lot of
issues of what, again from an epidemiologic standpoint, is called
confounding by indication.

Are any of the panelists aware of attempts to try to tease out in
assessing causality or potential causality of these drugs in the
accidents, the indication versus the drug effect itself?

DR. COUPER: I\'ll try and briefly answer that. I briefly mentioned a
group down in Australia, Melbourne, Associate Professor Olive Drummer
and colleagues. They did some culpability studies. They\'ve been doing
it over the last six years, and they\'re really nice studies.

They work at the Victorian Institute of Forensic Medicine, and so what
they\'ve done in the last \-- I think they\'ve looked at about 3,000
fatalities, and they cooperate with the police, so they get the full
police reports. They try and get weather conditions, the conditions of
the car, eyewitnesses, all sorts of things, blood results.

They interview the family members to see whether there were suicide
intentions or things like that. So, they\'ve tried to do that. They\'ve
tried to answer that question, and then if there\'s a single drug
involved or multiple drugs involved, and whether they think that drug
either caused or contributed or had no effect to the actual accident or
the fatality.

But I do agree with you, just because someone\'s crashed into a tree,
you don\'t know whether they were using their cell phone and were
distracted, a spider came down, and they just ran off the road or
actually it was because they\'ve actually fallen asleep or taken their
eyes off the road.

MR. JEFFERY: In the data from the BC, we looked at the driver accident
record, the police record accident, and the medical \-- and comments
from the coroner and interviewed the family. So, a lot of that data can
be flushed out, and typically in the coroner\'s reports for the
investigation, it depends upon their role and how far they\'re going to
go into investigating that accident.

But typically in our study, what I looked at, we looked at the blood
level and did \-- looked at the level to see whether it was a
therapeutic, toxic or a much higher level, and you could get some
indication from that.

MS. STEVENS: Looking at some of the population-based studies, there have
been a few that have tried to control for the presence of chronic
diseases to try to rule that out as a contributing factor, and that data
is difficult to get, but that attempt \-- it\'s important to be able to
adjust for the presence of other chronic diseases to try to get at why
the medication was in use.

DR. MEYER: Again, maybe I was unfortunate in the example of hitting the
tree, but, you know, insomnia, for instance, is in itself a cause of
day-time hypersomnolecence and, you know, altered sleep latency. So, I
think that confounds the interpretation of the results of
benzodiazepines taken as sleep aids, for instance.

Again, you know, you could do this with other indications, but it
strikes me as an issue in interpreting these data where causality is not
so \-- it may make a lot of sense, but it\'s not entirely clear from an
epidemiologic standpoint.

DR. TEMPLE: Dr. Stevens, could you say something about \-- a little more
about the design of the six studies you were referring to?

These weren\'t cases \-- these were sort of cohort studies, I guess, not
case control or just what was the design, and how good do you think they
are?

MS. STEVENS: Well, it varied. In some cohort studies, there was a
domestic case control study within a cohort study. I have those copies
of those citations, if you\'d like to see them.

DR. TEMPLE: Well, I\'m sure we would. We would like to be sure we have
them.

MS. STEVENS: Most of the medication information did come from records,
and they were prescriptions, you know, numbers of prescriptions that
were filled, that sort of thing. So, knowing whether people actually had
taken the medication was implied rather than actually known.

You want the whole study designs specifically? Is that what you\'re
asking?

DR. TEMPLE: Well, just some sense about how solid this is. We\'ve heard
about individual cases that on their face look as though something was
going on and that surely is one approach, but for a more quantitative,
how big is this problem kind of look, it seems to me you need something
like the studies you\'re talking about.

MS. STEVENS: Most of these were retrospective cohort studies. Most were
quite large, which I think is important if you\'re trying to get a sense
of the problem. It\'s a little hard to summarize six studies in terms of
design when they\'re all a little bit different.

DR. GALSON: Yes. I\'m not sure we can take up the time to go into the
detail right now, but it would be very important if you could make sure
to perhaps have a copy of your remarks and the studies that you\'re
referring to, either the references or the actual studies, that would be
real helpful for us as time moves on.

MS. STEVENS: Yes.

DR. GALSON: Thanks. Does NTSB want to have a question now?

DR. GARBER: Yes. I\'d like to pose a question of the DOT representative,
Mr. Allen.

I think I noticed in your last slide that you said the FRA found
incidence of only four cases of prescription or over-the-counter
medications that were in any way related to the accidents.

I\'m curious as to what over-the-counter medications the FRA is testing
for.

MR. ALLEN: Well, we have the capability to test for pretty much anything
in our laboratory. So, if we had an indication through our accident
investigation that this person was taking anything, we would work up a
protocol to look for that.

We don\'t go and look for everything in the PDR for obvious reasons. We
look for the standard eight, if you would, that we look for, which is
essentially the NIDA-5 plus barbs and benzos and alcohol.

I think I put this on here because of the context of the meeting here
today, that we\'re talking about over-the-counter and prescription
drugs.

DR. GARBER: Okay. But just so that we\'re clear, the FRA does not
routinely test for over-the-counter medications?

MR. ALLEN: No, sir, we do not.

DR. GARBER: And so, you routinely test for eight different substances?

MR. ALLEN: That\'s correct.

DR. GARBER: Of which two are prescription medications? The
benzodiazepines and the barbiturates, potentially amphetamines as well?

MR. ALLEN: Amphetamines and opiates, too.

DR. GARBER: Right. Is the opiate testing done \-- is that done in
accordance with DOT guidelines or is that separate from those
guidelines?

MR. ALLEN: Our protocols at our laboratory are \-- follow closely to the
DOT, but we go \-- our cut-off levels are lower and so forth because we
do have different mediums to look at with the blood and the tissue.

DR. GARBER: The only reason I ask that is that the DOT guidelines are
\-- it often is difficult to detect some of the synthetic opiates, the
hydrocodones and those type of opiates, with using those particular
testing guidelines. Is that \-- are those \--

MR. ALLEN: That\'s not a problem for us.

DR. GARBER: Okay. And you noted that 18 percent of the fatal pilots
tested for by the FAA did have over-the-counter medications in their
system, although it wasn\'t \-- there was no relation to the cause of
the accidents from those data.

Does that suggest that it may be useful for the DOT or anyone else, for
that matter, to be looking for those drugs to make that determination?

MR. ALLEN: Well, once again, I draw your attention to the scope of this
testing by the FAA was not commercial testing commercial pilots. This
was general aviation pilots. So, we don\'t have anything to go
one-for-one with the Department of Transportation\'s scope that it works
with with commercial aviation.

DR. GARBER: But just for a frame of reference, you said 18 percent had
over-the-counter medications. How many had alcohol detected?

MR. ALLEN: I don\'t know that off the top of my head.

DR. GARBER: Okay.

MR. ALLEN: I don\'t have that.

DR. GARBER: Okay. And just one question for the entire panel. A witness
in our last panel indicated that sedating antihistamines were probably
not a large problem with regard to transportation safety, based at least
somewhat on the adverse experience reporting, and I\'d just like to ask
each of the panelists just very briefly.

Do you agree with that assessment, that the sedating antihistamines are
likely not a problem, based on adverse event experience reporting?

MR. JEFFERY: In the BC data, we only had one fatal motor vehicle
accident caused by the antihistamines, and yes, I\'d agree with them. I
mean, on the scale of impairing drugs, it\'s at the lower level. There
are other drugs that we\'re more interested in, yes.

DR. GARBER: Any of the other \--

DR. COUPER: I would essentially agree with that. The cases, though, that
we\'ve seen with the sedating antihistamines, diphenhydramine for
example, the people are taking them in huge amounts. They\'re not
therapeutic doses at all. Just the toxicology, the blood results in and
of themselves must mean that they\'re taking way above the therapeutic
levels.

So, in that regard, yes, they are probably very sedating, but normal
therapeutic doses, no, we\'re not seeing those in our cases.

MS. STEVENS: Most of the epidemiologic studies that have tried to look
at these were looking at only the prescribed antihistamines, and there
is really no way of knowing whether people were taking over-the-counter
medications from the records. So, that really is something that needs to
be looked at, I think, a little bit further.

MR. ALLEN: I would have to say the same thing because we\'re, as you
just pointed out, looking for the prescribed medications as opposed to
the over-the-counter, and the data reflects that we have not found it in
our reviews.

DR. TEMPLE: The last two answers say there\'s no information. The first
two suggest that there was no finding. Can I ask you about those? These
are mostly cases where, for example, Dr. Jeffery, the cases where the
driver was doing something bizarre and that\'s what would be triggered.

Suppose the person just fell asleep. Would you have any information
about something like that?

MR. JEFFERY: Yes. Well, the one case that we had, that was the actual
case, where the driver actually fell asleep and went into the tree, but
the level of antihistamine we found was way high above the therapeutic.
So, we could only conclude from that that it was the antihistamine.

In a lot of these situations, we have to go back to see what we did with
alcohol with fatal motor vehicle accidents, how we came up with 80
milligram percent. We did a whole bunch of studies, found 80 milligram
percent was sort of the cut-off level. That\'s how we made our impairing
level, and what we\'re doing right now is we\'re back at that same level
with regards to drugs.

There\'s a committee of toxicologists looking at this data right now,
saying can we come up with blood levels of drugs that are impairing?
Twenty years ago, you\'d get a bunch of toxicologists in the room saying
no, we can\'t do that. However, we have now come to the point that we
may be able to do that for some drugs and that\'s what we\'re looking at
right now.

DR. TEMPLE: But the way you would do it would be to look at fatalities
and see what\'s there?

MR. JEFFERY: Yes.

DR. TEMPLE: And then compare that with some estimate of what would be
there in a normal population?

MR. JEFFERY: Absolutely.

DR. GALSON: Okay. I think what we\'ll do now is move to the Questions
from the Parties at the table, and I want to just take the opportunity
to instruct the audience, if you have questions, please think of them
and pick up a card from Lee Lemley standing at the back and then she\'ll
pass it up to us.

I noticed there are a few new people sitting at the tables. So, can we
quickly go around and have those of you that are new just introduce
yourselves and say where you\'re from?

DR. TILTON: My name\'s Dr. Fred Tilton. I\'m the Deputy Federal Air
Surgeon, FAA.

DR. GALSON: Great. Welcome. And then at the Union Table, there\'s
somebody new.

MS. HEAD: My name\'s Karen Head. I\'m with the Amalgamated Transit
Union.

DR. GALSON: Okay. Welcome.

MR. BRADLEY: My name is Bill Bradley. I\'m with the Consumer Healthcare
Products Association.

DR. GALSON: Okay. Why don\'t we this time start from the Government
Table, and let\'s see if you folks have any questions for the panel.

MR. CLARKE: I don\'t. No, I don\'t have any questions. I thought the
presentations stood on their own.

DR. GALSON: Okay. The Professional Panel, the sleep experts, in the back
there, anything?

(No response)

DR. GALSON: Okay. Advocacy?

MS. TARNEY: We have several questions.

DR. GALSON: Okay.

MS. TARNEY: Well, we\'ll start with a comment, which is, that it\'s
difficult to compare different accident studies for accidents due to
non-standardization. In other words, different analytical nanograms, no.
The cut-offs don\'t have them, whether you\'re using blood or urine,
also changes the outcomes.

The rest of the calculations, similar to what has been done for alcohol,
makes it difficult due to the drug use among what may be a normal
population and then that\'s not known.

So, I guess the question is, what is the standardization for accident
studies? The comment was, well, the standardization of accident studies
is necessary in the toxicological arena as well. Can anybody tell us how
we can standardize it from a toxicological standpoint? That\'s one
question we had at our table. We have some more.

MR. JEFFERY: Well, in the one study that I\'ve done, what you\'ve got to
look at is you\'ve got to try to rule out everything else, environmental
factors, weather, driving pattern, the whole bit to deal with did the
drug cause the accident, and this is the data now that all the
toxicologists are trying to put together, and it\'s hard to standardize
that because each laboratory in Canada is slightly different. Each state
is totally different.

It\'s the constraints of what we can do, but the more data we get, the
better it\'s going to be. So, I think it would be very hard to
standardize that collection of data.

MS. TARNEY: How do you see the variety of things being tested right now,
such as hair, saliva, as well as blood and urine in terms of
standardization and reliability?

DR. COUPER: I think Wayne Jeffery can probably talk about the saliva but
just on the hair issue, it\'s not really a relevant tissue in this
scenario because hair is an indicator of past exposure to a drug,
whether it was a week ago, a month ago.

If you tested my hair, it was probably a year ago. So, if you\'re
talking about the effects of the drug, you\'re talking about the drug
that\'s in your body within the last three or four hours or five hours,
however long. So, hair testing probably isn\'t relevant, but a lot of
saliva testing is being done.

MR. JEFFERY: Yes. Actually, as a toxicologist, blood is probably the
preferable sample. I mean, that\'s the level of drug which is causing
the impairing level.

Urine is the second best one for toxicologists to look at previous drug
usage, but a study which I\'ll be publishing very soon is on saliva
shows very good correlation to impairing results in the study with our
drug recognition expert officers in British Columbia.

So, saliva is a very good thing to show recent usage of a drug use. So,
I mean, blood is best, and from our point of view, however with laws and
that, you may not be able to get it. I think saliva is a very good
second substitute.

MS. STEVENS: I think it\'s important to remember that if a drug is fat
soluble, the blood level and level of impairment may not be that tightly
correlated, especially when we compare alcohol, where you can look at
the blood alcohol level and have a very good idea of what the impairment
is.

MR. ALLEN: In the FRA, we have found that having all the mediums
possible really helps our analysis of the situation.

We have been able to use encapsulated parts of the body and, of course,
tissue samples to rule out other findings in other parts of the body.
So, adding all the different possibilities that your rules and
regulations will allow you to harvest in an accident investigation
situation has been very valuable for us.

MS. TARNEY: Based on the variety of medications that people take, how do
you deviate from normal in a blood sample for impairment?

MR. JEFFERY: Could you repeat that question?

DR. COUPER: Or maybe rephrase at least.

MS. TARNEY: Based on the combinations, the many combinations of drugs
that people take, how do you compare that to what is normal, which also
has a variety of \-- a wide range of indicators? What is your deviation
for impairment?

I think that\'s one of the questions that people have about using blood
or urine or saliva samples.

MR. JEFFERY: Well, typically, when we analyze a blood sample, we\'ll
analyze from the drugs which are there. We\'ll not only do a qualitative
identification of what drug is present but really how much is there, and
that\'s what we look at in a blood sample. If there\'s two or three
drugs at very low levels, we have to make an opinion, are there additive
or what are the effects going to be, and we have to make \-- the
toxicologist will make a subjective decision in saying are the combined
effects of these drugs impairing or are they not impairing, and that\'s
where our training and experience comes through in the blood databases
that are published on whether these drugs are therapeutic or toxic.

MS. STEVENS: I think it\'s also something that gets into what was
covered this morning, is that standards of impairment, measuring
impairment, need to go beyond simply the biological measurement, so that
there is some correlation, and we haven\'t really gotten there yet.

DR. GALSON: Okay. The Carrier Industry Table, do you folks have any
questions for the panel?

DR. FAULKNER: No questions.

DR. GALSON: No. Consumer Product Industry, any questions?

DR. SOLLER: Yes, just a clarifying question to Dr. Stevens. Just given
the extensive use of RX antihistamines and in consideration of our AER
analysis that we showed this morning where we looked at RX and OTC
antihistamines, didn\'t Ray et al. study a cohort of more than 16,000
Medicaid elderly, finding that the relative risk of injurious crash
accidents was not a matter of concern? I think it was a relative risk of
around one, something like that.

MS. STEVENS: Yes, that\'s correct. However, he was only one of only two
studies that have looked at antihistamines in the population. That\'s my
concern, is that there\'s been so little, but he had a very thorough
assessment of people taking that because everything was covered.

DR. SOLLER: I just only was clarifying in relation to a prior question.
Yes, thank you.

MS. STEVENS: You\'re absolutely correct.

DR. SOLLER: Thank you.

DR. GALSON: Does the Union have any questions?

CAPTAIN POPIEL: No questions.

DR. GALSON: Okay. I think we\'ll cycle back to the Technical Panel. Does
NTSB have anything further?

DR. GARBER: Just one point of clarification for Mr. Jeffery. I believe
that you had mentioned a study that showed a 1.5 times increased risk
for antihistamines.

MR. JEFFERY: Yes.

DR. GARBER: Could you give us a little bit more detail on that
particular study and the numbers involved?

MR. JEFFERY: That was a study out of Saskatchewan, I believe, and they
looked at all of the population in the province of how many
prescriptions were given for antihistamines in different areas, then
went back to those people and looked at their driver records. This is an
older study that came back in the late \'70s or early \'80s. They were
looking at just not a few hundred, it was a few thousand people
involved.

DR. GARBER: So, this was a fairly robust study that showed a 1.5 times
increased risk for the antihistamines?

MR. JEFFERY: Yes. I can give you that citation.

DR. GARBER: Okay. And based on the \-- perhaps you can comment more on
Canada. Based on the use of these antihistamines currently in Canada,
and again I just want to clarify your previous answer, you feel that
that\'s not a significant risk, even though \-- even with the
potentially large population that\'s using those medications?

MR. JEFFERY: Well, you know, on the scale of one to 100, I mean,
antihistamines are at the lower level. If you take a look at the
benzodiazepines, which are widely prescribed, also, they\'re much
higher. I mean, yes, it is a significant risk, but it\'s on the whole
level, it\'s a much lower risk.

DR. GARBER: Are the antihistamines available over the counter in Canada
as they are here in the United States?

MR. JEFFERY: Oh, yes, absolutely.

DR. GARBER: Do you have a feel for what the level of those prescriptions
are vis a vis benzodiazepines?

MR. JEFFERY: Oh, the over-the-counter ones by themselves are used far
more widely than the prescription drugs.

DR. GARBER: Okay.

DR. TEMPLE: The Saskatchewan study captured prescription and
non-prescription?

MR. JEFFERY: Yes. It was through the whole area of prescription and
non-prescription.

DR. TEMPLE: And what about Wayne Ray\'s study? That must have linked to
a Medicaid database or something.

MS. STEVENS: It did. It was just among people 65 and older. So, the
Medicaid enrollees basically got all of their medications through that
system, and so \--

DR. TEMPLE: Including OTC?

MS. STEVENS: \-- those were captured. Hmm?

DR. TEMPLE: Including OTC? So, he would have captured that?

MS. STEVENS: He would have captured those, though they could have gotten
them, you know, outside of that system. Very few do.

DR. GARBER: Just a question for each of the panelists. In an ideal world
and recognizing, of course, that we don\'t live in such a world, how
would we go about \-- what would give us the data? What specifically
would give us the data that we need to make a determination from an
epidemiologic standpoint on whether these drugs are problematic in the
same way \-- in the same sense that, say, alcohol or any other issues
are problematic?

And then, as a follow-on to that, can we do that? Can we? Do we have the
capability of doing that?

MR. JEFFERY: Well, I think for alcohol, that was done by the Grand
Rapids Study, where they went through and took samples from the public
where accidents occurred. It was done over a certain amount of time.
That was easy to do with regards to alcohol, and if you want to get the
actual role of drugs in driving in the normal population, you would
basically have to duplicate the Grand Rapids Study.

DR. COUPER: And that probably couldn\'t be done for most of the drugs
because the Grand Rapids Study, I think, was based on breath alcohol
levels. So, you weren\'t being \-- it wasn\'t an invasive blood test or
a urine test. So, it was easy to do the breath test, and I doubt that
here in America, you\'d ever get that number of people. There were
thousands of people giving blood samples.

DR. GARBER: So, am I correct in interpreting your answers, that it may
not be possible to either include or exclude drugs definitively in the
way that alcohol was by such a study?

MR. JEFFERY: You could do it on a lower extent. There\'s just a recent
study published out of Montreal, from the Forensic Laboratory there,
where they took random saliva samples and urine samples from drivers in
the known public, and they were looking at about one to two percent of
the population that had these drugs on board and whether there were
accidents involved and whether they were charged with impaired driving
or some type of other offense. So, I mean, it\'s going to be very, very
difficult to do that.

DR. GALSON: Okay. I think \-- I\'m sorry.

DR. TEMPLE: What do you think of the following possibility, and, of
course, I\'m also interested in who you think might be willing to do it;
that is, to get blood samples from people \-- this sounds bloody, but
I\'m sorry. People in fatal crashes and compare the blood content of the
driver and the passenger as a possible indicator of an increased risk?

MR. JEFFERY: Well, that\'s the study that we actually did in BC. We took
blood samples from every one of the fatal motor vehicle accidents, and
typically in Canada, I can speak, that that is not routinely done. That
is only routinely done whether there\'s an investigation if they think
alcohol or drugs is involved.

Alcohol is done on a routine basis. Drugs is only done on one to two
percent, and you may get a lot of data involved if you had every fatal
motor vehicle driver killed within a certain period of time. If samples
were taken from that driver and analyzed, you would get, over a
two-or-three-year basis, a good data bank with regards to what drugs are
there.

I think some of the studies that have been produced already in Australia
and my study in BC and the ones in the States and in Europe start to
show, I think, the levels of drugs which are already there, and I think
we have a good handle on that, but it would give you a far more better
understanding of what drugs are involved in driving fatalities.

DR. TEMPLE: And perhaps you\'ve already answered this, but do you think
there have been enough studies of that type to finger benzodiazepines as
a problem? Do you think there is enough data yet on potentially sedating
antihistamines to give an answer one way or the other?

MR. JEFFERY: Basically, absolutely. I mean, we\'ve got enough data for
benzodiazepines. We have enough data now to show that we\'re not seeing
therapeutic levels of sedating antihistamines in fatal motor vehicle
accidents or in the impaired driving cases. There are very low levels of
less than one percent.

MS. STEVENS: I think if we want to look at whether there\'s an increase
in risk, you have to have a comparison group beyond the people who are
dying in motor vehicle crashes.

DR. TEMPLE: That\'s why I like the passengers.

MS. STEVENS: Well, they\'re also involved. I think that there\'s
probably more likely a correlation between the driver and the passenger.
You need to look at it in the population as a whole.

DR. TEMPLE: But before you leave that, that seems logical for alcohol or
an abused drug. It doesn\'t seem equally likely for, say, an
antihistamine, does it?

MS. STEVENS: Well, if you\'ve got two family members, everyone knows
that colds go back and forth, and it\'s possible, I think there\'s
probably some similarities there that couldn\'t be written off. So, it
might be a long shot.

DR. COUPER: If I could make a couple of comments to the last two
questions? The first question about the passengers, the study that I
mentioned, the culpability study done in Australia by Drummer, and I\'ll
try and get you some references for that, it really was a good study.

They did a comprehensive blood test, urine test, vitreous, liver,
kidney, a whole lot of samples from the fatalities. It wasn\'t only from
the drivers, it was any passenger in the car or any pedestrian that was
hit by a car. So, any road fatalities, they\'ve done that, and they also
used a control group as well. So, that could be a nice study for you.

Whether \-- one of the problems with us toxicologists is a lot of the
states have a lot of these data. I know in Washington State, we do
comprehensive drug testing on a lot of the fatalities. So, it\'s not
just blood, it\'s blood and urine. We don\'t just do alcohol and a drug
screen, we go further. We look for the over-the-counter and prescription
medications.

The problem with the toxicologist is we haven\'t published these data.
So, the data is probably out there in many of the states here and in
Canada and probably the rest of the world, but a lot of us just don\'t
publish that results.

DR. GALSON: Okay. I think we\'ll turn now to some audience questions. If
we have extra time, we\'ll go back to the panel again.

DR. ELLINGSTAD: Okay. We have four submissions here. One question, I
guess it\'s addressed to NTSB. Would NTSB like to see the DOT establish
a regimen for conducting post-accident or other types of testing?

I believe the record does show that the NTSB would like the Department
of Transportation to do that. We\'re waiting for them, of course, to
respond.

We have also a question for Dr. Jeffery. Would you care to speculate on
opiate prevalence data in Canada versus the United States related to
legal and over-the-counter availability in Canada but not in the U.S.?

MR. JEFFERY: Well, in Canada, what we have is Tylenol Number 1, which is
eight milligrams, which is over-the-counter. In the data that we see,
and the Number 1 drug of abuse abused in BC right now is Tylenol Number
3, which is the 30 milligrams of codeine.

In the impaired drivers in the fatal motor vehicle accidents, that is
the fourth class of drug we see, and in the narcotic group, codeine far
outweighs all of the other narcotics.

In Vancouver, we have a huge heroin problem. We don\'t see that. It\'s
the over-the-counter of codeine tablets and the Tylenol Number 3 which
are the major problems for the narcotics.

DR. ELLINGSTAD: Any of the other panelists wish to comment on what one
would expect in the United States?

(No response)

DR. ELLINGSTAD: We have another question that I believe was intended for
Mr. Allen regarding FAA studies from consecutive four-year periods which
showed the incidence of different kinds of drugs in fatal crashes among,
I presume, general aviation pilots. Are you familiar with that research?

MR. ALLEN: I know of the research. Dr. Tilton or Bob Clarke may be able
to \-- I don\'t have the study with me, but it\'s available, and we\'d
be glad to give that to whoever.

DR. ELLINGSTAD: Okay. If we could have that data or have those studies,
the citations for the record?

MR. ALLEN: We\'ll provide them.

DR. ELLINGSTAD: If I might add one question? We had \-- we\'ve been
talking about various kinds of ways of establishing the incidence
epidemiologically. Dr. O\'Hanlon this morning reminded us of the
Borgenstein Grand Rapids Study that basically provided that kind of an
indication of incidence with respect to alcohol.

Just very quickly, is there any kind of an analog to that with respect
to any of the medications we\'re talking about?

MR. JEFFERY: Not that I\'m aware of.

MS. STEVENS: There\'s very little with the incidence of medication use
in populations. Some of the studies have looked at limited number, but
they are either looking at medical prescription records or they ask
people, you know, what they\'ve taken which gets into a recall problem.

DR. ELLINGSTAD: Is this something that\'s affected by the
comprehensiveness of testing in the various transportation modes or are
we testing enough to accomplish that kind of empirical basis?

MS. STEVENS: Well, if you\'re looking to get the information about
medication use in the population, you would have to be testing
populations, not simply the people who are involved in the fatal
crashes. I don\'t think that that\'s a practical approach. So, it would
be indirect through prescription records and face-to-face interviews
would be the way that I would see you\'d have to get that information.

DR. ELLINGSTAD: Thank you.

DR. GALSON: Okay. Nearing the end of this session. Does the Technical
Panel have some more points they want to ask?

DR. GARBER: I just did want to mention that Mr. Allen mentioned the
comprehensive FAA toxicology evaluation that\'s performed on general
aviation \-- fatally-injured general aviation pilots.

The NTSB reviewed those data and uses those

\-- we use those in our accident investigation evaluation, much in the
same way that Mr. Jeffery and Dr. Couper have described for the studies
that they have done.

In our review of recent data from that, we find that over-the-counter
prescription medications to be factors in the accidents more often than
we find either alcohol or illicit substances to be factors in those
general aviation accidents.

I\'m curious as to whether (1) that sort of comparison has been done
with the data that you have, and (2) whether that surprises any of the
panelists, whether that seems consistent with the information that
you\'ve seen through the studies that you\'ve either done or reviewed.

MS. STEVENS: Well, I wonder if, since we learned to drive at an early
age and we drive for so long, if driving as a skill isn\'t quite
different from the skill that\'s needed as a pilot, and so that we could
compensate for a lot of impairments with our driving that may not be
possible when flying a plane.

DR. GARBER: Any comments from any of the other panelists?

MR. JEFFERY: Well, typically what we\'re seeing in the impaired drivers
in the fatal motor vehicle accidents, we\'re really not seeing just the
therapeutic levels. We\'re seeing high and above those or in the central
nervous system depressants, we see the impairment or the fatal motor
vehicle accident early on when they\'ve been taking the drug and
tolerance hasn\'t been developed at that time.

MR. ALLEN: Within the FRA program, as you know, Dr. Garber, we share
with the NTSB any specimens that we have from fatalities, and we have,
to my knowledge, never received anything back from the NTSB giving us
any data that would make us be concerned about the other drugs and
over-the-counter.

DR. GARBER: I\'m sorry. Does that database include the Florida accident?
That\'s one where the NTSB did find evidence of medication use.

MR. ALLEN: I don\'t know that off the top of my head. I don\'t know if
it was one of the ones that met our criteria.

DR. TEMPLE: This probably is a question that\'s as much for the previous
panel as it is for this one, but let me start here and maybe there\'s
some way for them to comment.

The various tests of driving function that you heard about earlier show
levels of impairment similar to blood levels \-- that induced by blood
levels of alcohol that everyone agrees apparently is a potential cause
of accidents, and at least so far in the epidemiology, however, you
don\'t see anything like that in any of the studies that have been done.

Do you have any thoughts about that disconnect or is it a true
disconnect? Are there enough data to conclude that there is a
disconnect?

I\'d also be interested in what some of the previous panel thought about
that, if there\'s a way to elicit that.

MS. STEVENS: Well, the epidemiology studies that I referred to did not
take blood measures. These were doses and use was extrapolated from
prescription records, so that it would be an apples and oranges kind of
comparison, at least for the studies I was talking about.

DR. TEMPLE: Well, but they would be able to see if use of any particular
drug was unexpectedly high, and the data we heard earlier in the day are
about taking ordinary doses of certain benzodiazepines and sedating
antihistamines and finding levels of impairment similar to those that
caused trouble when \-- similar to those \-- finding impairment similar
to what levels of alcohol that are known to be a problem cause, and yet
when \-- from the epidemiology the people have described, there doesn\'t
seem to be an association with the use of these agents or not much of
one, I guess with benzodiazepines there is, but not at least the
antihistamines.

Are you saying there\'s a methodological reason or maybe the driving
tests really don\'t predict that? I mean, I just wondered what your
thoughts on this were.

MS. STEVENS: I think that getting an estimate of exposure, how much
medication people are actually taking through the epidemiologic studies
that have been done is very difficult, and there\'s a lot of possibility
of error and not estimating correctly.

So, when you have somebody in a laboratory, and you know what you\'re
giving them, that really is different than looking at it in the
population and trying to imply from the records how much you think
people were taking and when.

DR. TEMPLE: I think Dr. O\'Hanlon might have an answer to this question.

DR. ELLINGSTAD: I think you\'re going to have to go to a mic. Why don\'t
you come up here to the podium?

DR. O\'HANLON: We\'ve studied tripolidine, diphenhydramine,
chlorpheniramine. Even after 50 milligrams of diphenhydramine, we saw
impairment one hour later, impairment equivalent to .07. It went down
pretty quickly with, as you\'d expect, from the pharmacokinetic profile
of the drug.

We never saw that great a degree of impairment again with another
sedating antihistamine. There was some with everyone, but it didn\'t
compare with some of the other antidepressants, some of the mood
stabilizers, some of the benzodiazepine hypnotics and anxiolytics we
studied.

That\'s why I remarked this morning what\'s this big deal about
antihistamines, except, of course, that the use is so prevalent.
There\'s no discrepancy, at least in our laboratory, the empirical data
agrees quite well with the epidemiological data.

By the way, a couple of comments I\'d like to make. There has been one
epidemiology study that shows a relationship between industrial
accidents and the use of sedating OTC antihistamines. I think it\'s by
Gilmore, but it\'s an old man\'s memory now talking, and you can better
find it in my former assistant\'s excellent article on behavioral
toxicity. His name is Jon Ramikers, and he published that in CNS Drugs
in 1998, I believe. It\'s a very fine summary of all the epidemiological
data published up to that time.

So, there has been one indication from epidemiology that sedating
antihistamines can do something, and besides that, Ray did not have
access to any sedating antihistamine records and said so in his 1992
article in the American Journal of Epidemiology.

Thank you.

DR. TEMPLE: Before you leave, so, you mean his study didn\'t \--

DR. O\'HANLON: Ray\'s study did not \--

DR. TEMPLE: It only included prescriptions which at the time \--

DR. O\'HANLON: \-- include sedating antihistamines. Only one
antihistamine was available for the prescription at that time, or a
couple of older ones, like hydroxyzine, but the main one was
terfenadine. That was the main one that showed up in his Medicaid
records.

DR. TEMPLE: I see. So, you\'re saying that the failure to find anything
is \--

DR. O\'HANLON: In that one case, in that one case, yes.

DR. TEMPLE: Okay. And just to be sure I understood what you said before,
you don\'t find most of them having major levels of impairments, \--

DR. O\'HANLON: No.

DR. TEMPLE: \-- and you\'re not surprised that nothing much shows up,
and even for diphenhydramine, the impairment is relatively short-lived?

DR. O\'HANLON: .07. I mean, that\'s not a good thing.

DR. TEMPLE: Right. And it doesn\'t last very long. So, it could depend
\--

DR. O\'HANLON: One to three hours, approximately.

DR. ELLINGSTAD: We did have a question from the audience that\'s
directed to Mr. Allen, and basically, the question is, how does the DOT
feel about NTSB\'s recommendation that the Department of Transportation
make prescription and over-the-counter drugs part of its testing
program?

MR. ALLEN: Well, it is already part of our rules in that we have rules
in each one of our modal policies that address that, and speaking for
the FRA, we think that our rules and the testing regimen that we have
right now within the FRA covers the basis for the risks that we see out
there.

I can\'t really speak for the DOT since, as you mentioned, I think,
before, that this is still an open recommendation from the NTSB to the
DOT.

DR. GALSON: Okay. A few more minutes, if the Technical Panel wants to
ask anything else.

(No response)

DR. GALSON: Okay. Any other questions from the parties?

(No response)

DR. GALSON: Okay. I think with that, then we\'ll end this second session
and have a 15-minute break, which brings us back here at about
2:32-2:33.

(Whereupon, a recess was taken.)

DR. ELLINGSTAD: We\'ll have a little smaller Witness Panel here, and
we\'ll grill them more exhaustively than we have previously.

I\'d again like to remind both the audience and our party participants
to generate your questions and pass them and the parties to get their
questions to the moderators. Again, with the smaller panel, we\'ll be
more liberal in terms of the questions that we can entertain.

Our third panel consists of representatives from State and Local
Government, and we will start out with Mr. William George, Deputy
Attorney General from Delaware.

Mr. George?

Witness Panel III - State and Local Government

MR. GEORGE: Good afternoon.

My name is William George, and I am the Deputy Attorney General for the
State of Delaware, and for the last 12 years, I\'ve had the sole
responsibility for the prosecution of homicide cases arising from motor
vehicle accidents, including commercial vehicles.

To address the issues involving the operation of vehicles by those who
are drug impaired, I will speak first about the types of laws and
regulations that exist at the state level and then about the problems
with enforcement of those laws.

In Delaware, we rely mainly, if not exclusively, on our DUI, our Driving
Under the Influence, statutes as our primary enforcement tool to
restrict transportation operators from operating vehicles while impaired
by medications.

Although geared towards and mainly enforced against those who operate a
vehicle while under the influence of alcohol, our statute is broad
enough to restrict all drugs, both legal and illegal.

Our statute specifically prohibits the driving of a vehicle while under
the influence of any drug or under the influence of a combination of
alcohol and any drug.

However, the enforcement and the prosecution of the drug impaired driver
is very difficult on many levels. The first is detection. For over 25
years now, the states, following the initiative of the Federal
Government, have been involved in a process of education, of
re-education, and of enforcement that has changed our views on alcohol
impaired drivers.

Our police officers, who are our first line of defense in the detection
of the impaired driver, are trained in the detection of alcohol. At our
academies, new officers are given the opportunity to watch other
officers drink alcohol and then gauge their impairment through the use
of standardized field tests and the use of an intoxilyzer.

The effects of drug impairment are very subtle, though, and unless the
impairment causes the outward and detectable signs usually associated
with alcohol impairment, it is possible that the drug impaired driver
may go undetected.

Even in those cases where signs of impairment are noticeable, where
field tests are given, the officer is likely to hit an impasse when the
intoxilyzer displays a 00 reading.

Specific methods of drug detection and documentation do exist, but they
are different from that of alcohol cases, and they are beyond the
training and expertise of most police officers today.

The second problem is the prosecution of these types of cases. A typical
DUI case follows a set pattern during the trial of that case. It begins
with the initial observations of the erratic driver by the officer, the
stop by the officer, the initial observations of the operator after the
stop is made, the establishment of probable cause based on standardized
and accepted field tests, and finally the introduction of an intoxilyzer
reading or, in rare cases, the introduction of a reading of a blood
sample.

In a drug impaired case, the intoxilyzer will not provide adequate
evidence, and unless the performance on the field test is so poor, it is
unlikely that a conviction could be obtained.

Even in those cases where a blood sample may have been obtained, the
quantitative effects of drugs have not been documented or accepted by
our courts to the same degree as alcohol has. Similarly, the urine
sample is inadequate and unlikely to be accepted into evidence at all.

The detection and prosecution of the drug impaired driver is a problem,
but there is a solution. First pioneered by the Los Angeles Police
Department with the assistance of NHTSA, the Drug Recognition Evaluation
and Classification Program was developed. Its purpose is to determine
whether a driver is impaired, and if so, whether the impairment is drug
related or medically related and then to determine the broad category of
combination of drug categories causing the impairment.

The drug recognition expert or DRE is a specially-trained police
officer. The officer is trained not only in the testing usually
associated with an alcohol case, but also in medical procedures that
include an eye examination, HGN testing, and an analysis of the vital
signs of the driver.

Although the DRE program has now expanded far beyond Los Angeles, it is
my opinion that it has not expanded far enough or fast enough to address
this problem. Certainly the Federal Government can and should take an
active role in expanding the kind of training of police officers. The
Federal Government should promote the acceptance of these types of
programs through education, just as it has actively promoted education
and enforcement of alcohol-related laws.

I thank you for your time and attention.

DR. ELLINGSTAD: Thank you, Mr. George.

Our next panelist is Dr. Jon May with the National Association of Boards
of Pharmacy in Gaithersburg, Maryland.

DR. MAY: Thank you.

I am a consultant to the National Association of Boards of Pharmacy, and
I bring you greetings from them. The Executive Director, as I speak, is
in Monterey, California, attending the NABP Executive Officer\'s
Conference.

In the parlance of the recently-completed World Series, I am a
pinch-hitter. I live in Gaithersburg, Maryland. I retired from the U.S.
Public Health Service in 1992, having spent 10 years with the Food and
Drug Administration.

When I talked to Dr. Garber after I was asked by NABP if I was available
for this meeting, he told me that we would have about a five-minute time
for a statement and that most of our input would come from the questions
from the panel and/or the audience.

So, I have a statement that has been prepared by NABP. If I read it real
slow, it\'ll reach five minutes. If I read it at my normal talking pace,
it will probably take three minutes. So, I will present the statement
from NABP, and then we will field questions, although we feel like
we\'re being targeted up here with only two. I came in an hour ago, and
there were five people sitting at this table. So, I\'m beginning to
worry a little bit.

Anyway, what we responded to was the question presented by NTSB, and it
goes, what types of local requirements serve to restrict transportation
operators from operating vehicles under the influence of potentially
impairing medications, and how are/can these requirements be enforced?

From the State Board of Pharmacy perspective, the scope of direct
authority over transportation operators is extremely limited.
Pharmacists who fall under the direct authority of the state boards of
pharmacy are required to affix warning labels to medication containers
dispensed to patients if the medication could affect a person\'s ability
to operate a motor vehicle or heavy machinery.

The medications causing the side effects are usually agents which cause
drowsiness by impacting the central nervous system. The labeling
requirement, although not specifically stated in the State Practice Acts
and regulations, is based upon good standards of practice that any
pharmacist would use in order to ensure that the patient is safe from
harm.

State pharmacy boards ensure that these practices are occurring through
random inspections and review of documentation for the specific
prescriptions. The only other means for regulating and responding to
such activities would occur if a patient was injured and formally
complained to the state board of pharmacy that they were not adequately
warned about the side effects of the medication. In this instance, the
pharmacist, not the operator, would fall under the jurisdiction of the
state board.

Although there is a clear indication to the pharmacist because of his or
her knowledge of medications of which medications could have sedating
effects, there is no federal mandate from the FDA designating these
medications and requiring a specific warning label.

Even if this requirement was in effect, NABP is not certain that such a
federal mandate would help resolve the problem identified by the NTSB.
Although it would place a specific legal mandate on pharmacists to affix
the appropriate label, the state boards of pharmacy would not have any
authority over operators who actually are prescribed and take the
medications.

The responsibility for pharmacists to make this warning known to
patients is inherently present in good practice standards and could
result in disciplinary action against the license of the pharmacist if
not followed.

NABP is willing to work with the NTSB and FDA to resolve the concerns
identified.

DR. ELLINGSTAD: Thank you, Dr. May.

We\'ll go for questioning to the Technical Panel. Who wishes to go
first? Dr. Garber?

Questions from Technical Panel/Parties and Discussion

DR. GARBER: And Dr. May, since you spoke last, I\'ll question you first,
if you don\'t mind, and if there are issues that I touch on, Mr. George,
that will \-- that have legal implications, I would hope that you would
jump in and respond to those as well.

In Australia, the pharmacy associations there sort of banded together
and got a standardized warning label that they use for a certain list of
medications. It\'s a red warning triangle that sits on the same sort of
stickers that are commonly applied in this country.

So, what I\'d like to ask is, do \-- is there any opportunity for
pharmacists in this country to do a similar sort of thing, and to what
extent do you feel that that might be effective on a voluntary basis?

DR. MAY: Well, I read that in the report, and I\'ll have to ask you a
question. I haven\'t seen it. Is the red triangle simply that?

DR. GARBER: Exactly.

DR. MAY: Does it have words?

DR. GARBER: It\'s just a warning.

DR. MAY: Nothing?

DR. GARBER: It\'s a red warning triangle, which is actually a very
common symbol in Australia for danger. It\'s a road signal that\'s
fairly commonly recognized as meaning dangerous conditions ahead.

DR. MAY: Okay. Well, it appears to NABP that there are several problems
with that. One, that does not mean that in the United States. In
Pennsylvania, on the back of an Amish buggy, it means go slow.

I don\'t think anybody here would recognize it. There would have to be a
tremendous educational program to tell people that that really has some
significance. What they put on now, as you know, is a little label on
the back side of a prescription label on a bottle that says caution or
warning, this drug may be sedating, may cause \-- do not operate
machinery, drive a car, etc. It is a warning.

It\'s a well-known fact that a lot of people who get prescriptions in
this country really don\'t understand the prescription label itself, let
alone some of the warnings that are attached to it, and sometimes there
are more than one warning attached to a prescription. There may be two
or three.

When they turn that over and start reading them, multiple warnings tend
to have a lessening impact on the observer. They see all this, and they
start wondering what it really means.

The one about sedation, and we\'ve all taken sedating antihistamines by
prescription or over-the-counter, and you were aware of these warnings,
and you read them, and they tend to really not excite you too much
because I\'ve taken them, and I\'ve not felt that I\'ve experienced the
effects.

I guess what I\'m saying is to put the red triangle on or something
similar to that, we\'re having a hard time understanding how that might
improve the label now that is in English. You can read it, and you have,
I think, a better understanding of it, unless again you can educate the
consumers that this now has a new meaning, like the radiation symbol in
this country. Everybody understands what that means, and if they see it
on any product, it catches their attention because they\'ve been
educated to it.

When I read this again in the docket, I had some problem with the
triangle concept, something without words, because I\'m not sure again
that you\'re going to be able to do this in the minds of the consumer,
that they see this little red triangle or yellow circle or whatever you
make it on a prescription, that it\'s going to have the same impact as a
label where, if they read it and understand English at a certain level,
they will at least comprehend what that little thing means.

So, I guess I would throw it back and say unless you\'re willing to
undertake a really massive education program when you undertake
something like this, I think you probably will have great difficulty
with it at first.

So, it\'s possible that it could work, but it would have to be proven
that it\'s any more effective in a way than what\'s put on there now.
Unless you mandate that a certain level developed by FDA, which we\'d
probably agree with, the agency, along with its consultants and the
public, looking at a prototype product would agree that that\'s better
than what\'s put on there now by pharmacists, we would be happy to do
that, if that can be improved, if you can get the attention of the
public who reads those labels, but that system in use in Sweden and
Australia may work there, although I haven\'t seen any data here that it
really works. It just says it\'s being implemented.

So, we\'re agreeable to something that improves the present system, but
it\'s a hypothetical to know whether that can be made to work in a short
period of time or even in a longer period of time.

DR. GARBER: So, do I understand correctly that the position would be
that if a warning label were developed that could be shown to be more
effective than current warning labels, that your organization would find
that to be an advantage over the current system and would voluntarily
use such a system?

DR. MAY: I would say that\'s true, using the caveat that I used, that it
is a better system and would have a better impact on the consumer or
even on anyone taking a product. That\'s right.

DR. GARBER: Okay. You mentioned that the requirement of affixed labels
is really a best practices requirement; that is to say, that it\'s done
because it is a standard of practice in the pharmacist community.

So, do I understand correctly then that there is no state law, federal
law, regulatory guidance that would suggest that you must put any
warning label on a prescription medication?

DR. MAY: Oh, no. There are some warning labels that are required to be
put on the medication, but what you would hope for, what we would hope
for would be if you could come up with a very effective warning, which
would help solve this problem, if that could be made a federal standard,
it would make it a whole lot easier for the 50 states to adopt as
opposed to state regulations which may vary all over the place. One
state may make it a regulation, another one may make it simply a good
practice.

Pharmacists put a lot of these labels on because it is good practice.
Whether or not there are state laws, I cannot tell you in all states.
I\'m here to talk about the overall general concept of trying to improve
the labeling put on there now.

It was mentioned in here by NTSB that something that was \-- I think I
read it, something that was in a mandate would work a lot better, but
again you have to prove that there should be a federal or state
requirement for it as opposed to standard practices.

DR. GARBER: And actually, my next question goes to Mr. George in regard
to that same issue.

How many states actually have laws that specifically prohibit use of
impairing medications? Do you have any feel for whether most or many
states have such laws?

MR. GEORGE: I can tell you what we have in Delaware. My thought is that
probably every state has a similar DUI statute that prohibits not only
the driving while under the influence of alcohol but of an impairing
drug as well. So, I would have to say that my feeling is that probably
every state has some statute.

DR. GARBER: You mentioned some of the difficulties inherent in trying to
prosecute a case involving medication versus one involving alcohol or, I
assume, illicit substances as well.

Does \-- do you believe that there are \-- that there is less activity
on the part of law enforcement in trying to determine whether people may
be impaired by drugs or perhaps even if that determination is made,
given the very difficult hurdles that may need to be cleared to
prosecute such a case, that such cases are not \-- even when found, may
not necessarily be prosecuted or evaluated completely?

MR. GEORGE: Well, I think the problem with an impaired driver, impaired
by medication, is that the impairment has to be such that they\'re
falling down drunk, like an alcohol-type case.

Police are limited in what they can do, based obviously on the
Constitution. Before they can take blood samples or urine samples or an
intoxilyzer, there has to be probable cause. So, the person that they
stop has to exhibit some type of outward signs of intoxication. That\'s
the first hurdle.

If they are impaired to the point where they can\'t do field tests, the
standardized field tests, then the next step would be the officer is
probably going to assume that they\'re impaired by alcohol. He\'s going
to probably take them back to the troop and give them an intoxilyzer.

The problem there is he\'s going to get a 00 reading, and he doesn\'t
know what to do then. It looks like the person\'s drunk. They\'re
showing no reading, and they\'re sort of stymied at that point, and
that\'s the problem with the training at this level in the state of
Delaware.

DR. GARBER: So, if we were to look at a database, a hypothetical
database of non-fatally-injured drivers or drivers who were potentially
at fault in a traffic accident, would it be safe to say that we would
probably under-represent the risks associated with the medications
simply because it\'s so difficult to detect, and if one detected,
difficult to \-- or suspected, difficult to prove?

MR. GEORGE: Absolutely. I would agree with that.

DR. GARBER: Okay. I may have a couple more questions, but that\'s all
I\'ve got for now.

DR. ANDREASON: This is a question for Mr. George, but Dr. May, if you
happen to know the answer to this, too.

What are the \-- do you have a list of drugs that are considered
impairing or is that statute fairly open to interpretation?

MR. GEORGE: When it comes to \-- the statute reads it prohibits the
driving of a vehicle while under the influence of any drug or under the
influence of a combination of alcohol and any drug, and we obviously
take that to mean both legal and illegal. So, that\'s exactly how our
statute reads. So, it would encompass legally-prescribed drugs, if it
impairs you.

DR. ANDREASON: Any drug?

MR. GEORGE: Any drug.

DR. TEMPLE: Is under the influence described further?

MR. GEORGE: It is defined, but I can\'t specifically say how it\'s
defined right now.

DR. TEMPLE: Is there something that implies, though, that your
performance is impaired?

MR. GEORGE: Yes.

DR. TEMPLE: Okay. But it doesn\'t give any hint as to what kinds of
drugs might be there? You\'re on your own?

MR. GEORGE: You\'re on your own.

DR. ANDREASON: So, if someone had a blood alcohol level that was, say,
below .02, and they were taking a non-steroidal anti-inflammatory drug,
that would be considered in combination with alcohol?

MR. GEORGE: Well, our statute has \-- sets out five different
definitions of being impaired. It speaks specifically to alcohol, and in
our state, a reading of .01 or above is considered under the influence.
A reading from .05 to .09 is presumptive evidence that you\'re under the
influence, and a reading of .05 and under is not considered under the
influence.

So, in your example, a reading of .02 and an indication that there was
some other drug involved, that case, if we were to take it to trial, we
would have to have evidence of beginning first with the field tests that
are performed by the officer, and I\'m assuming everybody knows what I
mean when I talk about standardized field tests. They\'re the walk and
turn test, the picking up the keys, the counting, the alphabet, reciting
the alphabet. In some instances, tests involving HGN, and those \-- the
performance on those tests would have to be so poor because that would
in essence be all the evidence to make or break this particular DUI case
because obviously when you take that individual back to do an
intoxilyzer reading, it\'s going to come back with an .02.

So, to prove that case, you\'re going to have to have pretty poor
performance on the field tests to be able to obtain a conviction. Now,
whether steroid drugs would cause a person to perform that poorly, I
can\'t speak to that.

DR. ANDREASON: What kind of field \-- now, you described a field test.
How do those correlate to, say, driving performance? I assume they\'ve
already been pulled over because of some erratic driving. Why do the
field tests need to be repeated?

MR. GEORGE: Because an officer can\'t take someone into custody without
probable cause. That\'s one of the fundamentals of our Constitution. The
officer begins his case by noticing the erratic driving. That gives him
the reasonable suspicion to stop the driver and then begin the process
of developing probable cause, what we call probable cause. The erratic
driving is the first thing.

The next thing that a trained officer will do is he\'ll go up to the
car, and he will look into it, you know, see if he gets the odor of
alcohol. There\'s initial signs of impairment, such as speech, looking
at their eyes to see if they\'re bloodshot, and some of these signs will
be the same if someone\'s impaired by medication versus alcohol.

Obviously if they\'re impaired by medication, you\'re not going to get
the smell of alcohol. He\'s going to ask for their driver\'s license,
registration, and he\'s going to look to see if they have difficulty in
the pulling out of the glove compartment or out of their wallet, if they
fumble with them, if they give them their Acme card instead of their
driver\'s license. Those are the first things that he\'s noticing.

At that point, as he continues to develop his probable cause, he\'s
going to ask the driver to get out of the car. Again, he\'s going to
note whether they had difficulty in getting out of the car, whether they
had to lean on the car, whether they stumble, and again, he\'s
developing probable cause. He doesn\'t have it yet.

He\'ll then give a series of field tests and note the performance. Now,
I\'m not an expert in field tests, but I know that NHTSA has done a
number of studies, and I can\'t tell you the percentages off the top of
my head, but I know that the studies have shown that if you fail certain
\-- and NHTSA, I think, recommends three standardized field tests, and
if you fail these field tests, there\'s a 70-percent likelihood that you
are probably under the influence of alcohol.

Combine that with an HGN test, which not all officers are trained to do,
your percentage goes even higher, that the person is most likely under
the influence. At that point, the officer has developed his probable
cause that he needs to either give an intoxilyzer or to take blood. So,
it\'s a step-by-step process to that point of actually being able to
give the field tests. You just can\'t stop someone, anyone you want and
say, hey, I\'d like you to do some field tests for me. It\'s a
step-by-step process.

DR. TEMPLE: Once that test establishes probable cause, then they can
make somebody exhale into an analytic procedure?

MR. GEORGE: At that point, he has established probable cause. He can
arrest the individual and either take them back to the troop and give
them the intoxilyzer or, in his discretion in our state, take the blood
test.

DR. TEMPLE: Okay. I was going to ask about saliva tests, but he can get
a blood test in Delaware?

MR. GEORGE: Well, our statute specifically requires a blood test. At one
time, it provided for a urine test, but that was never done, and it was
really meaningless.

DR. ANDREASON: Field testing does seem to be weighted to detect alcohol,
especially with horizontal gaze and walking a straight line, which are
cerebellar functions.

If someone was impaired, say, by other drugs that didn\'t affect
cerebellar functions, what would the officer be able to do? Must they
fail these tests in order to be tested or to obtain a blood test?

MR. GEORGE: Keep in mind, I\'m not a chemist, I\'m a practicing
prosecutor.

DR. ANDREASON: Right.

MR. GEORGE: However, I\'m not sure I totally agree with you. I do know
about the DRE program. We\'ve \-- I\'ve \-- we initially had a
conference in Delaware at one point where we brought out Sgt. Tom Paige,
who helped to develop it in L.A., and I know that with a drug
recognition expert, who is a trained police officer, who is ultimately
based on his training able to detect or determine seven broad categories
of possible drug impairment, they begin with the standardized field
tests.

So, the standardized field tests not only are geared towards alcohol but
are geared for drugs as well. The HGN test is geared not only for
alcohol but for drug impairment as well. The problem is, that\'s the
extent of the training for most police officers. The training necessary
to later determine whether it\'s a drug impairment is much more
extensive, and in Delaware, we don\'t have such a program. That\'s where
the problem comes with detection of drug impairment.

DR. TEMPLE: Do you have programs for obtaining blood samples from people
killed in accidents and other people in the car? Still thinking
epidemiologically from the last panel, but I just wondered if that was a
resource.

MR. GEORGE: Well, anyone who\'s killed in a motor vehicle accident is
taken to the state medical examiner\'s office. Keep in mind, Delaware
being so small, everything\'s sort of run at the state level. We have no
county district attorneys, no county MEs, and so, everyone in Delaware
who would be killed in an accident would be taken to the ME and an
autopsy performed and blood tests. So, yes, absolutely.

DR. TEMPLE: Do you know, have data ever been looked at to compare blood
levels of various substances of interest in drivers and passengers or
anything like that been published?

MR. GEORGE: I know that our Safety Council does publish yearly the
statistics involving fatalities, and I know that they keep track if the
driver of the automobile has \-- was intoxicated. I do know that.
Whether they look for other drug impairment, I don\'t know.

MR. KOTOWSKI: In the case where an enforcement \-- where a motorist is
stopped and is pulled over at the roadside and has been subjected to
these battery of tests and obviously there\'s some difficulty, when it
comes time when we have a blood test that is drawn, do we have to be
specific about a particular type of drug or is there just a general
screen or a general scan that would be taken of that particular drug
sample?

MR. GEORGE: Again that\'s a little bit out of my area of expertise, but
based on some experience I\'ve had in that, I know they always check for
alcohol. I know that they always check for certain illegal substances,
PCPs, cocaine, and several others.

I don\'t believe, unless they are specifically advised, that they would
look for an illegally-medicated type of drug, unless it\'s some type of
barbiturate, illegal barbiturate.

MR. KOTOWSKI: If you could, could you walk us through your procedure as
a prosecutor, some of the difficulties you would face, that if you had a
motorist that was stopped, that failed all these tests, had a blood
sample that was taken, came back positive for some type of a
prescription drug, that when you checked the PDR, it says that it is a
sedative-type medication? You have a reading that there was a certain
percentage or a certain level of this particular drug in that person\'s
blood system, the big AC level is about .07, what would you have to do
in order to provide for a successful prosecution about the establishment
of the effects of that particular drug?

MR. GEORGE: That case may be a little easier to speak to because we have
an .07 alcohol and that\'s within the range where the trier of fact,
whether it be a judge or a jury, could find a person under the influence
of alcohol or a combination of alcohol and drugs.

Again, any time that you have a finding where there\'s some type of drug
involved, and a finding where the blood alcohol is under 10, the
prosecutor has to really rely on the performance on the field tests to
prove that the person was impaired.

Without a very poor showing on the field test, you\'re going to have
difficulty in obtaining a conviction. It is possible, and I\'ve done
this in several cases, depending on the blood reading of the drug
that\'s detected, that we would bring in one of our forensic
pathologists, one of our assistant medical examiners, to speak to that
particular drug.

I certainly know in instances where we find illegal substances, like
cocaine or PCP, the medical examiners are usually quite willing to come
in and talk about the effects of that particular drug and whether it
would impair you or not, but again the issue for the trier of fact is,
was this person impaired?

They\'re going to be looking. They\'re going to focus mainly on the
field tests, and unless we have some kind of expert testimony regarding
the effects of that, that finding of the drug may or may not be that
important to us.

MR. KOTOWSKI: So, in most cases then, for any particular type of drug,
then it would almost necessitate the testimony of an expert witness?

MR. GEORGE: It would always require the testimony \-- well, no, I don\'t
want to say that. Again, if the field tests are just so poor, and again
I\'m going to kind of refer back to an alcohol-type case where the
person looks like \-- who is literally falling down drunk, then I\'m not
going to need an expert.

But if the field tests were so-so, then without an expert, there\'s no
case.

MR. KOTOWSKI: And the reference that you made to the DREs, the drug
recognition experts, do you know how long that training program lasts to
train an officer as a DRE officer?

MR. GEORGE: I don\'t, but I know that after the training, I think that
they require at least 90 hours of field experience with other DREs and
working at hospitals before they actually go out and start working on
the streets.

Part of the training for a DRE involves taking vital signs, measuring
the pupil, and I think that that training, the 90 hours, is done in
hospital emergency rooms.

MR. KOTOWSKI: And do you have any idea of how long it would take for a
drug recognition expert to make a stop, identify a person that\'s been
under the influence of some type of drug and be tested and arrested as
compared to a person that\'s under the influence of alcohol?

MR. GEORGE: Well, it\'s usually the DRE isn\'t making the stop. The stop
is made by another police officer, and the DRE is called in afterwards
to basically do the field tests and conduct this examination. As to how
long it takes, I don\'t know.

DR. ANDREASON: Dr. May, I had a question about how do you determine
which drugs you put a label on or a warning label on for supervision.

For example, is it from product labeling or is there some other source
of information that you use to place the label on?

DR. MAY: It would be my understanding that the pharmacist, from his
knowledge of the drug being dispensed, there is \-- when he opens up the
bottle of pills, if there\'s nothing on the federal label that says you
must put a sticker on this, but if he\'s dealing with antihistamines,
dealing with drugs that he knows to be sedating, whether it\'s the
benzodiazepines or antihistamines or whatever, from personal knowledge,
experience and training, he knows that label goes on there to warn the
person that this may cause problems if they operate an automobile or
heavy machinery.

I\'m not aware that there\'s any \-- I haven\'t worked in a pharmacy for
many years, but there was never a federal requirement that that label
had to go on there. When the state board people inspect and go back and
look at the prescriptions to see if they\'re adhering to this, they\'ll
look for any prescription that they know to be sedating, and these
don\'t carry any particular mark on the computer file or in a hard copy
file as narcotics would.

They\'re looking for the names of drugs and knowing what they cause, and
they\'re looking to see if in fact a label was put on there by the
pharmacist. They\'ll watch pharmacists fill prescriptions, but that\'s
how the system operates. It\'s a professional knowledge. There is no
chart they look at that says you have to put this on for this class of
drugs \-- for class of drugs but not specific drugs.

DR. ANDREASON: Another question is, do you have any idea how much
sedation is necessary before a label goes on? For example, I\'ve
received prescriptions for Naprosyn that have a warning label that it
could be sedating.

DR. MAY: To my knowledge, that information does not exist. Pharmacists
do not use that. You\'re getting Benadryl or you\'re getting another
antihistamine, you\'re taking one three times a day or you\'re taking
two every four hours, when the dose is much higher in one case over a
24-hour period, the same label goes on the product, warning, based on
the drug itself, because a lot of people will get a prescription,
especially over-the-counter drugs, and will overdose. They will take
more than the indication.

It says one three times a day, and it\'s an antibiotic, they may take
two. They may take more than the indicated. So, you put the label on
based on the pharmacology of the drug. If it has the property,
propensity to be a sedating drug, you put the warning on it, regardless
of the blood levels the patient may experience from taking it for
different levels of the drug.

DR. ANDREASON: Thank you.

DR. ELLINGSTAD: Anything else from our Tech Panel?

(No response)

DR. ELLINGSTAD: Okay. We\'ll go to the parties, and let\'s start with
the Advocacy Group this time.

MS. TARNEY: This is for Jon May. Are you of an opinion that
pharmaceutical care these days means that the pharmacist can be held
accountable for reaching or for resolving patient needs related to the
medication taken as directed?

If so, would you think it\'s possible in the present situation or the
near future that a pharmacist advises the prescriber and the patient to
use the least impairing drug in case the first time prescription for a
hypnotic, let\'s say, shows a severely impairing drug?

In other words, can the \-- do you see in the future where the
pharmacist could take the role of an advisor to the physician as well as
to the patient?

DR. MAY: I\'m glad you raised that. Yes, I firmly believe in that. NABP
believes in that, and all of the pharmacy professional associations I
know believe in that. The paradigm has shifted where pharmacy is no
longer just filling prescriptions, counting them, licking them, stamping
them, pouring. That\'s being done by technicians hopefully, and the
pharmacist is counseling the patient. The pharmacist is specifically
making sure the patient understands the drug they\'re getting, what did
the doctor tell them about it. If that\'s inadequate, reinforcing what
they need to know.

The Keystone Group met several years ago and developed a mandated
written information system for people receiving prescriptions under a
federal statute. It was a rider to a federal bill, and one of the things
missing in that, in my opinion, is, although they give very good printed
information today when you get a new prescription, you get an insert
that tells you all about that drug. There\'s a tremendous amount of
information in there in the case of sedating antihistamines, in the case
of benzodiazepines, etc. It warns about this particular drug.

But unfortunately, what a lot of pharmacists are doing is putting that
little information pamphlet on the bag with the prescription, and they
slide a piece of paper in front of you, and when you look at it, it says
do you wish to be counseled? That\'s inadequate in my opinion. That\'s
inadequate in NABP\'s opinion, because too many people say, oh, no, I\'m
in a hurry, I don\'t need it. They X it out, and they go, and unless
they open up that pamphlet and read the information, they really don\'t
know much more about the drug than what was provided to them.

The role of the pharmacist, in my opinion, and it will happen over a
period of years, is he will take every patient, and he will go over that
drug with them, and he will not only show them the pamphlet, but he will
reinforce parts of it.

One of the beauties if you go into a system where you\'re worried about
these drugs that can cause these problems with pilots and with operators
of heavy machinery as well as the consumer is they have to be made aware
of the very thing you\'re talking about. These drugs have potential
dangers to them, and you can reinforce that best when that person gets
that prescription at the pharmacy, and the pharmacist tells them that.
Oh, by the way, do you see this little label on here? See this little
red triangle or whatever? This means that this product has the potential
for.

You focus it in their minds, so when they leave, then they read the
information pamphlet, that\'s going to stay with them. They\'re going to
react to that. They\'re going to be aware of that. They may continue to
ignore it, but you\'ve made your point of reinforcing it in their minds.

Today, that does not exist adequately enough, but it is changing because
the role of the pharmacist is changing, working more closely with
physicians in delivering health care, not just delivering a
prescription, and making sure that the ultimate end result occurs when
they take that prescription. They\'re taking it right. They\'re taking
it in the right amount of time, and they know what they\'re taking.

So, that\'s what pharmacy is coming to, and that can fit in well with
this type of approach where you\'re changing \-- hoping to change a
labeling system and an awareness on the part of the public that these
drugs are not just innocuous things you\'re taking, and they get that
reinforced in their minds in some respects by getting no information
from either the doctor or the pharmacist in some cases. They just get
this prescription that says take one three times a day, and they start
taking it.

No awareness of what this is supposed to do or the side effects that can
result from it, unless they get counseling, unless they read this
information they get. So, that\'s a long way of saying yes, I agree with
you, and that\'s what pharmacy is changing to, and if that was done
today in this instance, you would not see some of these accidents, I\'m
sure, because the patients would have been told right up front beware,
this drug can really produce sedating effects and don\'t do some of
these things, along with an education program for people like pilots,
etc., that\'s the other aspect of this.

It kind of intrigued me when I read it. You can do all the labeling you
want in the world, but unless you educate the segment of the population
that has responsibility for flying \$20 million airplanes with 300
people in them that they shouldn\'t take certain drugs or if they are,
they should advise their surgeons that operate over them that they\'re
doing this and get permission to do it, get some awareness of it, we\'re
going to continue to have problems, and you do focus on education in
here, but that\'s a big aspect of it, also.

I\'m talking about the pharmacists educating people when they pick up
prescriptions as well as labeling. Labeling can only go a certain way.
The rest of it is education and making people aware of what they\'re
supposed to do and the danger of these drugs they\'re taking and some of
the side effects.

MS. TARNEY: Do you see the role of the pharmacist also to question a
physician if the pharmacist is seeing something that is not safe?

DR. MAY: Absolutely. When I graduated from pharmacy school in 1959, I
was \-- we were all afraid to call a doctor. We were afraid of what
he\'d say. What the hell are you calling me for? Just fill the
prescription, and I ran into people when I was with the government and
at NIH. NIH physicians basically told me that. You fill the
prescription, I wrote it, don\'t question me.

Today, that\'s totally changed. Pharmacists are calling physicians and
saying, in hopefully a tactful way, doctor, I\'ve talked to the patient,
and this drug, I think this drug is either contraindicated or are you
aware that the patient is already taking another drug which they
probably weren\'t aware of. They\'re interacting with the physicians
because the bottom line is the outcome of the case, the patient getting
better taking the drug.

The only way to do that is if pharmacists start becoming more
interactive, working with nurses and physicians, to make sure that the
system really benefits the patient, not the physician, not the
pharmacist. They\'re secondary to the patient and that\'s another whole
shift in this thing coming.

I can go on for hours about these protocols being developed between
physicians and pharmacists today, where the pharmacist actually delivers
care. They do \-- they take blood. They determine Dilantin levels. They
determine levels of drugs, working with physicians under protocol,
because the physician then can spend more of his time doing the
diagnosis, doing the prescribing but not having to do some of that other
information. They\'re counseling patients who have asthma, so that they
don\'t go back to the doctor and say Doc, this medicine isn\'t working,
when you find out they\'re not using the inhaler right. They learn to do
that from the pharmacist.

A system that works hand-in-hand is going to result in better care in
this country. So, that\'s changing rapidly today, I\'m happy to say.
It\'s moving forward in every state in the Union.

DR. ELLINGSTAD: Okay. Let\'s go to the Government. Mr. Clarke?

MR. CLARKE: Mr. George, you indicated that the procedure seems to be
field tests and then an intoxilyzer and then blood possibly or can you
go from positive results in a field test straight to blood and skip over
the intoxilyzer?

MR. GEORGE: That\'s at the discretion of the police officer. Another one
of the possible tests is what we call a PBT, a portable breath test.
That gives an initial unscientific, I guess, reading of the blood, and
if that were to come back 00, if the person has been done so poorly on
the field test, then the officer, in his discretion, can have a blood
sample taken.

In fatal cases, we usually take blood because we\'re \-- we don\'t do an
intoxilyzer. We take \-- once we\'ve developed a probable cause, we\'ll
have blood taken because we\'re always suspicious of whether there\'s
alcohol, drugs or a combination of both involved.

MR. CLARKE: You mentioned that there was some number of drugs that you
test for, in addition to alcohol, and I presume those were all illegal
drugs.

If you get a situation in which you\'ve gotten poor field test results
but zero readings, say, on an intoxilyzer and this other test, and you
get some kind of positive readings on any of these illegal drugs, what
success do you have then in prosecuting those cases?

MR. GEORGE: Well, again, it\'s really going to depend on the field tests
because I\'m not sure it makes much difference. Obviously with an
illegal drug, it\'s more prejudicial when you present it to a jury, but
ultimately again, the issue is one of impairment, being under the
influence.

When we get the blood test back, if it\'s a legal drug or an illegal
drug, I\'m still going to have to prove that the person was impaired by
that particular drug. I suppose you can take small amounts of cocaine
and still drive a car and not be impaired, just like there are a number
of legal drugs that you can take and not be impaired.

The problem that we have is when we get that blood test back, and I take
it to one of my experts, and I say, look, at this reading and tell me
what it means, and if it\'s a legal drug, he\'s probably going to tell
me, well, that\'s a therapeutic dose. That\'s very nice. What does that
mean? There was a therapeutic dose in this person\'s blood. Does that
mean he was driving under the influence? I don\'t know.

MR. CLARKE: So, if you get low levels of any of these drugs, but you\'ve
still got poor field test results, you don\'t have the basis for going
forward with the prosecution?

MR. GEORGE: Without the poor field tests, we won\'t have the basis.
Again, you know, the therapeutic dose, the fact that it\'s in the blood
may be relevant, may not be, but we\'re really going to have to rely on
the field tests to be able to prove that.

MR. CLARKE: Is that the most convincing aspect of a prosecution or are
these quantitative measures more compelling?

MR. GEORGE: No. The field tests are absolutely the most compelling part.
Really, as far as drugs are concerned, and unless the dose is just so
high, the quantitative effects really can have a lot of meaning to the
prosecution.

MR. CLARKE: Are there any cost considerations associated with making
decisions to draw blood as opposed to just relying on the intoxilyzer
results? If you were routinely doing this on large numbers, how would
\-- what would that do to your budget?

MR. GEORGE: Well, again, the decision is at the discretion of the police
officer, and then I think \-- and I\'m not a police officer, but I would
think that some of the factors that go in his decision whether to take
blood or intoxilyzer is that the intoxilyzer is easier. He has to go
back to the troop and do it, takes about 30 minutes all together. He\'s
at the troop. He can write his reports versus having to take a blood
test requires him going to the emergency room \--

MR. CLARKE: Right. But we\'re talking about situations here where
presumably the intoxilyzer tests are negative. In other words, just \--
we\'re looking at just effects of prescription or OTCs, without
confounding effects of alcohol.

MR. GEORGE: Well, if he\'s already given an intoxilyzer, then he\'s not
going to take blood, too. He makes that decision at the time.

MR. CLARKE: So, to get a zero reading on the intoxilyzer, you can take
blood?

MR. GEORGE: Probably not.

MR. CLARKE: Even though he had poor field tests?

MR. GEORGE: He\'s going to probably assume it was alcohol. He made the
decision before he leaves the scene and of whether he\'s going to take
the blood or intoxilyzer, and once he makes the decision, he\'s not
going to do both.

MR. CLARKE: But I guess my question is, if he does poorly on the field
tests, giving the officer an indication of probable cause, then goes
back to the police station, I presume that\'s where they go, and then
gives them an intoxilyzer test and gets zero, then what happens?

MR. GEORGE: He\'s unlikely to then \-- on just a regular DUI, it\'s very
unlikely that he\'s then going to take him to a hospital and do blood
work.

MR. CLARKE: So, I guess what I\'m trying \-- what has to be present for
the person, for the officer to decide to draw blood? A pretty bad field
test and the intoxilyzer or just one or the other?

MR. GEORGE: Well, maybe I haven\'t made myself clear. The officer has
some \-- can do either. He can either give an intoxilyzer or he can
decide to have blood taken. In fatal cases, we make the decision right
at the scene that we\'re going to have blood taken. We\'re not even
going to bother with the intoxilyzer.

Once the officer takes that person into custody, arrests them, he makes
the decision, am I going to take him to the emergency room and take
blood or am I going to take him down to the troop and give him the
intoxilyzer? He makes that decision at the scene. He doesn\'t know what
the reading\'s going to be, but he\'s making the decision of these two
options. I\'m going to do one of them.

Once he makes that option, he takes them back to the troop. He gives
them the intoxilyzer. He comes back 00. In a DUI case, it is very
unlikely that he then is going to turn around and take the person back
to the emergency room and take blood.

MR. CLARKE: I guess also, I\'m looking at it from your point of view as
a prosecutor. You\'ve got this information in hand, say poor field test
results, zero \-- he just went right to a blood test because that\'s it,
and you\'ve got zero blood alcohol but maybe trace levels of some of
these five illegal drugs, one or more of them say, let\'s say one that
you\'re talking about. What do you do as a prosecutor at this point?

MR. GEORGE: I\'m going to talk to my experts and try to determine if the
therapeutic level \-- what the therapeutic level of that particular
drug, what it means. Will they testify that that level is impairing?

But even with their testimony that that is an impairing level, I\'m
going to still need poor field tests to be able to convict that person
of driving under the influence. The level itself, unless it\'s just
incredibly high, is not going to be sufficient to sustain my burden,
which is to prove someone guilty beyond a reasonable doubt.

MR. CLARKE: Thank you.

DR. ELLINGSTAD: Let\'s go to the Professional Group.

MR. GELULA: Thank you. I have two questions, the first for Mr. George.

Today, we\'ve mostly been focused on sedating medications, drug
interactions and combination of sedating medications with alcohol, but a
number of studies have also shown that total hours of wakefulness or
sleep deprivation can cause impairment as great or equal to alcohol
intoxication.

I\'m wondering if, in your experience, there\'s been any evaluation or
roadside tests whether there\'s any effort to judge whether there\'s an
additive effect of sleep deprivation or time of day, the circadian
effect, and such. Would those factors come in?

For instance, if it\'s been adjudged that the person has been up for the
past 24 hours, is that a factor that you use in trial?

MR. GEORGE: Absolutely, and I have done a number of commercial vehicle
cases. In particular, I finished one up about a year and a half ago that
you may be familiar with. A truck driver coming down a major roadway in
Delaware came up on a red light.

All the cars were stopped, and he plowed into this row of cars. The van
that he initially struck was totally demolished, burst into flames,
people burned to death, and we ultimately were able to show that over a
\-- he had a GPS system in his truck, and we were able to show that over
approximately 55-57 hours, that he had been on the road for close to \--
all but for about 13 hours, just way over his hours, and that obviously
was a factor in whether we were going to charge him.

Keep in mind that not every fatal motor vehicle accident involves a
criminal prosecution. In Delaware, we need to rise to the level of what
we call \"criminal negligence\", which is a much higher standard than
just simple negligence.

People who negligently kill other people are not prosecuted criminally.
They may be sued, but they are not prosecuted criminally. So, we had to
make a case of criminal negligence. Obviously part of that case was the
fact that he didn\'t see all these cars stopped at a red light. He
plowed into them at 60 miles an hour, but the other major factor in that
particular case was the number of hours that he had been up, and I think
that played a very important factor in our successfully convicting that
driver.

MR. GELULA: Thank you.

And Dr. May, I\'m curious if in your experience or if there\'s evidence
to suggest that patients might be substituting an over-the-counter drug,
if they make that choice, instead of going for the filling of a
prescription or, for instance, a hypnotic because they might believe
that the OTC brand is safer. Do patients make that kind of decision?

DR. MAY: I missed the last \-- your last comment, the last words you
used.

MR. GELULA: They might believe that the OTC brand is safer than the
prescription drug. Do they make a substitution?

DR. MAY: I really can\'t comment on other than drugs that exist for both
prescription and over-the-counter. There are people who will buy a
Motrin prescription, a high-dose prescription, low-dose
over-the-counter, people buy low-dose over the counter because they
don\'t go to a physician to get a prescription. I\'m sure that goes on.

Other \-- going to other drugs, I really can\'t comment on that.

MR. GELULA: Thank you.

DR. ELLINGSTAD: Thank you.

The Pharmaceutical Industry? Would you make sure your button is up?

MR. LISTER: I\'m Steve Lister. I\'m with the Consumer Healthcare
Products Association.

DR. ELLINGSTAD: Could you say your name slowly, so we can get it?

MR. LISTER: Sure. Steve Lister.

DR. ELLINGSTAD: Lister?

MR. LISTER: Lister, like mister. I\'m with the Consumer Healthcare
Products Association, and I don\'t think I have any questions for the
panel.

DR. ELLINGSTAD: Thank you.

The Union Group?

CAPTAIN POPIEL: No questions.

DR. ELLINGSTAD: Thank you.

And finally, the Transportation Industry Group?

DR. FAULKNER: Yes, I have a question for Dr. May. Habla Espanole?
Sprechen sie Deutsche?

The reason I ask is, you know, we\'re in an international business with
airlines, trucking, things like that. I certainly admire and support
pharmacists working and explaining things, but we\'re going to hit
language barriers, and one thing I\'ve encountered or it\'s been
encountered here is warning labels will often have pictures, but those
vary from someone sleeping in a bed to drowsy eyes to the like.

Has there been any move or is your organization advocating for perhaps
more picture-type warnings for perhaps the illiterate or people from out
of country for warnings?

DR. MAY: Yes. NABP is certainly in favor of these pictograms that we put
on prescriptions or on over-the-counter drugs particularly to let people
know.

Giant Pharmacies in this area have been very active in that for years,
putting \-- getting the suppliers of their products to put certain
pictograms on there.

We\'re fully aware of the Spanish problem or the language problems,
rather, and communities where there are major populations of Hispanic
people, etc., or in California, where there are Asiatics or Asians,
there are pharmacies that label prescriptions in that language and put
warnings on in Spanish.

If someone speaks Spanish predominantly, you\'re not going to hand them
a product that\'s labeled necessarily in English. So, there\'s a lot of
that going on to help the patient again get the medication, so they can
get the ultimate outcome from it. But a lot more needs to be done.

DR. ELLINGSTAD: Okay. Thank you.

And we have some questions from the audience from Dr. Galson.

DR. GALSON: Yes. We\'ve got one statement and really two questions. I
think I\'ll do the questions first, and if we have time for the
statement, I can read that. This is for Dr. Jon May.

Would mandating the pharmacist to educate the patient in regards to
certain medications causing sedation and warning labels be more
effective than the current practice?

DR. MAY: I heard it, but you\'ll have to say that again.

DR. GALSON: Would mandatory requirement on the pharmacist that they
counsel patients be more effective than the current system, which is
voluntary?

DR. MAY: Well, for Medicare patients, the system is mandatory, but what
happens is when the law was passed and then it was implemented, there
were some segments of the industry that wanted to be sure, this is my
perspective on it, wanted to be sure that this was not a very harsh
implementation of the law requiring that if the patient was standing
there, that I had to be the pharmacist and do the counseling.

So, it was made so that some of the counseling, a technician could
actually ask the patient, do you want to be counseled, and then if they
said yes, they would call the pharmacist out, but you can get around
that by the way you ask questions obviously. You don\'t want to be
counseled by the pharmacist, do you? Well, if you ask it that way, why
would I want to be counseled by the pharmacist for?

When I go into my drugstore, as I say, I won\'t name them, I get a piece
of paper laid in front of me. Even if they didn\'t know me, the very
first time, instead of the pharmacist coming out and saying what do you
know about the medication you\'re taking, and I would have said I don\'t
know anything about it, and he would have counseled me.

They slap a piece of paper, and I\'m a pharmacist. I\'ve gone through
this. I play games with them sometimes. I got tired of playing games
when I used to tell them I\'m a pharmacist, what should I know about the
drug I\'m taking? One of them looked me in the eyeball and said, \"What
do you want to know about the drug you\'re taking?\" This guy ought to
be selling cars, not a pharmacist.

If you do it very proactively, you do get that type of counseling, but
it is, to answer the question, it is a requirement today that Medicare
patients get this.

What the states have done is they said you can\'t just counsel Medicare
patients, Medicaid patients. So, we\'re going to counsel all patients,
and they do indeed do that, but they do it but with varying degrees of
success. Some stores are very proactive and the pharmacist will go out
and go through the very litany of things I talked about, using basically
a system developed by the U.S. Public Health Service, Indian Health
Service. It\'s an excellent approach.

What do you know about the medication you\'re taking? They know right
off the bat, they need to tell them something, as opposed to a piece of
paper in front of you. The guy\'s running late anyway. His car is
double-parked. You\'ve got to be kidding me. I don\'t need counseling,
marks the block. They\'ve fulfilled their obligation. They fulfilled
what the state allows them to get by with in the implementation of OBRA
\'87.

It became convoluted in my perspective, and I think in NABP\'s. If the
law was implemented the way I talked about it, where every pharmacist
and every owner allowed the pharmacist to do this, every chain drugstore
allowed the pharmacist to do this, to be very proactive and counsel
patients, we would have a lot less problems than we have today, but a
lot of that still is being resisted, although more and more \-- I\'ll
say, chain stores because they are the biggest pharmacies today. The mom
and pop stores are gone, basically.

They have to develop an attitude that that is worth spending the money
on to allow the pharmacist to counsel the patients and not go through
this what I call \"shell game\" with a piece of paper. So, there is a
law. It is being implemented, but it could be implemented much more
stringently to the benefit of the patient if it\'s allowed to happen,
and I don\'t think it will happen over the next short period of years.

DR. GALSON: Okay. The next question is, is there a way for a pharmacist
to determine whether the patient is taking another drug obtained from
another pharmacist across town? If not, is there something like this
enforced?

DR. MAY: Yes. Well, I\'d have to say yes partially. In many drugstores
today, including a lot of the chains, they have a computerized entry
system, where, particularly if you\'re getting all your prescriptions
filled at, say, Giant in this area or CVS, in their computer, you go to
one store, you go to multiple stores, all the drugs you\'re taking are
going to show up in that print-out, and when a pharmacist fills a
prescription, he puts it in the computer to have a label generated,
he\'s going to have that sheet printed out right away that has all the
information on it.

They\'re not stacked up in a pharmacy in a full amount. That\'s
generated by the printer right as that prescription\'s being filled. The
label comes out and that sheet comes out. The information is developed
by other retail pharmacists. It\'s developed by information groups that
have the data. All of that comes out of the printer, a
computer-generated printing system.

So, the information is there, and it can get to the patient, if the
pharmacist does the proper role of counseling.

DR. GALSON: Okay. Of course, every pharmacy chain has got their own
system. They\'re not linked together.

DR. MAY: The fact of the matter is, in this country today, 95 percent of
all pharmacies \-- this is year-old data. I don\'t know what \-- 95
percent of pharmacies one year ago had computer systems in the pharmacy.
Even small pharmacies realized they had to have this system. They just
buy the software. They buy the system. It costs \$2 or \$3,000, but they
have to have it basically if they are to operate. It prints out the
material safety data sheets.

DR. GALSON: No. I\'m saying that Rite-Aid doesn\'t talk to CVS, doesn\'t
talk to \--

DR. MAY: Oh, they talk through the NACDS, which is the National
Association of Chain Drugstores.

DR. GALSON: The computer systems aren\'t linked.

DR. MAY: Oh, right. No, their computer systems aren\'t linked
chain-to-chain, no.

DR. GALSON: Okay. The other question is, does NABP believe that
counseling should only be given to the drug prescribed or should a
pharmacist question the individual on what other drugs they\'re taking
and provide counseling? I think you really answered that already.

DR. MAY: Well, let me just add one thing. That is done by the fact that
in a chain particularly, knows all the drugs being taken. They see that
a certain drug may be contraindicated because they go to multiple
physicians for one. Everybody doesn\'t go to the same cardiologist that
go to a GP that go to a dermatologist.

There are already prescriptions. They\'re all getting filled by, say,
Giant because they\'re loyal to that. That will become known to the
pharmacist, that they\'re getting this drug, this drug and this drug,
and there are one or two or three contraindications, so they shouldn\'t
be taking it.

They will then call the doctor and say are you aware that Dr. So and So
is prescribing this? Oh, my God, no. Got to get him off of that, and
there is an interaction to stop that from happening. It\'s on-going.
It\'s very effective. It should be increased in all pharmacies but yes,
that is happening.

So, including the inclusion of over-the-counter drugs because they ask
the patient, when they get them as a new customer, what other drugs are
you taking by prescription, what other drugs are you taking
over-the-counter. They give them a sheet of paper. They fill it out and
that data is entered into that company\'s computer, and all of that\'s
in there. They\'re taking these over-the-counter.

Now, the patient can say oh, I don\'t want him to know what I\'m taking
over-the-counter because the doctor may not know all of them, but it\'s
asked by chains. It\'s asked by pharmacies and that data is entered into
the computer system, and it\'s all there, including software that has
warnings for overdoses, warnings for drugs that are contraindicated and
interact with each other. They get a message coming out. These drugs
should not be taken together. They then call the doctor, call the
patient. All those things are in play today.

DR. GALSON: Okay. If there\'s time, I\'ll read the statement quickly.
There is a drug recognition officer in the audience, and he wanted folks
to know that in the program, most states use urine, not blood. Only nine
states have a blood demand, and the DRE determines the impairment. The
body fluid confirms the drug.

DR. ELLINGSTAD: Okay. Thank you, everyone. We\'re right on schedule
again.

What we\'ll do now is take about a five-minute stand-up and stretch
break in order to switch our panels. I\'d like to remind all of the
witnesses who have presented that we \-- if they have not turned in the
copies of their presentation, we need them, and if they\'ll check with
the people at the desk out in the lobby, we\'ll collect that.

Thank you.

(Pause)

DR. GALSON: Okay. I think we\'re ready for our last panel for the day,
our fourth panel, Members from the Military, and I want to welcome
Colonel Saenger and Captain Fulton, respectively, from the Air Force and
the Navy.

We\'ve been starting from the right side. So, Captain Fulton, if you
want to start first.

Witness Panel IV - Military

CAPTAIN FULTON: Thank you.

Good afternoon, and I guess it\'s almost evening. But I\'m Captain
Dwight Fulton. I\'m the Director of Aerospace Medicine for the United
States Navy.

As such, I am the medical representative for really only one of the
operational arms of the U.S. Navy and am best able to focus my comments
therefore on how we in naval aviation address the issues outlined in the
goals for this particular meeting, those goals being essentially data
available to define the role of impairing medications in accidents and
related issues, how the potential for medications to cause impairment
might be best assessed, and then how this risk would be most effectively
communicated to the public or, in this case, to our naval air crew.

As relates to data available to define the role of impairing medications
in accidents and related issues, accidents involving naval aircraft
trigger a safety investigation. It is conducted by our Aviation Mishap
Board, made up of personnel from within the mishap squadron and from
without.

Included in these investigations is the flight surgeon assigned to that
specific squadron. The flight surgeon\'s responsibility is to identify
any medical or human factors that may have been causative factors
contributing to that particular mishap.

Part of the flight surgeon\'s responsibility is to conduct drug testing
for prescribed narcotics or other non-prescribed illicit medications, to
conduct a review of any involved air crew medical records, to obtain
72-hour histories on all involved air crew, and to conduct a physical
exam on any of the air crew that were involved in that mishap.

If, in the course of this work-up, it is found that the air crew was on
any medications, it is also that flight surgeon\'s responsibility to
determine if the side effects or the therapeutic effects of these
medications could have contributed to that specific mishap.

As an aside, in many of our operational sites, the cognizant medical
treatment facility completes an accident report on anyone who presents
with injuries related to a specific accident. These reports are usually
maintained locally, unless the accident exceeds an indicated number of
lost work days, and then the report gets submitted up the chain of
command to the Naval Safety Center. Therefore, the Naval Safety Center
is a repository for some limited number of accidents that meet specific
criteria.

These non-standardized accident reports generated on the local level
will usually ask for any medications that the person involved in the
accident may have been taking.

As relates to how the potential for medications to cause impairment
might be best assessed, in naval aviation, there is no physical testing
process in place to assess the potential for medications to cause
impairment in air crew. There was some work done at the Naval
Aeromedical Research Lab in Pensacola, Florida, in past years, looking
at establishing a battery of tests to assess the cognitive effects of
different medications recommended for naval aviation, but to date, no
specific battery of tests has been approved.

Currently, medications that are considered for use in naval aviation are
reviewed by the Aeromedical Advisory Council at the Naval Aerospace
Medical Institute in Pensacola, Florida. Information considered in this
review process includes any recent medical literature and science
regarding the potential side effects of the proposed medication, the
known uses of the proposed medications in the civilian and military
communities, and the current stand of our sister services on these
particular medications.

As relates to how this risk would be most effectively communicated to
the public, and in this case, our public is naval air crew, in naval
aviation, it\'s our flight surgeons and our aviation technicians who are
messengers out there in the fleet.

The flight surgeons are trained on the medications that are compatible
with naval aviation and are responsible for monitoring their air crew to
ensure that there is no use of undesignated medications. They do this
through spending time with the air crew in their spaces and through
annual assessment of an air crew\'s medical history and physical status.

During these annual assessments of medications, air crew are reminded
that they are not to use any medications without the flight surgeon\'s
consent.

In addition, a pilot is reminded that if he is seen by a physician other
than a flight surgeon, he is grounded until a flight surgeon has
reviewed the medical care and treatment provided by that other
physician.

In addition, the flight surgeon conducts safety briefs in the squadron
spaces, and the issue of medications is one of those issues that\'s
briefed on a regular basis.

This naval policy on medication and air crew is further reinforced by
our line community in our OPNAV Instruction 3710.7R, which is the
Guidance on General Aviation Policy. This guidance reinforces that an
air crew man should not take any medications, over-the-counter or
otherwise, without the explicit approval and supervision by the flight
surgeon.

Again, I\'m not really astutely aware of how medication is used, use is
monitored and controlled with other forms of transportation than the
Navy, but I would be glad to research and provide any information to you
on these specific areas, if requested.

DR. GALSON: Thank you very much.

The next speaker is Colonel Arleen Saenger from the Air Force.

COLONEL SAENGER: Good afternoon.

I\'m Arleen Saenger. I\'m the Chief of Aerospace Medicine in the Air
Force Office of the Surgeon General. As such, I am analogous to Dwight
and that of the Director of the Aerospace Medicine Program for the Air
Force.

Our programs regarding aviators are very much analogous and essentially
the same as they are for the Navy. So, I\'ll touch briefly on that, but
I\'ll also touch a bit on what ground safety data I was able to get from
our Air Force Safety Center.

I\'m going to address the two specific key questions. How has the U.S.
Air Force addressed the use of medication by transportation operators,
and how effective have our efforts been?

Additionally, what is our experience in assessing, communicating and
preventing the risk of sedating or impairing medications in vehicle
operators, and how are our applicable laws or what we would call
instructions or regulations enforced?

First, aviation and then ground. As I said, the mishap investigation for
aviation mishaps is essentially the same for the Air Force as it is for
the Navy. So, I won\'t go into that in any detail.

Our Air Force Instruction on Medical Standards specifically addresses
the use of medications, both prescription and over-the-counter, by air
crew and what we call special duty personnel. For instance, air traffic
controllers and others.

Medications are not allowed to be taken without the specific permission
of the flight surgeon, just like for the Navy. There are certain
medications which we can waiver for our air crew use which the local
flight surgeon can allow the air crew to use once a period has passed so
he can determine there\'s no adverse side effects. There are other
medications where you have to request formal waiver from higher
Headquarters.

In no case is the aviator allowed to perform flight duties while taking
a medication that would be sedating or impairing.

Medications that are sedating or impairing result in a grounding, a
temporary grounding or NIF duties, not to include flying action, and the
aviator cannot go back to flying duties until cleared by the flight
surgeon.

As with the Navy, we also require the flyer to report to the flight
surgeon\'s office after being seen by any provider outside of the flight
surgeon\'s office. They are to consider themselves grounded until
otherwise cleared by the flight surgeon.

As for education on the use of medications, like the Navy, this is a
frequent briefing topic with our aviators. We drill it into their heads
at every opportunity. It\'s a mandatory briefing item at squadron safety
meetings. It is discussed in encounters in the squadron informally.
It\'s discussed in the encounters in the flight surgeon\'s office, both
by the doctor and by the technicians, the aeromedical technicians. So,
we educate, educate, educate.

We feel it\'s been very effective in our Air Force aviator population.
There have been no mishaps, aircraft mishaps in the Air Force where the
use of medication, prescription, over-the-counter, licit, illicit of
otherwise, has been found contributory.

How do we enforce it? Again through mostly education. We know our
population. We have a very defined population that we see on a daily
basis. We know them. We know their families. We know the squadron, and
education is a key to that.

The commander can take administrative action if anybody is found to be
self-medicating without reporting to the flight surgeon. I don\'t have
any data on how often that has ever happened, though.

Mishap data. We do toxicologic testing on all aircraft mishaps,
regardless of cost, in terms of cost of the mishap, that is. We do
screen for carbon monoxide, ethanol, amphetamines, barbiturates,
benzodiazepines, cocaine, opiates and bencyclidine. We also screen for
various typical over-the-counter and prescription medications, too, on a
varying basis.

Ground mishaps are a different issue. We\'ve got a fairly robust
database for aviation mishaps, but for ground mishaps, it is a different
issue, as was noted in the NTSB Board recommendations from January of
2000.

There is a manual that addresses wheeled vehicle drivers. It\'s an Army
field manual and an Air Force joint manual. That is the only regulation
or instruction that we have that governs wheeled vehicle drivers, and
the only note in that instruction is a note to a table where it states,
\"The driver is responsible for notifying your supervisor or NCO of any
change in your status; for example, inability to drive due to a physical
condition.\" So, we really don\'t have any regulations or rules, other
than that, governing medication use by ground vehicle operators.

Education is problematic, also. There is no systematic education for
ground vehicle operators. We rely solely upon the medical provider and
the pharmacist in educating the patient on the side effects of the
medication that they\'re being prescribed or that they might be buying
over-the-counter.

How effective is very difficult to determine due to the policy issues of
not having any rules governing it and relying solely on provider and
pharmacist education but also on database issues.

Currently, the Air Force collects data on ground vehicle mishaps only
for Class A mishaps, and those are mishaps which involve a total cost of
a million dollars or more, a fatality or a permanent total disability.

The database that we do have has a very limited search capability.
Nonetheless, the Safety Center did a review of about 12 years of motor
vehicle Class A mishaps. Almost all of these involved fatalities. Of 986
Class A mishaps during that time, there were only two in which drug use
was found to be contributory. One was for cannabis and one was for
cocaine. However, this is not complete data.

Testing is not required. In fact, in only 55 percent of these cases was
testing done on the involved driver. Testing is only required if, in the
opinion of the police officer on the scene, is necessary or if the
member\'s commander directs it.

Enforcement\'s also problematic, unless there is some legal military
action to be taken on the part of the commander, and we have no data
regarding numbers or anything of that nature.

For our future directions, the Safety Center has recognized there\'s a
very large knowledge gap here, and we are developing a program to
require human factors investigation on all mishaps, air and ground, all
classes, all cost classes. So, everything ranging from a \$2,000 mishap
with a minor injury all the way up to a million dollar mishap or loss of
life, air or ground, will have human factors investigation, and as part
of that, it will include drug testing, but that\'s being developed
currently.

There will be a database that will go along with that, the information
systems, to support that, but it\'s a future thing. Right now, we don\'t
have a very good ground mishap reporting data collection system.

That\'s it for the Air Force. Glad to take any questions.

DR. GALSON: Great. Thanks very much.

We\'re going to first start with questions from the Technical Panel, and
Dr. Andreason, do you want to start?

Questions from Technical Panel/Parties and Discussion

DR. ANDREASON: Sure. Thank you very much for your presentations.

First of all, I just wanted to say that my dad was an Air Force officer
in a fighter squadron. So, some of my questions will be based on his
experience.

It\'s my understanding that you do have a list of acceptable drugs for
flight crew. How did that list come about?

COLONEL SAENGER: It\'s evolved over the years. It also has evolved
somewhat as the Navy has, where we get consultant input. We pull the
other services, our sister services in the U.S. and also our allied
services for their experience with the medication. Literature research.
But a lot of it is simply based on a body of usage, and those drugs are
specifically listed in our Air Force Instruction 48.123, which is
Medical Standards.

DR. ANDREASON: So, you have a review board that kind of reviews these as
they come out, is that correct?

COLONEL SAENGER: Not as the drug comes out, no, but if somebody in the
field raises the issue or if one of the major command flight surgeons
raises the issue of this might be something we\'d want to consider
allowing for use in air crew, then the background research and the
decision process starts.

We have an Aerospace Medicine Corporate Board, which is composed of all
the flight surgeons, the command flight surgeons for the various Air
Force major commands, along with individuals from the Aeromedical
Consult Service at Brooks Air Force Base and the School of Aerospace
Medicine at Brooks Air Force Base, and it becomes a joint decision,
based on research, and sometimes it\'s just gestalt.

DR. ANDREASON: Well, that pretty much answers my question, but maybe to
beat the horse a bit more. Could you perhaps take me through some
hypothetical steps about how, say, a new ostensibly non-sedating
antihistamine might make it on to this list?

COLONEL SAENGER: That was done specifically with a literature review, an
extensive literature review. Part of the problem with literature review
is we\'re concerned with some neuropsychiatric side effects and some
subtle impairing side effects that are not necessarily addressed during
the testing for the FDA for approval to use it.

So, it\'s extensive literature review and consultants, specialty
consultants, subject matter experts. We gather their inputs, and we go
over the results of that and debate it a lot, and then we come to a
thumbs-up/thumbs-down decision and take a vote.

DR. ANDREASON: So, now in the United States, because of the user fee
initiative, drugs are often released first in the United States instead
of other countries. There\'s not a lot of data outside of what\'s in the
labeling.

Does that mean that, say, a new antihistamine might not make it on to
the flight crew list until this type of research was done in the
academic community or, say, as part of a Phase IV commitment?

COLONEL SAENGER: Yes. We wouldn\'t jump on something the day it was
released. We would want to see at least a year or preferably more of
post-marketing data that we could look at.

CAPTAIN FULTON: One other thing to comment on, too, is that when a
medical \-- usually or at least in terms with the Navy, when we start a
particular medication or introduce a new medication, it\'s a gradual
process to bring the medication on.

A lot of times, we just don\'t bring it on and then, okay, you can start
using this medication carte blanche. What we do is we waiver some of our
individuals to be on these medications for a particular period of time.
By being on a waiver, then they\'re closely \-- more closely monitored
by the flight surgeons than a drug that was not considered disqualifying
and could be used on a regular basis.

So, they\'ll watch for a period of time, and then, after they\'ve \--
that medication, we see in the air crew that it hasn\'t caused any
significant impairment or side effects, then that drug will be upgraded
to a not-considered-disqualifying drug, and those individuals can then
use it without having a waiver, as long as it\'s prescribed by a flight
surgeon.

COLONEL SAENGER: It\'s very much like that in the Air Force, too.

Another thing that we do, I believe, that Navy does, also, is we\'ll
start with the back-end, so to speak, of the aircraft and move forward,
and we may allow a medication used with or without a waiver, but with a
waiver usually, for a load master or an air battle manager, and then,
after we gain experience with it at that level, approve it for use in
our aviators.

DR. TEMPLE: These things are done systematically? There\'ll be a
servicewide decision that the flight surgeon can allow use of something,
so everybody will know about it, and do you record the results?

COLONEL SAENGER: Yes, there is.

DR. TEMPLE: It\'s not just local option?

COLONEL SAENGER: No. No, it\'s not just local option. We\'ll publish a
policy memorandum, and then when it comes time to change the
instruction, we\'ll add it.

DR. TEMPLE: And have you sent your lists to us, and can you?

COLONEL SAENGER: Yes, I can.

DR. GALSON: Let me just exercise the prerogative of the chair here and
ask you, what\'s the status of the sedating antihistamines on these
lists?

COLONEL SAENGER: We allow non-sedating with waiver.

DR. GALSON: Sedating?

COLONEL SAENGER: No.

DR. GALSON: Under no circumstances?

COLONEL SAENGER: Under no circumstances.

DR. GALSON: You wouldn\'t want to say which or which, would you?

COLONEL SAENGER: Allegra and Claritin.

DR. GALSON: Okay. Sorry to interrupt there. Please continue with the
Technical Panel questions.

DR. TEMPLE: I\'m sure we\'ll be interested in the list, and, you know,
any other on-the-way things that you\'re working on. I mean, how to gain
information about this sort of thing is part of the problem here. So,
how you do it in a relatively controlled environment is going to be very
interesting.

CAPTAIN FULTON: It\'s interesting because I just came back from a
standardization meeting over in England regarding all of the
English-speaking Air Forces. The British were present, the Australians,
New Zealand, Canada, and all the services from the United States, and
one of the things that \-- one of the information-gathering things
we\'re going to be doing over the next year is identifying what the
processes are that the different services have to evaluate these
medications, and where they\'re going with these particular processes,
because right now, I don\'t think any of the services, at least based on
the meeting that I was at, have a systematic process by which we do
testing on the particular medications, tox screens, although I believe
that the Air Force has a process that they\'re working on and to bring
into action, and I know that the Navy, like I said in my introductory
remarks, looked at a process several years ago, but I think that that
kind of died, and there\'s no process in place right now.

COLONEL SAENGER: What I was referring to is a process for doing what
we\'re calling \"one of\" occupational evaluations. The issue is we
don\'t have the resources to do systematic research, as we did, for
instance on my Centapro, in order to determine whether that was allowed
in air crew, in pilots, or not.

If we\'ve got an aviator whose not had an adequate response to an
allowed medication for his or her condition, and you try a medication
that\'s not on the list, and it works really well, how do we assess them
for allowing them to have a waiver or not?

The proposed process that we have, it\'s due to start fairly soon now,
the Consult Service, I don\'t believe we\'ve had our first patient down
there under this protocol yet, is to bring the individual down off the
medication, do the neurocog testing. If they are in fighters, put them
in the centrifuge, put them back on the medication for a period over the
weekend, retest them because we want to know before and after.

It\'s an N of 1, but for that individual, it\'s a mechanism for allowing
them to fly on that medication that\'s not currently on the air crew
waiver list.

DR. ANDREASON: They do that down at Brooks?

COLONEL SAENGER: Yes, at the Aeromedical Consult Service, Brooks.

DR. ANDREASON: Are there any drugs that are considered impairing that
are not necessarily sedating that are not allowed in the Air Force?

COLONEL SAENGER: Impairing from a psychological standpoint? Yes. We tend
to think of impairing in terms of neurocog, but there is G tolerance
issues that we both have to address.

DR. ANDREASON: Neurocognitive. That\'s kind of what we\'re driving at.
So, in that sense, it would be blood loss or blood profusion problems?

COLONEL SAENGER: Yes.

DR. TEMPLE: Wait a minute. The beta blockers have a number of things
they do that might make you think a person couldn\'t respond to an
emergency.

Are there any things that affect neurocognitive function that are not
sedating that are on your list? I think that\'s the question. That\'s
what they wanted to know.

CAPTAIN FULTON: Without having a list sitting here right in front of me
to answer that specific question, I can\'t.

DR. TEMPLE: Okay. You can imagine people would worry about amphetamines,
not because they sedate you but because they distort the way you react
to things.

COLONEL SAENGER: Yes.

DR. GALSON: Does NTSB have any questions?

DR. GARBER: Yes, and I know this is going to sound strange to my
military colleagues to even ask this question, but I assure you that
from a civilian perspective, it is meaningful.

The military prohibits the use of all medications for their air crew,
unless those medications have been specifically evaluated and determined
to be safe for their use.

Why has the military taken that approach; that is to say, prohibiting
everything and allowing only a few things, as opposed to allowing
everything, unless it has been proven to be impairing?

CAPTAIN FULTON: I\'ll take a stab at that one, okay, but (1) I think it
gives us a little bit tighter control over what medications individuals
take, you know, and I think that, you know, if we allowed everything, if
we allowed everything, we wouldn\'t have any control over what
medications are taken.

DR. GARBER: So, you would be civilians?

COLONEL SAENGER: We would be civilians. I suppose it reflects the
different philosophies. It\'s safe until proven unsafe or it\'s unsafe
until proven safe, and if we allowed everything, it would be an issue
just the span of control to allow everything and then have to prove
specific things on faith in order to disallow them. It would be a lot
harder to do than just say no, we\'re going to disallow everything, and
then what we can prove through experience, research, whatever to be safe
is more approachable, more obtainable.

DR. GARBER: Do you find it odd that a different approach is used in the
civilian community?

COLONEL SAENGER: No. There\'s lots of other examples of that, too. Plus,
we have a more controllable population. When you know your population,
and it\'s very defined, and you control their medical records, and you
see them at the club, and you see them at the commissary, you can \--
you have greater span of control and greater span of influence. You\'re
dealing with a totally different population on the civilian side.

DR. GARBER: Dr. Temple reminds me that we actually \-- that from what
you\'ve told us, that the military ground approach is actually very
similar to the civilian approach throughout transportation.

Is there a reason that the military uses a different approach for their
ground personnel than they do for their aviation personnel?

COLONEL SAENGER: Well, being the Air Force, we tend to emphasize
aviation, which is, you know, the ground is still important. I think it
just hasn\'t been given the attention which is why the Safety Center has
brought the issue up through their line channels and through the Air
Force Surgeon General saying this is a major safety issue, also, and we
need to start attending to and dealing with this.

The Army may have some more data on ground, but, unfortunately, he\'s
not here. So.

CAPTAIN FULTON: I think one of the other issues to look at, too, is when
\-- I\'m not sure about the Air Force on this, but I know with the Navy,
when we have a mishap, we look at all the people that may have been
involved in that mishap, okay, and so, you know, for us in a lot of
circumstances, that includes ground crews, and that includes the people
who are from those areas.

So, if there\'s a mishap investigation done, and we do toxicology
evaluation on the pilot, well, we may also do toxicology evaluation on
the air crew that worked on that airplane to make sure that that wasn\'t
a causative factor that\'s involved in that particular mishap, and the
other area that concerns us very much in the Navy obviously is the
flight decks on aircraft carriers, where we have a large number of
people, and as a matter of fact, we\'re working on the process now and
trying to include the process by which we monitor the people that are on
the flight deck and what medications those individuals are taking.

DR. GARBER: So, I think what I\'m hearing is that as with the civilian
community, this is an area of emerging concern for the military
services?

COLONEL SAENGER: And the Air Force does check on aircraft mishaps, if
there\'s a ground personnel or air traffic control personnel,
maintainers, flight line people involved. They are tested, also.

DR. GARBER: Thank you.

MR. KOTOWSKI: In the toxicology evaluations from mishaps, the prescribed
test, is it blood or urine?

COLONEL SAENGER: Blood and urine, depending. I\'d have to look at the
table to see which is which.

MR. KOTOWSKI: And is there a preference over one type of test versus
another?

CAPTAIN FULTON: Not that I know of. I think that to be honest, all of
our blood tests, most of what we send off are blood work-ups through the
Armed Forces Institute of Pathology, and they run all of our blood
tests.

COLONEL SAENGER: And for air mishaps, it\'s the same.

MR. KOTOWSKI: And then the results of those blood tests, are there
cut-off limits that are established as to whether or not it\'s a
positive reading or is it any trace amounts that\'s recorded as a
positive reading?

COLONEL SAENGER: I\'m not sure of the answer to that either, but I know
they report the amounts. Whether there\'s a cut-off, I don\'t know.

CAPTAIN FULTON: We can find that answer out for you.

DR. GALSON: Okay. Why don\'t we move on to the parties\' questions,
starting with the Union Table? Any questions for the panel?

MS. HEAD: This is for Colonel Saenger. You talked about the
self-identification requirement for ground operators. You spoke about
that you had a manual, and you said that they only require it for ground
operators, that they notify if they have a change in their physical
condition.

How is that requirement enforced? Is it \-- what happens to an operator
if they do self-identify or what happens if they fail to self-identify?

COLONEL SAENGER: We don\'t have a database on that, so the data\'s not
being collected, but I can tell you that if somebody was involved in a
ground mishap, and they had been taking a medication that impaired them
or if they had a physical condition that impaired their ability to drive
or their judgment, and they had not identified that to their supervisor,
then you could take UCMJ legal action against them, but I have no data
on whether numbers have been done or anything.

MS. HEAD: Do you know if they\'re given any guidance for what it means
to have a change in physical condition? Are they given any guidance as
to what medications may \-- if they\'re taking Claritin or something.

COLONEL SAENGER: Not that I know of, again because we don\'t have a
systematic education program for ground vehicle operators.

CAPTAIN FULTON: One thing that I will mention is maybe \-- I\'m not sure
that this is unique to the military, but one thing, most military
doctors really get ingrained, and if they see a patient in the clinic,
one of the first questions that they ask them before they leave that
clinic is what do you do? What is your job?

Because it\'s so imperative that we understand what that job that
they\'re doing because that really affects a lot of times the type of
medication that we choose to put them on or whether we send them back to
limited duty or whether we send them back to full duty.

Because certainly, I think that the thing that scares me most is when
civilian providers see our military folks, and those civilian providers
don\'t think to ask the question of what do you do, what is your job,
because they\'ll send those people back on medications that I as a
military physician wouldn\'t send that person back to do that particular
job.

COLONEL SAENGER: Same with the Air Force.

DR. GALSON: Okay. Any other questions? Yes?

CAPTAIN POPIEL: Colonel Saenger, Captain Popiel, Randy Popiel, Allied
Pilots. Just a couple quick questions, more of a clarification.

Are all the drug and alcohol tests done in the military, are they done
post-accident or do you have a random screen?

COLONEL SAENGER: We have random drug testing in the military, also.

CAPTAIN POPIEL: In regards to the flight surgeon and his authorization
to prescribe medications to your crew members, do they generally \-- do
your flight surgeons generally stay within the prescribed list that the
Armed Services provides to them or will they vary? Will they make the
initiative and approve something other than what\'s on that list?

COLONEL SAENGER: They\'ll generally stay within the list, and if an
approved medication doesn\'t work, and they have to put them on a
medication that\'s not on the approved list, then they would have to
ground the flyer and request a waiver.

CAPTAIN POPIEL: Are any forms of antidepressants allowable and currently
approved?

COLONEL SAENGER: No, not for the Air Force.

CAPTAIN FULTON: Not for the Navy.

CAPTAIN POPIEL: Are any sleep medications approved for use by crew
members on required rest periods?

COLONEL SAENGER: Yes. Yes, we do. We have ground use of Senota, Ambien,
and sorry, I\'m blocking, but one more. We do have three. There are
three sedative hypnotics that are allowed for ground use during crew
rest for the air crew.

CAPTAIN POPIEL: Is there a clearing period after the crew member has
taken the medication?

COLONEL SAENGER: There is a bottle-to-throttle time for each. For
Senota, it\'s four hours. For Ambien, it\'s eight, and Restoril, it\'s
12.

CAPTAIN FULTON: And it\'s the same \-- the Navy \-- we call them
performance maintenance drugs, and it\'s Restoril and Ambien are the
ones we use, and there is a period after which they can\'t fly.

COLONEL SAENGER: We call those operational drugs, too, instead of
therapeutic drugs.

CAPTAIN POPIEL: So, your time for your crew member to operate the
equipment would be probably shorter than what the FAA would allow? Is
there a general rule on the clearing drug would be twice the dosage
time?

COLONEL SAENGER: We base it on roughly twice the half-life of the
medication. That was a very recent change. We just changed that last
month for the Air Force. It had been 12 hours flat before.

CAPTAIN FULTON: Yes, and I\'m not sure what the times are, what the
absolute times are after they\'ve been taking those medications. I think
it\'s six to eight hours.

CAPTAIN POPIEL: Thank you.

DR. GALSON: Great. Transport Industry, do you have any questions?

DR. FAULKNER: Yes. Tom Faulkner from the Air Transport Association, and
also I\'m a flight surgeon in the Navy Reserves. So, I thank you, first
of all, because in the military, as I was trained, you spend at least
half your time in the squadron spaces getting to know your pilots, and
the pilots had no choice but to see you, versus when they get out in the
civilian world, let freedom ring, and the old adage is the pilot\'s
physician and their aviation medical examiner will never meet.

So, it\'s kind of \-- when we talk about a list and things like that, it
also goes into the culture in the military versus out there in the
civilian world. It may not be quite the right thing to chase with a list
for the civilian population.

Can either one of you comment on your service\'s stance on supplements,
and why you have that stance on supplements?

COLONEL SAENGER: For the Air Force, we have specifically prohibited
ephedra compounds in air crew and special duty personnel. Regarding Air
Forcewide, I know that there\'s a DoD Tri-Service Working Group with FDA
and CDC and perhaps some of you are on that, also, that is looking at
the herbal supplement issue, but there\'s not been a DoDwide directive
yet, and there\'s not been an Air Forcewide directive on nutritional and
herbal supplements for all members.

CAPTAIN FULTON: I\'ve just been looking at a string of e-mail on this,
and that\'s the \-- you know, and there\'s a lot of questions coming up
as to why not, and I guess that, you know, earlier, Arleen mentioned,
you know, I \-- the Navy stance still is, and we stick by our stance, is
that we do not allow use, unless it\'s \-- they\'ve talked to the flight
surgeon about it.

The flight surgeon is aware that that specific \-- that particular
individual is on a particular medication and is monitoring that
medication extremely closely. Certainly there\'s certain drugs, like
anabolic steroids and those things, you know, that are not going to be
approved, but again it has to be monitored by a flight surgeon if to be
used at all.

COLONEL SAENGER: That\'s really the same for the Air Force. We do have a
little trifold information pamphlet that we have available for the docs.
We tried not to take a \-- the names have changed so often of those
compounds, that to put a name \-- a list of names against it, we put it
out by those that have been generally, not to use this phrase
deliberately, but generally recognized as safe, and a list of those that
we know that there may be problems with in terms of performance and
safety issues and provide that guidance to the flight surgeons for them
to use when they\'re talking to their flyers and folks about the use of
supplements, and, of course, we\'re supposed to ask that question with
every single patient encounter, not just what medications they\'re
taking but what supplements and herbal and nutritional supplements
they\'re taking.

DR. GALSON: Okay. I think we want to move on, looking at the time here.

The Consumer Healthcare Products Industry?

DR. SOLLER: Bill Soller, CHPA. We have no questions.

DR. GALSON: Okay. Advocacy Table?

MS. TARNEY: We have no questions.

DR. GALSON: Professionals, the sleep people?

MR. DROBNICH: Just one quick question to clarify. Darrel Drobnich,
National Sleep Foundation.

As your guidelines stand now, your rules and regulations don\'t apply to
the flight deck crew or support personnel, maintenance and so forth?

CAPTAIN FULTON: Well, I\'m not going to say that they don\'t apply
because they really do apply. Our flight deck personnel are \-- the
problem is, is that \-- the main problem with that is we don\'t have as
tight control over the flight crew with flight surgeons as we would like
to have, okay, and we\'re getting tighter control over them with flight
surgeons now.

As a matter of fact, we just went out with a message, Navy message again
stating that a flight surgeon has to review flight deck screens that are
done on anybody that works up on the flight deck, and that if an
individual is put on \-- that works on the flight deck is put on
medications, it has to be reviewed by a flight surgeon to determine
whether that individual should be working up on the flight deck with
that particular medication.

MR. DROBNICH: So, \--

CAPTAIN FULTON: So, we are trying to tighten those standards.

MR. DROBNICH: So, a mechanic or a flight deck personnel would have to
get approval before they can be put on a medication to continue work on
the flight deck?

CAPTAIN FULTON: We would just like the flight surgeon to evaluate the
medication he\'s on to determine it\'s okay for him to work up there in
that position.

MR. DROBNICH: So, it\'s not the same waiver process as the pilot would
have to go through?

CAPTAIN FULTON: No. It\'s a different \-- it\'s not as stringent a
process as we do with the pilots.

MR. DROBNICH: Okay. And my second quick question is actually following
up on what Dr. Andreason mentioned about certain drugs, like
hypertension drugs, that might cause insomnia or have nightmare problems
with that, that might impair performance the next day.

How is that handled by the military? Drugs that \-- like hypertension
\-- I would imagine \-- is that an approved drug?

COLONEL SAENGER: We have multiple anti-hypertensives that are approved.
Generally, what we do is we require a mandatory grounding period before
you ask for the waiver, and it ranges anywhere from a week to four
weeks, and it\'s precisely to address those issues that just one or two
doses might not tell you.

MR. DROBNICH: And I guess that would be followed up with interviews with
the patient, to say are you having any sleep problems associated with
this drug?

COLONEL SAENGER: Exactly. Any of the aeromedically-significant side
effects.

CAPTAIN FULTON: When a \-- and I know this works the same in the Navy
and the Air Force. When an individual\'s put \-- is grounded, he has to
be put back up by a flight surgeon and that involves a face-to-face with
the flight surgeon in order to be able to be put back on a flight
status, and specifically addressing (1) is the condition that he was
grounded for and (2) if it were medications he was put on, how are you
doing with those specific medications? If you\'re doing okay with it, we
can let you go ahead and continue flying.

MR. DROBNICH: Thank you.

DR. GALSON: Okay. Government Table?

MR. CLARKE: I just have a couple questions, and it\'s by way of
education for my benefit more than anything else.

How many folks typically does a flight surgeon have oversight of? 10s?
20s? 100s?

COLONEL SAENGER: A typical flight surgeon at a clinic or a hospital
would enroll up to 750 and that includes the active duty member,
plus/minus family members. Some places have more family member
involvement than others. So, it\'s dozens and dozens.

MR. CLARKE: And, I mean, in terms of aviators, people who are in
aircraft either as pilots, co-pilots, aviators, what have you, anybody
that\'s in a flight status, how many of those kind of people do they
have oversight of?

The reason I\'m asking is, you were mentioning that they have intimate
knowledge of these people. So, I assume it\'s a relatively small number?

COLONEL SAENGER: It\'s a fairly small number, and it depends on the
squadron, is it a transport squadron or is it a fighter squadron, as to
how many pilots and other air crew members will actually be in that
squadron, but generally speaking, each aviation squadron in the Air
Force has a flight surgeon that is their doc.

MR. CLARKE: And so, how many flyers typically are in a squadron or how
many air crew are in a squadron?

COLONEL SAENGER: A hundred or 200 or, you know, it varies. You might
actually have two squadrons that you care for, depending on how short
the base is.

MR. CLARKE: So, they can have intimate knowledge of each one of those
individuals?

COLONEL SAENGER: Yes. We\'ve got a very defined population that we know
very well.

MR. CLARKE: In the event that a flyer or an air crew member for whatever
reason has to take one of these drugs that are not on the list, does
that automatically disqualify them from flying?

COLONEL SAENGER: It does.

MR. CLARKE: So, when they go see the flight surgeon, what happens then?
I mean, is there any conditions under which the flight surgeon can allow
that person to fly?

COLONEL SAENGER: If it\'s a sedating medication or \--

MR. CLARKE: Any medication.

COLONEL SAENGER: Well, if it\'s on the list that the flight surgeon may
allow them to fly as long as \--

MR. CLARKE: No, no. No, no. You have a list that you\'ve approved.

COLONEL SAENGER: Yes.

MR. CLARKE: So, everything else is not \--

COLONEL SAENGER: We\'re dealing off the list?

MR. CLARKE: Yes, everything is off the list.

COLONEL SAENGER: They would have to be grounded while they were on the
medication, and if it was for a temporary condition, as soon as they are
finished with the medication, and the condition has resolved, and they
see the flight surgeon again, and they get \--

MR. CLARKE: Is that \--

COLONEL SAENGER: \-- returned \--

MR. CLARKE: \-- for any member of the air crew?

COLONEL SAENGER: Yes, it is.

MR. CLARKE: The front to the back of the plane?

COLONEL SAENGER: Yes, it is. If they\'re an air crew member or special
duty personnel, also. So, that includes people who jump out of
airplanes, combat controllers, air traffic controllers.

MR. CLARKE: And there\'s no differentiation by type of aircraft or type
of operation or any of that kind of thing?

COLONEL SAENGER: No. We do have some differentiation, though, in terms
of \-- sometimes we will waiver a medication for use only in
non-high-performance aircraft. We won\'t put them in single-seat
fighters with it.

MR. CLARKE: All right. Well, that was my next question. Is this concern
based primarily on the nature of the environment in which these people
are operating?

COLONEL SAENGER: Yes, it is.

MR. CLARKE: In other words, it\'s a relatively very severe \--

COLONEL SAENGER: It\'s an operational risk management process that we go
through, yes.

MR. CLARKE: Does that logic then follow over why you don\'t apply the
same thing to your ground crews, that the operational environment
doesn\'t put the person in as much risk?

COLONEL SAENGER: Actually, no. I think it\'s simply been neglected.
It\'s an emerging concern as expressed for the military as well as for
yo\'all.

MR. CLARKE: Okay. Thank you.

CAPTAIN FULTON: If I could make just one other comment? Excuse me. Real
quickly.

DR. GALSON: Certainly.

CAPTAIN FULTON: It\'s background. You know, as I think Arleen says, it
is something that\'s emerging, you know. We\'re taking more of an
interest in the ground crew. I mean, we do have in place \-- there\'s a
DoD instruction that people that operate heavy machinery or they operate
have to go through a screening. You have to go through a screening
process by a physician before they\'re allowed to operate that
particular machinery.

So, in that respect \-- and they are educated at that point, in that
point on the visit, about medications and about the importance of
letting someone know that they\'re on those particular medications as
part of that screening process, but then it\'s the follow-on with the
ground crew that we really don\'t have down well.

MR. CLARKE: I guess from an operational point of view, does this have
any limiting effects on your ability to perform your missions? I mean,
at any one period of time, let\'s take an aircraft carrier, where people
are in close confined spaces. You get the flu or something running
through the place.

What does that do to your operational capability?

CAPTAIN FULTON: If people have the flu, they\'re grounded until they\'re
over the flu.

MR. CLARKE: Do you get large numbers of folks on the ship having the
flu?

CAPTAIN FULTON: Well, that\'s one of the things that we have to deal
with on a day-to-day basis, you know. An operational tempo is obviously
going to influence some decisions that are made out there by the
commander and by the flight surgeon, but at least we know that in that
situation, whatever is done, people are being monitored.

MR. CLARKE: So, there is some latitude?

CAPTAIN FULTON: Well, it\'s not a whole lot, but operational commitments
sometimes requires it. I mean, before, we never considered using the
performance-enhancing drugs, the performance maintenance drugs, okay,
but understanding that where there\'s a high operational tempo, there
may be a requirement to use those particular medications in order that
those people get the rest that they need so that they can continue doing
their job. So, there is latitude in areas such as that.

MR. CLARKE: This population that you\'re dealing with, though, is for
the most part young and very physically robust, though, are they not?

CAPTAIN FULTON: That\'s correct.

MR. CLARKE: Thank you.

DR. GALSON: Okay. I think what we\'ll do is move to the Public Questions
now. If we have a little bit of time, we\'ll circle back to the
Technical Panel.

DR. ELLINGSTAD: These will probably be brief because I believe that
they\'ve been answered, but we have two questions, a statement and a
comment, and the questions first.

Besides prescription and over-the-counter drugs, what is the view of the
Air Force and the Navy concerning herbal use, and how is it being
evaluated? I believe you spoke to that.

Is there anything you\'d like to add?

(No response)

DR. ELLINGSTAD: Okay. The other question, specifically to Colonel
Saenger, was, what sedative drugs are allowed for aviators for
operational use, and how is their use governed?

I think you also indicated, and my understanding is, that by operational
use, this would not be in the performance of the air crew duties.

COLONEL SAENGER: It\'s on the ground, yes.

DR. ELLINGSTAD: Okay. The statement is that the Air Force Research Lab
at Brooks Air Force Base is beginning to field a drug assessment
protocol using the F-PASS Performance Assessment Tool.

Would you like to comment on that?

COLONEL SAENGER: I\'m not familiar with that one. I can\'t comment.

DR. ELLINGSTAD: Okay. Well, we can arrange a get-together afterwards,
and the other comment is that a Joint Working Group, Army, Navy and Air
Force, investigated terfenadine, the first non-sedating antihistamine.
The process involved self-report, mood symptoms testing, physiological
testing and performance testing.

Is there any comment that you would wish to make about that?

COLONEL SAENGER: I\'m not familiar with that report either.

DR. ELLINGSTAD: Okay. What we will ask is, with respect to both of these
things, if the submitters of these questions can provide that
information for us, we\'d appreciate it.

DR. GALSON: And we\'ll put it in the docket, and it\'ll be available for
anybody else who wants it.

We have a few more minutes to circle back to the Technical Panel to see
whether there are any remaining questions for these two witnesses.

(No response)

DR. GALSON: Okay.

DR. ANDREASON: I just had one.

DR. GALSON: Okay.

DR. ANDREASON: I just wanted to confirm that you said that SSRIs were on
the not-approved list, is that correct?

COLONEL SAENGER: That\'s correct.

DR. ANDREASON: Or not on the approved list?

COLONEL SAENGER: They\'re not on the approved list.

DR. ANDREASON: Correct. Okay.

DR. GARBER: And just one follow-up question. I heard from at least one
of you that medication, other kinds of prescription medications have not
been found causal in military \-- I think it was Air Force major
mishaps.

I\'m assuming that does not mean they were not found in any mishaps;
they were just not identified as being causal to the mishap, is that
correct?

COLONEL SAENGER: That\'s correct, and the data I asked for was causal.

DR. GARBER: Okay. And having been an Air Force flight surgeon myself and
having investigated a number of accidents, my experience was that in
many cases, the condition of the aircraft and its occupant did not
permit an appropriate specimen to be evaluated to determine perhaps time
of use of a medication, and therefore such a determination could not in
fact be made.

Is that your experience, and is that the case with many of the aviation
accidents in the military?

COLONEL SAENGER: I can\'t address what percent of aircraft mishaps
involved such total destruction that we can\'t even collect the sample,
but that does happen, especially \--

DR. GARBER: Not just collecting a sample but collecting a sample which
would give you information as to determine cause; that is to say, it may
not be all that useful to have a liver sample to show us whether an
individual may have been impaired by a medication.

COLONEL SAENGER: Yes, that does happen, but I don\'t know the rate.

DR. GALSON: Okay. We\'re very appreciative of how busy you are at the
Defense Department, and we\'re very thankful that you could come by
today and help us out.

With that, we\'ll close a few minutes early. I want to just \-- just a
reminder. We\'re going to start bright and early tomorrow, 8:00, same
place, and we look forward to your continued participation.

Thanks.

(Whereupon, the meeting was adjourned, to reconvene tomorrow morning,
Thursday, November 15th, 2001, at 8:00 a.m.)