FOOD AND DRUG ADMINISTRATION

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CENTER FOR DRUG EVALUATION AND RESEARCH

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NONPRESCRIPTION DRUGS ADVISORY COMMITTEE

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Meeting on

Safety Issues of Phenylpropanolamine (PPA)

in Over-the-Counter Drug Products

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Thursday

October 19, 2000

The meeting was held at 8:00 a.m. at the Holiday Inn Gaithersburg, Two
Montgomery Village Avenue, Gaithersburg, Maryland 20879, Dr. Eric P.
Brass, Chairman, presiding.

[PRESENT]{.underline}:

Eric P. Brass, M.D., Ph.D., Chairman

George A. Blewitt, M.D., Industry Liaison (non-voting)

Louis R. Cantilena, Jr., M.D., Ph.D., Member

Susan Cohen, Consumer Representative (voting)

Ralph D\'Agostino, Ph.D., Consultant (voting)

Janet Daling, Consultant (voting)

Janet Elashoff, Consultant (voting)

Edwin E. Gilliam, Ph.D., Member

Sio Gilman, M.D., Consultant (voting)

Julie A. Johnson, Pharm.D., Member

Steven Kittner, M.D., MPH, Consultant (non-voting)

Y.W. Francis Lam, Pharm.D., Member

Richard A. Neill, M.D., Member

Hari Cheryl Sachs, M.D., Member

Donald L. Uden, Pharm.D., Member

Steven Warach, M.D., Ph.D., Consultant (non-voting)

Henry W. Williams, Jr., M.D., Member

Sandra Titus, Ph.D., Executive Secretary

[Hemorrhagic Stroke Project Investigation]{.underline}

Walter N. Kernan, M.D.

Lawrence M. Brass, M.D.

Joseph P. Broderick, M.D.

Ralph I. Horwitz, M.D.

Lewis B. Morgenstern, M.D.

Catherine M. Viscoli, M.D.

Janet Lee Wilterdink, M.D.

[Consumer Healthcare Products Association Panel]{.underline}

R. William Soller, Ph.D.

George L. Blackburn, M.D., Ph.D.

Philip B. Gorelick, M.D., M.P.H., FACP

Charles H. Hennekens, M.D., Dr.P.H.

Robert Hirsch, Ph.D.

Brian S. Hoffman, M.D.

Philip D. Walson, M.D.

Noel S. Weiss, M.D., Dr.P.H.

[FDA Representatives]{.underline}

Robert DeLap, M.D., DDE

Charles J. Ganley, M.D., DOTCDP

David Graham, M.D., M.P.H., OPDRA

Linda Katz, M.D.

Russell Katz, M.D., Neuropharm Division

Lois La Grenade, M.D., M.P.H., OPDRA

Robert O\'Neill, Ph.D.

Robert Sherman, M.D., DOTCDP

Yi Tsong, Ph.D., OPDRA

[Public Speakers]{.underline}

David E. Schteingart, M.D., Chattem

Brian Strom, M.D., M.P.H., Whitehall Corporation

Sidney Wolfe, M.D., Public Citizens Health

Research Group

A-G-E-N-D-A

page no.

Call to Order, Introductions

Eric Brass, M.D., Chair 5

Conflict of Interest Statement

Sandra Titus, Ph.D., Executive Secretary

NDAC 7

Open Public hearing

Brian Strom, M.D., M.P.H.

University of Pennsylvania

representing Whitehall Corporation 10

David E. Schteingart, M.D.

University of Michigan

representing Chattem 18

Sidney Wolfe, M.D., Director

Public Citizen\'s Health Research Group 22

Regulatory History of

OTC Phenylpropanolamine Hydrochloride

Robert L. Sherman, DOTCDP 32

Final Report of the Yale Hemorrhagic

Stroke Project

Walter Kernan, M.D., School of Medicine, Yale 41

Questions from the Committee to

Yale Hemorrhagic Stroke Project 65

Comments on the Yale Study by Consumer

Healthcare Products Association

R. William Soller, Ph.D., Senior Vice

President and Director of Science and

Technology, CHPA 92

Noel S. Weiss, M.D., Dr.P.H.

University of Washington 96

Dr. Lewis Kuller, M.D.

University of Pittsburgh 101

Robert Wallace, M.D.

University of Iowa 107

I-N-D-E-X (con\'t.)

page no.

Dr. Philip Gorelick

Chicago 111

Dr. Charles Hennekens 117

Questions to the Consumer Healthcare

Products Association 126

FDA Presentations

Epidemiological Consult on the Yale Study and

Recommendations to OTC Division

Lois La Grenade, M.D., M.P.H., Office of

Postmarketing Drug Risk Assessment 144

Questions 165

Summary of Issues

Charles Ganley, M.D.

Director, DOTCDP 177

Discussion by the Committee 181

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

(8:03 a.m.)

CHAIRMAN BRASS: Good morning. I\'m Eric Brass from Harbor - UCLA Medical
Center, and I\'d like to welcome you all to this meeting of the
Nonprescription Drugs Advisory Committee to discuss safety issues of
Phenylpropanolamine in Over-the-Counter Drug Products.

I\'d like to begin by going around the table allowing people to
introduce themselves. We have a number of consultants with us today.
I\'d like to remind members of the committee and our consultants to
please always use the microphone when raising issues. Please be sure to
press the on/off button prior to talking, and I strongly advise if you
do not want your side comments recorded to turn off the microphone when
you are done speaking. Perhaps we could begin with Doctor Warach.

DOCTOR WARACH: Steven Warach from NIH.

DOCTOR BLEWITT: George Blewitt, industry representative for NDAC.

DOCTOR KITTNER: Steven Kittner from University of Maryland. I\'m a
neurologist/epidemiologist.

DOCTOR GILMAN: Sid Gilman, University of Michigan. I\'m a neurologist.

DOCTOR UDEN: Don Uden from the University of Minnesota, member of NDAC.

DOCTOR GILLIAM: Eddie Gilliam, family nurse practitioner from Tucson,
Arizona. Member of the NDAC Committee.

DOCTOR ELASHOFF: Janet Elashoff, biostatistics, UCLA and Cedars-Sinai.

DOCTOR NEILL: Richard Neill. I\'m a family physician from the University
of Pennsylvania, member of NDAC.

DOCTOR DALING: Janet Daling, University of Washington and Fred
Hutchinson Cancer Research Center, epidemiologist.

DOCTOR WILLIAMS: Henry Williams from Howard University, a member of
NDAC.

DOCTOR SACHS: Hari Sachs, pediatrician, member of NDAC.

DOCTOR TITUS: Sandy Titus, the Executive Secretary for NDAC.

DOCTOR LAM: Francis Lam from University of Texas Health Science Center
at San Antonio. I\'m a member of NDAC.

MS. COHEN: Susan Cohen and I\'m the consumer representative.

DOCTOR JOHNSON: Julie Johnson from University of Florida and a member of
NDAC.

DOCTOR D\'AGOSTINO: Ralph D\'Agostino from Boston University and the
Framingham Study, a biostatistician/epidemiologist.

DOCTOR CANTILENA: Yes. Hi. I\'m Lou Cantilena from the Uniformed
Services University, a clinical pharmacologist.

DOCTOR SHERMAN: Bob Sherman, FDA\'s Division of OTC Drug Products.

DOCTOR LA GRENADE: Lois La Grenade, epidemiologist, Office of
Postmarketing Drug Risk Assessment, FDA.

DOCTOR KATZ: Russ Katz, FDA Neuropharm Division.

DOCTOR GANLEY: Charlie Ganley, Director of Over-the-Counter Drugs.

DOCTOR DELAP: Bob Delap, Office of Drug Evaluation, FDA.

CHAIRMAN BRASS: Thank you very much.

I\'ll now turn the floor over to Doctor Titus for the conflict of
interest statements.

DOCTOR TITUS: The following announcement addresses the issue of conflict
of interest with regard to this meeting and is made part of the record
to preclude even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the committee participants, it has been determined
that all interest in firms regulated by the Center for Drug Evaluation
and Research which have been reported by the participants present no
potential for an appearance of a conflict of interest at this meeting
with the following exceptions.

Since this issue to be discussed by the committee at this meeting will
not have a unique impact on any particular firm or product but rather
may have wide-spread implications with respect to an entire class of
products, in accordance with 18 USC 208(b), each participant has been
granted a waiver which permits them to participate in today\'s
discussion. A copy of these waiver statements may be obtained by
submitting a written request to the agency\'s Freedom of Information
Office, Room 12A30 of the Parklawn Building.

We would like to note for the record that Doctor George Blewitt is the
non-voting industry representative and is on the committee to represent
industry\'s interest. As such, he has not been screened for any conflict
of interest.

With respect to FDA\'s invited guests, FDA would like to disclose that
Doctors Samuel Suissa, J.P. Mohr, Janet Wilterdink, Catherine Viscoli,
Lewey Morgenstern, and Ms. Melinda Cox were part of the Yale
investigators which includes two members of the Data Monitoring Board.
Data from the results of the Epidemiological Study designed to assess
the risks of hemorrhagic stroke associated with the use of
phenylpropanolamine will be part of today\'s discussion. We believe this
information should be made public to allow the participants to
objectively evaluate their comments.

In addition, Doctors Wilterdink, Morgenstern, Suissa and Ms. Cox also
reported that they have been involved in studies concerning
phenylpropanolamine for a variety of pharmaceutical firms.

Finally, Doctor Steven Kittner would like to disclose for the record
that he has been involved in studies of phenylpropanolamine in
over-the-counter products through his prior review of case reports of
intracerebral hemorrhage for the FDA. He has also conducted a study of
ischemic stroke in young women that includes some questions on
phenylpropanolamine use.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.

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

CHAIRMAN BRASS: Thank you very much.

We will move on to the open public hearing. I would ask that each
presenter during the session come forward to the podium for their
presentation, identify themselves, their affiliation and any sponsorship
associated with their appearance today. Most importantly, if they could
each be sure to stay to the 10 minute absolute time limit.

Our first presenter in the open public hearing will be Doctor Brian
Strom.

DOCTOR STROM: I\'m Brian Strom from the University of Pennsylvania
School of Medicine. Suffice it to say, University of Pennsylvania likes
titles, but I\'m a general internist/clinical pharmacologist and
epidemiologist. I\'m head of epidemiology and biostatistics at the
University of Pennsylvania, and what I do mostly for my life is study
the effects of drugs.

I am also in this role a consultant to Whitehall-Robbins Healthcare, who
asked me to provide an independent critique, independent of everything
else that you\'ve heard today and independent of them, of my sense and
reactions to the Yale Hemorrhagic Stroke Project.

The Yale Hemorrhagic Stroke Project was initiated primarily due to a
series of case reports about hemorrhagic strokes. I think this was an
extremely appropriate action, given the severe limitations and
spontaneous reporting that we all know about in their ability to
evaluate cause. Until the Yale Study was done, the available data were
these spontaneous reports and other epidemiological studies that were
negative studies already published but were not felt to be absolutely
convincing.

This was a huge, ambitious study. It was thoughtfully designed.
Unfortunately, however, as finally done, it generated some methodologic
issues and problems which is presumably why we\'re here today discussing
it. What I\'ll briefly do is discuss it in the conventional way
epidemiologists approach such evaluations, talking about chance, talking
about confounding and talking about bias.

First talking about chance. This study started out with power that was
marginal statistical power. It was designed to detect an OR of five with
a one-tail statistical test. The result means that there are very small
numbers of exposed cases and exposed controls and very fragile results,
and I\'ll bring this out more specifically in a few minutes.

As stated very clearly by the authors, there were three co-equal aims or
five, depending on how you count them, seeing this as two of the aims
had sub-aims. One could argue, therefore, because of the multiple
testing, that the true alpha shouldn\'t have been .05 but should be
.0166 or .01 if you consider this five equal aims.

The inconsistent results that you see in the sub-groups by gender and by
indication and the inconsistent results between PPA and other
sympathomen medics suggest chance as an explanation as well. And
finally, the quote/unquote \"dose response relationship\" was in fact
never tested statistically. That is, whether or not the higher dose
users were at increased risk over the lower dose users and, looking at
the data, almost surely that comparison is not statistically
significant.

Let me show you the five key findings very specifically. This is the
first of three co-equal aims looking at all PPA. As you can see, the 27
exposed cases, 33 exposed controls, and no statistical difference.

Moving on to the second co-equal aim. In fact, these are two different
aims. Looking at the results by indication within the cough/cold
preparation, again even by conventional uncorrected criteria, there was
no statistically significant difference with 22 and 32 exposed
individuals.

Moving on to appetite suppressants, however, it is now statistically
significant, borderline significant if you use the criteria of .0166 or
not significant if you use the criteria of .01, and it is totally based
on six exposed cases and one exposed control. And this is what I meant
by a fragile finding, that essentially the entire results of the study
rest on these seven individuals.

The third co-equal aim which again was really two aims were results in
women. Part of that was all PPA first use. This is a borderline
statistically significant result using conventional criteria. It is not
statistically significant if you correct for multiple testing and is
based on seven exposed cases and four exposed controls.

And the last finding which was statistically significant was appetite
suppressants in women and, again, it\'s based on six exposed cases and
one exposed control. So the numbers here are very small and very fragile
which is important to the rest of what I\'m going to be describing.

Second general category of what epidemiologists worry about are
confounding variables, variables other than the presumed cause and the
presumed effect, which can be related to the cause and effect and,
therefore, can create false associations or mask real ones.

In this study, the confounding variables were controlled using
conditional logistic aggression, but the sample set, which is certainly
an appropriate approach to use in a match case control study, but the
sample size here was dramatically small for that level of sophisticated
mathematical modeling. A better approach would have been to use
stratification and/or exclusion although even there it could be
problematic with only one exposed control to try to do stratifications.
Again, the numbers are just too small.

Moving on to biases. One of the key biases epidemiologists worry about
is mis-classification bias that is confusing cases as controls or
confusing controls as cases. I am not a neurologist, and this is better
addressed to our neurologic colleagues. But my neurologic colleagues
questioned whether or not it was valid to combine subarachnoid
hemorrhage and primary intracerebral hemorrhage given they are quite
possibly two different diseases.

Another bias that epidemiologists worry a lot about is information bias.
In this case, it\'s the biased information about drug exposures. Getting
valid drug histories is always very difficult to collect
retrospectively. It is particularly difficult to collect, if you think
about it, from stroke patients. People who\'ve had strokes are going to
have a hard time recalling what drugs they took and telling you about it
resulting in unequal recall in the two groups.

In this study, great effort has been taken, and the authors are really
to be congratulated, to collect good exposure data, but their validation
procedure assures specificity, not sensitivity. In other words, you know
that because of the great care that they took, you know that the people
who said they were exposed really were exposed, but you don\'t know how
many exposures were missed because people didn\'t remember it and very
few missed exposures in the control group would have totally massed this
association, eliminated this association, given as it is they had only
one exposed control. Increasing that to two or three would have
eliminated the results.

Moving on to selection bias. The selection bias is any quality in the
way the two groups were selected into the study in a way that places
them at unequal risk of exposure. The ideal case control study should be
population-based. You define a population, draw all cases from that
population, and draw controls as a random sample from the population.

In this case, the cases were not representative of an entire population,
however, since they were from isolated hospitals, many of them tertiary
care hospitals, not from a defined population but rather individual
hospitals in a number of places in the country. This is unlike the
control group which did attempt to get a random sample of the
population.

The completeness of case ascertainment was never defined \-- never
identified. And finally and very importantly, only 41 percent of those
cases that were identified were enrolled in the study, and though most
of this is an inherent problem of studying stroke patients and is not a
criticism at all of what the investigators did, it leads to an enormous
room for bias in a study that is inherently fragile in its initial
findings to begin with.

Finally, the controls. No information is given on the process and
success of the random digit dialing process.

So in concussions, this is an ambitious and well-described study. It has
a major risk of information bias and selection bias, however. The study
was under-powered from its initiation leading to fragile results,
subject to change, therefore, with even small errors, and given the
nature of the disease that is being studied and the situation, this is
subject to, in fact, large errors. At best, the study suggests the
possibility of an association between the use of this common drug and
the very uncommon outcome. In fact, documenting how uncommon the outcome
and exposure is by simply the very small number of exposed cases they
could find over many years in a wide geographic area.

The study certainly doesn\'t prove this association so, to me, this
association remains uncertain. Thank you.

CHAIRMAN BRASS: Thank you.

Our next presenter will be Doctor David Schteingart.

DOCTOR SCHTEINGART: Good morning, and I\'d like to thank the committee
for the opportunity to address the committee on this important issue.

My name is David Schteingart. I\'m a professor of internal medicine at
the University of Michigan in the Division of Endocrinology and
Metabolism. I\'m board certified in internal medicine and endocrinology
and am a fellow of the American College of Physicians. I\'m the Director
of the Obesity Rehabilitation Program at the University of Michigan.
I\'m also the Director of the University of Michigan Training Program
and Clinical Research. I\'m appearing here as a consultant for Chattem.
I\'ve been studying and treating obesity for at least 35 years.

The focus of my comments will deal mainly with the role of PPA in the
treatment of obesity and evidence of efficacy based on studies that we
have conducted sponsored by Thompson Medical. It is accepted by the
medical community and confirmed by consensus development conferences
that overweight and obesity are a major medical problem because of their
co-morbidities and associated risk for increased mortality. These major
co-morbidities include type 2 diabetes, dyslipidemia, hypertension,
atherosclerotic cardiovascular disease and stroke. Excessive weight also
causes osteoarthritis, obstructive sleep apnea, and alveolar
hypoventilation, which are common ailments in people with severe
obesity. There are also significant psychosocial and economic
consequences of being obese.

Periodic national health and examination surveys have shown a
progressive increase in the prevalence of obesity in the United States
over the past decade in spite of efforts of public education and the
availability of foods with reduced fat content and clear nutrient
composition labeling. Currently, 22.5 percent of the population is obese
and up to 24 percent of American children are overweight.

Obesity afflicts in greater preponderance certain segments of the
population such as African-American, Hispanic and Native American
citizens. These individuals also lag in health care access and proper
nutrition counseling. Obesity also has a major impact on the cost of
health care in this country. It was estimated that in 1995 the cost of
treatment of obesity amounted to approximately \$100 billion per year.
To make things worse, most people seeking treatment of obesity were not
covered by their health insurance for this condition and had to pay for
this treatment out-of-pocket.

Treatment of obesity results in major health improvement and reversal of
its co-morbidities with discontinuation of treatment such as insulin
therapy and anti-hypertensive drugs. This improvement may also lead to a
decrease in mortality risk. Treatment of obesity involves medical or
surgical approaches. The mainstay of medical treatment includes reduced
calorie diets, exercise, behavior therapy, and medications that reduce
appetite or decrease food absorption. Drug treatment of obesity by
currently approved prescription drugs is expensive and, again, not
covered by most health insurance. Phenylpropanolamine is the only
permitted over-the-counter non-prescription appetite suppressant. Its
cost is much lower than that of most prescription drugs. PPA has been
recommended for short-term treatment of obesity based on studies on the
efficacy and safety of the drug published periodically over the past two
decades.

In 11 of 16 double blind placebo controlled studies employing 900
subjects, the weight loss achieved with PPA was significant greater than
placebo. Two of the most recent studies published in the early 1990s by
Greenway and by our own group confirm the efficacy of the drug for
short-term treatment of obesity and its relative safety. Our study
involved 101 subjects, 15 to 45 overweight but otherwise healthy. These
individuals were on a 1,200 calorie diet.

During the double blind placebo controlled phase, as indicated on this
transparency, subjects took placebos for two weeks and then were
randomized to placebo or PPA for six weeks. The subjects on PPA, the
left hand side column, showed a statistically significant greater weight
loss than the placebo group. Next transparency, please.

A subset of these subjects chose to continue on their medication,
placebo or PPA, for a total of 20 weeks. The difference in weight also
continued. The PPA group lost 5.1 kilograms and the placebo group 0.4
kilograms by the end of the study. No difference was observed in blood
pressure, pulse rate or subjective complaints between the two groups and
no serious adverse events were reported.

These studies concluded that PPA is an effective and safe adjunct in the
treatment of obesity. These studies, because of their design, were
considered by the FDA to be the most convincing evidence of the
effectiveness of PPA in the treatment of people with mild or moderate
obesity. The degree of weight loss achieved with PPA was comparable to
that obtained with currently approved prescription drugs.

In conclusion, obesity is a serious chronic medical disease without
effective cure. Any assessment of potential risk must take into account
the significant benefit conferred by drugs like PPA when used as an
appetite suppressant. Weight reduction improves morbidity and mortality.
The loss incidents of side effects with PPA relative to the benefits of
weight reduction should help place this issue into proper perspective.

Thank you very much.

CHAIRMAN BRASS: Thank you.

The next presentation, the open public hearing, will be by Doctor Sidney
Wolfe.

DOCTOR WOLFE: Good morning.

We do not accept any money from the pharmaceutical industry. We do not
get money from anyone who has an interest in this other than the public
who supports our organization.

In this testimony and in a petition we have filed about an hour ago with
the Food and Drug Administration, we are asking for an immediate ban of
all uses of PPA in over-the-counter products including appetite
suppressants and as a decongestant in cough and cold preparations.

We agree with the determination of FDA\'s Office of Postmarketing Drug
Risk Assessment, OPDRA, that quote \"PPA should not be generally
recognized as safe\" unquote. Since the only categories for
over-the-counter drug ingredients, which is the way over-the-counter
drugs are evaluated, are Category I, generally recognized as safe and
effective, or Category II, not generally recognized as safe and
effective, this would place it in Category II. The other category is
insufficient evidence. I think that we are way beyond that at this
point.

We also agree with the recommendation from the same part of FDA, OPDRA,
that quote \"PPA containing appetite suppressants, and separately the
same recommendation, cough/cold remedies should no longer be available
as over-the-counter products.

The background for the recent well-designed Yale Epidemiological Study
that found PPA increases the risk for hemorrhagic stroke includes a long
history of published serious adverse events including hemorrhagic
strokes attributable to PPA going back to 1979. These cases are
attributed to the drug because they usually occur shortly after
ingestion \-- the design of this study was strokes within the first
three days of PPA \-- and because of the lack of other plausible
explanations, especially in otherwise healthy younger people.

Additionally, there\'s been evidence for the specific mechanism or for a
specific mechanism by which these strokes are induced by PPA. Similar
evidence has existed for probably 30 years for the stroke-producing
properties of amphetamines, once the most common drugs used for obesity.
Both PPA and amphetamines are known to cause cerebral vasculitis, severe
inflammation of the blood vessels of the brain which, probably in
combination with the blood pressure raising effects of the drugs, can
result in cerebral or subarachnoid brain hemorrhage and strokes.

In addition to strokes, other serious adverse reactions attributed to
PPA include acute psychosis, convulsions, acute renal failure, heart
damage, and hypertension, and there\'s abundant evidence, including from
randomized control studies for hypertension in the literature. The
similarities between amphetamine, phenylpropanolamine and ephedrine I
think are well known to most of you, and the reason for putting the
structures on the chart is simply to say that these are not just
chemical accidents. There are a lot of pharmacologic properties, adverse
effects, that are shared by all of them.

Ten years ago in a review published from the Uniform Services University
for Health Sciences, Doctor Larkes Lake looked at 85 publications in
which there were 142 case reports of problems usually occurring shortly
after the initiation or use of PPA. They included 24 intracranial,
either cerebral or subarachnoid hemorrhages, eight seizures and eight
deaths, mostly due to stroke. The most common ones were acute
hypertension, headaches, and two-thirds of these reactions occurred in
women and two-thirds of them were in patients under the age of 30.

Further information about PPA and strokes comes from FDA\'s own
Spontaneous Adverse Reaction Reporting System. In an FDA memo dated
August 6, 19991, FDA Medical Officer, Doctor Heidi Jolson, reported
there had been a total of 44 cases of strokes, 35 hemorrhagic in PPA
users reported to the FDA until then. Subsequent update of that raised
the total to 51 cases of hemorrhagic strokes. Given the reporting
artifact, which is generally thought for prescription drugs to be only
one in 10 that actually occurred get reported, sometimes thought for
others such as over-the-counter to be one in 20, some think one in 100.
This means hundreds if not thousands of cases of PPA-induced hemorrhagic
stroke have occurred.

As far as the Yale study, which will make up the bulk of the discussion
today, funded by CHPA, I believe the results are quite clear,
particularly if it\'s put in the context of a large number of other case
control studies, retrospective studies. The difference between a
retrospective case control study and a randomized control trial are that
by randomizing and going forward, there really can\'t be or isn\'t any
difference between the groups that you\'re looking at. In a
retrospective study, there is and all of the precautions, including
enormous input from epidemiologists and from the FDA\'s epidemiologists,
made the design of this study as good as it can be, better than most
case control studies.

More importantly though, it\'s not clear to me why this study needed to
have been done. I think that the literature back 10 or more years ago
was clear enough. It\'s one thing to have long-term problems where the
problem occurs long after the time that the drug was started and it may
be difficult to place the cause and effect next to each other. But here,
when it occurs so shortly afterwards, the literature of case reports I
think made it very, very clear so that the context in which this study
needs to be looked at is the context of 20 plus years of case reports on
hemorrhage and other problems caused by the drug.

The methodologic criticisms which you\'ve started hearing and will hear
more of are over-shadowed by the fact that the same consultants who are
now raising these criticisms could presumably have been retained by CHPA
before it signed off on the design and details of the study before it
began. For every case control study, there are always those who find
something wrong with it because it lacks the perfection of randomized
control trials.

What is notable, however, is that when case control studies are found to
implicate a drug or device in connection with the disease, there\'s an
extraordinarily skewed representation of industry-funded critics there
to say nay or maybe not. PPA is just another example in a long history
of many serious public health hazards caused by drugs or medical devices
which were allowed to continue endangering people much longer than they
should after sufficient evidence for action was available because of
industry-funded nit-picking with the methodology of the studies, often
case control studies such as the one being discussed today.

Other examples which we\'ve been involved in where there was a delay
includes aspirin and Reye\'s syndrome where the same organization, the
predecessor of it, Non-prescription Drug Association, fought for years
to the detriment of many children who died and had brain damage from
Reye\'s syndrome to pretend that there was no relationship between
aspirin and Reye\'s syndrome. It delayed for years the labelings on
those. Hyper-absorbent tampons and toxic shock, DES and clear cell
vaginal cancer and DES daughters menopausal estrogen and uterine cancer.
Eventually, action to ban and restrict was taken in each of these
instances but much later than it should have been.

Even without any case control or other epidemiological study, most of
the time that FDA takes action to take a drug off the market, there
haven\'t been any epidemiological studies and the reason is that the
number and specificity and relationship between the drug or device and
the event is clear enough from well-documented case reports. Spontaneous
reports to the FDA are documented up to a point and as well as they
possibly can be, but when you look at the published literature on a lot
of these things, you see clear evidence whether some of the drugs that
have just come off the market in the last while, Rezilin, Durac,
Propulsid, Pozocor, Repoifloxocin, Trobafloxacin, Burke Shiley heart
valve, no epidemiologic studies before they came off the market on
safety and yet the case report sufficed.

It\'s been more than 20 years since the first alarms were raised about
the dangers of PPA and about the fact that there\'s no evidence in the
long term that diet drugs such as PPA actually help to lose and retain
weight. In 1981, a study using another weight reduction drug,
Fenfluoramine, looked at people who just got the drug, got it combined
with behavior therapy or got behavior therapy alone. The initial \-- and
you saw data like this. The early weight reduction was actually the same
in all three groups. The interesting thing was that the group that had
just behavioral therapy kept their weight down much better than the
others, and the theory was that in any long-term basis and it\'s, of
course, the long term in which weight reduction makes any sense. Short
term doesn\'t really make much difference \-- in the long term that the
use of a drug actually retarded the beneficial effects of behavior
therapy.

Long ago in 1979, [The Medical Letter]{.underline}, an independent
authoritative source of evaluation of drug therapy, wrote quote \"There
is no good evidence that phenylpropanolamine or any other drug can help
obese patients achieve long-term weight reduction.\" The 20 or so weeks
that you saw on that chart is not long-term. The only satisfactory
treatment for obesity is a life-long change in patterns of food intake
and physical activity.

Many early researchers who investigated PPA commented that the drug
should not be available over the counter. One group of researchers in
1987 stated quote \"The over-the-counter availability of PPA-containing
medications may be inappropriate and in need of revision since it does
not appear to be in keeping with current standards of public safety.\"
End quote. Since then, hundreds more American patients have suffered
stroke, psychotic episodes, heart damage, and other known adverse
effects of PPA for no documented benefit in the long term.

During the last couple of weeks, through colleagues around the world, we
conducted a very informal survey of the availability of
phenylpropanolamine over-the-counter in various countries. With the
exception of South Africa, it is not available over-the-counter for
weight reduction anywhere else. There are a few countries where it is
available for cough and cold over the counter but in more countries
it\'s available by prescription. One of the more interesting comments
that we got was from Greece where apparently recently
phenylpropanolamine has been placed under the Controlled Substance Act
in Greece.

In light of the voluminous medical literature documenting
life-threatening adverse effects of PPA such as hemorrhagic strokes and
the confirmatory evidence of this in the industry-funded epidemiological
study, it is not possible for PPA to remain in the OTC category of safe
and effective, Category I. Thus, since all this evidence mandates and
FDA\'s own OPDRA Division has concluded that it should not be generally
recognized as safe, the only choice is to remove the drug from all OTC
products. We hope this will be accomplished as quickly as possible. The
longer the delay, the larger the toll of preventible strokes and other
serious damage to the public.

Just two other comments. If you were considering today the switching of
phenylpropanolamine from prescription only to over-the-counter, I think
the answer would clearly be no, and the reasons for it would be the same
as why it should no longer be considered. Doctor Janet Wilcock, to whom
we addressed our petition an hour ago to take these drugs off the market
over-the-counter, has repeatedly said, and I fully agree with her, that
there are a number of out-moded drugs on the market. In many cases,
they\'re dangerous and that as well as the FDA\'s more common function
of reviewing the possibility of reviewing new drugs coming on the
market, it has another important public health function to get out-moded
drugs off the market. PPA is a classic example.

Thank you.

CHAIRMAN BRASS: Thank you. We\'ll now move to the regular program with
Doctor Sherman providing us a regulatory history of OTC PPA.

DOCTOR SHERMAN: Good morning. I\'m Bob Sherman with FDA\'s Division of
OTC Drug Products and the Center for Drug Evaluation and Research. I\'d
like to briefly describe the OTC drug review and provide some background
on the regulatory history of phenylpropanolamine hydrochloride or PPA.
I\'ll describe the events leading up to this Advisory Committee meeting
to discuss the results of the Yale Hemorrhagic Stroke Project and its
implications.

The OTC drug review began in 1972 as a three-phased review of the safety
and effectiveness of the active ingredients in 26 classes of OTC drugs.
The first phase of the review involved Advisory Review Panels comprised
of independent experts. The panels developed a report in which the
active ingredients were placed into one of three categories based on
data submitted to FDA. The panel reports were then published in *The
Federal Register* as an advance notice of proposed rulemaking. A public
comment period followed allowing interested persons to submit comments
and additional data.

Based on the panel\'s recommendations and any new information, the
second phase of the review is FDA\'s proposed rule published in *The
Federal Register* as a tentative final monograph. This is followed by a
second public comment period that allows for comments on the agency\'s
proposal and additional data. The stars indicate where we are in the
review of PPA. FDA has not yet published a proposed rule for PPA.

In the third phase of the review, FDA considers any additional comments
and new information and publishes a final rule or final monograph in
*The Federal Register.* The panel has placed active ingredients into one
of three categories: Category I, generally recognized as safe and
effective; Category II, not generally recognized as safe and effective;
or Category III, insufficient data to permit final classification.

Under the monograph system, ingredients placed in Categories I, II, or
III may remain on the OTC market until the publication of the final
monograph in *The Federal Register.* At the final monograph stage,
ingredients in Category II and Category III become non-monograph and
must be removed from the OTC market with only Category I ingredients
being included in the final monograph and allowed to remain on the
market. FDA has been awaiting the results of the five year Hemorrhagic
Stroke Project before publishing a proposed rule or tentative final
monograph regarding PPA.

As you know, PPA is marketed for two OTC indications: as a nasal
decongestant and as an appetite suppressant. Because these are two
separate rulemakings, PPA was reviewed for each indication by separate
Advisory Review Panels, and FDA will publish separate final rules for
each indication. PPA need not be placed in the same category for both
conditions of use.

This table shows what the panels recommended and what FDA published in
the ANPR for each rulemaking. In September 1976, FDA published the
Cough/Cold Panel\'s recommendations for nasal decongestants. These
included single PPA doses of 25 milligrams every four hours or 15
milligrams every eight hours with a total daily limit of 150 milligrams
as a Category I nasal decongestant. When the Weight Control Panel
submitted its report to FDA, this panel also recommended single PPA
doses of 25 to 50 milligrams and a timed-release dose of 150 milligrams
with a total daily limit of 150 milligrams as Category I for weight
control.

However, before the advance notice of proposed rulemaking for weight
control products was published, FDA became aware of case reports of
blood pressure elevation with higher doses of PPA than were marketed for
weight control at that time. Because of this safety concern in the ANPR,
FDA specifically requested information regarding PPA\'s effects on blood
pressure and the dissolution rates of timed-release products. FDA also
limited weight control doses to those that had been on the market since
1975, single doses of 25 to 37.5 milligrams and a timed-release dose of
75 milligrams with a total daily limit of 75 milligrams.

Because the safety issues regarding PPA were the same for both
rulemakings, PPA was deferred from the 1985 proposed rule for nasal
decongestant drug products. PPA was also deferred from the nasal
decongestant final monograph published in 1994 but may still marketed
under the provisions of the OTC review.

A proposed rule concerning PPA as a nasal decongestant will be published
along with the proposed rule for weight control products.

After reviewing the blood pressure study submitted in response to the
agency\'s request, FDA concluded that PPA causes a biphasic blood
pressure response. That is, initially blood pressure rises above
baseline, a pressor effect, then falls below baseline, a depressor
effect. The pressor/depressor effects are dose-related. The blood
pressure effects diminish with repeated dosing, and tolerance to the
pressor effects develops within a few hours. FDA further concluded that
the data were inadequate to respond to the agency\'s safety concerns.

As FDA was completing its review of the weight control data, the House
Small Business Subcommittee on Regulation, Business Opportunities and
Energy held a hearing on September 24, 1990 to examine dieting, weight
control products containing PPA, and federal research efforts on
obesity. Testimony included claims of wide misuse and several scientific
witnesses called for removal of PPA from the OTC market. Subsequently,
FDA received two submissions in rebuttal to the testimony given at the
hearing and objecting to the data used to support claims of misuse of
diet drugs. On May 9, 1991, FDA held a public meeting to discuss the
safety and effectiveness of PPA for weight control use.

Although PPA\'s effects on blood pressure and safety concerns relating
to hemorrhagic stroke were discussed, FDA had not yet determined that
PPA was effective for weight control use, and much of the meeting
focused on PPA\'s effectiveness as an appetite suppressant.

FDA later concluded in 1994 that 75 milligrams controlled-release PPA
combined with a reduced calorie diet is effective for temporary OTC
weight control use. FDA also concluded that existing data on single
doses of PPA were inadequate to support its effectiveness for weight
control.

Prior to the public meeting, FDA reviewed its spontaneous reporting
system for case reports associated with PPA from 1977 to 1991. Twenty
two reports of intracranial bleeding suggested that PPA may be
associated with an increased risk of hemorrhagic stroke. This will be
discussed in detail by FDA\'s Office of Postmarketing Drug Risk
Assessment.

Most of these reports were associated with first day use of PPA and with
weight control products, although it was estimated that cough/cold
products accounted for 80 percent of PPA products sold. FDA concluded
that a case control study of hemorrhagic stroke would be the most
feasible approach to test this hypothesis.

Some of the factors that made an assessment of PPA difficult were the
small number of adverse events, the lack of complete information in the
case reports, the apparent rapid tolerance to the hypertensive effects
of PPA, the low rate of reports associated with widely used cough/cold
products, and no accurate estimate of the degree of under-reporting.
That is, no information on the actual number of adverse events that the
case reports represented.

Because of these difficulties, FDA consulted three independent
epidemiologists to comment on the agency\'s evaluation of the stroke
data. The consultants were Doctor Janet Daily and Doctor Steven Kittner,
who are with us today, and Doctor Jack Whisnant of the Mayo Clinic. The
consultants agreed on a number of important points: that FDA\'s
conclusions were reasonable, that interpretation of the data depended
critically on the reporting rate of adverse events which was unknown,
that although the available data did not show a causal relationship and
association between PPA and an increased risk of stroke could not be
ruled out, and that a case control study of hemorrhagic stroke was
recommended.

In 1992, based on the available data, FDA concluded that although an
association between PPA and an increased risk of stroke could not be
ruled out, it was not necessary to remove PPA from the OTC market while
additional data were obtained.

At a meeting in November 1992, the Non-prescription Drug Manufacturers
Association or NDMA, now the Consumer Health Care Products Association
or CHPA, proposed the stroke study along with a voluntary labeling
program that included stronger warnings for PPA weight control products.
In March 1993, NDMA submitted a draft protocol from the Yale
investigators. FDA expressed several concerns including the proposed
sample size and the choice of exposure window.

Through follow-up meetings and correspondence between FDA, NDMA and
Yale, a revised final protocol was agreed upon and submitted by NDMA in
April 1994. The study began in September 1994 and took approximately
five years to complete.

In 1996 FDA published a proposed rule that would require stronger
warnings on all OTC PPA products. The proposed warnings advised
consumers not to combine a weight control or cough/cold product with any
other sympathomimetic drug, that taking more than the recommended dose
can be harmful and, in the case of appetite suppressants, stating
clearly that taking more will not increase weight loss and can be
harmful.

Because the Hemorrhagic Stroke Project was ongoing and the results of
the Yale study could impact on this proposal, it has not yet been
finalized.

That brings us today\'s meeting to discuss the implications of the Yale
study and FDA\'s options regarding PPA as an OTC drug. We will hear from
the Yale investigators discussing the results of the Hemorrhagic Stroke
Project. We will also hear from representatives of the Consumer Health
Care Products

Association voicing some concerns about the study. The OTC Division
consulted FDA\'s Office of Postmarketing Drug Risk Assessment to
evaluate the Yale study and present its recommendations to the
committee, and they will provide a detailed discussion of that review.

The Division of OTC Drug Products is seeking the committee\'s
perspective and recommendations concerning PPA in light of the new
information that the Yale study provides in order that FDA may reach a
decision regarding this widely used over-the-counter drug.

Thank you.

CHAIRMAN BRASS: Thank you.

We will now hear a presentation of the final report of the Yale
Hemorrhagic Stroke Project by Doctor Kernan.

DOCTOR KERNAN: Thank you.

Although the Hemorrhagic Stroke Project has sometimes been referred to
as the Yale Project, it really wasn\'t just the Yale Project. Throughout
this study, research took place at four universities around the country,
and I\'m pleased to tell you that investigators from all four involved
research institutions are here today. From Brown University, Janet Lee
Wilterdink, from the University of Cincinnati, Joseph Broderick, from
the University of Texas at Houston, Lewis Morgenstern, and from Yale
University, Lawrence Brass, Ralph Horwitz, myself, and Catherine
Viscoli.

Throughout the research, we also assisted in this study by a Scientific
Advisory Group which operated independently of both the sponsors of the
project and the investigators. I\'m also pleased to announce that all
three members of the Scientific Advisory Group are here today including
Doctor Louis Lasagna from Tufts University who is chairman of that
group, Doctor J.P. Mohr from Columbia University, and Doctor Sammy
Suissa from Magill University.

Although the investigators and members of the Scientific Advisory Group
would like to claim responsibility for the conduct of this research, we
could not have done it without the research staff including the research
coordinators and interviewers at each of the sites. Joining us here
today as representatives of that group are Carrie Crumpf from Yale
University, Laura Sauerback and Janice Carrazella from Ohio and the
University of Cincinnati, Naomi Tomasian and Carol Cerilli from Brown
University, and Melinda Cox from the University of Texas.

By way of background, some of which you\'ve heard already, during 1999
to 1993 at least 18 published case reports described hemorrhagic stroke
after phenylpropanolamine or PPA use. Most of these reports involved
young women taking PPA for appetite suppression, often as a first dose.
Some case reports, however, involved cough/cold remedies. In 1992,
manufacturers and the Food and Drug Administration joined to recommend
the conduct of a study specifically designed to examine the association
between PPA and risk for hemorrhagic stroke.

The Hemorrhagic Stroke Project had the following co-equal specific aims.
Among women, to estimate the association between hemorrhagic stroke and
PPA, both in appetite suppressants and as a first time use, either as a
cough/cold remedy or an appetite suppressant. Among men and women
together, to estimate the association between hemorrhagic stroke and PPA
use. For any exposure, either as an appetite suppressant or cough/cold
remedy, and by type exposure.

The case control design was selected for the Hemorrhagic Stroke Project
for the following reasons; Hemorrhagic stroke is a rare event among
young persons affecting less than 25 per 100,000 per year. To examine
risk for hemorrhagic stroke among young PPA users, a prospective cohort
study would be unfeasible because hemorrhagic stroke is rare and a
clinical trial would be unsuitable because of logistic and ethical
reasons. Therefore, a case control design is preferred in circumstances
where the outcome event is rare.

Case recruitment is described on this slide. There were four research
sites from which patients were recruited including sites in Connecticut
and Massachusetts comprising a network of 23 tertiary and non-tertiary
care hospitals. These represented all of the major hospitals in
Connecticut. Ohio and Connecticut and Kentucky with 17 hospitals. Again,
this was a network which attempted to recruit all cases of hemorrhagic
stroke in its area. Texas with one hospital and Rhode Island with two
hospitals.

At each site, patents were recruited by active surveillance including
monitoring of admission logs and discharge logs and also on-site
surveillance personnel who attempted to notify us as early as a patient
was admitted to that institution.

Case eligibility is described here. The inclusion criteria included men
and women ages 18 to 49 years who had been admitted with a primary
subarachnoid or intraprankmal hemorrhage that was not related to trauma.
Exclusion criteria included the inability to participate in an interview
within 30 days of the stroke event. I\'d like to explain this for a
moment. This meant that we did not enroll patients who died or became
noncommunicative as a result of their stroke event. For these patients,
in order to obtain exposure data regarding PPA, it would have been
necessary to interview proxy respondents. That is, spouses or friends.
Other research in the pharmacological and methodologic literature
suggest that proxy respondents do not provide reliable information about
drug exposures. In designing the trial, we actually modeled the effect
of using proxy respondents and concluded that the use of those
respondents would have resulted in a very inaccurate estimate of the
odds ratio.

Other exclusion criteria included a history of brain lesion or stroke
and residence in the hospital for over three days when stroke symptoms
began.

Control subject selection is shown here. Eligibility for controls
included men and women, ages 18 to 49 years of age with no history of
stroke. The method for identifying controls was random digit dialing
and, during this process, control subjects were matched to case subjects
for age, gender, telephone exchange and race.

The ascertainment of exposure data is shown on the next two slides. A
critical concept for our research was that of focal time. Focal time was
defined as the date and time of day before which PPA exposures are
counted. For the specification of focal time, it proceeded as follows.
For case subjects, focal time was the date and time of day that marked
the onset of symptoms plausibly related to hemorrhagic stroke that
caused the case subject to seek medical attention.

For control subjects, the focal time was set within seven days of the
control subject interview data, and it was matched to the case subject
for day of week and time of week. Additionally, all control interviews
had to take place within 30 days of the case subject\'s hemorrhagic
event in order to control for season.

The interview methods consisted of a structured interview that was
delivered and conducted by a trained interviewer who used a calendar as
a memory aid. This calendar was marked with holidays and events of
personal importance to each subject, again to aid their recollection for
specific exposures. Subjects were unaware of the study hypothesis and
subjects were asked to recall cold symptoms in the two weeks before the
focal time and medications used to treat them. These questions were
asked equally of case subjects and control subjects to be sure that they
had equal stimulation to recall of specific exposures of importance to
this research.

Subjects were also asked about other medications used in the two weeks
in an open-ended format. Only PPA exposures rated definite or probable
by subjects were counted for this research.

The sample size calculation is as follows. It was based on the aim to
determine if PPA as a first use increases risk of hemorrhagic stroke
within 24 hours among women ages 18 to 49 years. It was based on the
estimate that .502 percent of controls would be exposed to PPA within 24
hours of focal time, and it was based on a one-tailed test of
significance at the 0.05 significance level and an 80 percent power to
detect an odds ratio of 5.0. The result of our calculation was the need
to identify 324 female case subjects and 648 control subjects which was
rounded up to 350 and 700.

We were interested in studying men as well and, to study men, we added
the same number of male case and control subjects to essentially double
the study sample size.

In the statistical analysis, we compared case and control subjects on
several demographic, clinical and pharmacologic features. We used
logistic models to estimate both adjusted and unadjusted matched odds
ratios and, finally, we performed stratified analyses to look at PPA
effects within groups defined by selected clinical features.

All logistic models included the following: black race, which we
included because matching was not perfect between our cases and
controls; history of hypertension and current cigarette smoking because
these are major risk factors for hemorrhagic stroke; and other features
that, when included in the basic model, changed the odds ratio by 10
percent. I will note that education was the only baseline feature we
examined that met this criteria.

The next few slides present our results. Nine hundred thirty eligible
case subjects were identified. Among these, 222 were not enrolled, 182
because the subject was not contacted within 30 days and 40 because the
physician or the subject declined to participate in our research. Seven
hundred eight patients were enrolled. However, six were excluded from
subsequent analysis, three because no control was identified, two
because the interview took place more than 30 days after the stroke
event, and one because of an uncertain focal time. This left a final
case group of 702 subjects that would form the basis of my subsequent
presentation.

Control matching is shown here. For 674 case subjects, they were matched
to two controls for a total of 1,348 control subjects. Twenty eight case
subjects were matched to only one control for a total of 28 control
subjects for them. The total case group again is 702 and the total
control group is 1,376.

The quality of control matching is as follows: All controls were matched
to cases based on gender, telephone exchange, age and race. That was our
intention. Controls were successfully matched to cases on gender and
telephone exchange. There was 100 percent matching success. Ninety nine
percent of controls were matched to cases on age and 96 percent of
controls were matched to cases on race. Because of imperfect matching
with race, race was included as an adjustment variable in subsequent
modeling.

Selected features of case and control subjects are shown on this slide.
The first three features refer to matching variables. For female gender
and age, the proportion of patients with these features in the case
group and controls was very similar. Black subjects comprised a slightly
larger proportion of the case group than the control group. The other
features from here down were not matching variables. Compared to control
subjects, cases were less educated, they were more likely to be current
cigarette smokers, they were more likely to be hypertensive, they were
more likely to report a family history of hemorrhagic stroke, more
likely to consume two or more alcoholic beverages per day, and more
likely to report cocaine use. Compared to control subjects, however,
case subjects were less likely to use nonsteroidal anti-inflammatory
drugs, but they were more likely to report use of caffeine in drugs or
nicotine in drugs.

This slide shows the association between PPA and risk for hemorrhagic
stroke among women. This slide is similar to several others that follow,
and so I\'ll show you its structure. In this column are listed the PPA
use definitions. No use, any use within three days, cough/cold remedy
use within three days, appetite suppressant use within three days, or
first use. First use was defined as use of PPA within the prior 24 hours
but no other use within a two week period. These next four columns show
the data for cases and controls according to percent that reported
exposure under the use definition and number.

Results here are shown in an unmatched format for clarity of
demonstration. The odds ratio, however, is a matched odds ratio and the
matching variables I\'ve shown the adjustment features were race,
hypertension, cigarette smoking, and education. In this column is the
one-sided P value for this research because we were only interested in
the adverse effect of PPA, not for a benefit in reducing risk for
stroke.

So what are the results? No use of PPA was reported by 92.7 percent of
cases compared to 95.1 percent of controls for an odds ratio in this
reference group of 1.0. For any use within three days, the percentages
were 5.5 and 2.7 for an odds ratio of 1.98 and a p-value of .024. For
cough/cold remedy use, the percentages were 5.2 and 2.5 for an odds
ratio of 1.54 and a p-value of .116. For appetite suppressant use, the
percentages were 1.6, 0.1, and the odds ratio was 16.58 with a p-value
of .011.

For first use, the percentages were 1.8 and 0.5 for an odds ratio of
3.13 and a p-value of .052. All first use involved cough/cold remedies.

The results for men are shown on this slide. No PPA use was reported by
96.9 percent of cases compared to 95.4 percent of controls for an odds
ratio of one in this reference group. For any PPA use within three days,
the percentages were 1.9 and 2.1 for an odds ratio of .062 and a p-value
of .203.

For cough/cold remedy use among men, the percentages were 1.9 among
cases, 2.1 among controls for an odds ratio again of .062 and p-value of
.203. For appetite suppressant use, there were no exposures among either
cases or controls and an odds ratio could not be calculated. For first
use, the percentages were 0.3 and 0.2 for an odds ratio of 2.95 and a
p-value of .241. Again, all first uses involved cough/cold remedies.

This slide shows the association between PPA and risk for hemorrhagic
stroke among the entire cohort including men and women. No use was
reported by 94.6 percent of cases, 95.2 percent of controls for an odds
ratio in the reference group of one. For any PPA use within three days,
the percentages were 3.8 and 2.4 for an odds ratio of 1.49 with a
p-value of .084. For cough/cold remedy use, the percentages were 3.1 and
2.3 for an odds ratio of 1.23 and a p-value of .245. For appetite
suppressant use, the percentages were 0.9, 0.1 for an odds ratio of
15.92 and a p-value of .013. For first use, the percentages are 1.1, 0.4
and the odds ratio is 3.14 with a p-value of .029.

In the next few slides, I\'d like to consider key biases which we
considered in the design and analysis of the Hemorrhagic Stroke Project.
These included confounding, selection and information bias and under
information bias I\'ll specifically mention temporal precedence bias,
ascertainment bias and recall bias.

For confounding bias, the definition of a confounder is an extraneous
variable related to PPA use and risk for hemorrhagic stroke that wholly
or partially accounts for the apparent effect of PPA on stroke risk. The
confounder is related to both the exposure and the outcome. Safeguards
against confounding in the Hemorrhagic Stroke Project included matching
cases and controls on age, gender, race and telephone exchange, all of
which were considered potential confounding variables.

Furthermore, we also conducted adjustment for other potential
confounding variables by both modeling and stratification, and I want to
show you the results of that. This slide shows the effect of adjustment
on the matched odds ratio among women. In this column are the PPA use
definitions you\'ve seen before. In this column the unadjusted odds
ratio and in this column the adjusted odds ratio. Again, it is adjusted
for smoking, hypertension, race and education.

For any PPA use within three days, the unadjusted odds ratio is 2.14 and
the adjusted odds ratio is 1.98. For cough/cold remedy exposure, the
numbers are 1.7 and 1.54. For appetite suppressant use, 12.19 and 16.58.
For first use, 3.50 and 3.13. What these analyses show is that
confounding may have an effect in the overall results of the Hemorrhagic
Stroke Project. However, the magnitude of the odds ratios, both under
the unadjusted and adjusted numbers are quite similar.

Another way of accounting for confounding is stratified analysis. In
this slide, we show a stratified analysis for women without a history of
hypertension or smoking. Again, this column shows PPA use definition.
This column shows results for 121 cases and 438 controls. Again, the
data here is presented in an unmatched format. We present the unmatched
adjusted odds ratio in this column. Previously you had seen the result
of the matched odds ratio. We chose to present the unmatched odds ratio
here for two reasons. First, it allowed us to get a larger sample size.
Secondly, in our own analysis in which we look at the matched odds
ratios and the unmatched odds ratios, the results are remarkably
similar. The odds ratios are almost identical.

For no PPA use, the percent of cases reporting exposure is 90.1 compared
with 96.8 in the control group for a reference odds ratio of one. For
any PPA use within three days, the percentages are 7.4 and 1.4 for an
unmatched adjusted odds ratio of 5.61 and a p-value of less than .001.
For cough/cold remedy exposure the percentages are 5.8 and 1.1 for an
odds ratio of 5.04 and a p-value of .008. For appetite suppressant use
percentages are 1.6 and 0.2 for an unmatched odds ratio of 8.16 and a
p-value of .102. For first use the percentages are 3.3 and 0.5 for an
unmatched odds ratio of 6.3 and a p-value of 0.38.

This alternative stratified analysis, the results from this, are similar
to the analysis from the overall cohort in that the odds ratio for
appetite suppressant use and first use are still elevated. It is
different from the analysis in the overall cohort, however, in showing
that the odds ratio for any PPA use and cough/cold remedy use are
elevated and now statistically significant. We also would like to point
out that in this analysis the magnitude of the odds ratios are really
quite similar. They all range between five and 8.16.

Other than confounding biases, there are other biases we\'d like to
discuss that I mentioned earlier. One is selection bias. The definition
of selection bias is selective referral to or less from the study of
case or control subjects based on PPA exposure. Safeguards in the
Hemorrhagic Stroke Project included active surveillance for case
subjects and enrollment of all eligible case subjects at the
participating institutions. We believe that these safeguards were likely
to be quite effective.

Another bias that we\'d like to discuss is temporal precedence bias.
This is a systematic error in which an exposure to PPA is counted
although it occurs after the onset of hemorrhagic stroke and possibly in
response to sentinel disease symptoms. I\'d like to describe sentinel
symptoms in more detail. We were very concerned about this potential
bias when we designed the study.

Sentinel symptoms, the definition is commonly as follows: a transient
headache hours or days before the onset of symptoms that lead a patient
to seek medical attention. Remember that the symptoms that led a patient
to seek medical attention defined our focal time. That headache, rather
than when attention is sought, may mark the onset of hemorrhage. The
implications for the Hemorrhagic Stroke Project are as follows: A
patient may be classified as exposed to PPA when the medication was
actually taken after the first occurrence of hemorrhage.

Safeguards that we employed in the Hemorrhagic Stroke Project were
twofold. First, we planned analyses using an alternate focal time, that
is, the onset of the sentinel symptoms, and most of our subjects, case
subjects who reported sentinel symptoms, had an alternate interview date
and secondly, we planned an analysis excluding patients with sentinel
symptoms, and I\'d like to show you that analysis.

This slide shows the odds ratios by sentinel symptom status of case
subjects. In this column are the exposure categories you\'ve seen before
and here are the matched odds ratios for case subjects with no sentinel
symptoms of which there were 548 and for case subjects who reported
sentinel symptoms of which there were 154. The matched odds ratios under
any PPA use definition was 1.33 for cases reporting no sentinel symptoms
and 2.19 for cases reporting sentinel symptoms.

For cough/cold use, the odds ratios were 1.12 and 1.71. For appetite
suppressant use, the odds ratio among cases reporting no sentinel
symptoms was 12.10. We could not calculate the odds ratio for subjects
without sentinel symptoms because there were no exposed controls. For
first use, the odds ratios were 3.34 and 2.70.

These results suggest that temporal precedence bias may have played a
role in the Hemorrhagic Stroke Project, particularly for the definitions
of PPA exposure, any PPA use, and cough/cold use. You see the odds
ratios increase. For first use, we were surprised that the odds ratio
actually declined. Temporal precedence bias may still play a role in
that event, although not in the expected direction. Not forcing a change
in the expected direction.

The other thing we\'d like to point out is that in the group of case
subjects without sentinel symptoms, the findings, the major findings
from this study are unchanged. That is, the odds ratio is significantly
increased for appetite suppressant use and for first use of PPA, even
when you exclude these patients with sentinel symptoms who we thought
might artificially actually increase the odds ratio.

The next bias I\'d like to describe is ascertainment bias. The
definition is as follows: Unequal ascertainment of exposures in cases in
control subjects. Safeguards in the Hemorrhagic Stroke Project included
a highly structured and scripted interview from which interviewers were
instructed not to deviate, blinding of subjects to the study hypothesis
and standard exposure verification procedures.

I\'d like to describe the exposure verification procedures because we
think that this is a critical component of our research. I do not
believe that this slide will be easily seen from the back of the room,
and I do apologize. There were 67 patients who reported cough/cold or
appetite suppressant drug use that subsequently we had reason to believe
constituted a possible PPA exposure. The container was available for 52
of these reported exposures. Of these 52, 39 were brand name exposures.
Of these 39, 37 brand name exposures included brand names for which
there had been no recent formulary change, and we knew that these brand
name medications included PPA, so patients were then classified as being
exposed to PPA.

Among the 39 who reported brand name exposure, they reported exposure to
two brand names for which a formulary change had been reported in
available industry information. We then verified these medications by
referring to the lot number on the medication. Actually on the package.
Among the 52 subjects who were able to show us the container from which
they took their pills, 13 of those exposures involved non-brand name
products. We again verified all of those using a lot number. We took the
lot number and went to the manufacturer and confirmed that all 15
exposures, the 13 non-brand name and the two brand name with formulary
changes, all included PPA.

The container was not available for 15 subjects. Ten of these reported
exposure to a brand name product. We then showed these subjects a book
that we had prepared that had pictures of the products and patients were
able to identify their project definitely in all cases, and we counted
those individuals as exposed to PPA. Two of the 15 subjects who did not
have a container reported prescription PPA use. We verified the content,
the actual drug and its content, with the pharmacy, and all patients in
this group were categorized as exposed to PPA.

For three subjects, however, they reported brand name medication use but
did not have the container. Since we didn\'t have a lot number for those
individuals and couldn\'t show them a definite picture of the product,
we counted them as unexposed. We also, even if we had pictures or could
find a container, we are aware that formulation changes take place
commonly among non-brand name over-the-counter cough/cold remedies, and
we felt it was not appropriate to attempt to classify them as exposed.

Recall bias definition is commonly as follows: The tendency of case
subjects compared with control subjects to have more or less accurate
recall of exposures. Safeguards in the Hemorrhagic Stroke Project
included a structured interview, and this included specific questions on
use of appetite suppressants, URI symptoms, upper respiratory tract
infection symptoms, and use of medications for those symptoms. These
questions, again, as I mentioned earlier, were asked equally of case and
control subjects to try and equally stimulate their recall of
medications and exposures of interest in this study.

We also had a short interval between the focal time and the interview
date. It was less than 30 days for case subjects. I believe the average
was approximately 14 days, and an interval of less than seven days
between the focal time and the date of the control subject interview.
The average was about three and a half days. We had a shorter interval
between the focal time and the interview date for controls to try and
overcome the greater stimulation for recall that case subjects would
have because of their serious health event.

I\'d like now just to comment briefly on potential explanations for the
different findings for cough/cold remedies and appetite suppressant use.
Potential explanations include biology. That is, it\'s possible that
individuals who choose to use appetite suppressants are somehow more
susceptible to adverse consequences of PPA. We know that individuals who
took appetite suppressants were female. We don\'t know about other
characteristics that may have placed them at risk for hemorrhagic
stroke. Our study was not designed to address the biology of hemorrhagic
stroke or means by which PPA might increase risk for hemorrhagic stroke.
We can only speculate.

Bias and chance we have previously discussed. I\'ve mentioned several
biases that we considered in designing the study, and we\'ve addressed
them. I\'ve also addressed the issue of chance by reporting p-values.

I\'d like though to briefly mention dosage. We wanted to know if
patients who used appetite suppressants were taking a larger dose of
PPA. This slide shows exposure type, appetite suppressants, cough/cold
remedies, and it shows PPA dose in 24 hours before the focal time. For
appetite suppressants, there were three subjects who took PPA, case
subjects who took PPA in the 24 hours before focal time. The average
dose consumed was 250 milligrams. For cough/cold remedies, there are 18
exposed case subjects. The average or the mean dose of PPA consumed was
161 milligrams with a range of 20 to 730. So this analysis suggests that
yes, consumers of appetite suppressants may have been exposed to higher
doses of PPA. But is higher dose associated with increased risk for
hemorrhagic stroke? And that is addressed on this slide.

This shows the dose response for any PPA use and risk for hemorrhagic
stroke. In this column is the dose of PPA in the 24 hours before focal
time. Here\'s the adjusted matched odds ratio and the p-value. For
individuals who consume more than 75 milligrams of PPA, the odds ratio
is 2.167 with a p-value of 0.084. For individuals who consumed less than
or equal to 75 milligrams, the odds ratio was 1.16 with a p-value of
0.397. By the magnitude of the odds ratios, it would suggest that risk
for hemorrhagic stroke may be related to dose of PPA consumed.

To summarize our main findings, among women, use of PPA and appetite
suppressants within three days was associated with increased risk for
hemorrhagic stroke. First use of PPA was associated with increased risk
for hemorrhagic stroke, as well. Since all first use involved cough/cold
remedies, increased risk was found for both formulations of PPA,
cough/cold remedies and as an appetite suppressant. Among men, there
were no exposures to PPA in appetite suppressants and there were too few
exposures to PPA in cough/cold remedies and for first use to conclude
that risk for hemorrhagic stroke is different from women.

In conclusion, the results of the Hemorrhagic Stroke Project suggest
that PPA is an independent risk factor for hemorrhagic stroke. The data
provide valid information for use in completing a contemporary
assessment of the safety of PPA.

Thank you.

CHAIRMAN BRASS: Thank you.

We have time for the panel to raise questions for the Yale presenters. I
want to remind the panel that we will have lots of time for questions
throughout the morning as well as the afternoon so, to the degree
possible, if we could focus our questions now on issues with respect to
the design and clarification of the interpretation.

DOCTOR GILMAN: We heard this morning from Doctor Strom that it is
questionably valid to combine subarachnoid hemorrhage and primary
cerebral hemorrhage in your study. Can you comment on that?

DOCTOR KERNAN: I\'ll preface my comments by saying that I\'m joined in
answering your questions by the group of investigators who I introduced
earlier, and I\'d like to address this question, if I could, to Doctor
Joseph Broderick from the University of Cincinnati.

DOCTOR BRODERICK: Thank you.

I do think this is a very important question. It\'s actually something
we\'ve considered as investigators. Just a little preface. Our group in
Cincinnati has been working on intracerebral and subarachnoid hemorrhage
since the mid-1980s. It\'s one of the reasons why we were very
interested in participating in the study. And we\'ve done
population-based incidence studies as well as case control studies where
we\'re looking at genetic environmental risk factors.

And it should be very clear that bleeding in the brain or around the
brain has a lot of different mechanisms and intracerebral hemorrhage and
subarachnoid hemorrhage have very different mechanisms and we think that
we are looking at that as a type of stroke because it is a very severe
type of stroke with a mortality of about 40 to 50 percent for both
sub-types. However, I do think there may be some clues about mechanism
in that many of the cases that were exposed were subarachnoid
hemorrhage.

Now, what you may not understand is that the main cause or mechanism for
subarachnoid hemorrhage is an aneurism or blister on the blood vessel,
and it may be that that\'s a necessary type of defect in a blood vessel
that predisposes towards a rupture in the setting of elevated
hypertension. So I do think it\'s very important that you separate the
two diseases. We are doing that, but I can say that it also may give
some clues as to mechanism.

For instance, women have a higher risk of subarachnoid hemorrhage than
men and higher risk of aneurysms, and so this may be a way in which you
could explain the biological effect of transient increases in blood
pressure, particularly when associated in two-thirds of exposures with
previous hypertension and smoking and then add an additional factor. So
that\'s, I guess, my response to that issue.

DOCTOR GILMAN: I have one more question. Doctor Strom also commented
that valid, I quote, \"Valid drug histories would be much harder to
collect from stroke patients resulting in unequal recall.\" I wonder if
the investigators would address that question.

DOCTOR KERNAN: We did address that question. First of all, we attempted
to interview case subjects as early as possible after the onset of their
event, and the same was true for control subjects, as I mentioned. We
were primarily concerned that patients who demonstrated language
impairment would have difficulty accurately reporting their exposure to
PPA. We completed an analysis in which we looked at odds ratios and
exposure histories among individuals with a history with mild aphasia in
our cohort and individuals who did not have mild aphasia, and the
principal findings of the study were unchanged. There was a tendency for
individuals with aphasia to report slightly less PPA use, but when we
eliminated those individuals from the analysis, the results of the study
were unchanged.

So we don\'t feel that there is evidence in our study to suggest that
the enrolled case subjects were any less likely to accurately recall PPA
exposure than the control subjects. Recall that we did not enroll
deceased subjects obviously but we did not enroll patients who had
serious impairment in communication.

We also would like to point out, I think, that other case control
research would suggest that individuals who have a significant health
event are quite keyed in to recalling events immediately prior to that.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I\'d like to ask two questions. On your fourth
slide, you give a list of specific aims and there was a comment made
earlier about multiple testing which I think we\'ll have to grapple with
later on. Your aims start off with women, appetite suppressant, first
use, then go to the combined population. Could you just go over the
history. Is this what was really motivating the study or was it general
use and then breakdowns?

DOCTOR KERNAN: At the time this study was designed, the FDA in
particular was particularly interested in women and women who used PPA
as an appetite suppressant and for first use. The study was actually
sized to look at women who used PPA as a first use, and so that was
always really the major focus of this study. That\'s historically how
this evolved. We considered these co-equal aims. I would like to point
out that these co-equal aims are not independent but they all share the
same exposure of PPA.

Does that answer your question adequately?

DOCTOR D\'AGOSTINO: Yes, it does. Thank you. And the other question. You
may have said it along the way and I\'m sorry if I missed it, but you
gave the chart of the verification of PPA exposures and, if I heard you
correctly, there were three exposures non-brand that you removed later
from consideration as exposures.

DOCTOR KERNAN: That\'s correct.

DOCTOR D\'AGOSTINO: Where did they fall? Were they cases of the
controls?

DOCTOR KERNAN: Can I ask my colleagues to comment on this? I don\'t
recall whether those three were cases or controls. This is Catherine
Viscoli from Yale University.

DOCTOR VISCOLI: One was a female case used as a first dose. She
couldn\'t recall if she\'d used Contac, Sine-aid or Sine-Off, and that
may or may not contain PPA. The other two were controls. Actually, there
was an error on the slide. One was Alka-Seltzer Cold which does contain
PPA. But he didn\'t have the container and he didn\'t have access to the
product ID chart. But we did rerun it with him as exposed. Didn\'t
change the analysis.

DOCTOR D\'AGOSTINO: That was going to be my next question. Did you do a
sensitivity analysis to say what if they were included, and you\'re
saying you did it and it didn\'t change the results.

DOCTOR VISCOLI: Didn\'t change it.

DOCTOR D\'AGOSTINO: Thank you.

DOCTOR NEILL: Richard Neill. My limited understanding of subarachnoid
hemorrhage is that given its relationship to occur in patients perhaps
with a pre-existing blister on a blood vessel, that many of these
patients are going to die before they ever make it to the hospital, and
I\'m curious about the recruitment efforts that were made or
surveillance efforts that were made to identify cases that may have
escaped hospital admission discharge criteria and whether efforts were
made to identify cases that occurred as deaths and therefore excluded by
virtue of monitoring death certificates, that type of thing.

DOCTOR KERNAN: Doctor Broderick has a comment and then I have a comment
on that.

DOCTOR BRODERICK: From our previous epidemiologic studies, about 10
percent of cases of subarachnoid hemorrhage will die in the community
and you only get them because of coronary reports, and that\'s pretty
consistent actually with studies from Rochester, Minnesota as well. We
did not in the course of this during the entire years look for all the
autopsy reports of those patients, so at most, we would miss 10 percent
of cases.

One thing about subarachnoid hemorrhage cases though is once they get to
the hospital, they\'re actually more likely to survive and to be able to
talk to people whereas the hemorrhage, the intracerebral hemorrhage
cases, are more likely to have hemorrhage in the brain which affects
their ability to speak and so that\'s why in the study you see actually
more subarachnoid hemorrhage cases than intracerebral hemorrhage cases
which is actually the opposite of what you would expect because
intracerebral hemorrhage is about twice as common as subarachnoid
hemorrhage. But unfortunately, if you have your brain affected and you
can\'t give a history, those patients will be excluded. So that\'s why
we see a difference here in this case group.

CHAIRMAN BRASS: Doctor Cantilena.

DOCTOR CANTILENA: Yes. If I can ask a question, actually back to the
exposure slide you had. Under brand name you have excluded, if I
understood you correctly, formulation changes. Is that true?

DOCTOR KERNAN: I\'m going to ask Catherine Viscoli to comment on that,
who oversaw the verification procedure.

DOCTOR VISCOLI: We checked anything with possible formulary change by
lot number. Basically, that was for the dose analysis because a
well-known brand changed the dose of PPA in it during the period. But we
didn\'t exclude them. We checked them with lot number.

DOCTOR CANTILENA: Okay. So you\'re not excluding them. It\'s just that
\--

DOCTOR VISCOLI: No. We just verified the dosage.

DOCTOR CANTILENA: For the dose. Okay. Thank you.

CHAIRMAN BRASS: I have a couple of questions. Did you do any
differentiation between immediate release preparations and delayed
release preparations, particularly in the first-use case cohort?

DOCTOR KERNAN: We\'ve not completed that analysis yet, but we intend to.

CHAIRMAN BRASS: Second, in terms of the concern about confounders and
imbalance of those confounders, to the degree you can within the model
that was generated from this population, can one compare the impact of
confounders like hypertension and smoking to other large databases and
attempt to provide model validity to the current cohort with respect to
the magnitude of these effects?

DOCTOR KERNAN: We\'ve spent a great deal of time among ourselves and
with consultants talking about the dependability of our models, and I
would like to ask my colleagues from New Haven to comment more fully on
this, and I wonder if Doctor Horwitz or Doctor Viscoli would like to
address this issue.

DOCTOR HORWITZ: We have considered these issues extensively, as Doctor
Kernan has indicated. I think there are opportunities for us as we
currently see them to use external data sets for validation of the way
in which we\'ve adjusted for these confounding factors. We do, however,
believe that the methods that we employed provide internal consistency
and coherence in the analysis. Both the methods of modeling that we
employed as well as the methods of stratified analysis provide a
consistent and coherent presentation of the risk between
phenylpropanolamine and hemorrhagic stroke, and it\'s the coherence and
consistency of those analyses using different methods that allow us to
conclude that we had adequately adjusted for confounding factors.

CHAIRMAN BRASS: And finally, I\'d be interested if on the back of
envelopes you have done some absolute risk calculations, and I\'d be
particularly interested in numbers like the number of \-- assuming your
point estimates are correct on relative risk \-- what the number of
PPA-associated events in the United States per year would be or the risk
assumed in buying one package of PPA-containing products, etcetera.

DOCTOR KERNAN: We have completed this analysis, and I want to preface
this by saying that we think that this analysis is really an estimate,
and we\'re reluctant to give it too much credence, although we think
it\'s an important analysis. The average incidence of hemorrhagic stroke
for individuals between about 20 and 50 years of age is somewhere around
20 per 100,000. Certainly for individuals between about 25 and 50, 20
per 100,000 per year is a reasonable rate for the incidence of both
hemorrhagic stroke and subarachnoid hemorrhage combined.

That comes out to a daily risk of about .6 patients per million per day.
We use this to calculate what\'s considered a number needed to harm.
That is, the number of women who would need to take an appetite
suppressant in order to experience a hemorrhagic event. And we come up
with estimates that vary between about 110,000 and 1,400,000. That is,
under these assumptions, and these are assumptions which may be taken, I
think, thoughtfully, the risk would appear to be of about that magnitude
and that would be the daily risk.

CHAIRMAN BRASS: Yes, sir.

DOCTOR KITTNER: As a follow-up to that question which may already have
been asked, assuming that this is a causal relationship, did you perform
any back-of-the-envelope calculations on the number of strokes in the
country which would be attributable to this exposure every year?

DOCTOR KERNAN: We have not completed that analysis and estimation.

CHAIRMAN BRASS: Doctor Daling.

DOCTOR DALING: You asked a number of drugs that these women took. Did
you find any other associations with other drugs in this population?

DOCTOR KERNAN: We\'re in the process of completing that analysis. I did
show you results for cocaine, nonsteroidal anti-inflammatory drug use,
nicotine in drugs and caffeine in drugs, and we\'ve not completed a
thorough analysis for those medications, but there was an association or
there may be an association with caffeine, nicotine and cocaine. Cocaine
has been well-reported. The association with nicotine in drugs probably
is because smokers take nicotine supplements and smoking is a risk
factor for hemorrhagic stroke. The relationship with caffeine taken as a
drug needs to be further explored, and we can only regard that as a
very, very tentative exploratory finding.

Does that answer your question?

DOCTOR DALING: I was interested. Didn\'t you ask other medications?

DOCTOR KERNAN: I\'m sorry. Say that again.

DOCTOR DALING: Other medications. What some would consider a medication.

DOCTOR KERNAN: Well, these were caffeine and nicotine taken as drugs. We
have not yet looked at other medications thoroughly.

CHAIRMAN BRASS: Doctor Katz.

DOCTOR KATZ: I had a couple of questions. We know that you excluded
patients who had very bad outcomes, either death or couldn\'t
communicate, because proxy information was considered to be unreliable.
Could you tell us how many patients fell into that category that you
excluded and can we say anything about what would have happened if you
could have gotten valid exposure information from them? In other words,
what biases might have been introduced by excluding them? Did you do any
sort of \-- I don\'t know \-- sensitivity analyses including the worse
case scenarios, that kind of thing?

DOCTOR KERNAN: Again, I believe it was about 182 eligible case subjects
who were excluded because they died or were noncommunicative. Do you
want to provide a more precise estimate?

CHAIRMAN BRASS: I think you actually had that on a slide.

DOCTOR VISCOLI: We identified about 1,700 hemorrhages. Of those, about
600 \-- 400 died and 180 were not communicating within 30 days.

DOCTOR KERNAN: In terms of the effect of excluding those patients, I
think we have no way of knowing what is the effect. We did do extensive
modeling during the planning phase of this study which demonstrated that
we simply could not obtain an accurate estimate of the odds ratio by
using proxy data. This is Doctor Larry Brass, Lawrence Brass, from Yale
University.

DOCTOR LAWRENCE BRASS: Just to follow up on that. In considering this
though and how it might affect the results, we also looked at other
known risk factors for hemorrhagic stroke, and there\'s really no
evidence to suggest that they would result in better outcomes. In fact,
known risk factors, if anything, were to increase worse outcomes and
worse severities so, if anything, by including them we would expect to
have higher rates of risk factors, higher rates of medications that
might be associated with hemorrhagic stroke and so on. So, if anything,
it would move us away from the null hypothesis.

CHAIRMAN BRASS: Doctor Kittner.

DOCTOR KITTNER: One of the questions that was raised about the validity
of the study was the possibility of recall bias, and just to follow up
on one of the previous questions. Certainly drugs like aspirin are well
known to the public to be associated with an increased risk of bleeding.
That\'s a well known complication. Did you look to see whether the risk
in the study was specific to PPA or whether there was also an increased
risk associated with aspirin use?

DOCTOR KERNAN: This relates to the question that was asked earlier, too,
about other drugs we\'ve looked at and I recall that we have looked at
aspirin and dextromethorfan as well. There was essentially no difference
between cases and controls in the proportion that reported use of
aspirin. We found this striking since aspirin is well known or much more
well known, I think, that PPA to be related to risk for bleeding and
hemorrhagic stroke. But there was no difference between cases and
controls for this exposure. This led us to have greater confidence that
recall bias may not play an important role in this study.

CHAIRMAN BRASS: Doctor Johnson.

DOCTOR JOHNSON: I\'m just a little confused about the questions about
other drug use. Table III of the documents we received, it looks like it
has a fairly long list of drugs that you looked at, aspirin,
dextromethorfan, sympathomimetics. So these have been looked at.

DOCTOR KERNAN: They have been. Yes. I\'m sorry. I had forgotten that
when I answered the question earlier. We\'ve looked at those that are in
that table. They\'re actually, I think, reported in the May 10 report to
the FDA.

CHAIRMAN BRASS: Doctor Warach.

DOCTOR WARACH: There\'s a suggestion in the literature that Hispanics
may have a higher risk of hemorrhage. How did your case and control
groups compare as far as composition for Hispanics?

DOCTOR KERNAN: We have not completed that analysis yet, although one of
our investigators, Doctor Lewis Morgenstern, is very interested in that
question. We do have only a small portion of Hispanics who are enrolled
in the study. I believe they comprised about five percent or less of the
overall cohort. So we will have very limited power to make any comment
about that group of patients.

CHAIRMAN BRASS: Yes

MS. COHEN: Do you have any idea how many of those people in trial took
more than what was prescribed in their medication? It\'s the over-use of
medication that I\'m interested in. If some is good, more is better. So
how much did you find out about how they actually used the drug?

DOCTOR KERNAN: The median dose consumed with 24 hours was, I believe, 75
milligrams which means that essentially half of the subjects in this
study, case or control, were consuming greater than 75 milligrams.

MS. COHEN: So that more than the label indication?

DOCTOR KERNAN: More than 75 milligrams. Yes.

MS. COHEN: Yes, and then what does that tell you in terms of the patient
population that\'s using this medication?

DOCTOR KERNAN: It only tells me that the median dose was 75 milligrams.
We can\'t comment on how our population differs from subjects who did
not get into the study because we don\'t have information on patients
who don\'t get into the study.

MS. COHEN: Then were your results stratified as to those who took the
exact dose versus those who took much more?

DOCTOR KERNAN: Yes. In the last couple of slides I presented the dose
response analysis showing that the odds ratio associated with higher
doses of PPA was higher than the odds ratio associated with lower doses.
So we are concerned about a potential dose relationship.

MS. COHEN: One of the things I\'d like to see are the labels. If I
missed it in the literature, I\'m sorry, but I\'d like to see the labels
of the company, the medications.

CHAIRMAN BRASS: The gift shop will be open during the break. I just want
to clarify, and this will probably come up later, but I think for many
of the decongestant products, the label will permit more than 75
milligrams per day so that I think correlation to label has to be done
cautiously and by‑-

MS. COHEN: Well, is there a disclosure to the results of something like
that on the label?

CHAIRMAN BRASS: I think that will come up later.

Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I think you\'ve said it, but I have a long history
looking at PPA that should be known. I was on the miscellaneous internal
committee and so forth looking at the efficacy and over the years I keep
getting asked to look at some of the data and my recollection is 10 - 13
years ago before the stroke study that when you looked at the reported
cases, you also found that they were using a lot of other drugs. Not
medications, but they were cocaine users and things of that nature. How
intense was the effort to find out what other drugs were being used?
I\'m really talking about illegal drugs.

DOCTOR KERNAN: You\'re talking about illegal drugs.

DOCTOR D\'AGOSTINO: Right.

DOCTOR KERNAN: Yes. In our ascertainment of the exposure information, we
ascertained every exposure to every prescription and nonprescription
drug that a patient consumed, so we have very detailed information on
this. Equal efforts were made to ascertain PPA-containing and
non-PPA-containing drugs. Among our group of case subjects, there were
many individuals who were consuming other medications. I presented you
with preliminary results for the use of cocaine in the control and case
group showing that case subjects were more commonly exposed to cocaine
than control subjects. When we adjust for cocaine exposure, however, it
does not change the main findings of our study.

DOCTOR D\'AGOSTINO: You have seven exposures in the appetite
suppressant. What was the result for those seven in terms of cocaine?

DOCTOR KERNAN: Catherine, can I turn to you to ask if you\'re aware of
that. Among the seven individuals who were exposed to appetite
suppressants, were any also using cocaine?

DOCTOR VISCOLI: They were all women and none of the cases who were using
appetite suppressants were also using cocaine.

CHAIRMAN BRASS: Doctor Katz.

DOCTOR KATZ: Yes. I\'m interested to know how you\'d address Doctor
Strom\'s concern specifically with regard to the problems raised by
small numbers, particularly in the one cell in which you had a very
large odds ratio, both with regard to the fragility of the results, as
he called it. In other words, one or two exposures in the controls would
have made it disappear. And also with regard to the appropriateness of
the conditional logistic regression that you used and whether it was
valid with these numbers.

DOCTOR KERNAN: We spent, again, a great deal of time among ourselves and
with our consultants discussing the most appropriate method for
completing an analysis which accounts for confounders and I\'m going to
ask Doctor Ralph Horwitz, who\'s really spear-headed our efforts in
this, to address specifically your comments. Doctor Horwitz was with
Doctor Lawrence Brass, principal investigator for the study.

DOCTOR HORWITZ: We, too, were concerned, as Doctor Strom indicated, in
the numbers of exposed subjects in the appetite suppressant group. I
should state first that the exposure prevalence in the control group
that we achieved in the study was almost identical to that which had
been developed or postulated in the design of the study. We had
available to us in 1993 when we were designing the study information on
marketing and sales of PPA by age group and by region of the country
that allowed us to estimate what the exposure prevalence would be among
controls to appetite suppressants and the estimated rate that we used in
sample size estimation turned out to be almost identical to the observed
rate that was found in the study.

So we went in recognizing, all of us went in recognizing that the
exposure prevalence for appetite suppressants in young women as a first
dose or as a first dose was a very relatively small number, would
require a large sample, and we set an odds ratio in calculating and
estimating the sample size at a value of five in recognition of those
concerns. So we think that the study was designed with that expectation
and we met those anticipated exposure levels.

The other protections are really protections in the design and conduct
of the study and we did everything that we believe is available to do in
current state-of-the-art methods for case control research to identify
and verify exposures to PPA in this case to ensure that they haven\'t
been mis-classified and I think we have considerable confidence in the
quality of those procedures and in the quality of the work that was done
in the field to ensure that there is adherence to the methods and
protocol of the study.

We have conducted, as has the FDA in their own internal analysis,
sensitivity analyses, to look to see what would happen if, as a result
of the sparse exposure data, you were to change the classification of
one or more subjects per category and, in general, as indicated in the
report that you saw earlier, the data are quite robust and resistant to
small changes in classification. So we started out with an exposure
prevalence that we were able to estimate from marketing data and met
that exposure prevalence. We used the best methods that we could to
ensure verification and identification of subject exposure and I believe
that the results are resistant to small changes and misclassification.

CHAIRMAN BRASS: Yes.

DOCTOR BLEWITT: Two questions. One goes back to the dose issue and the
slide about the over 75, under 75, and I wonder whether you\'ve analyzed
the dose with over 150 versus less than 150 milligrams. We haven\'t
calculated odds ratios for that dose range at this point.

DOCTOR BLEWITT: Secondly, on the slide of PPA and risk for hemorrhagic
stroke in men, there\'s an adjusted odds ratio of .62 and my question is
does this, in a sense, suggest a potential protective effect with this
low odds ratio in men?

DOCTOR KERNAN: There are very few exposures among men in the cohort, in
the overall cohort, to any PPA and no exposures, as you know, to
appetite suppressant use. We believe that we really can\'t conclude that
PPA is either a risk for hemorrhagic stroke or protective against
hemorrhagic stroke in men with the data that we have. The confidence
interval around our estimates are just too wide. I can\'t think of a
reason why PPA would be protective. I would not interpret that odds
ratio of .062 as suggesting that it is protective.

DOCTOR BLEWITT: Does it argue, nonetheless, for performing a two-tailed
test?

DOCTOR KERNAN: Again, I don\'t think so. There are very few exposed
males. That estimate for the odds ratio has a very wide confidence
interval around it, and I wouldn\'t place a great deal of meaning on its
absolute value at .062. And furthermore, the decision to use a
one-tailed test was based on reasoning that we were not looking for a
beneficial effect of phenylpropanolamine.

Doctor Horwitz, you want to comment.

DOCTOR HORWITZ: I\'d just like to add that in retrospect we were really
quite under-powered to make any inferences at all about odds ratios in
the sub-group of the patients who were men. If we had it to do over
again and we were designing the study, we would probably have sampled a
much larger proportion of men because the exposure prevalence in men was
so much lower than it was in women.

CHAIRMAN BRASS: Yes.

DOCTOR DELAP: I have a question about the interviews, structured
interviews that were collected. The people who did those interviews, how
much did they know about the study hypotheses?

DOCTOR KERNAN: They knew about the study hypothesis. They knew that the
study really had two broad objectives. One was specifically to look at
the association between PPA and risk for hemorrhagic stroke but that all
the investigators who had designed the study had had an equal interest
in looking at other risk factors for hemorrhagic stroke.

Protections. The question has been raised as to whether the fact that
interviews were unblinded had an influence on the acquisition of study
data. These interviewers were highly trained, went through in the use of
the instrument and adhering to a very tight script for the use of the
instrument.

CHAIRMAN BRASS: Yes.

DOCTOR GANLEY: Yes. I just want to get some clarification on your
exposure of three days and trying to think about that. Does that mean
that someone who had taken a PPA three days prior and then had a stroke
would be included plus it would also include people who were
continuously \-- they were on the third day of therapy?

DOCTOR KERNAN: That\'s correct.

DOCTOR GANLEY: So do you have a breakdown of what the exposure was in
that regard based on if this is something that\'s related to increasing
blood pressure and they\'ve been taking it for three days?

DOCTOR KERNAN: Two answers to that. One, I can tell you within the group
of individuals who took appetite suppressants, three of them were
exposed within 24 hours, three were exposed in a broader time interval.
We have done a preliminary analysis looking at recency of last exposure
to PPA, so defining use as last exposure within 24 hours, last exposure
two days before focal time, last exposure three days before focal time.
We\'re reluctant to draw too many conclusions from this analysis because
it\'s based on small numbers, but it does appear that the risk of
hemorrhagic stroke is concentrated among individuals who\'ve used
phenylpropanolamine on the index day or the day before. But again,
that\'s a very tentative conclusion.

CHAIRMAN BRASS: All that data is actually in Table VI that allows that
differentiation to be made because of the timing of the last dose.

Also related to those themes. When you did the dose analysis, was that
based solely on the last dose or did you also try a cumulative three day
dose relationship?

DOCTOR KERNAN: We\'ve done several analyses. I\'d like to ask Catherine
Viscoli if she would comment on the constancy between the findings from
the dose response analyses using different definitions of exposure. We
looked at a magnitude of last dose, total amount taken in 24 hours, and
total amount taken within three days.

DOCTOR VISCOLI: You saw the 24 hour dose which showed a doubling of the
rate although, based on small numbers, you can\'t draw a firm conclusion
from that. When we looked at the three day dose above the median of 150
milligrams and at or below that, we didn\'t see any dose response.

CHAIRMAN BRASS: Are there any other questions from the panel? Yes.

DOCTOR GILLIAM: Would you comment on the statement made earlier that you
should use .01 as your level of significance instead of .05 due to
repeat testing.

DOCTOR KERNAN: This issue was considered during the design of the study
and there\'s a member of the investigative team who I think is
well-equipped to comment on this. Doctor Horwitz, if you\'d like to
comment.

DOCTOR HORWITZ: We did address this issue up front. I think as was
indicated earlier, the hypotheses were pre-specified. They were highly
inter-dependent. We set the alpha level as we did in recognition of the
fact that these were not analyses that were conducted post hoc but
really were pre-specified and inter-related.

CHAIRMAN BRASS: If there are no additional questions, we will adjourn
for our morning break. We\'ll come back at 10:20. 10:20 please.

(Off the record at 10:07 a.m for an 18 minute break.)

CHAIRMAN BRASS: The next set of presentations will be comments on the
Yale Study by the Consumer Healthcare Products Association. Doctor
Soller\'s clock is about to start. The next set of presentations will be
led by Doctor William Soller, Senior Vice President, Director of Science
Technology at the CHPA. Doctor Soller.

DOCTOR SOLLER: Thank you, Doctor Brass, members of the committee. Good
morning. I\'m Doctor Bill Soller, Senior Vice President and Director of
Science and Technology for the Consumer Healthcare Products Association,
a 119 year old trade organization representing the manufacturers and
distributors of nonprescription medicines and dietary supplements.

Our presentation is in three parts. I have background comments and will
be followed by Doctor Noel Weiss and the Independent Expert Panel which
reviewed the Hemorrhagic Stroke Project Study, and I will close with
proposed next steps. I\'d like to start by answering the question, what
did we know about PPA when the HSP Study was started?

First, we knew and know now that PPA is considered by FDA as an
effective nasal decongestant for colds, flu, allergy as reviewed in the
OTC monograph and in two NDAs for 75 milligram sustained release
product. We also know that PPA is considered by FDA as an effective
appetite suppressant producing a three to four pound greater mean weight
loss over baseline versus placebo in both six and 12 week studies along,
of course, with diet and exercise.

I remind you of the significant morbidity and mortality associated with
obesity in the United States and with NIH\'s recommendation that even
over-weight people lose weight to help reduce or reduce the risk of
blood pressure, elevated total cholesterol and elevated blood sugar.
Note that the differences in the total daily dose for these two
indications, 150 milligrams per kilogram per day for cough/cold and 75
milligram per kilogram per day for weight control.

We knew that PPA was reasonably safe for continued marketing based on
the adverse experience reporting profile from spontaneous reports to FDA
and industry. Typically, there is a low number of reports per year with
no clear signal or trend, and this is the current picture as well with
an average of about two spontaneous reports per year over the last 10
years.

Based on many clinical studies on normotensive, controlled hypertensive,
obese and non-obese individuals in single, multiple and ascending dose
models, PPA causes no clinically meaningful elevations in blood
pressure, other vital signs, CNS stimulation or subjective effects at
recommended dose. The largest of these studies is by Blackburn et. al.,
and Doctor Blackburn is available today for Q&A.

In addition, two retrospective epidemiologic studies were available, one
derived from the database of the Boston Collaborative Drug Surveillance
Program and the other from the National Hospital Discharge Survey
Database, and there was no indication of a signal in either
epidemiologic study. In somewhat more detail in the first of these
studies by Aselton and Jick reviewing the Boston Collaborative Drug
Surveillance Program database, they reported over the \'77 to \'82
period many fewer hospitalizations for PPA versus non-users for a
thrombotic or nonthrombotic cerebral vascular event shown here one for
PPA covering seven million person days versus 275 for non-users covering
520 million person days.

In addition, we reviewed the National Hospital Discharge Survey database
calculating morbidity ratios for observed to expected hemorrhagic
strokes in the context of diet aid use by women 15 to 44 years of age
and, with the background of hemorrhagic stroke rate calculated at about
or estimated at 16 per 100,000 in women 15 to 44 years of age, we
estimated morbidity ratios of .02 for first dose paradigm and .36 for
exposure under multiple dosing paradigm. So at that time, these
epidemiologic studies supported a favorable safety profile for PPA.

At the start of the HSP Study, a hypothesis had been generated despite
clinical epidemiologic support for PPA safety as well as demonstrated
clinical benefit. The consensus was, therefore, OTC continued marketing
with additional study to optimize our understanding of PPA safety
profile based on PPA\'s known efficacy, favorable AER profile, and
favorable clinical findings on blood pressure.

Our involvement with the HSP Study was very limited. We had input on
design and funding, of course, but virtually no involvement on the
conduct and analysis, and we understood that we may face clearly
positive or clearly negative or ambiguous findings needing an advisory
committee deliberation such as today. When we received the initial
report, we were struck by an apparent over-interpretation of the study
results and contacted leading epidemiologic and statistical experts,
many of whom are here today. These experts are shown here. Doctors
Blackburn, Hennekens, Hirsch, Hoffman and Walson will be present and/or
be available for you for your Q&A during discussion.

And we also contacted an independent expert panel for a second view
about the HSP Study and, at this time, I\'ll turn the podium over to
Doctor Noel Weiss who chaired this panel of leading members of the U.S.
epidemiologic community. Doctor Weiss.

DOCTOR WEISS: I\'m Noel Weiss. I\'m an epidemiologist at the University
of Washington. A lot of my research is focused on clinical epidemiology,
and I was quite interested in taking on this challenge when I learned of
it. Next slide. The challenge specifically was to head an independent
expert panel. We met in April of this year at the request of the CHPA to
review the study. We were told that we should be independent and free to
express our opinions, which we would have done anyway had we not been so
instructed, and with the panelists \-- and you\'ll see their identities
in a moment \-- collectively we had expertise in the design, conduct and
analysis of case control studies as well as some expertise in neurology.

If I can have the identity of the panelists. There\'s Doctor Gorelick, a
neurologist from Chicago, and then three epidemiologists, Doctor Kuller,
Doctor Wallace, and myself. It\'s unusual for epidemiologists to
associate with neurologists, but Doctor Gorelick did have an MPH and we
thought it was okay. Next slide.

We were given some materials to review, the protocol of the HSP study,
the interview manual, some case summaries. The most important thing to
us was the draft of the HSP study report, and we also had available an
industry statistical assessment at that time. Next.

We did what epidemiologists do. We evaluated the study and tried to
determine for ourselves how likely the association that was demonstrated
was genuine or was it possible that either some sort of bias,
confounding or chance might have contributed. Next slide.

Conclusions. When you get three epidemiologists, with or without a
neurologist, it\'s difficult to come up with a consensus and especially
if two of those epidemiologists are Lewis Koller and Noel Weiss.
Nonetheless, we were abler to identify a small range of conclusions that
we could actually agree on. There were a larger number of independent
opinions that there wasn\'t any consensus on. But what I\'m going to
present to you are the opinions that we did share.

The first was that we were impressed with the magnitude of the
undertaking and the scope of it. Trying to study a rare disease, a rare
exposure and an exposure for which it\'s almost essential to obtain
interview information about it. The combination of all those things
means that you have to do really a very large, ambitious study, and this
was such a study. We felt, however, that there were numerous
methodologic issues that confronted it and that ultimately limited the
amount that could be interpreted and we were concerned specifically with
chance, bias and confounding as plausible alternative explanations.

A key feature. Some of us gave different emphasis to this. For me, this
is a particularly important one. The low level participation of
potential study subjects, especially among the controls. How important
this is can not be determined, but it could have potentially large
degree of importance, not emphasized so far this morning and I don\'t
think it\'s going to be emphasized in the FDA assessment of the study,
was really the very substantial under-ascertainment of potential
controls. Even among those identified as potential controls, some 35
percent were actually recruited into the study and if you were able to
take into account those households where it was not possible to
enumerate potential controls, that percentage would even by lower. That,
to me, really makes it difficult to place a lot of confidence in
whatever data were obtained from those people who did agree to take
part.

The last two points on the slide. There are differences between cases
and controls in terms of various confounding variables. There was a lot
of attention paid in the analysis and in this morning also to how that
was dealt with and, to the extent that these variables could be
measured, I think the efforts were good ones to try to control those.
However, first, some variables could not be measured well and, second,
the small number of subjects limits one\'s ability to control for
confounding. Next, please.

We felt in the interpretation that there was selective emphasis of
sub-groups which could be misleading and that fits in with the next
which is no clear biological rationale to support a causal association.
Not so much an underlying biological rationale like elevated blood
pressure which conceivably could play a role, even though the elevations
are temporary and modest, but there wasn\'t a clear biological rationale
to support the difference across sub-groups. Why an association in women
and not men? Why an association with appetite suppressant drugs and not
for colds and such when the typical doses given for colds are higher
than for appetite suppressants? It wasn\'t a consistent picture.

We also felt that even if an association were real, it\'s quite clear
from this study plus additional data that if there is an increased risk,
that has to be weighed against the benefits of these drugs \-- and
again, we\'re not sure that an increased risk is present \-- but if it
is, it seems to be very, very small.

Not speaking now as the head of the panel but just as somebody who\'s
here this morning, I just wanted to respond to Doctor Wolfe\'s comment
that this seems to be another example of a case control study which has
shown an association and which has found an important relationship that
likely is causal. He made analogy to the association between aspirin and
Reye\'s syndrome, DES and vaginal adenocarcinoma, estrogens and
endometrial cancer. I\'m familiar with the data on all those studies
and, at least in my personal opinion, neither the quality of the
evidence nor the quantity of the evidence in this instance is anything
like those others and should be viewed quite very much on its own.

Now, as I said, the other panelists will speak in more detail about some
of these issues, and the first will be Lew Kuller.

DOCTOR KULLER: Thank you very much. My name is Lew Kuller. I\'m an
epidemiologist at the University of Pittsburgh, and I\'m going to review
certain aspects of the study in relationship to its interpretation.

First, I want to say that when you see up here that this was a failed
study, it has absolutely nothing to do with the design, which was
outstanding, nor the investigators, who were equally outstanding, but
every one of us does failed studies and, if we didn\'t, then we would
basically not understand that we have done failed studies, which would
even be worse.

Why do we say that this is probably a failed study design or failed
study problem? And there are two problems, as I see it. One of them is
that only 41 percent of the potential cases are in the study, and you
can\'t say anything about the other cases because you\'re not really
sure what they are. But most important, there\'s a very substantial
problem in selecting the controls, as you\'ll note. A hundred and fifty
one telephone numbers had to be identified to find one potential control
and then three eligibles when they did find the potential was basically
into the study.

To just show you what this could mean in terms of selection bias \-- the
next one, please. If you look here, they tried to basically match on
social class, which is important, or education because education drives
a tremendous amount of human behavior, and you can see here that this is
just a major, major problem and it\'s not adjusting for education in the
analysis. It\'s the problem you really don\'t know what the people are
who didn\'t get into the study, the controls, the ones who didn\'t
answer the telephone and, most important, the ones who did answer the
telephones and told you they didn\'t want to participate and basically
when you see this, you get very, very nervous. Twenty percent of your
cases with less than high school and only nine percent controls and
reverse for college education. And that probably accounts for some of
the data which we\'ll see.

Now, very interesting thing to do is to presume that the prevalence of
use was similar \-- and I just put four percent \-- was similar to the
use in the cases, that is, 3.8 percent in three days, and then say of
the 4,200 controls that they didn\'t get in the study, if their use was
four percent, you\'d get 168 users and it would turn out that the
overall prevalence of use in the controls would be 3.6 percent. We have
absolutely no idea what the use rate was in the 4,200 which basically
didn\'t get in and certainly have no idea, even in the larger number, of
those 101 telephone calls and there\'s no way of answering that
question. It\'s just a major question mark, but when they see the small
differences that occurred in this study and the small numbers, that is a
very worrisome observation that you have this huge number of people who
didn\'t get into the study. Next slide, please.

Now, there\'s also a problem, a rather interesting one, and that is
rather if you turn this around, look at the data, why is there greater
use in the controls in two weeks to three days prior to the event? If
you look at the data here, you get basically the overall use is 5.4 and
4.8, but it\'s 1.7 and 2.5. There\'s actually more use of controls from
three days to two weeks and it\'s just a little bit of a problem in
terms of defining the date of exposure because it doesn\'t make any
sense why you should see something of this magnitude. It\'s almost as
great as the other magnitude. You should note also that the first use,
eight and five, is where most of the action is in this whole study. A
total of eight and five cases. Next one.

Now, the argument was raised that men weren\'t exposed, but this is not
true. Actually, the exposure rate in the controls in the men and women
is not significantly different and, if you leave out the appetite
suppressant group of women, it turns out basically \-- and look just at
the nasal decongestant controls, it turns out it\'s 2.5 percent and 2.1
percent. The only difference in this whole study is the 5.5 percent in
the women cases, the men cases. The controls in the men and women are
exactly the same, and there should be enough power to test the
hypothesis in the men because the use in the controls in the men is the
same. The interesting thing. There\'s no use in the men who are cases.
Next.

Likewise, it\'s a rather peculiar phenomenon if we look at cough and
cold suppressants that was noted, and this is not a power issue. It
turns out that the risk is 1.5 in the women, but it\'s 0.62 in the men
and, again, it\'s hard to believe that this is a protective in the men.
It may be a biological basis related to subarachnoid hemorrhage. The
only problem is then if you believe that, as it turns out, there are
only four subarachnoid hemorrhage cases in the women who are not
hypertensive or cigarette smokers. Every other one of them women with
subarachnoid, while a large number of the women that are cases with
intracerebral hemorrhage, a larger number, there are very few of them,
were neither hypertensive nor cigarette smokers. So this is a
subarachnoid hemorrhage phenomenon. Again, it\'s not internally valid.

I just point this out. It\'s small numbers. I get a little nervous. Six
and one is an odds ratio of 12 for appetite suppressant but prior use in
men is one case in eight controls. It goes exactly the opposite way, and
this would be a bonanza in men because it would prevent cerebral
hemorrhage and, of course, that\'s totally unlikely.

Now, we talked a little bit. Somebody mentioned about the use, and I
just want to point out that the nine cases basically in current users
within the first three days, and this is in the group in the study that
are reported in eight/five controls and just to point this out. One of
the women \-- this is everybody \-- drank 10 cups of coffee a day, one
eight and a half cups, one had 10 glasses of soda, one had eight glasses
of soda a day, one had six glasses of soda a week and a prior history of
stroke, one with one glass of soda and a history of stroke, and two of
the cases had just prior headache and nothing and, of the five controls,
six cups of coffee a day, six glasses of soda, two cups of coffee and
one had just a cup of tea. But it\'s hard. If you look at this, you have
eight or nine cases to deal with in your whole study and basically at
least four of those people were basically red hot consumers of either
coffee or soda in huge amounts per day and they\'re not typical of the
U.S. population by a long shot.

Well, thank you very much.

DOCTOR WALLACE: I always hate to follow you, Lew. Good morning. I\'m Bob
Wallace from the University of Iowa where I do epidemiology and
preventive medicine. Noel and Lew and Phil and I have really had mostly
a lot of unanimity with respect to our concerns about this study, which
is certainly a good faith and logistically very daunting study to do, so
I\'m beginning to worry that many of my own feelings are going to be a
little bit redundant, but I\'m going to go through this fairly quickly.

Some of the concerns. Again, I think based on what the investigators
have suggested and the panelists and other comments, I think almost
everything has been suggested. I\'m very concerned about sample size
with respect to dose and every epidemiologist wants to see whether they
could grade the exposure, that is, the amount of exposure, and see that
there\'s a lesser effect than those with lesser exposure, and so it
would really be nice, for example, if we could look at those separately
who were exposed three days prior to the event versus those who are
exposed in the 24 hours. And again, it\'s very, very difficult to do
because of the difficulty of capturing that kind of exposure.

I\'m also concerned about other events that occur. I talked to my
neurosurgical colleagues. Not a systematic survey, I will quickly add,
on my part. The issue of cocaine came up. The issue of alcohol came up
which I was somewhat aware of and I just want to say that a lot of the
effects of alcohol, particularly the acute effects of alcohol, are on
alcohol withdrawal and so yes, it is a risk factor to drink more than
two glasses a day, two drinks a day of conventional alcoholic beverages.
On the other hand, I would hope that the same care with which the study
of PPA use in the period prior to the event, the same care and the same
rigor is taken for looking at alcohol use and the cessation of alcohol
use.

Everybody has made the case that more than half of the cases couldn\'t
be studied. I don\'t have an easy solution for this myself, but it\'s
not different than an animal study in which half the mice got away, and
one is always worried about it.

Lew has covered control selection, and I think I\'ll go on. We all face
the problems with control selection. As you know, everybody gets
telephone solicitations to the point where they screen calls and do all
sorts of other things, and it\'s very hard for us epidemiologists to
come along and try to find a population that\'s referent to the general
community because everyone is out there doing it also.

I wanted to quickly say \-- and it\'s a point that\'s probably been made
half a dozen times today \-- that these cases are different. I think
this is really a collection of different kinds of diseases. Now, I\'m
not going to argue whether they\'re cousins or distant relatives, but
they are at least a little bit different, and I thought Doctor Broderick
gave a good explanation talking about mechanisms that may be a little
bit different but I\'m also worried about risk factors that might be
different. My own search of the literature, for example, found very
little in the way of risk factor studies of arteriovenous malformations
which are part of the case load. Maybe somebody has information, and I
would like to see that. But I believe this is a series of closely
related diseases that may not be the same, either in their etiology and
their mechanism and their genetics and family history and so forth, and
it would be really nice if we could look at them separately.

Again, a lot of the risk factor questions have been addressed and, in
fact, I saw a little bit of information that I wasn\'t aware of. I\'m
personally concerned about alcohol use and withdrawal, particularly in
that period before the event. I\'m very much interested in caffeine use,
in part because caffeine in my view does raise blood pressure and Lew
pointed out that we\'re looking at a population, we may be tapping into
a population that\'s a little bit different. I\'m amazed. Maybe it\'s
just being simple-minded, but 10 glasses of soda a day or eight and a
half or six. That is just a lot and I\'m wondering if we\'re looking at
behavioral patterns that we don\'t in fact fully understand, and I\'m
also interested in undiagnosed hypertension and we carry around the
dogma that half of people with hypertension don\'t know that they have
it and, since hypertension is such a dominant factor in subarachnoid
hemorrhage, I\'m always worried that in fact there\'s this reservoir out
there that we really don\'t know how to measure because once they\'re in
the hospital with their events, blood pressure fluctuates a lot and
it\'s very difficult to tell, and I am interested in the cocaine
history, as has been mentioned several times. So these are the data that
you\'ve already seen that, in fact, Doctor Kernan presented and I hope
it looks the same.

I\'m very concurrent, as Lew was just before me, that there is really an
important class difference, social class difference between cases and
controls. Some of that may be due to the nature of the disease, but I
want to know how much of these differences that we\'re seeing in fact
can be explained by what I think are dramatic differences in social
class that are really not explained by ethnicity although, like the one
panelist, I did see that Hispanics may have an increased risk,
particularly in some counties in the southwest. But I am interested in
why there are these differences. For example, a 17-fold difference in
the history of cocaine use and issues with respect to caffeine and body
mass and so forth.

So in summary, for me, this is a logistically extremely difficult and
daunting activity and I think personally that there are enough issues
left open that it\'s very hard to make a judgment.

DOCTOR GORELICK: Good morning and thank you. Next slide, please. I\'m
Phil Gorelick and I hail from the great city of Chicago where I serve as
professor and Director of the Rush Center for Stroke Research and the
section of cerebral vascular disease and neurologic critical care. I am
a board certified neurologist and, over the years, I\'ve developed a
busy clinical in-patient and office consultative practice. I do have
familiarity with case control studies. I have been the PI of four such
studies and, as Noel mentioned, I do have a master of public health
degree in epidemiology, though my daughter used to refer to it as the
miles per hour degree. Next slide, please.

I\'ve had a long-standing interest in the role of drugs in stroke. I\'ve
previously published as a co-author a paper on the topic which included
a review on PPA, and I\'ve spent a good portion of my career studying
alcohol and stroke in case control form. Next slide, please.

What I\'d like to do in the next several minutes is give you an overview
of a clinical neurologist\'s view of the risk factors for hemorrhagic
stroke and key clinical points to consider when evaluating the
Hemorrhagic Stroke Project. We will have an opportunity to look at some
of the details of these specific cases as I walk you through the ones
for appetite suppression. Next slide, please.

As you\'ve heard, hemorrhagic stroke makes up about 15 to 20 percent of
all strokes. As you\'ve heard previously, there\'s two types:
intracerebral which we abbreviate here as ICH and subarachnoid as SAH.
Generally speaking, the intracerebral is more common and usually but not
exclusively it\'s caused by a rupture of a deep artery in the brain and
the blood is within the brain tissue. The subarachnoid, as has been
previously mentioned, is usually due to a blister on the blood vessel
which ruptures and then blood forms around the base of the brain and
over the coverings of the brain.

The other type of malformation is an AVM or arteriovenous malformation
which is an abnormality or tangle of blood vessels that has an abnormal
connection directly between the arteries and veins. This can also cause
subarachnoid hemorrhage. So as you can see, there are different causes
and these may produce different outcomes and we must consider the
underlying health status in evaluating the contributors to risk. Next
slide, please.

Well, here are the hemorrhagic stroke risk factors by sub-type.
Intracranial hemorrhage on your left, subarachnoid on your right. And
these are from the American Heart Association Risk Factor Panel, of
which I was a member of the writing committee, and from other sources.
The factors that are highlighted or bolded are the lead factors so, for
intracranial hemorrhage, hypertension, heavy alcohol use,
anti-coagulants. This problem increases with age so the older are a
little higher at risk. There tends to be more men. African Americans and
drug abuse has also been implicated, specifically cocaine.

On the subarachnoid hemorrhage side for these important risk factors,
the one that seems to stand out substantially is cigarette smoking
though, again, hypertension, alcohol, heavy alcohol use also come in.
This is a disease in which there tends to be a disproportionate amount
of subarachnoid hemorrhage in younger person as compared to ischemic
stroke and specifically women seem to be a higher target and then again,
African Americans have a very high risk. So these are the major risk
factors for these two types. You\'ll see there\'s some overlap. Next
slide, please.

Let\'s look specifically at the Hemorrhagic Stroke Project with some of
the neurologic considerations. As you\'ve already heard, there\'s a
higher frequency of independent risk factors for hemorrhagic stroke in
the case group as compared to the controls and specifically such things
as cigarette smoking, hypertension, alcohol use, cocaine use and so on.
So this is an established factor in these cases. Interestingly, if you
look at the individual cases which we\'ll do shortly, history of AVM or
aneurism was in at least four of the six appetite suppressant cases.
Next slide, please.

Let me walk you through this table of the appetite suppressant cases to
show you some of my concerns. I\'m not showing the cough/cold
information, but they also had risk factors, but to simplify the
presentation we\'ll look at this. In the far left hand column you notice
that case three had an arteriovenous malformation as the cause. The
other five cases had subarachnoid hemorrhage and, of those, an aneurism
was identified in one, two, three cases. These UNC cases mean that there
was a subarachnoid hemorrhage but no aneurism or other vascular
malformation was found.

Of interest now, let\'s look in the cigarette smoking category, and you
can see bolded in yellow that one of the cases was a current smoker, a
pack per day. Another case was a current smoker, one and a half packs a
day. Another case was a currently smoker, two packs per day. Another
case was an ex-smoker. Let\'s look in the hypertension column. One of
the cases that smoked also was hypertensive. Another case had
hypertension as well.

Let\'s look in the alcohol use column. This patient was drinking three
drinks per day. We have a patient who had a history of abuse of alcohol
but denied use more recently. Here\'s one who was drinking eight per
week and here\'s one who is drinking 13 per week. So what I\'m pointing
out here is that all of these cases, generally speaking, had risk or
most of them had traditional risk factors for intracerebral hemorrhage
or subarachnoid hemorrhage, as you can see here. Next slide, please.

Another issue for me has to do with the attributing PPA as a factor
here. I\'ve concluded, based on my analysis, that even if the
association is real, the number of cases attributed to PPA has to be
extremely low and then we\'re left without a biologically plausible
mechanism. Next slide, please.

So here\'s my conclusion and, again, I\'ve shown you all of these risk
factors in these cases and simply the PPA exposed cases and the HSP had
typical risk factors for hemorrhagic stroke. We\'ve shown you
hypertension, we\'ve shown you smoking and alcohol consumption.
Aneurysms in AVM appeared to be responsible for at least four of the six
cases in the appetite suppressant group and, finally, insufficient
control of these risk factors as confounders contributes to uncertainty
surrounding the interpretation of the HSP results.

Thank you.

DOCTOR SOLLER: Thank you very much.

I\'d like to now introduce Doctor Charles Hennekens.

DOCTOR HENNEKENS: Thank you, Doctor Soller. My name is Charles
Hennekens. Since last October, I\'ve served as a consultant in
epidemiology to the CHPA when I first learned of the Hemorrhagic Stroke
Project. Ralph Horwitz and Larry Brass have been colleagues and friends
for decades. Since honest scientists have honest differences of opinion,
I trust they\'ll remain so after today.

Let me begin by congratulating the investigators and their staffs from
Yale, Brown, Cincinnati and Texas. They\'ve done yeoman\'s work in
assembling over 2,100 participants. As an epidemiologist who\'s
conducted case control studies, I applaud as well as sympathize and
empathize with their outstanding efforts.

My issues relate less to the design but more to the analysis an
interpretation of this study. The Independent Expert Panel has presented
their cogent joint as well as individual perspectives about the real
likelihood that chance, bias and/or uncontrolled confounding each could
easily explain the observed findings in the HSP. I\'d like to highlight
several major issues that derive from the initial epidemiology and
biostatistical reviews conducted by myself and Bob Hirsch, who\'s here
in the audience today and is professor of biostatistics and medical
statistics at G.W. and also a consultant to CHPA.

With respect to chance, this is a large study of over 700 cases and
1,400 controls, but it\'s crucial to recognize that even the most robust
and informative overall test of the hypothesis that PPA is associated
with hemorrhagic stroke is based on just 27 exposed cases and 33 exposed
controls. This overall finding does not achieve statistical
significance, even using what I believe to be an inappropriate one-sided
test that yields a p-value of 0.085 which is about one-half of the more
appropriate two-sided p-value of 0.17.

The fact that a two-sided p-value is more appropriate is in part because
of convention but also because this study was designed in the context of
a totality of evidence that included, on the one hand, some concern from
adverse event reports and, on the other hand, some reassurance from
prior epidemiologic studies.

My own view is that regardless of whether the investigators, sponsors,
and FDA agree to using one-sided p-values in the design, the most
important point in the analysis is that several of these major analyses
go from statistical significance to non-significance when one goes from
a one- to a two-sided p-value. Further, while the overall finding is
based on a total of 60 participants, the sub-group of women taking PPA
as an appetite suppressant is based on a total of only seven
participants, six exposed cases, and one exposed control.

Interestingly, one of these six cases had also used PPA as a cough and
cold remedy. In the analyses, she is counted twice, once as a user of
PPA for cough and cold suppression, but also as a user of PPA for
appetite suppression. Interestingly, her BMI was 19 which compares with
the U.S. average of about 27. Had she been classified only as a user of
PPA for cough and cold suppression, the two-sided p-value would no
longer be statistically significant for the test of the sub-group
hypothesis that PPA used by women as an appetite suppressant increases
the risk of hemorrhagic stroke.

Indeed, if the primary aim were to study the association between PPA
used as an appetite suppressant and hemorrhagic stroke, I would have
studied 2,100 women, not 1,153. Perhaps most importantly, chance would
remain a plausible alternative explanation, even if this were a
randomized double blind placebo-controlled clinical trial of PPA versus
placebo. But, in fact, this is a retrospective case control study with
additional limitations of bias and uncontrolled and indeed
uncontrollable confounding.

With regard to bias, selection is an inherent limitation of all case
control studies and is a major problem in the HSP because the response
rates are low in differential. Parenthetically, I would accept the
investigators\' estimate of 75 percent for cases because I think the
failure to enroll the fatalities limits the generalizability, not the
validity, of their estimates. However, as has been pointed out, the
participation rate and controls is about 35 percent.

Observation bias is also likely because cases were hospitalized with
hemorrhagic stroke and 40 percent were aphasic at the time of the
interview and the controls were selected from random digit dialing.
Among patients with aphasia, I believe I would not just have more
difficulty verifying exposure but an even greater problem with the
timing of the use. So the likelihood for noncomparability between cases
and controls due to selection and observation bias is substantial and
also impossible to assess.

With respect to confounding, uncontrolled confounding is clearly present
because cases reported a significantly higher prevalence of numerous
major and independent risk factors for hemorrhagic stroke. These include
race, family history of hemorrhagic stroke, history of hypertension, a
major risk factor for intracerebral hemorrhage, cigarette smoking, a
major risk factor for subarachnoid hemorrhage, alcohol use, illicit drug
use including cocaine, and lower socioeconomic status.

Further, the interpretability of even the state-of-the-art methods of
statistical adjustment for confounding used by the investigators are
seriously limited by the fact that the crude analysis for the sub-group
of women using PPA as an appetite suppressant is based on six exposed
cases versus one exposed control. This problem of a very small sample
size for the sub-group analysis is compounded further by the fact that
all these major and independent risk factors are statistically
significantly higher in the cases than in the controls. So the
sophisticated multi-variant model does give an estimate of a so-called
adjusted relative risk but one must question what it means when the
crude analysis is based on six exposed cases and one exposed control.

Further evidence of problem with this sub-group analysis derived from
the fact that controls for all these positive confounders in an analysis
of a robust sample size would reduce the size of the adjusted relative
risk but, in fact, this adjusted estimate was higher than the crude.
This, to me, is an unfortunate but logical consequence of the analysis
of case control study having one exposed control resulting in a
misleading apparently adjusted estimate due to a simple inability to
control for confounding in any analyses of data of this sort.

But my only concerns today are not about the HSP or even its
over-interpretation but relate to making a recommendation for a policy
statement based on as yet insufficient totality of evidence. Any
judgment of where do we go from here should be evidence-based given
where we are today. I would caution that any attributable risk estimates
assume causality. The absence of causality gives attributable risk
estimates of zero. So in my view, attributable risk estimates or
population-attributable risk estimates are appealing but unwarranted at
present.

I certainly understand the intuitive appeal of making a recommendation
for a policy statement for a drug use as an appetite suppressant or for
cough and cold suppression for which there appears to be other
alternatives. It also has some intuitive appeal that a premature
recommendation may appear preferable to waiting for a sufficient
totality of evidence. Nonetheless, I remain hopeful that sound
scientific reasoning will prevail over emotion.

There are examples where a sufficient totality of evidence turned out to
be completely contrary to possible early signals. These include breast
implants where FDA\'s early regulatory action led to permanent and
irreversible psychological damages to those with the implants and legal
damages to defendants that remain largely unaffected by a current
totality of evidence that is far more reassuring than alarming.

In conclusion, I urge more research, not any recommendation for a policy
statement that is premature and unwarranted based on the current
totality of evidence. Mark Twain once said, you can always tell when
academics are in dispute because the emotions are so high and the stakes
are so low. This may well be true for all of us as speakers here today,
but it\'s certainly not true for you, the Advisory Committee.

Thank you very much for your attention.

DOCTOR SOLLER: Thank you. In conclusion, I\'d like to comment on FDA\'s
OTC policy in this area and provide industry\'s recommended next steps.

FDA\'s OTC policy is that product availability and labeling should be
scientifically documented, clinically significant and important to the
safe and effective use of the product by the consumer. The value of this
three part policy can not be under-estimated. The first hurdle
scientific documentation focused us to look very closely at the quality
and strength of the underlying data before reaching clinical or end use
conclusions.

Based on the expert epidemiologic review, the first hurdle of FDA\'s
policy is not met by the HSP Study. Because of inherent limitations, its
small numbers of exposed cases and controls, inherent bias, inadequate
control for confounding, concerns about chosen statistical methods, the
HSP Study does not provide the quality and the extent of scientific
documentation necessary to support a change in OTC status of PPA.

However, prior to the HSP Study, industry was committed to further
research on PPA and this commitment remains unchanged. While limited
value in terms of its questionable results, the HSP nevertheless shows
us that the exposure to PPA among patients with hemorrhagic stroke is
small, rare, and it provides insights on possible optimum design for
future studies.

Hence, we recommend the next three steps to be. Further epidemiologic
research. This might be undertaken either in conjunction with PHS or
there may be other models to do this and certainly with greater peer
input on the design, conduct issues, and analyses, all of which we\'ve
been talking about this morning. Second, we think it would be prudent
for FDA to finalize the labeling requirements that it has proposed for
PPA that include recommendations relating to maximum dosage use,
contraindications with specific conditions that are listed, various end
use precautions and drug/drug interaction information.

And third, we think it would also be prudent to step up surveillance
through voluntary submission of serious AERs from companies to FDA and
the companies would be interested in working with FDA to identify a
procedure to do that.

I thank you for your attention, and I would now like to open this up for
Q&A to the panel and the committee.

CHAIRMAN BRASS: Thank you very much. Perhaps I\'ll begin with a couple
of clarifications. Would you agree that the HSP can not be used to
exonerate PPA as associated with stroke?

DOCTOR SOLLER: Well, I think if we look at the questions to the panel
with getting ahead, 3(c), we think that the association is uncertain. We
don\'t think, 1) that it has been shown and we wouldn\'t say that it
would be C2 in that particular question where you would walk away and
say this has demonstrated a negative.

CHAIRMAN BRASS: If I could ask for clarification from Doctor Gorelick
who used the phrase \"extremely low to estimate the absolute risk.\"
Could he clarify what \"extremely low\" means?

DOCTOR GORELICK: I would ask Doctor Hennekens to address this issue.
He\'s made a couple of comments about this in our group. Charlie.

DOCTOR HENNEKENS: We\'re a little out of synch because I thought I said
that absolute estimates are premature and unwarranted. However, I think
working with Doctor Hirsch we looked at the HSP data and some outside
data and came to some conclusion of a population attributable risk
percent estimates of about \-- it was between seven and nine percent or
something like that, I think it was. But I think these are very
treacherous on the base of the available data.

CHAIRMAN BRASS: So we should ignore the extremely low conclusion?

DOCTOR HENNEKENS: No, I\'m not saying you should ignore the extremely
low conclusion. I\'m saying that if you have an uninterpretable study
with a really difficult study to interpret with regard to making
assessment of whether there\'s a valid statistical association, to go
further and say that on the basis of even the extremely elevated risks
that are seen in some of these sub-groups that using those to assess the
impact on the population would be premature and unwarranted.

CHAIRMAN BRASS: In terms of the confounding variables, I just want to
clarify. Was there a hinting that there may be an interaction between
PPA and other risk factors or that no conclusion can be drawn?

DOCTOR HENNEKENS: Well, I\'ll take a first stab at this and ask Doctor
Weiss perhaps to comment. I think the issue is \-- and I think one of
the major contributions of this study will enhance our quantitative
estimates of the risk factors for hemorrhagic stroke, both intracerebral
and subarachnoid here, and they are so significantly different. Seven of
the major risk factors for hemorrhagic stroke are significantly higher
in the cases than in the control, so it\'s difficult to assess that with
noncomparability of this sort that one can begin to achieve control for
the differences between the cases and controls when you have only one
control to deal with in the analysis.

Noel, do you want to make a statement about that?

DOCTOR WEISS: Clearly, to address the question of interaction, the
investigators are in a better position than the reviewers, but I think
it\'s safe to say that the numbers are so small, it\'s hard enough to
even find the main effects, much less whether there\'s a particularly
stronger effect, depending on the presence or absence of other risk
factors.

CHAIRMAN BRASS: Doctor Katz.

DOCTOR KATZ: I\'ll address this question to Doctor Soller or really
anybody who wants to answer it. Is there any evidence that the magnitude
of weight also that has been documented in adequately controlled trials
has any consequences for the public health concerns that we\'ve heard
about related to obesity?

DOCTOR SOLLER: We\'re not aware of any long term studies that have been
done on weight control agents, OTC weight control agents that would look
long term out over a period of 10 - 20 years is what you\'re suggesting?
No. Not aware of that.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I want to ask a couple of questions. One is in terms
of the statistical \-- or make a statement \-- in terms of the
statistical analyses. You don\'t necessarily keep going back to square
one for your allocation of alpha. I mean I understood from the way this
was presented is that there was a hypotheses being driven to set this
study up and it was first focused on women, appetite suppressant, first
use. There\'s these procedures called closed procedures. There\'s the
sequential procedures where you do in fact run through a sequence of
hypotheses tests at the five percent level and you keep hitting a five
percent level until you stop, and that is until you don\'t get the five
percent level to be significant.

The way this was set up, I\'m not completely convinced that one
couldn\'t have said go through the sequence of hypotheses that are set
up at the five percent level for women appetite suppressant, for first
use, five percent level, and then to full males plus females and I
don\'t necessarily want to raise a debate here, but I think that the
discussion of taking the alpha and dividing it by the number of
potential hypotheses is not really where one has to focus on the
appropriate hypotheses allocation of alpha. I think that there are many,
many other ways of addressing it which would have said that what was
done was in fact correct.

I have another question after that.

DOCTOR SOLLER: I think Doctor Strom was addressing the point that you
were addressing, and I don\'t know whether he has additional comment
that he might want to make in that regard.

DOCTOR STROM: I think the key thing to realize here is this was not a
sequential type of analysis of the kind you\'re describing. These were
three co-equal aims that were related to each other, and that was the
way it was originally planned from the beginning. So if in fact one of
the aims was positive and the others were not positive, it was still
interpreted as a positive study, and that\'s in fact what was done here.
Of the three aims which are really five aims, some are positive and some
were not positive.

DOCTOR D\'AGOSTINO: The point I\'m making is that I gave as an example
you could have done it sequentially, you could have approached it
differently, and you\'re dealing with safety, not efficacy here, and you
might want to say that I don\'t really necessarily want to have alpha
divided by number of tests when I\'m dealing with safety. There are real
issues, I think, in the alpha allocation that are not being really
brought out correctly.

DOCTOR SOLLER: Yes, I certainly agree with you that that could have been
done. That\'s not what was done, however.

DOCTOR D\'AGOSTINO: They said they were going to use alpha .05. Let me
go to another question. There have been some comments about using
hemorrhagic stroke and then the sub-types. Are the experts telling us
that because the end point was hemorrhagic or the cases were defined as
hemorrhagic stroke without the differentiation of sub-type and then
later on the same sub-type becomes so fragmented that that was a major
mistake, that you can\'t use hemorrhagic stroke as a case definition?

DOCTOR SOLLER: Brian.

DOCTOR D\'AGOSTINO: I mean it took two years to generate the protocol.
Nobody thought of hemorrhagic stroke \--

DOCTOR SOLLER: I would like him to address this, Doctor D\'Agostino, if
I could, since he brought it up in his comments.

DOCTOR STROM: Again, I\'m not a consultant to CPHA. I should also be
clear I am not a neurologist. I\'m a general internist as well as
epidemiologist. There are a lot of people here, I think, who are better
qualified to answer than I. But my understanding from my neurology
colleagues is these are different diseases and should be treated
differently. They may be cousins. They may be related. They may be
separate, but when you combine two different diseases into a separate
case group, it\'s problematic. Why that was originally decided and the
fact that there were five years and they could change \--

DOCTOR D\'AGOSTINO: The statement has tremendous ramification on a lot
of cardiology trials that are going on now.

DOCTOR STROM: True, but I think the important thing to realize is these
diseases may or may not have different risk factors. PPA may be a risk
factor for one and it may be a risk factor for the other, it may be a
risk factor for both. If they are different diseases, if it is a risk
factor for both, if they really are different diseases, then that is
further evidence that it\'s due to bias rather than biology because you
would expect the risk factors for the two things to be potentially
different.

DOCTOR GORELICK: I think what we found in the case review, as you
witnessed, is that in the appetite suppressant group there were five
subarachnoids and one AVM and we were dealing with the traditional
intracerebral hemorrhage case that we normally would, and so there is
some suspicion here that the two things may be different.

DOCTOR D\'AGOSTINO: Thank you.

CHAIRMAN BRASS: Ms. Cohen.

MS. COHEN: As a consumer member with a cold, a cough and overweight, I
feel very comfortable on these subjects, and I have some questions to
ask, and please, Doctor Brass, don\'t send me to the gift shop or the
National Library of Medicine.

If a consumer came to me and asked me why PPA is necessary for appetite
depressant or for cough, what kind of answer can I give them? My next
question is why and how does PPA affect behavior modification? Does it
affect the brain cells? Why is it necessary? And lastly, as the wife of
a scientist who was at NIH for 41 years, I really need to understand so
I can complain to consumers where there\'s such a strong defense by the
scientists of the use of PPA since it\'s not in the category of an
anti-biotic. I really need to understand these things so I can go to a
consumer and say, this is what I learned at this meeting and this is
what I understand.

DOCTOR SOLLER: Let me answer the second question first and then return
to the first one. In terms of behavior modification, it\'s thought that
PPA as an appetite suppressant takes the edge off the appetite. It by
itself without additional steps that are taken in terms of diet as well
as in terms of exercise is very difficult to pull out a statistical
significant clinically meaningful effect in the clinic unless you add
those in, and the package insert does talk about encompassing this into
an overall program. So it makes it easier for a person to engage in that
kind of weight loss. And as a nasal decongestant, it causes
constriction. It\'s not behavioral modification because it\'s direct
effect in the nares and clears the nasal congestion.

Now, in terms of necessary, my comment that I made earlier in terms of
the policy and the fact that we shouldn\'t under-estimate it speaks
directly to that. There\'s a susceptibility to move into the second and
third part of that policy, and the policy is that the availability of
the product, the labeling should be scientifically documented,
clinically significant and important to the safe and effective use of
the product to the consumer, and you\'re jumping to the third portion of
that. In fact, the importance of this policy in a deliberation like this
is to come to an assessment as to whether the study rises to the level
of scientific documentation that would lead you into the second and
third phase.

So in terms of our focus today and the way we look at PPA and the way we
consider where we have been on this particular project as we look back
over the last number of years is that from the ambiguities and the
concerns that have been raised with the Yale Study, in reality, we\'re
back where we were prior to starting the study, and that\'s why the
industry remains committed to additional research and the trying to come
to grips to get the appropriate documentation.

MS. COHEN: Doctor Brass, may I? Would you permit me? I still don\'t
understand. Indirectly I do understand, but I don\'t understand how I
can answer a consumer saying that PPA is necessary. I don\'t understand
how it\'s classified, what its efficaciousness is, if you\'ll pardon the
big word, but I don\'t understand that. And the other thing, in your
studies, did you do a study with behavior modification exercise and a
low calorie intake versus with the PPA and how long? And I think someone
asked here, how long did you follow it after? A year, two years? I still
don\'t think I can go intelligently \-- maybe I\'m missing something \--
and telling consumers what I need to know to answer in an intelligent
fashion.

DOCTOR SOLLER: Well, in a broader issue, that type of questioning could
be applied to many self-care products.

MS. COHEN: Well, hair color products I don\'t need. We\'re talking about
PPA in blind \--

DOCTOR SOLLER: No, but I\'m talking about an overall perspective in
terms of how you look at the self-care category and you could say, why
do you need many of these? You could just tough it out. The point here
is that once you look at the information that is supporting or not
supporting PPA, you look at the level of scientific documentation and
determine whether it rises to the level to suggest a change in
availability or alterations in labeling because the benefits that are
available in terms of nasal decongestion and appetite suppression are
real, and we heard comments earlier today from Doctor Schteingart that
related to the demonstration that PPA can reduce weight in both the
clinical setting.

CHAIRMAN BRASS: I think we\'ll hold off on that further until this
afternoon.

Doctor Gilman.

DOCTOR GILMAN: Sid Gilman. I\'d like to go to the issue of whether this
group was looking at an improper end point by looking at hemorrhagic
stroke, so-called. What they were looking at were patients who had
extravasation of blood into the spinal fluid or around the brain or into
brain tissue. These result, in the case of subarachnoid hemorrhage, from
what is called a berry aneurism, a small outpouching of a vessel that is
thin and that ruptures. There are risk factors for it, including
hypertension and high blood pressure.

They\'re also looking at stroke in the brain. Again, hypertension is a
risk factor for it. Those hemorrhages occur from actually little small
outpouchings at the branch points of vessels often, but they represent
extravasation of blood in brain. Arteriovenous malformations are
hereditary disturbances probably in which if a patient has, quote,
\"stroke,\" hemorrhagic stroke, there\'s extravasation of blood in the
brain around these malformations. So even though these are somewhat
different neuropathological entities we\'re dealing with, they\'re all
characterized by hemorrhage in the brain and it strikes me that these
are appropriately grouped together if there\'s a question about a risk
factor.

So I guess I\'m a little‑- perhaps Doctor Gorelick would clarify this. I
don\'t see that there is an improper rationale in grouping these cases
together personally.

DOCTOR GORELICK: I think the answer is we don\'t know and the reason why
I\'m saying that is because you see that there was a plethora of
subarachnoids and AVM in the appetite suppressant and it was not
intracerebral hemorrhage. The reason why I say we don\'t know is because
you see there\'s cross-over of risk factors between the two groups. So I
don\'t think we know the answer for sure about what this particular
agent, if it does anything at all to heighten risk, is doing in terms of
these different pathophysiologic sub-types. I don\'t think we know that
yet. So I think it\'s probably still debatable.

DOCTOR GILMAN: But if we don\'t know it, then is there a reason not to
group them together?

DOCTOR GORELICK: Well, the downside would be if it affected one type and
not the other because of confounding chance or bias and then you ended
up with the wrong results in terms of making a recommendation.

DOCTOR GILMAN: It seems like that would bias you against finding an
association.

DOCTOR GORELICK: Exactly.

DOCTOR GILMAN: Can I just go on for a moment? So for example, if we were
looking at the risk of an anti-coagulant agent, for example, if we were
looking at Cumadin, a drug that people take to, quote, \"thin the
blood\" so that people who have stroke or heart disease because of poor
flow through the brain and through the heart, the blood is less inclined
to clot. If we\'re looking at people on Cumadin and we wanted to see how
many of these people had hemorrhagic stroke, we would include
subarachnoid hemorrhage and cerebral hemorrhage and arteriovenous
malformations. So the grouping would be fine. We apparently do not know
the biological basis of whatever PPA does, but still I think there\'s a
clear rationale for grouping these cases together myself.

DOCTOR HENNEKENS: If I may make a comment. I would agree completely with
Doctor Gilliam based on the current totality of evidence, and I think
one of the real contributions of this study will be to look at the
similarities and differences in the risk factor data they have collected
for intracerebral and subarachnoid hemorrhage because I think we want to
focus back on where we are today. We\'re starting off with a study that
has lumped the two, looking at the small numbers and trying to make
heads or tails out of them.

But I think a real important contribution would be to look at the
qualitative and quantitative differences in a study of this size. It\'s
an important study with regard to that point, and I think that, in the
absence of those data, I personally think it\'s certainly reasonable to
have both in there.

CHAIRMAN BRASS: I think we need to go on. Doctor Kittner.

DOCTOR KITTNER: Since the topic of the end point has come up, I\'d just
like to make a comment. One of the points we\'ll get to later on in the
meeting is that there were a number of a prior reasons why, based on the
case report literature, why the study was commissioned. I\'m just going
to mention one of them, and that is that the case report literature was
very heavily weighted towards hemorrhagic stroke, and that kind of a
priori evidence, this is in the face of the fact that ischemic stroke is
more common than hemorrhagic stroke. So there was a specificity of
response which led to the original study.

I think that as we\'re reviewing \-- I hope we\'ll come back to this \--
as we\'re reviewing the data, we can not view this study in isolation
independent of the preliminary evidence upon which the study was based.
The preliminary evidence suggested diet pill use in women. I\'ll stop
there.

CHAIRMAN BRASS: Yes, I\'d ask you to because that\'s going to be
intensely discussed this afternoon.

Doctor Daling.

DOCTOR DALING: This is for Doctor Gorelick. In your table where you
review the seven cases, six cases and one control, would you comment on
the fact that only one of the six cases was what we consider over-weight
or even in the upper 25 percentile of body weight and two were actually
quite thin that would have fallen in the first 15 percentile. So why
were they taking these drugs if they were very thin?

DOCTOR GORELICK: Okay. I\'ve reviewed the case report forms and I
didn\'t get a \-- that type of information was not available to me.

CHAIRMAN BRASS: Isn\'t it BMI?

DOCTOR GORELICK: No, no. The reason why somebody who has a low BMI or
relatively BMI, you\'ve got two cases here, 19 and 19, why they would be
on the agent, so I don\'t know. This study is a snapshot in time, if you
will, and we don\'t know.

DOCTOR DALING: But doesn\'t that affect your interpretation of the
results?

DOCTOR GORELICK: Oh, yes. I mean it certainly could.

DOCTOR DALING: Whereas the control BMI was 38 so that was clearly
someone who was quite obese. That makes you wonder why they were taking
these drugs.

DOCTOR GORELICK: The tendency, I think, in the literature \-- and this
has not been substantially proven \-- is that people who are on the lean
side might be at higher risk for hemorrhage.

CHAIRMAN BRASS: Doctor Elashoff.

DOCTOR ELASHOFF: Yes. In terms of slide 17 which showed how much
caffeine use there was, as I recall from reading the stuff prior to
initiation of this study, there was a decision to take caffeine out of
the appetite suppressants because of its potential to do harm, but it
looks like it may not have done any good to take it out if people are
drinking that much caffeine during the day.

DOCTOR SOLLER: Caffeine was taken out of the products in 1983, in and
around that time. There was an abuse issue that was related to things
called \"black beauties,\" street-like drugs, and that was all embroiled
in that particular issue. It was taken out and now is marketed solely as
PPA and I would ask you, Doctor Blackburn or Doctor Hoffman, whether
they have any additional comments that they might want to make in
regards to caffeine and this issue.

DOCTOR HOFFMAN: Brian Hoffman. It\'s hard for me to say very much. I
think caffeine to someone who\'s never been exposed to caffeine or
hasn\'t been exposed to it recently can have effects on blood pressure,
probably in part by stimulating release of catacholamines from the
adrenal medulla and possibly the sympathetic nervous system. John Oates
and his colleagues at Vanderbilt a number of years ago did some elegant
studies on people who take caffeine daily, and my recollection of their
work is that after seven to 14 days these effects of caffeine disappear,
that we become tolerant to those effects of caffeine.

So if these people suddenly went from no coffee to 10 cups of coffee on
the day of their event, that might have been significant, but if this
was a long-term pattern, I\'m not sure of any pharmacological data to
indicate that would be of pharmacological significance.

CHAIRMAN BRASS: I think because of the time we\'re going to move on to
the FDA presentation with a reminder that there\'ll be ample opportunity
for further discussion this afternoon.

DOCTOR LA GRENADE: Good morning. I am Lois La Grenade from the Office of
Postmarketing Drug Risk Assessment and I represent the team of
epidemiologists and biostatisticians who reviewed not only the Yale
Study concerning phenylpropanolamine and the risk of hemorrhagic stroke
but the entire issue of the safety of this drug and the risk of
hemorrhagic stroke.

First of all, I\'ll take you through the format that my presentation
will take this morning. I\'ll give you a historical background of the
safety events that led up to this Advisory Committee today. I\'ll go
through two case reviews of reports received by our spontaneous
reporting system. I will not spend a lot of time reviewing the Yale
hemorrhagic stroke study. Doctor Kernan has already done an excellent
job of this. I will, however, highlight certain important aspects of the
study. I will address some of CHPA\'s concerns. I will summarize the
results of the Yale Study and attempt to assess the public health impact
of these results. And finally, we\'ll give our overall conclusions.

Prior to 1984, the agency received several case reports of PPA
associated with hemorrhagic stroke. In 1984, as a result of these
reports, Doctor Bob O\'Neill, who was with the agency then and is still
with us today and I\'m happy to say is present at this meeting and
sitting at the table, O\'Neill and Van de Carr did a case control study
because of these reports to try and examine this issue. They used
Medicaid data from Michigan and Minnesota.

In 1991, our office reviewed the postmarketing experience of the
spontaneous reports received on hemorrhagic stroke associated with PPA
use. Between 1991 and now, we continue to receive reports of hemorrhagic
stroke associated with PPA use. I\'ll spend a little more time
discussing O\'Neill and Van de Carr\'s 1984 study.

That study showed an association between PPA use and hemorrhagic stroke
compared with other adrenergic decongestants. This study, however, had
important limitations which I must point out are inherent in all studies
which are retrospective and involve automated claims databases including
some of the studies referred to earlier by CHPA. For example, the Jick
Study.

The limitations were that in a retrospective study it is very difficult
to validate the outcomes, to validate the diagnoses, to validate the
exposures. They were limited to using prescription only PPA use since
OTC use was not captured in the databases that they used. Because of the
problems of ascertaining the exposure, they had to use a 60 day exposure
window. These problems lead to important and substantial
misclassification which tends to bias the results towards the finding of
no association. It is, therefore, all the more important that they did
find an association between PPA use and hemorrhagic stroke, although
this association was not found to be statistically significant.

To show you the strength of the signal that we received in our
spontaneous reports. The 1991 review showed that of all the adverse
events reported for PPA use, 14 percent were concerning hemorrhagic
stroke with the use of PPA compared to less than one percent of
hemorrhagic strokes found as an adverse drug event for all other drugs
in our database.

The 1991 series went back as far as 1969 which is the date on which our
database begins and it reviewed all adverse events reported with PPA use
up until the end of January 1991. We found that there were 29 domestic
cases of stroke associated with PPA use, 22 of which were hemorrhagic
stroke. And I must point out, since there has been considerable
discussion on whether we should have used intracerebral or subarachnoid
hemorrhage that, in fact, the cases represented both intracerebral
hemorrhage and subarachnoid hemorrhage. Seventy three percent of the
cases at that time were associated with appetite suppressant use and 27
percent with cough and cold preparation use. They were predominantly of
young age with a median of 27 for appetite suppressants and 35 for cough
and cold and predominantly females. Fifty five percent of the
hemorrhagic strokes occurred with first use of PPA.

This led to the generation of the hypothesis that PPA-containing
products, both appetite suppressants and cough and cold preparations,
particularly first use, are associated with an increased risk of
hemorrhagic stroke in young women.

As part of our preparation for this Advisory Committee today, we updated
the review of cases in our adverse event reporting system. We started on
February 1, 1991, which was the date on which the last review ended, and
we went up to mid-July of this year. We again found 22 cases of
hemorrhagic stroke. There were four well-documented deaths, all of which
were in females. Eighty six percent this time were with cough and cold
preparations and 14 percent with appetite suppressants. Females still
predominated and the median age remained 35.

The median time to onset after the last dose was four hours. The median
duration of use was 24 hours. Eighty two percent of the strokes occurred
within three days of PPA use. All cases occurred with preparations
containing 75 milligrams of the sustained release of
phenylpropanolamine. We note that in this series there is a shift in the
demographics with far more cough and cold users than the previous
review, the 1991 review, but the median age remains the same.

Just to show you a sort of typical case report. We would have a young
person, otherwise healthy, who develops a cough or cold. In some cases,
a runny nose is what was listed on the form. That person takes a
PPA-containing product and within a few days, with absolutely no
warning, develops a catastrophic event, a hemorrhagic stroke, is
hospitalized and either dies or is permanently disabled.

Twenty two cases in the first 20 years, 22 cases in the second nine year
period, a total of 44, might look like an unsubstantial number but I
must hasten to point out that there is substantial under-reporting, even
for prescription drugs in spontaneous reporting databases such as ours.
Perhaps as low as one percent. Further, there is no legal requirement
for manufacturers to report non-monograph drug adverse events and many
PPA-containing products are in fact non-monograph drugs.

In addition, there is less attribution of these cases because there is
no physician, no learned intermediary, who is aware of the PPA exposure
and, in general, under-reporting for over-the-counter products is far
less than for prescription products. All these features contribute to
the under-reporting and it must be borne in mind that the figure of 44
dis literally the very tip of the iceberg.

Now we come to the Yale Hemorrhagic Stroke Project which was a
case-control study designed to study phenylpropanolamine use and the
risk of hemorrhagic stroke. It was sponsored by CHPA and designed and
conducted by the HSP Yale group. Our record show, as Doctor Sherman
outlined to you this morning, that the protocol was extensively reviewed
on many occasions by Yale, CHPA and the agency. It was designed to test
the specific hypotheses generated by our data, and this is very
important for us to remember as we consider this. It was not data
dredging. It was a purpose-designed study.

The objectives of the study, as you have heard before, were that among
men and women age 18 to 49 to estimate the association between PPA use
and hemorrhagic stroke generally and by type of PPA use, whether
cough/cold or appetite suppressant.

The third hypothesis was among women age 18 to 49 years to estimate, A)
the association between first use of PPA and hemorrhagic stroke and, B)
PPA use and appetite suppressants and hemorrhagic stroke. I must again
point out from the agency\'s point of view, this hypothesis #3, parts A
and B, was the single most important from our viewpoint as it was
generated by our data.

The study design was a case control method which, as Doctor Kernan
pointed out, is best suited to rare events such as hemorrhagic stroke in
young people. It\'s best suited because it is most efficient in terms of
the number of cases required. It can capture all the cases in a
specified time period and in a specified population. It\'s very
efficient in terms of timeliness of the results. The results are
available much more quickly than with a cohort study and it is far less
expensive generally.

The strengths of this design were that it was targeted to test specific
hypotheses. It was a prospective study. That is to say cases were
enrolled into the study as they occurred making it much easier to
validate the diagnosis and to ascertain the exposure. Controls were
identified and enrolled into the study as the cases occurred. All of
this was prospective. In general, the study was carefully designed to
minimize bias. It was conducted with great attention to detail and it
was carefully analyzed. The internal consistency shown across the
various strata that were analyzed attest to the carefulness of the
analysis, and we must out that it is to date the largest hemorrhagic
stroke study ever to be completed.

The limitations were in the relatively small sample size and power. As
you have heard this morning, it was powered to detect an odds ratio of
five or greater. I must hasten to point out that this was not for
scientific nor public health reasons but for practical considerations.
As it was, the study took longer than six years to complete. rom the
design stage to the actual handing in of the report was in fact almost
eight years. Had it been powered to detect a lower odds ratio, say an
odds ratio of two, it would have required a far larger sample size and
might have taken 10 or 15 years to complete. We do not think that this
was reasonable to wait so long for an answer.

Now to address some of CHPA\'s concerns. They were concerned about the
relatively small sample size, that it would give low statistical power
to the study, that it made the results subject to exposure
misclassification, that the low sample size could introduce important
biases and the results might not, therefore, be robust.

We counter that by saying that this was the largest study ever of
hemorrhagic stroke. Low power normally reduces the probability of
detecting a difference if one really exists. In spite of the low power,
this study was able to demonstrate a major difference. Bias is usually a
product of poor study design and conduct. The Yale Study was
well-designed with internal safeguards to protect quality assurance, and
the internal consistency in the subset analyses underscores the
robustness of the data.

CHPA was concerned about potential confounders: aphasia, smoking,
hypertension, race, education. Each of these was adjusted for in the
analysis. There are two ways of controlling for analysis, by matching or
by adjustment during the analysis process. Generally speaking in
epidemiologic studies, you match on three or four major confounding
factors and you deal with the others in the analysis stage. It\'s not
necessary to match for every single confounding factor. It would make a
study impractical, impossible to complete. It\'s far too large and it\'s
far too complex.

This slide will demonstrate two things. It shows the internal
consistency of the data and the fact that aphasia and hypertension were
not in fact significant confounding factors. In the first column, you
see the odds ratios as they were presented for appetite suppressants and
first use of cough/cold. In the second column, you see the analysis
performed on the subset of the subjects without hypertension. You see,
in fact, that the odds ratios remain practically the same.

In the case of cough and cold, it increases a little bit. In the third
column, you see the analysis conducted on subsets without aphasia, and I
must point out that the majority of subjects did not have hypertension
and were not aphasic. In the column of subjects without aphasia, the
odds ratios again remain the same and, in fact, increases with cough and
cold suggesting that subjects with aphasia were, in fact,
under-reporting their PPA use rather than the converse.

They were concerned about misclassification, that it could skew the
results and that the areas that they had most concern with were
participant recall and product identification. We respond, as Doctor
Kernan pointed out, that the subjects were blinded to the exposure of
interest so they had no way of knowing what the investigators were
after. The interviewers used a highly structured questionnaire and an
exposure verification process which included the product identification
booklet. Record bias was minimized by the short interval between the
event and the interview for both cases and controls, and this was
conducted within 30 days.

There is no data to suggest that there was differential
misclassification that would generate a spurious association and, in
fact, misclassification typically biases the odds ratio towards the
finding of no association.

On the issue of surrogate responders, CHPA has been concerned that
exclusion of fatal and severely aphasic cases was inappropriate, that
excluded cases could be different in their exposure to PPA and other
risk factors, and that analysis based on survivals only may introduce
survival bias.

We respond that this was modeled in the design stage of the study. Even
modest use of surrogate responders would have introduced overwhelming
misclassification error, and this was verified in the design stage by
the modeling. And CHPA at the time agreed with this finding. The
misclassification error introduced by surrogate responders would have
been so large as to render the study impossible of detecting an
association and, therefore, it would have made no point in doing the
study at all.

As we pointed out when we showed the earlier slide, aphasic subjects may
in fact be under-reporting their PPA exposure. There is no data to
suggest that PPA exposure is related to the severity of the stroke or to
survival after a stroke, and perhaps the most important point of all is
that several epidemiologic studies show that use of surrogate interviews
is a major source of bias in epidemiology studies.

In addition, we conducted our own analyses on the raw data submitted by
Yale University, and we confirmed the major findings. We were able to
explore the dose response relationship and found that, in fact, there
was dose ordering. That is to say that the risk of hemorrhagic stroke
increased with higher doses of PPA. We were able to conduct sensitivity
analyses to examine the sparse data bias due to small sample size, and
we found that this was really not operative in the study. We have a
slide available of this if anybody wants to see it afterwards. We will
have our statistician speak to the issue, if necessary.

Now we come to the results. The Yale Study supported an increased risk
of hemorrhagic stroke associated with PPA use. The findings were
statistically significant among appetite suppressants users and
first-day users of PPA as a cough/cold remedy, and you will remember
that this is what we were interested in from the agency point of view.

Now another job of epidemiologists is not just to assess the strength of
the association and the relative risk but to assess the public health
impact of such a risk, and that\'s called attributable risk, and that is
defined as how much of a disease can be attributed to a certain exposure
and, in turn, how much of the risk \-- and risk is defined by the number
of new cases per year, the incidence of disease \-- how much of the risk
can we hope to prevent if we were able to eliminate the exposure to the
particular agent.

Now, before we do that, we thought we\'d show you the extent of usage of
PPA products in the United States. Take the year 1999, for example. Six
billion dose units were sold. Seventy five percent of it was sold in OTC
products. In a population of approximately 300 million, as the United
States is, six billion doses sold annually translates into 20 dose units
for every man, woman, and child in the population. That\'s extensive use
by any standards. We know that this is doses sold, but there must be a
correlation between doses sold and doses consumed. Otherwise, they
wouldn\'t keep selling it.

This slide shows the distribution of dose units sold annually by
indication, and we see here that 98 percent, the lion\'s share of PPA
use sold, is for cough and cold. It\'s in the preparation for cough and
cold remedies, and only two percent for diet preparations. This is
important, these figures, when we come to assess the public health
impact. In order to assess the public health impact, we extrapolated
from the study population to the general U.S. population.

In order to do that, we had to assume that the population was similar to
the United States population generally, and we tested these assumptions
by looking at the demographic data of the study population, comparing it
to the general population of the United States, and we used Census
Bureau data to help us do that. The minor differences were that whites
were slightly over-represented in the study population and blacks and
Hispanics slightly under-represented. Nevertheless, we thought that the
differences were sufficiently small that we could use the population to
generalize to the U.S. population.

The total number of hemorrhagic strokes in the study that occurred in
the study period was 1,714. Various people have pointed out this morning
that only 41 percent were actually used as cases. Of the cases, eight
cases had first use of PPA as a cough and cold remedy and six cases had
PPA use as an appetite suppressant. We went again to the U.S. Census
Bureau data to find the exact figure for the population in the 18 to 49
age group and, as of August this year, the estimate was 130 million
people in this age group. We went to the published literature to find
the background incidence of hemorrhagic stroke, and we got an estimate
of eight per 100,000. We took our estimate from population-based
incidence stroke studies. Had we used a higher incidence that was quoted
this morning of 20 per 100,000, our estimate would have been even
larger, but we used the more conservative estimate.

Combining our incidence estimate and the population estimate, we get
10,400 hemorrhagic strokes per year in the 18 to 49 age group in the
U.S. If we\'d used the larger figure, it would have been at least twice
that number. And this shows our calculations. I must point out that
always attributable risk calculations are imprecise. They give you a
rough estimate, a ball park figure, and, by our calculations, we found
that between 120 and 290 strokes could be attributable to PPA use for
cough and cold as a first use and 90 to 220 for appetite suppressants.
The figures vary depending on whether you correct for the number of
cases that actually did occur, the number of cases of hemorrhagic
stroke, or whether you just use the number of the cases that were used
as cases in the study. This gives you a total number of cases possibly
attributable to PPA use of 200 to 500 in the 18 to 49 age group.

We have data that shows that PPA use continues in the over 50 age
population. We have every reason to believe that biological effects
continue in the over 50 population. The incidence of strokes is
increased in the over 50 population, and we believe that there must be
some strokes also in the over 50 population. So if we look at the entire
attributable risk for the entire population of the United States, it is
going to be much greater than the 200 to 500 that we have estimated
here, and this is annually.

Another function of epidemiologists when an association has been
detected is to try to make a causality assessment. The criteria for
causal associations include the following. Temporal relationship and, in
all our cases reported to the agency, PPA use has preceded the event. It
has come before hemorrhagic stroke. So we have that. That\'s temporal
relationship. Strength of the association is measured by the magnitude
of the relative risk or, in this case, the odds ratio. And clearly, 16
for an odds ratio for appetite suppressant is a large magnitude.

3.1 for cough and cold is a lower magnitude but we think that this may
result from the wide variety of doses that was experienced in the study.
The doses of PPA exposure range from 6.5 to in excess of 150 milligrams,
and we do believe that the risk of hemorrhagic stroke is related to the
dose so that this odds ratio would represent people taking the low dose
diluting the effect of people taking the higher dose.

In the Yale Study, dose response is another measure of causal
association, another criterion. The Yale Study showed an increased risk
of hemorrhagic stroke with doses of PPA above 75 milligrams per day. We
conducted our own exploratory analyses which did show dose ordering.
That is to say that there was an increased risk with doses of PPA
greater than 75 milligrams per day. In our current case review, the 2000
case review, all 22 reports were with 75 milligram preparations of PPA.

Now we come to biological plausibility. PPA is a sympathomimetic amine
and common to all sympathomimetic amines is that they have a
demonstrated pressor effect. That is to say they raise the blood
pressure. They cause hypertension. There is clear cut tachyphylaxis.
That is to say that the pressor effect is reduced with continued doses
of the drug. The pressor effect is also greater for the sustained
release preparations.

The studies alluded to earlier on this morning were studies that were
done in small sample sizes, 12 and 25 patients, and the mean elevation
in blood pressure was found to be four millimeters of mercury. In fact,
this cartoon represents the distribution of blood pressure spikes in
response to PPA challenge in a large population. The spike represents
the mean, but there are many, many people who would have a much larger
increase in their blood pressure in response to PPA challenge. That
would not be reflected just in the mean. There are many, many outliers,
and we suspect, we postulate, that perhaps people who develop
hemorrhagic strokes with PPA are those who have a much higher increase
in their blood pressure in response to PPA challenge.l

What we also don\'t know is whether people remain static in their
response to PPA challenge, whether at one time they will have a larger
increase and at another time a smaller increase. We do not have these
data available to us. We can only go by what we know.

Consistency with other knowledge. Again, we believe this criterion is
satisfied. We have had numerous case reports in the literature. Just to
mention two. Kase in 1987. He reported 10 cases, two of which were his
own.

The Lake Study has already been referred to this morning. Lake reported
the largest series of adverse events associated with PPA use, and he
reviewed all the cases that had been reported in the literature up to
that time. In his series, he found 24 cases of intracranial hemorrhage,
15 of hypertensive encephalopathy or seizures, all with onset within 24
hours and most at the 75 milligram per day dose. Then we have O\'Neill
and Van de Carr\'s study which, with all its flaws, did show an
association, and we have our own in-house case reviews.

The only criterion for causality that has not been met is replication of
the study, and we have pointed out before that it would take another 10
or 15 years to replicate the study. The question that we must ask
ourselves is is it in the public health\'s interest to wait another 10
or 15 years so that this could be replicated or do we have so many other
criteria fulfilled for causal association?

In summary then, we have a hypothesis of an increased risk of
hemorrhagic stroke with early PPA use generated from our case reports.
We have a well-designed prospective case control study that strongly
supports our hypothesis, and the criteria for causality have largely
been fulfilled. We estimate that, at a minimum, 200 to 500 strokes per
year in young people are potentially preventable.

We conclude that the use of PPA as treatment for cough and cold symptoms
and as an appetite suppressant confers an increased risk of hemorrhagic
stroke in young people, that there is a substantial burden to this risk.
In excess of 200 to 500 hemorrhagic strokes per year are attributable to
PPA use, and there is evidence to suggest that the risk of hemorrhagic
stroke may be higher with PPA doses at or above 75 milligrams per day.

Finally, I\'d like to thank the members of the team who all contributed
substantially to my presentation this morning. Thank you.

CHAIRMAN BRASS: Thank you.

Doctor Ganley, did you want to make remarks now or did you want to \--
Okay.

Yes, Doctor Daling.

DOCTOR DALING: I\'d like to ask in your attributable risks calculations,
why did you use only first day or first use for your cough and cold
remedies whereas you used the three days for the appetite suppressant,
and how did you get the data on first use?

DOCTOR LA GRENADE: This was provided in the study. We used, in fact, the
odds ratios that were statistically significant.

DOCTOR DALING: Well, then it would be your odds ratio for first day use
or three day use of 1.23 which is actually \--

DOCTOR LA GRENADE: That was proposed use as a cough/cold remedy.

DOCTOR DALING: I guess I\'m wondering why you use the \-- why did you
just use the significant ones because certainly, if you were looking at
any three days use and it was not significant so it was actually
consistent with a protective effect.

DOCTOR LA GRENADE: We used the data that we were testing for in our
hypothesis generated by the agency and which were also the ones that
were found to be statistically significant in the study.

DOCTOR DALING: So the attributable risk for any three day use could be
actually a protective effect.

DOCTOR LA GRENADE: No.

DOCTOR DALING: Well, the confidence interval goes below one.

DOCTOR LA GRENADE: The data do not support, as Doctor Kernan pointed
out. We can\'t use that sort of thing. We have to use what was
statistically significant and what were the hypotheses that were
generated by our data.

CHAIRMAN BRASS: Doctor Cantilena.

DOCTOR CANTILENA: Yes. To follow up on the information in your slide 41
with response to the effect on blood pressure. Are you aware of any
information with regard to gender differences in terms of the response
from the drug?

DOCTOR LA GRENADE: I am not aware of gender response in response to this
particular drug. I don\'t know whether anybody on my team has
information to that effect. There is one possible contributory
explanation in that women are generally smaller than men and we have
found in our agency spontaneous reports that more of the adverse events
occur in women and it may be that the doses that are prescribed, that
are recommended, are the same for men and women and women are a little
smaller in body size. That\'s just one possible explanation.

CHAIRMAN BRASS: Doctor Lam.

DOCTOR LAM: In one of your public health impact slides on slide #34, the
background incidence of hemorrhagic stroke was over 100,000. Was that
due to drug alone or was there any other risk factor associated with it?

DOCTOR LA GRENADE: That is all risk factors.

DOCTOR LAM: So to estimate the 10,000 hemorrhagic stroke would be also
either drug or PPA risk factor.

DOCTOR LA GRENADE: All causes of hemorrhagic stroke. Yes.

CHAIRMAN BRASS: Doctor Blewitt.

DOCTOR BLEWITT: Yes. In slide 17 and 20, you had indicated that it
wasn\'t reasonable to carry the study out any longer, and I frankly
wonder, since we\'re here today, there seems to be a lot of controversy
about the results of the study, whether in fact it wouldn\'t have been
reasonable to carry this study over a long enough time so that you could
get conclusive results.

DOCTOR LA GRENADE: It perhaps ought to have been designed to test a
smaller odds ratio, but we have to live with the decisions that were
made back in 1991-92.

DOCTOR BLEWITT: In slide 19, reduces probability of showing a difference
\-- major difference observed despite low power and, in spite of that
low power, couldn\'t those differences be due to chance?

DOCTOR LA GRENADE: Not for the two statistically significant odds
ratios. I mean the p-value was, in fact, the conventional .05. That\'s
one thing. And while we\'re on the subject of p-values, I must point out
that a p-value of .05 means that the results could have been obtained by
chance alone five percent of the time, and that\'s the conventional
statistical cut-off point when we\'re looking at efficacy. For safety,
we don\'t need to be as certain. We could accept that we could be wrong
10 percent of the time and right 90 percent of the time when we\'re
looking at safety issues or even lower. We could accept, for example,
being wrong 20 percent of the time on a safety issue.

DOCTOR BLEWITT: I\'ve seen that. In the slide 11 on under-reporting of
cases, I guess intuitively that goes against my view of the natural
history of a serious side effect. You mention that there\'s substantial
under-reporting for Rx drugs, possibly as low as one percent. Seems to
me that a condition as serious, you know, if someone is concerned that
there\'s a possible relationship with PPA and stroke and that there\'s a
literature on this, usually the natural history is that this actually
provokes a lot of activity, that people then begin to report these kinds
of occurrences at greater frequency.

In other words, if you get a stomach upset from aspirin, you\'re not
going to see much of that. But if there\'s a serious side effect such as
a stroke involved, it would seem to me that reporting would be a much
higher percentage. I just wondered about your comments on that.

DOCTOR LA GRENADE: Doctor Graham will answer those comments.

DOCTOR GRAHAM: I\'m David Graham. I\'m part of the study team.

With under-reporting, there are several things to take into account.
One, as surprising as it seems, serious and catastrophic events commonly
are not reported. Even with resulin and liver failure, we probably only
got 10 or 15 percent of the cases that occurred. And there everybody
knew about the exposure. With PPA taken in an over-the-counter setting,
it\'s like the only person who might know about the exposure is the
patient themselves. No one else is out there necessarily thinking about
it.

In response to the question does publicity about events stimulate
reporting to come in, it\'s been show that you can get stimulation of
reports very close to in time to a very major publicity event but that
that stimulation wears off within a month and, with PPA, I haven\'t seen
anything in the newspapers over the last seven or eight years that have
been beating the drug that PPA causes stroke, so I don\'t think that one
can point to a publicity effect as being responsible for reporting.

CHAIRMAN BRASS: Doctor Johnson.

DOCTOR JOHNSON: I have a question. It\'s really just a clarification.
Back on slide six. Doctor Lam was just asking about this. So the 14
percent versus the .8 percent, can you explain that again? That means
that 14 percent of all strokes that were reported?

DOCTOR LA GRENADE: No, of all adverse events that were reported for PPA,
14 percent of them were strokes.

DOCTOR JOHNSON: Okay. Thanks.

CHAIRMAN BRASS: Doctor Elashoff.

DOCTOR ELASHOFF: Apropos of the under-reporting issue, of the cases that
took PPA in the Yale Study, were any of them reported as adverse events
to the FDA?

DOCTOR LA GRENADE: We don\'t know the answer to that question. We don\'t
have the data on the cases that were reported. We don\'t have the
identifying information.

DOCTOR GRAHAM: We do know that we don\'t have any cases reported from
the state of Connecticut where most of the cases in the study occurred.

CHAIRMAN BRASS: Doctor Kittner.

DOCTOR KITTNER: It\'s with some chagrin that, as a neurologist who
specializes in young strokes and have a very wide referral practice for
stroke in young adults over the past 10 years, I\'ve never personally
reported any PPA exposure to the FDA. That is my responsibility.

CHAIRMAN BRASS: Thank you for that confession.

Lois, could you say something a little more expanding on slide 21. Part
of the critique of the cases in controls and the imbalance in the risk
factors is described in your slide 20 and you discussed in particular
the lack of difference with regard to hypertension or aphasia in terms
of what the observed risk factors were. That goes a long way towards
saying that there is an imbalance, it\'s not responsible for what we\'re
likely to be seeing. What occurs for the other potential confounders
that people are concerned about and where might there be some residual
concern still left?

DOCTOR LA GRENADE: Perhaps one member of the team might want to answer
that question. Doctor Yi Tsong.

DOCTOR YI TSONG: I didn\'t do the analysis besides a few of the most
important risk factors, and I think probably Yale has that in their
report. I wonder if any person from Yale can address this issue.

CHAIRMAN BRASS: I think they presented the hypertension one earlier
today where the stratification again showed that the odds ratio was
sustained in the stratification analysis for hypertension and for
smoking, as well.

I just want to observe with respect to the spontaneous reports that
there continues to be approximately two per year which, if you took the
one percent reporting rate, would match pretty well the 200 cases that
was projected from the HSP analysis.

Any other comments or questions?

DOCTOR BLEWITT: Just a comment. I just wonder, Mr. Chairman, whether
it\'s appropriate at all at some point to find out whether CHPA has any
question or their consultants as to whether their concerns have been
addressed adequately here and whether they would have an opportunity to
ask questions themselves or at least comment on the analysis.

CHAIRMAN BRASS: Yes. I don\'t think it would be appropriate for CHPA to
question. I\'m not Jim Lehrer and so I don\'t want to moderate that
debate. So I think in the course of the afternoon discussion, I think
there\'ll be an opportunity for CHPA to comment on various points that
might arise.

Doctor Ganley.

One question while Doctor Ganley gets set up.

DOCTOR NEILL: This is for FDA staff. I thought I heard a comment that
PPA is also used in non-monograph OTC medications, and that\'s been my
experience when I walk down the street, and I\'m curious about the
extent to which PPA exists in those medicines, what kinds of places I
might find those in, and whether or not any of those kinds of uses are
represented in the data in NHSP or in FDA adverse event reporting
system. I\'m talking about medicines that are not specifically marketed
for cough/cold or for appetite suppressant but that sit on the shelf
and, because there\'s no specific claim made except in very vague terms,
aren\'t covered by monograph.

DOCTOR KATZ: Well actually, on the shelf there are both monograph and
non-monograph products that do contain PPA. There are cough/cold
products that are not monograph products that are there. So I don\'t
know if that addresses your question because not all of the cough/cold
products that are out on the shelf now are monograph. Some are NDA.

There are also PPA in some Rx products, so that the database that we get
into the FDA of reports would include NDA products as well as monograph
products, if any are reported under the monograph. So the monograph
though is totally voluntary reporting. The NDA is required reporting if
there are serious adverse events.

DOCTOR NEILL: I guess what I\'m imagining is a health food store where
products that contain PPA might be on the same shelf with products used
to boost energy, stimulate awareness, keep college students awake at
night. I don\'t have a good sense for the extent to which those products
exist or not compared to other similar uses for caffeine-containing,
pseudoephedrine-containing other similar class type medicines are there.

DOCTOR DELAP: I think there are clearly other products out there
available to consumers that include PPA in them. I\'m thinking of some
of the supplements that contain ephedra alkaloid type constituents of
which PPA can be grouped as one. Obviously, that\'s a whole different
situation as far as how much we know about those products and how the
adverse experiences come in to us.

CHAIRMAN BRASS: Do you want to just comment on that, Doctor Soller.

DOCTOR SOLLER: Bill Soller, CHPA. I\'d just like to comment. The
products that you may be thinking about are dietary supplements that
contain ephedra and PPA can be a component of ephedra but it represents
about 10 percent or so by weight of what the ephedra is in that
particular product and, in most products, even less than that. That was
discussed at a meeting in August.

But in terms of the presence of PPA in a product that would represent
itself for weight control and place on it under the active ingredients
PPA, we\'re not aware of any and I\'m not saying that that doesn\'t
occur.

DOCTOR NEILL: No. I\'m talking about products that might contain PPA
that specifically do not make a claim for cough/cold or for appetite
suppressant but exist on a shelf by virtue of the FDA\'s exclusion from
considering those medicines.

DOCTOR SOLLER: It can\'t be. Wouldn\'t be a dietary supplement. It would
be a drug, and it couldn\'t be labeled that way or it would be
misbranded and action could be taken on that particular product. So
there\'s a regularity \--

DOCTOR NEILL: My understanding is that misbranding occurs when there\'s
a specific claim of efficacy made, and I understand that those aren\'t
products that we\'re considering today. I\'m just wondering whether or
not PPA exists in other preparations for which no specific claims are
made and so aren\'t being considered here but still exist on the shelf.

DOCTOR SOLLER: Well, I can tell you that we\'re unaware of that, and we
don\'t believe that that\'s happening. I won\'t say that it doesn\'t
happen because somebody hasn\'t decided to do it in the extreme but, at
least as we understand the market place, I don\'t believe that that is
any kind of reflection of what\'s going on.

CHAIRMAN BRASS: Thank you.

Doctor Ganley.

DOCTOR GANLEY: I just wanted to first start off by thanking Sandy Titus,
who\'s our Exec. Sec., who has done an enormous amount of work in
preparing for this meeting and also for tomorrow\'s meeting.

We\'ve developed a group of questions and we\'ve tried to address them
in the order that we think is a logical sequence. The first group of
questions address the analysis and interpretation of data from the
Hemorrhagic Stroke Project. We\'re particularly interested in looking at
this data in totality but also as a function of the condition of use. As
Bob Sherman had noted earlier, PPA is involved in two rulemakings here,
one for decongestants and one for appetite suppressants.

The other is as a function of dose. As Bob Sherman has also noted, there
is some differences in the recommendations for dosing for each of those
rulemakings, and obviously as a function of first dose which would apply
to both rulemakings.

I think the second portion of questions takes into account the totality
of data and then based on the information, that is the adverse events
reports, the pharmacodynamic effect and the HSP Study, is there an
association between PPA use and the risk for hemorrhagic stroke?

When we talk about generally recognized as safe, I think reality tells
us that drug products do present some risk for consumers and that no
product is absolutely safe. To be generally recognized as safe, an
ingredient must have a well-characterized, acceptable safety profile
under the conditions of use. In the OTC monograph world, when we talk
about conditions of use, we\'re referring to the clinical indication,
dosing and labeling. It\'s totality of the package. I think it\'s also
important to note whether it\'s the prescription product or an OTC
product. The burden of proof and the burden of submitting data falls on
the industry to show us that it\'s safe. It is not the burden of the
agency to prove that it\'s unsafe.

I think other considerations to take into account, that adverse events
resulting in serious morbidity or mortality are especially concerning,
especially for products in the OTC world. We\'ve already heard from
numerous individuals already that the OTC adverse event reporting is
limited. Companies that market drugs under OTC monographs are not
required by regulation to provide safety reports to us and, at a
minimum, I think the consumers need to be adequately informed. If there
are adverse events associated with the use of a product, they ought to
know about them.

On the other hand, generally we make risk benefits assessments. There\'s
been some discussion of the benefit of these products and I think we
would all acknowledge that PPA treats relatively benign conditions and,
although they\'re very effective, for example, in decongestants, we also
have to keep in mind that there is a great public health benefit by
providing easy access to medications for self-care.

Finally, I just want to point out. There had been some concern about the
recommendations in the OPDRA review that that was the position of the
agency, and I think that is the position of the reviewers. It\'s
important to us to listen to the Advisory Committee recommendations that
will help us to bring closure to the PPA rulemaking. This is the best
data that we\'re going to see pertaining to this issue, and I think we
have to realize at that point in time that we do have to make some
decisions.

The next step for the agency is to proceed with rulemaking and designate
PPA as either Category I, Category II or Category III. Those conclude my
comments.

CHAIRMAN BRASS: Are there any questions or clarifications for Doctor
Ganley from the committee? If not, we\'ll break for lunch and reconvene
promptly at 1:30. Thank you.

(Whereupon, off the record at 12:34 p.m. to reconvene at 1:30 p.m.)

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

(1:34 p.m.)

CHAIRMAN BRASS: I\'d like to begin the afternoon session with the
discussion of the issues raised by the presenters this morning. The
discussion will be focused obviously by members of the committee, but I
would like to encourage the committee members during these deliberations
to raise questions as appropriate to any of the presenters from this
morning which will aid the committee in addressing some of these issues.

The discussion this afternoon will be focused around a series of
questions, as always, but I want to emphasize prospectively that the
questions are divided into two thematic areas. One is a group of initial
questions which are specific to the HSP and try to reach some
understanding of what the HSP is and how it can be used. The second set
of questions recognize that in terms of the overall assessment of safety
for phenylpropanolamine, the HSP can not be examined in isolation but is
part of an accumulated experience and database and attempts to integrate
the HSP into the other information to try to reach some overall
conclusions and recommendations.

So I will read the first question and may or may not modify it as I read
it along, as always. Do the results from the HSP Study suggest that PPA
is safe from risk of hemorrhagic stroke in subjects 18 to 49 years of
age or do the results suggest that there is an association between PPA
and hemorrhagic stroke in subjects 18 to 49 years of age \-- and I\'m
going to add another clause \-- or is it inconclusive with respect to
that association?

And the sub-questions have to do with whether the conclusion can be
drawn across the entire study population, that is, gender and product
non-specifically, with respect to the first dose of PPA in subjects
using PPA as an appetite suppressant and subjects using PPA as a
decongestant, is there a dose relationship?

In addressing these questions, please discuss any strengths or
limitations in the design and/or conduct of the HSP that may affect the
interpretation of data. Is there consistency or lack of consistency in
these results? What member of the committee would like to begin the
discussion? Doctor Gilman.

DOCTOR GILMAN: Well, first, I think it might be helpful to address these
questions by looking at men because, as I read the data, heard the data
presented, I heard nothing to implicate PPA in hemorrhagic stroke in
men, probably because there was no exposure to PPA as appetite
suppressant and very few people took PPA who were men for cough/cold
remedies. So we might be able to first clear the decks, in a way, by
just saying well, there\'s no evidence or evidence is inconclusive that
it has any effect in men. Then we could go on to women. That would make
the discussion maybe simpler.

CHAIRMAN BRASS: Well, in thinking about that, again just reacting to
that proposal, I think one has to differentiate that there was no study
hypothesis about men and that it was the overall population that
included men and the prospective sub-group analysis was to look at
women. To the degree a sub-set related to men would have been done, the
numbers would have been small, and that also would have been
predictable, as I understand it, because the study wasn\'t powered
around use or vet rates in men, so it\'s not surprising inclusive
sub-group analysis perhaps.

DOCTOR GILMAN: Right, and so we could simply start off by saying the
data are inconclusive with respect to its effects in men period and then
deal with women.

CHAIRMAN BRASS: I\'m sorry. To my understanding \-- well, in my mind,
it\'s not the same to conclude. One might conclude that there is a
significant effect in the general population, a significant effect in a
sub-group of women, no significant effect in a sub-group of men. With
those three observations, it would be inappropriate to say that there is
no data in men because the general population is positive.

DOCTOR GILMAN: I didn\'t want to say there were no data. I just said
that the data are inconclusive for men period.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: Not to suggest a different strategy and so forth,
but in terms of thinking of this first question, I really think that we
want to remember the hypotheses that drove the study, and it was very
much women. I\'m not saying we shouldn\'t look at the men first and so
forth, but it was really driven very much for the females, very much for
the appetite suppressant, very much for the first use, and all the
questions about alpha and so forth I don\'t think \-- really, I think
it\'s quite really appropriate. I think it\'s really appropriate to
analyze as they did. Now, how we sort of chip away at that is up for
discussion, but I think it\'s the meat of the discussion in terms of
where we want to think about things as what\'s happened in those
females.

DOCTOR GILMAN: Well, since you mentioned that, to me, the data are more
than suggestive that there is significant risk in women, so I would say
yes, the results suggest that PPA is not safe for women when used with
other type of exposure. In other words, the data are quite convincing to
me that there is a large risk with taking PPA for hemorrhagic stroke in
women.

CHAIRMAN BRASS: To put you on the spot a little bit more then, would you
like to summarize the features of HSP which were most persuasive to you
and why the limitations identified did not dissuade you from that
conclusion.

DOCTOR GILMAN: I was impressed with the quality of the case control
study. I was impressed with the quality of the interrogations that went
on, with the objectivity of the interrogations, the fact that the
interrogators who obtained the histories were blinded to the main
purpose of the study.

CHAIRMAN BRASS: No. The questioners did know the main purpose of the
study.

DOCTOR GILMAN: Did not. Correct.

CHAIRMAN BRASS: No, they did. The people being questioned did not. The
questioners were aware‑-

DOCTOR GILMAN: Excuse me. You\'re right. I mis-spoke. Yes, you\'re
right. The subjects answering the questions did not know the purpose.
And for a rare disorder such as this, I thought this was a well-done
study, extremely well-done study.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: Yes. Just to reiterate what you said this morning in
terms of the end point. There was a lot of discussion about the end
point being inappropriate. I\'m not sure I followed, and I thought your
comments were right on target in terms of how I think of clinical trials
and being put together. Just to say again what was just said now, I
think the study was well-designed, well-executed. There were lots of
potential biases. It took 10 years to put together, and no matter what
we do. If we say at this point, if we finish saying let\'s run another
study, this study can\'t be dismissed. I mean we would only be in the
position where we may make confirmation of this or not but this study
can\'t be dismissed and so I think chipping away \-- and I\'m not sure
this is the sequence I\'d want to chip away at because I think the women
who were alpha-type suppressant to first use and then you sort of build
up and it isn\'t necessarily solely driven by alpha of .05/.05 but how
do the hypotheses that led to the study lay out and how do the end
points get suggested.

I think all of those things were quite appropriate, given the history of
this drug and the concerns of it.

CHAIRMAN BRASS: Germane to that, I\'d like to pose a question to any of
the neurologists on the panel or actually anybody else. The question of
biological plausibility came up many times earlier today, and I heard
two different common sense appeals. One, why is this unique to women and
why were there so many subarachnoid hemorrhages?

But to me, those are actually conversely strengthened, explained each
other because it\'s my understanding that gender is in fact an
independent risk factor for subarachnoid hemorrhage and so that if there
was an interaction exclusively, that kind of enrichment might be what
one might have anticipated in a true association. Would any of the
neurologists comment on whether that is reasonable or not?

DOCTOR GILMAN: I think that\'s eminently reasonable and, again, I think
there\'s good rationale for grouping together subarachnoid hemorrhage
with intracerebral hemorrhage with arteriovenous malformations with
hemorrhage. Presumably there\'s some sort of hemorrhagic diathesis
connected with use of PPA. So I think there\'s very good justification
for the grouping. And, in addition, this was an hypothesis-driven trial
based upon what could be called anecdotal evidence, at least frequent
reports, actually quite compelling frequent reports.

CHAIRMAN BRASS: Yes, Doctor Daling.

DOCTOR DALING: I guess I\'d have to say I\'m not convinced at all from
the study that there is a problem. I find it very large concern to me
the response rates. We do RDD all the time. We certainly get response
rates higher than 70 percent. They only got a response rate of 41
percent. And one thing we found from doing these studies is that people
with high BMI are less likely to respond and participate in studies, so
I think that\'s a potential bias.

But I think my biggest concern is the inability to control from
confounding. It was clear from their data that these women who used this
drug were likely to be smokers and drinkers, and I don\'t see how you
can control when you only had one exposed control for these confounding
factors.

CHAIRMAN BRASS: Doctor Elashoff.

DOCTOR ELASHOFF: No. No evidence has been given as to what PPA users,
how they differ from other people. Only evidence has been given as to
how the cases differ from the controls and, in fact, it\'s not at all
surprising that the cases have all these confounding effects because, if
only a certain number of the strokes are due to PPA, most of the rest
have to be due to the standard things that they\'re due to. So the fact
that the two groups differ markedly in all those features is only to be
expected.

DOCTOR DALING: If you look in this report, they clearly show the
characteristics on smoking of the people who use PPA, and 50 percent of
them were smokers whereas the control population, only 30 percent were
smokers.

DOCTOR ELASHOFF: That\'s cases, not people who use PPA.

DOCTOR DALING: No. Controls.

DOCTOR ELASHOFF: Cases versus controls.

DOCTOR DALING: They have a table in here.

CHAIRMAN BRASS: Use the microphone.

DOCTOR DALING: There\'s only seven PPA users in the whole study \-- I
mean appetite suppressant one.

DOCTOR ELASHOFF: They showed all the \-- they didn\'t do it by appetite
suppressant. They only had one, and that was a non-smoker. But if you
look at page 37, they give the PPA exposure and how many are smokers and
you can count how many are smokers. Two, four, six, eight, nine out of
20 and nine out of 20 is more than 30 percent.

CHAIRMAN BRASS: Then with respect to the confounders, you actually raise
two separate points. First, your concern, and this was raised also about
the response rate in the recruiting controls. Am I correct that in order
to effectively recruit a control they had to agree to a personal
interview? In other words, it was more than just will you talk to me on
the phone. There had to be some physical contact between the program and
the \-- if you go to the microphone. They can\'t see you shaking your
head.

DOCTOR KERNAN: Yes. That\'s correct. When we identified controls, we had
to enroll and interview that control within 30 days of the case\'s
strike event, so we were under terrible pressure to get people in and,
once a control agreed to participate, they had to participate in an
in-person interview.

CHAIRMAN BRASS: So Doctor Daling, so the rates for RDD control
recruitment that you cited in terms of expectations, did they include a
direct personal interview?

DOCTOR DALING: When you do \-- I\'m just quoting from what was presented
this morning, but you have to take into consideration, first, not only
how many that you get to that agree but the people who hang up on you
and so forth. That makes it very different, and my understanding from
what I\'ve read was that it was 41 percent.

CHAIRMAN BRASS: But again, you cited an expectation of 70 percent. What
I\'m trying to understand is your \--

DOCTOR DALING: We get 70 percent or better.

CHAIRMAN BRASS: \-- to come to a personal interview?

DOCTOR DALING: That\'s right. In their home.

CHAIRMAN BRASS: Okay. And then in terms of the confounders, so you were
unconvinced by the stratification analysis?

DOCTOR DALING: They only had one control to stratify it by. I mean you
only had one exposed control, yet if you looked at the exposed controls
for weight control, you will see that people who use PPA in general \--
I assume these are general population \-- that they\'re more likely to
be smokers than are the general population.

CHAIRMAN BRASS: I think Doctor \--

DOCTOR DALING: Why is that wrong?

CHAIRMAN BRASS: Because these are in the cases.

DOCTOR DALING: Okay. I\'m talking about the controls.

CHAIRMAN BRASS: Who are you comparing it to? What are you comparing the
controls to?

DOCTOR DALING: Controls in general. Thirty percent were smoking.

CHAIRMAN BRASS: Yes.

DOCTOR DALING: Smokers. If you look on page 37, nine out of 20 of the
controls who used the drug or close to 50 percent were smokers. That\'s
different than the 30 percent overall, indicating that people who use
this drug are more likely to be smokers. The data is right here.

CHAIRMAN BRASS: Okay.

DOCTOR D\'AGOSTINO: The stratification analysis though talked about
those who didn\'t smoke, didn\'t it?

DOCTOR DALING: Well, there was nobody in that strata for weight control.
I mean for the smokers, there was only one person in weight control who
used it in the controls. That was \--

DOCTOR D\'AGOSTINO: You\'re talking about exposure but I\'m talking the
analysis is saying here are the non-smokers. Now what happens with the
exposed and non-exposed and the non-smokers.

DOCTOR DALING: Well, the one control was a non-smoker.

CHAIRMAN BRASS: Okay. I think the point is that that\'s irrelevant in
the stratification analysis because that included cases that were
non-smokers only and compared the cases who were non-smokers and cases
that were not hypertensive and had the same trend analyses.

DOCTOR DALING: The problem is you needed more controls in this study so
that you could adjust for some of these confounders. One is not enough.

DOCTOR D\'AGOSTINO: You\'re saying you need more exposed individuals.

DOCTOR DALING: Yes.

DOCTOR D\'AGOSTINO: Not more controls.

DOCTOR DALING: And they knew at the outset that \-- he said that this is
exactly what we\'d expect, that we would only have one person who used
this for weight control who was in the control group, one person. He
said .5 of one percent were expected to be using this for weight
control.

DOCTOR D\'AGOSTINO: This is an event with very small probability
attached to it.

DOCTOR DALING: Use of this drug.

DOCTOR D\'AGOSTINO: No. It\'s the cases and controls, then how many of
the controls are exposed to the drug is what you\'re \--

DOCTOR DALING: Yes. How many of these controls would you have expected
to have used this drug?

DOCTOR D\'AGOSTINO: Very, very few.

DOCTOR DALING: Only one who used it for weight control.

DOCTOR D\'AGOSTINO: And that\'s what they saw and they saw more exposed
individuals in the cases, and that\'s what was driving the analysis.

DOCTOR DALING: That\'s true, but it\'s difficult to control for
confounding in a study of this size with that many controls with only
one exposed control.

CHAIRMAN BRASS: In terms of the one control who was exposed, the issue
of the sensitivity analysis I think is extremely important and to the
degree to which having two or three instead of one would have affected
the outcome. I understand the FDA did such an analysis. Could you just
comment on that sensitivity analysis very briefly just with respect to
if that one had been two or three.

DOCTOR YI TSONG: Is there any way we can use the slide I have on the
machine from the FDA\'s presentation, slide #84? I think we need to use
74 to start with. Regarding the one exposed control, let\'s think about
it this way. Suppose we have a study, have 100 cases and 100 controls,
and we try to do a study and find out there is no exposed on the control
but all are exposed in the case. Does that mean there\'s more
association or more? Means there\'s no association. We are hung up on so
much about one exposed control. If there\'s no exposed control, you get
even more significant results. So we have to consider it that way rather
than one control, there must be some mistake. If we can prove there is
misclassification, then it\'s a problem. If there\'s no
misclassification, that\'s not a problem.

Okay. Let\'s go to slide 74.

CHAIRMAN BRASS: While it\'s coming up, Doctor D\'Agostino, do you want
to \--

DOCTOR D\'AGOSTINO: Yes. Again, I think the discussion is that if you
made the study bigger and bigger and bigger, you would have started
seeing some of the controls with the exposure and the argument or the
discussion is that the study wasn\'t big enough in terms of number of
controls, but I think that you do have the sensitivity analysis and I
think the sensitivity analysis might bring some clarification on that.

DOCTOR YI TSONG: The original slide I prepared was to address the
comments raised by CHPA regarding if we have four additional exposed in
the control, the total result is totally different. I mean the four
additional exposed sounds like a small number, but if we consider those
exposed misclassifications, that essentially means that\'s 80 percent
misclassification which is supposed to be exposed but classified
non-exposed. This is extremely impossible to have 80 percent
misclassification.

So instead, what I tried to do is use a mathematical formulation to
correct assume the percentage of misclassification and to correct the
odds ratio. So we can go to the next table. Next slide, please.

In this one, I give a different scenario. The first column is the
probability of misclassification of case exposed and the second column
is the probability of misclassification of control exposed and then we
have a corrected odds ratio based on our \-- data. As you see, if we go
to all the misclassification up to 40 percent in the control arm but no
misclassification in the case arm, then we still have about the 7.1
correct odds ratio. I think this is extreme misclassification
assumption.

DOCTOR DALING: Can I say I\'m not quarreling with the misclassification.
I\'m quarreling with the inability to control for confounding.

CHAIRMAN BRASS: I understand. Okay.

DOCTOR DALING: That\'s what I\'m quarreling with.

CHAIRMAN BRASS: Please wait until you\'re recognized.

DOCTOR HENNEKENS: I wanted to make a comment about my concern about the
over-reliance on statistical methods as a way to overcome an inadequate
sample and to expand on Doctor Daling\'s point, you have a comparison of
six exposed cases versus one exposed control. That exposed control does
not smoke cigarettes and three of the six cases do not smoke cigarettes.
So a quote/unquote \"stratification analysis\" on cigarette smoking
leads you that once you adjust for smoking in this analysis, you\'re
comparing three versus one. Not significant.

If you\'re controlling for hypertension, the control did not have
hypertension but two of the six cases had hypertension. So you\'re left
in a stratification on hypertension for four versus one. And I think the
most extreme example of these data is if you stratify by a BMI of
greater than 35. You have none in the cases and one in the controls.
This is what happens when you have such small numbers. There is no
amount of statistical analysis that can overcome the inadequacy of the
sample to control for confounding.

I accept the crude analysis. I do not accept any technique that tries to
control for confounding. It simply can not be done, and I think to go
ahead to make recommendations for policy, if that\'s the sub-group
you\'re interested in, would be very premature and unwarranted.

MS. COHEN: I have a couple of concerns. The end product of this are
consumers, and I don\'t know how one can make a total decision on the
safety or efficacy without seeing what the insert is, and I happened to
pick something up and it talked about decongestants and they mention
thyroid disease, diabetes, prostrate. What about interactions with other
disease? I\'d like to know about that, but I also want to know if this
board, whatever they decide to vote, if they vote that this can continue
on the market, I want to see what information is given to consumers. I
want to make sure that consumers are safe and understand what they\'re
taking because so far no one has really, to my satisfaction, described
to me what PPA does.

CHAIRMAN BRASS: Okay. You can look on the screen. We\'ll have in a
second a representative package label for a PPA-containing product and
so that everybody will be able to see those things. I think there\'ll be
a couple of interesting points. Everybody has commented about the
percentage of users who were hypertensive in the group, and there
already exists a warning with respect to hypertension on this label. Do
you have some specific questions about this label?

MS. COHEN: I can\'t read it and, if I can\'t read it, consumers can\'t
read it. I mean can other people read it? Do I need to change my
glasses? I\'m serious. Can you read it?

CHAIRMAN BRASS: Yes, I can.

MS. COHEN: Would you do it for me then?

CHAIRMAN BRASS: Would you like the whole label read in?

MS. COHEN: Well, I think we need to know if we\'re talking about safety,
and I still want to know about \--

CHAIRMAN BRASS: I think we\'ll go on to other questions and perhaps you
can go up to the screen and read the label.

MS. COHEN: No. I think everybody in this room should know what that
label says if we\'re talking about safety.

CHAIRMAN BRASS: What is your concern about the labeling with respect to
safety?

MS. COHEN: I want to know what precautions are given to consumers if
they take over 75 milligrams, for instance, if they have thyroid, if
they have prostate, if they have heart disease. I want to know what else
this label will tell consumers so they\'re going to know what they\'re
taking and what they\'re taking it for. I don\'t know if anybody else
agrees with me. I don\'t want to be the lone consumer in the world.

CHAIRMAN BRASS: I will read you the warnings. Do not use if you are now
taking another product containing phenylpropanolamine, a prescription
monoamine oxidase inhibitor, certain drugs for depression, psychiatric
or emotional conditions or Parkinson disease for two weeks after
stopping the MAOI drug. If you do not know if your prescription contains
an MAOI, ask a doctor or pharmacist before taking the product. Ask a
doctor before use if you have high blood pressure, thyroid disease,
heart disease, diabetes, glaucoma, or breathing problems such as
emphysema or chronic bronchitis, difficulty urinating due to enlargement
of the prostate gland or have been reading too fast.

(Laughter)

MS. COHEN: Okay. And this is an OTC drug. Okay. So \--

DOCTOR SOLLER: Could I make a brief comment, Mr. Chairman?

CHAIRMAN BRASS: Please.

DOCTOR SOLLER: I will mention that FDA has proposed labeling and that
the products that we\'ve reviewed have essential elements of that
labeling and, ma\'am, we take this labeling very seriously. It\'s
important that it be driven by the information that we have. I think
it\'s relevant that there is a statement that tells consumers not to
take more than the recommended dose and it\'s accompanied by a statement
that says taking more can be harmful.

For PPA weight control products, there\'s a statement that it shouldn\'t
be used by people under 18 years of age. There are statements about
appropriate drug/drug interactions that should be looked out for and
potential contraindications. And that\'s not unlike other labeling in
other categories of OTC medicines. It\'s entirely consistent in its
construct and the kinds of concepts that are being conveyed to
consumers.

CHAIRMAN BRASS: Remember, our discussion now is on questions related to
the HSP and I don\'t think, while the labeling issues are important, I
don\'t think they\'re germane to the questions on the table. Doctor
Cantilena.

DOCTOR CANTILENA: Yes. Just a question about the package insert that you
just showed us.

CHAIRMAN BRASS: I\'m trying to get us back on to the HSP.

MS. COHEN: This is what it\'s about.

DOCTOR CANTILENA: It is related to that. Is that the current one or is
that what was available as the study was actually going on?

CHAIRMAN BRASS: Doctor Soller.

DOCTOR SOLLER: Well, Lou, I would have to look side-by-side, but I can
say to you that I think it\'s probably the same one that was going on
when the study was initiated. You\'re asking me to look at what\'s here
and comparing up there. What it looked to me was the one that was on the
major PPA-containing products, national brands as well as the house
brands. I mean if you want me to take a look more closely and report
back to you during this meeting, I can do that.

DOCTOR CANTILENA: Yes. Specifically in terms of the contraindications
and those kinds of things.

DOCTOR SOLLER: Basically they were there. Yes.

DOCTOR CANTILENA: So those were in effect a label that was extremely
similar to this, if not identical, was in platy for the subjects who
actually ended up in the study. Is that true?

DOCTOR SOLLER: I would say reasonably similar for the major brands and
at least one of those had something that was in drug facts-type of
format. The house brands and at least one other national brand was not
in that kind of format, so there were differences in the labeling and it
was not across the board entirely consistent with what was proposed by
FDA, the reason that we suggested that there be a push to standardize
that particular labeling. When that happens, it would also be
standardized into the format that I know you\'re familiar with, the
panel ANDAC has reviewed, that\'s the new OTC label format.

DOCTOR CANTILENA: Okay. Thank you.

CHAIRMAN BRASS: Doctor Elashoff.

DOCTOR ELASHOFF: With respect to confounders, I don\'t think any
epidemiological study no matter how big or how well done, can prove
without a shadow of a doubt that it\'s the drug in question that is the
cause rather than some confounder. The issue though is does the study
suggest that one ought to be worried about the drug in question.

CHAIRMAN BRASS: Doctor Gilman, since you did such a fine job of getting
us into the two sub-populations, what is your feeling about the general
population, the all-exposed population without a gender breakdown?

DOCTOR GILMAN: Well, based upon the data as we have seen them, I would
say that the results in the HSP Study show that PPA is not safe from the
risk of hemorrhage in the population as a whole.

CHAIRMAN BRASS: Does that elicit any comment? I just want to follow up I
think on something that Doctor D\'Agostino was suggesting and actually
was prompted by the comment from the CHPA group, and that is I endorse
the concept that one has to be very careful about getting into sub-group
analyses and to the degree they can be helpful, that\'s fine but when
the sub-group analyses get even smaller, people are concerned about the
small numbers in the primary end points which were prospectively defined
adequately powered to address those issues and then confuse how
sub-group analyses aren\'t clear. I think that\'s not surprising and,
while it is okay to talk about them, I think that one has to focus the
primary conclusions on the primary hypotheses that were posed by the
study which, in fact, included women prospectively as a sub-group and
the general population and the degree to which confounders were not
balanced, one has to rely on overall general principles to assess
whether or not they mitigate the response.

DOCTOR D\'AGOSTINO: Again, I think the issue is that if this were a
clinical trial in other settings or epidemiologic case control, you say
you look at the global and then you look for consistency across the
sub-groups. You don\'t look for statistical significance across the
sub-groups. I think the concern that\'s being raised is that some of
these sub-groups and some of these variables, these confounders, may be
what\'s driving the analysis. When you look at the sub-groups, none of
them are inconsistent but we don\'t have the ability to perform a test
that, as Janet just said, it\'s going to be everyone\'s satisfaction.
But I think it is a good point to bring this back to what the study was
designed to actually do and see what happens at that level.

DOCTOR DALING: Doctor Delap, did you have a comment earlier?

DOCTOR DELAP: I think my comments have been addressed in the discussion
here. Thank you.

DOCTOR KULLER: Can I make a comment?

CHAIRMAN BRASS: Please.

DOCTOR KULLER: I think there\'s two questions here which still need to
be resolved. First, this man/woman situation. The use of PPA in the
control group in the men and the women is exactly the same. It is not
statistically different. It is not low use of PPA in the men, and the
number of cases in the study is very similar for men and women so that
yes, subarachnoid hemorrhage may be more common, as we know, in women
but in this study, the number of cases in men and women is not terribly
different and the use of PPA, especially if you exclude the use in
obesity drug, is 2.5 percent versus 2.1 percent in the controls.

The interesting observation is that there is no exposure in the male
cases, but that has absolutely nothing to do with PPA use in the
population. It only suggests that there might be a difference in the
characteristics of the cases.

The second problem, which hasn\'t been resolved and was pointed out by
Doctor Daling a few moments ago, is that internally the study is superb
but I just don\'t understand how one can resolve the issue that the
controls are almost the same as basically going on a street corner and
asking people whether they took PPA or not. I mean when you have that
small a control group, when you have to make 100 and some phone calls to
find one potential control and then only one out of three who you
actually find ever get into your study, I don\'t understand how you can
possibly interpret the control group in terms of the use of PPA when the
whole study is based on eight cases that use PPA versus five controls.
This is not a twelve-fold risk across the population. It\'s eight versus
five, and when you have that much of a problem with selection of
controls, even though the rest of the study is superb and it is and
everything they talked about and the FDA presentation, we all agree. But
the problem is you still have the controls are just like doing a survey
by asking people on the street who you\'re going to vote for or what do
you think of something. That\'s not the way we do studies and, when you
have that problem, it\'s almost impossible to interpret the results.

CHAIRMAN BRASS: If I could just ask you to clarify something you just
said. I thought in the control, the use of PPA was higher in the women
than the men.

DOCTOR KULLER: It\'s 2.5 percent versus 2.1 percent if you exclude the
women who were taking the appetite suppressant and, if you don\'t, then
it\'s 2.7 versus 2.1 and that is not even close to statistically
significantly different. It is strikingly different among the cases. 5.1
in the women and 1.9 percent in the men, but that has nothing to do with
PPA in the community. It has to do with the use of the drug in male
cases versus female cases and the number of cases is 319 men and 383
women in the study. So it\'s not a function of there aren\'t any men in
the study. This is not a power issue in men. It\'s a very interesting
observation that men are essentially protected and women basically have
what\'s reported to be a risk in the study. But you can\'t attribute
this to low use of PPA in men or basically to not enough stroke cases in
the men to interpret the data.

DOCTOR HORWITZ: I just wanted to make a comment on Doctor Kuller\'s
observations. We agree with Doctor Kuller about the total number of
cases among men and women which are very similar in that the overall
exposure prevalence for PPA between men and women is not greatly
dissimilar. I think where we may disagree is that if you look among the
controls for males, there were no appetite suppressant users among males
and there was only one male user for first use of cough/cold.

So the reason we raised that concern and why we felt that there was an
issue of this study being under-powered for that purpose was that there
were no male appetite suppressant users and only one male first use of
PPA in cough/cold products. It was that part of the analysis which was a
pre-specified part of the hypothesis of this study for which we felt
that we had insufficient exposure among the controls and left it
difficult for us to answer specifically.

DOCTOR KULLER: But Ralph, you have to admit you only have four women who
are first exposures in the controls, also, so you have one man and four
women in the entire study and that would be a little shaky in terms of
interpretation. There\'s only four women in the control group that are
first users and there\'s one man, so that\'s your entire presumption.

I think the more likely hypothesis is that there\'s something different,
either the distribution of cases between intracerebral and subarachnoid
between men and women or likely that the drug behavior, whatever it is
or whatever else is going on here, is strikingly different between men
and women. It\'s a rather interesting observation, but I don\'t think it
can be washed out by power.

DOCTOR HORWITZ: I\'ve learned over the years not to try and get into a
dispute with Doctor Kuller. The emotion would be high and the stakes
would be low, I\'m sure. I did, however, want to point out that when we
said with regard to first use in women the .5 percent, Doctor Daling,
that we had referred to earlier had to do with the expected exposure
prevalence for first use among women of .5 percent. You may feel, Doctor
Kuller, and I understand that, that the four exposed women in that
category represents a small number. It was the anticipated number that
led to the sample size estimation that .5 percent was what we
anticipated from the market data, that .5 percent was what we found in
actually conducting the study. Those four exposed controls‑- you and I
may wish there were more \-- nevertheless were the basis for the sample
size estimations that we used in the planning of the study.

CHAIRMAN BRASS: Doctor Gilman.

DOCTOR GILMAN: I don\'t think that the data show us any evidence that
men are protected. What we saw was that there were very few effects in
them, but that shows no \-- to me, there\'s no evidence of protection in
men.

CHAIRMAN BRASS: Doctor Blewitt.

DOCTOR BLEWITT: I propose that we go back to your question, question A,
and I\'d like to step back from all the details of this issue and just
make a few comments if I may. First, it\'s my belief that the study
results are not conclusive. Now, that\'s not to say, however, that there
isn\'t useful information that can be potentially gathered from a study
of this size. I personally don\'t think that we\'re going to‑- for the
committee\'s sake, I don\'t think we\'re going to resolve the
epidemiological and statistical debate that\'s been going on here. It\'s
just not possible, particularly where the data are described as fragile,
some of the results appear to be inconsistent.

My own reading, general reading of it, not being an expert, is that I
really felt that the populations differed significantly as to make them
non-comparable. I felt that comparing hospitalized versus
non-hospitalized was not wholly appropriate. I felt that the cases
differing significantly on seven different factors was important. I felt
that there was a substantial difference in the patterns of use of the
drug in cases in controls and so forth.

So my approach was to basically pretend that 27 cases were brought to me
to take a look at, 27 charts, and say what do you think about these?
There\'s a concern that maybe phenylpropanolamine is the culprit in all
of this, and give us your feeling. And my approach to that would be to
take each of the cases and to look at the dose that was given, the
timing of the dose, what concomitant medications might be taken, what
concomitant disease states might be present and the general
demographics.

And so I went to page 37, Table 6 here, and without getting into too
much detail because I\'m not looking at hospital charts. This is the
study report manuscript. But just in what I could perhaps gather from
looking at this chart compared to what I might be able to get if I were
able to look at the cases in some depth and I found that if I looked at
the case group, there were, in addition to what\'s been said about
smoking and hypertension and so on, a lot of cases where the dose in
three days was exceeded. I see a 600, I see an 890, a 480, 640, 600. I
see the last dose in some cases being 150, 150, 150. I also see one
which is low as 20.

So it leads me to question what\'s going on here and it leads me to say,
well, is there a value in taking a look at these cases individually on
that basis and could that lead you to a population that would perhaps be
at risk for taking the drug? If a substantial percentage of these people
have taken it beyond the labeling indications, I think that\'s a factor.
If there are coexistent illnesses or medications, we\'re not entirely
clear on medications, then those are factors, too, which would govern
your judgment on that. So I would suggest that perhaps taking a look at
these cases in depth, given that I really feel that it\'s going to be
very hard to resolve the issues with regard to statistics and
epidemiology. So that would be my comment.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I think what was just stated is actually very
important, but I also want to remind us of where we sit here. I mean 10
years ago, we had cases being reported and what you said would be very
compelling. What do they consist of? Do they overdose? Are they taking
other drugs and so forth? Because there was data that was indicating
that in females with appetite suppressants, first users, there was this
very long-term epi study and what you are suggesting now is that let\'s
forget that this is a well-designed study, that there were cases, there
were controls, and run to looking at the individual cases. I would think
that because it was a study that was well-designed and so forth, we
should look at what the analysis of the study says and, if we come up
with something, if we said the study is completely inconclusive, we say
that we don\'t think there\'s any relationship, then it ends but, if you
say there\'s a relationship, then you ask the question, well, what\'s
driving the relationship? Is it over-use and so forth?

And so what I\'m suggesting is that let\'s remember that this was a case
control study that was prospectively put together and I think we need to
look and we should look at how the hypotheses played out and then
certainly for interpretation, if we think there\'s a relationship, to do
exactly what you said. I think we have to be compelled to do what you
said.

DOCTOR BLEWITT: If I may respond. I don\'t think that I\'ve heard anyone
here today say that this study wasn\'t properly designed. In fact, I
think even those who have perhaps critiqued the study have all agreed
that this is a well-designed study. I think that a lot then goes to the
execution and really basically what comes out of the study. You can have
the best of intentions, the best protocol design, as you know, but that
doesn\'t necessarily mean that what you\'re going to get at the end is
what you had desired to accomplish in the first place. So I agree with
you. I don\'t see that as an issue.

I think the issues have been raised in terms of how the data were
collected and whether they were validly collected and so forth. I mean
that\'s what it comes down to. What is it that you have at the end, not
what you have at the beginning.

CHAIRMAN BRASS: I\'m sorry. You had a comment earlier.

DOCTOR LA GRENADE: I was going to point out that in the random digit
dialing selection they were trying to match the controls to the cases.
So when they phoned the first person, you have to match the case on
certain criteria. So it wasn\'t just as though you didn\'t respond, and
I think this is a factor that we probably have lost sight of in the
discussion. I just wanted to bring it back to the attention of the
committee.

CHAIRMAN BRASS: Thank you.

Doctor Cantilena.

DOCTOR CANTILENA: Yes. Just in follow-up to George\'s comment. I mean if
you look at that Table 6, George, I guess what I\'m hearing you say is
that it may not be less of a problem or as much of a problem because in
five of the females and one of the males they exceeded the recommended
dose in three days. But I sort of look at it in another way in that this
is, in essence, an actual use study and really those five females but
not the male certainly exceeded the last dose but only by a factor of
two for an appetite suppressant dose. So it really, in essence, comes
down to an extra pill and they ended up on the case list.

So I think the way I\'m hearing you, I just wanted to ask you to clarify
that because, as I see it, this is really sort of telling you that
perhaps the safety margin is not as it should be if you can just exceed
the dose really slightly by a factor of two to two and a half, I guess,
in the column for the dose in three days and still end up here on the
list. I mean we\'re talking about an over-the-counter and it\'s, in
essence, sort of an actual use.

DOCTOR BLEWITT: Well, it is a case where a couple of tablets can make a
difference. The labeling has been adjusted in fact to bring the total
daily dose to the lowest reasonable dose that would not cause side
effects. So it initially was somewhere \-- it\'s been backed up. For
instance, it\'s as if you\'re asking me well, if you took a 400
milligram ibuprofen tablet, wouldn\'t it be okay to take an 800
milligram, and so there is a point at which you draw the line for
medications and I think that that applies here as well.

DOCTOR WEISS: Could I just clarify the issue about the method and the
conduct of the random digit dialing. The concern of the Review Committee
wasn\'t that a large number of calls had to be made to identify a
matched individual. We understand that process would require a large
number. Our concern was that among those persons who are identified as
potentially eligible, only approximately 35 percent of them actually
were recruited into the study.

The reasons why non-participation is of concern, of course, is that
participants and non-participants may differ in a lot of ways that are
important to the exposure in question. I\'m not saying this actually
occurred, but it\'s conceivable that if a potential control is
identified and asked to be participate in an interview but that control
has a cold, is not feeling well, they may preferentially choose not to
participate. If that does happen, then in the controls that are selected
you\'re going to have an under-representation of the use of PPA.

There is certainly some reassurance in the fact that the proportion of
users of PPA was roughly that predicted in advance, but I doubt that
that prediction focused on the four geographic areas in the particular
age group that was in question. I think there was a good reason to pick
some controls and the worry still is that they may not really represent
the population at risk for this condition.

CHAIRMAN BRASS: Doctor Kittner.

DOCTOR KITTNER: I think everyone agrees that the study was well-designed
and I heard a statement that it was not well-executed. I think that
there\'s no consensus that I\'ve heard around the table that it wasn\'t
well-executed. In fact, I think that if we were to repeat this study and
spend another five years, we\'d likely be back around the table here
with very similar data and very similar issues. Many of the issues are
really inherent. This is actually the largest case control study ever
conducted in hemorrhagic stroke and, what\'s more, it\'s in a low
instance population. We\'re talking about stroke at any age and here we
have a stroke in young adults which is the largest study ever conducted.
So I don\'t think that if we come and redesign and do a study we\'re
necessarily going to be in a better position in five years.

CHAIRMAN BRASS: I think it\'s important, again just to try to maintain
some focus, I think the issue of whether or not we conclude something
from HSP needs to be separated, whether we conclude anything or not,
help us in the policy decision making, and I think those are two
separate issues, and your point, which I agree with, is germane to when
we try to extrapolate from HSP into decision making.

Ms. Cohen.

MS. COHEN: I have a question I don\'t know the answer to. I noticed on
the labeling that children 12 years \--

CHAIRMAN BRASS: I\'m sorry. Only things related to the HSP
interpretation.

MS. COHEN: Well, I think this is important, Doctor Brass, because
someone can answer it. It said that children 12 years of age and older
and adults can take up to 150 milligrams a day, and I think I need to
know if that\'s a safe amount. This is about safety and consumers.

CHAIRMAN BRASS: Other comments about the HSP.

DOCTOR DELAP: I think we are interested in the comment that was just
made, but I\'m hoping that we\'ll get some discussion of the dose a
little later on.

CHAIRMAN BRASS: That\'s correct.

DOCTOR DELAP: I think we have that under question D. I don\'t want to
lose that.

MS. COHEN: Thank you very much.

CHAIRMAN BRASS: Yes.

DOCTOR WARACH: I do have a reservation about the conclusion of the
association with the hemorrhage risk for two concerns. One is the
problems with adjuster controlling for all the potential reasonable and
relevant confounders. The other one that had been mentioned only
slightly in passing earlier today was the problem with self-report with
regard to cocaine or other illicit drug use and cocaine is a recognized
risk factor for hemorrhage. It\'s likely to be unreported. Perhaps even
more so in the group that suffered the stroke and is feeling a bit
guilty about their abuse behavior. So I think the study is very
suggestive of this association, but I have that reservation and I would
say it\'s ultimately inconclusive on that point.

CHAIRMAN BRASS: Do the investigators happen to have any information
about tox screening on the cases. You\'d think that in young patients
presenting that it would commonly be done.

DOCTOR KERNAN: We don\'t have any recorded information on toxicology
screens.

CHAIRMAN BRASS: I assume you\'re going to want votes. Yes, I was afraid
you\'d say that. Okay.

DOCTOR NEILL: I\'m going to save you from voting for a minute. A couple
of comments about the study. The first is that with regard to the issue
of being able to assess for confounding or not, I\'ve been convinced
that this is not a study that can help me control for that and yet to
the extent that it\'s been attempted, it hasn\'t shown any difference in
their results.

To the extent that it was designed to answer a specific question in the
overall population and a co-equal aim in women to answer a specific
question, it answered those questions and very clearly overall the
answer from this study, however imperfect, is yes, there\'s an
association.

The second comment I\'d like to direct to FDA staff, but I\'ve got three
comments so don\'t answer until I get my little third one in. Earlier I
was asked by Doctor Soller to use science as a base for my decision and
it\'s my impression that PPA is OTC by virtue of historical accident
rather than virtue of science and I wonder if, after my next comment,
you could reconcile the expectation that I\'m supposed to use the
results of the aggregate data to make a decision about OTC safety for
this with FDA\'s statement earlier that the burden of proof for safety
is with the manufacturer.

CHAIRMAN BRASS: I\'m sorry. I\'m going to interrupt again because we\'re
going to get to the issue of how whatever we conclude about HSP is used
for decision making.

DOCTOR NEILL: Okay.

CHAIRMAN BRASS: So I really want to stay‑-

DOCTOR NEILL: Can I move on to my third comment then?

CHAIRMAN BRASS: Thank you.

DOCTOR NEILL: You can just let that float in the air. With regards to
the small numbers that makes it so difficult to control for confounding
in men and lack of men using appetite suppressants, I saw some data that
suggested that the overall use in the general population is
overwhelmingly for cough/cold preparations and I haven\'t heard anybody
comment on what seems to be the massive over-representation of
hemorrhagic strokes occurring in people using it for appetite
suppressants. I don\'t have an explanation for why.

Fully a third of these cases come from people using it for that
indication when they represent a tiny, tiny percentage of the overall
use and, if nothing else, that suggests to me that I ought to believe
these fragile results.

DOCTOR SOLLER: Doctor Brass, just quickly. I think what\'s important
here relative to the scientific documentation in that standard is really
what we heard a little bit earlier, that maybe there\'s not an
evidentiary standard for safety, that it more becomes well,
subjectively, how do I feel about this data set? And I think what the
policy does, it drives us to a much more rigorous view of that.

The comment was the burden of proof for safety is on industry. The
agency has acted in approving NDAs and, as far as I know, NDAs for
products are approved in the context of safety and effectiveness. I
think, therefore, the question here is whether there is a sufficient
evidentiary standard and it must be rigorous. That\'s why you\'ve been
brought in because obviously you\'ve got, I think, what the industry
looks at is a major polarization within the epidemiologic community and
some very important players within that community raising very, very
significant concerns. And I think that that\'s very important. And if
you come to a point where you are going to keep the evidentiary standard
where it should be, then I think for this study you end up being
uncertain that is has shown what you\'re suggesting it has.

CHAIRMAN BRASS: From the FDA\'s perspective, before we go into voting,
are there issues that you think have not been discussed about HSP that
you would like to hear discussed that would be helpful from your
perspective?

DOCTOR DELAP: I think the discussion has been a very good one, and some
of the salient points that I\'ve picked up are that the numbers of
events on which you\'re basing a conclusion of an association are
relatively small. We knew that that was going to be the case going in, I
think, when the study was designed because power was at the margin, even
with this fairly ambitious study. I\'ve heard the discussion that it\'s
hard to analyze satisfactorily for confounding in a setting where you
don\'t have so many events to base those kinds of analyses on. I think
we hear that, as well.

We\'re looking at this again from the standpoint of we had some concerns
in the early \'90s, particularly about women, particularly about weight
control products, and this study grew out of that. So we\'d like to have
your answers as to how we should interpret the results of this study in
the setting of all the information that\'s led up to today.

DOCTOR HENNEKENS: I wanted to respond to Doctor Neill\'s comment about
the overall results. I believe that if one sets aside the concerns that
you have a 35 percent articulation rate in controls and an inability to
control confounding, especially in the sub-group analyses, if one looks
at the overall test of the hypothesis of whether taking PPA for either
cough or cold suppression or appetite suppression is associated with
risk of hemorrhagic stroke, the overall analysis, to my thinking, is
based on 27 versus 33, and that is not statistically significant.

DOCTOR NEILL: I guess I would respectfully disagree. What I see is an
elevated odds ratio with a p-value of .089 which, while it isn\'t .05,
is high enough when considering items of safety to make me concerned
about that. I don\'t think the study was designed to answer the
question, but I haven\'t heard an explanation for why people using this
for appetite suppression as an indication would be over-populated in
either of the two groups.

DOCTOR HENNEKENS: I certainly agree with your point that you might want
a different standard for safety than for efficacy. However, I also feel
that my opinion is that if you follow guidelines that are emanating from
these data, they\'ll be lots of drugs you throw off the market when
there\'s nothing wrong with them and lots of drugs you leave on the
market that are causing fairly large effects that you\'re missing
because of using rules like this. It goes both ways.

DOCTOR NEILL: I guess one other point that was brought up several times
is that in addition to the very low response rate, there\'s this
unaccounted for dead folk who obviously, by their absence, would tend to
make it more difficult to show an effect which is why I remain impressed
that there is an effect that\'s demonstrated despite their absence.

CHAIRMAN BRASS: Doctor Gilliam.

DOCTOR GILLIAM: My concern, I guess, is with the safety, too, and using
the figure that are given, about 10,000 people a year in this age group
have a stroke, and the FDA was saying that they can attribute \-- if you
believe the statistics, that there\'s 200 to 500 strokes in this age
group that could potentially be prevented, that\'s two to five percent
of the strokes in this age group. I think that\'s of concern. Plus also
the fact that people are not taking this in the recommended doses.

CHAIRMAN BRASS: I\'m almost going to give up but again, it is quite
possible to conclude that there\'s an association based on HSP but when
we get to risk versus benefit, etcetera, and vice versa, despite the
absence of an association of the trial, one might conclude.

Doctor Gilman.

DOCTOR GILMAN: I think it\'s a good idea to go back and take an omnibus
position now because this is a trial that was conducted prospectively
with a set of hypotheses to test with case control methodology that was
superbly followed and the result was significant. As I see those data,
they are significant. It\'s not a feeling. It is what the data show me
anyway. So I\'m not troubled, as some people in the room seem to be, by
the quote \"small numbers.\" They were predictably going to be small
numbers. We have what was predicted at the very beginning of the design,
and so it should be no surprise to us now that we\'re dealing with small
numbers, but the numbers show a significant risk for hemorrhagic stroke,
particularly among first users and in women.

CHAIRMAN BRASS: Doctor Katz.

DOCTOR KATZ: I agree the point of which was the primary outcome and
adjusting for multiple comparisons. These are very important issues and
we worry about them all the time and overall, given one of the so-called
co-equal outcomes, it didn\'t make it nominally statistically at .08 I
guess was the thing. But as Doctor La Grenade said earlier, I just want
to reiterate this point. Apparently from the point of view of the FDA,
even though there were technically three or five co-equal outcomes
apparently, I\'m told that the one outcome in which the agency was
specifically interested in as the ultimate primarily‑- if I can speak
for the team and I really shouldn\'t, they\'re here, they can speak for
themselves \-- was the sub-group in which the statistically significant
finding emerged. In other words, women taking it as an appetite
suppressant. And that finding, if you consider that to be the primary,
if you believe that, holds up to any sort of \-- pretty much holds up to
any sort of reasonable adjustment procedure for the p-value.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I think that it\'s been over and over again and
those who are aware of the history know that it\'s exactly what you just
said. You can argue on the other side is that the investigators put a
study together and they came up with five hypothesis and gave them all
equal weight. I would argue, even in the light of them giving it all
equal weight, those significant values using .05 as the cut-off can\'t
be ignored.

CHAIRMAN BRASS: Okay. I\'m going to try to synthesize some questions
that we can actually vote on. Before we start, I want to remind
everybody that Doctors Warach, Blewitt and Kittner are not able to vote
though they\'re able to participate in the discussion. And all the
questions are going to have the following form. They\'re all going to be
about the HSP Study. I\'m going to follow my own rule. And there\'s
going to be three options on each question.

So the three options are going to be that the HSP Study suggests that
PPA is safe from risk of hemorrhage, that the results suggest that there
is an association between PPA and hemorrhagic stroke or 3) inconclusive
between those two alternatives. And I\'m going to identify populations
and uses and we will vote on them individually. So the first option will
always be safe, 2) will be associated, 3) will be inclusive. Is that
strategy okay? Okay.

So the first population I\'m going to ask the question about has to do
with women between the age of 18 to 49 using PPA as an appetite
suppressant. Safe, associated, inconclusive. All those who feel that,
based on the HSP Study alone, that PPA is safe in that population,
please raise your hand.

All those who feel that PPA is associated with hemorrhagic stroke in
that population, please raise your hand.

DOCTOR TITUS: There are 13 \--

CHAIRMAN BRASS: Thirteen. Well, I\'ll read it at the end.

And all those who feel the data are inconclusive, please raise your
hand.

DOCTOR TITUS: One. So the tally is zero for safe, 13 for there is an
association, and one inconclusive.

CHAIRMAN BRASS: The next population will be women between the age of 18
and 49 using the product as a decongestant, and that\'s any decongestant
use. Is that clear? In other words, I\'m not talking about first dose
only. I\'m talking about any exposure as a decongestant. People have
that?

All those who feel the product is safe for that group, please raise your
hand.

All those who feel there\'s an association in that group, please raise
your hand.

All those who feel it is inconclusive in that group, please raise your
hand.

DOCTOR TITUS: So for the females in the 18 to 49 year age for
decongestants, there were zero who thought it was safe, there were six
who thought there was an association, and there are eight inconclusive.

CHAIRMAN BRASS: Next are women 18 to 49 using any PPA product on first
exposure. Okay. Is that clear? First use risk in women regardless of
product class. Okay? All those who feel the product is safe in that
group, please raise your hand.

All those who feel that there is an association in that group, please
raise your hand.

All those who feel the data are inconclusive in that group, please raise
your hand.

DOCTOR TITUS: For females in the ages of 18 through 49 on their first
exposure to PPA, we have zero who thought it was safe, we have 13 who
thought there was an association, and we have one inconclusive.

CHAIRMAN BRASS: We will now do those same three classes for the general
population. So no gender specificity. So without respect to gender,
using PPA products as appetite suppressants, those who feel the product
\-- I\'m sorry. It\'s a clarification question? Please.

DOCTOR GILLIAM: This is just in the 18 to 59 general population or the
population as a whole?

CHAIRMAN BRASS: The HSP population, so the 18 to 49. I\'m sorry for not
clarifying that.

Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: You want us to vote on the women data, the female
data, overwhelming the combined data?

CHAIRMAN BRASS: That could be an interpretation of what I just said
because I think that, again, in terms of the compilation of the data,
one of the hypotheses were all exposure.

DOCTOR D\'AGOSTINO: Or you could also be saying that there\'s
consistency in males and females and sub-group shows it just on females.

CHAIRMAN BRASS: Well again, in my mind, this goes back to the original
hypotheses of the study. One could vote that the result could be
significant for women and in the general population, either because the
effect is generalizable or in the general cohort the data in women
statistically drove it so that it was significant odds ratio. I think
which of those occurs has implications for the interpretation of what
action should be taken but from a study design primer hypothesis, I
thought it would be worth putting on record. But I appreciate the
clarification.

Doctor Gilman.

DOCTOR GILMAN: I have concern about doing this though. This is the
reason that I suggested that we just eliminate men from the beginning.
The problem is that we have a set of hypotheses driven by the principal
question which is about women and stroke and, accordingly, the study was
designed with that in mind and now, since there are only two choices,
there are men and there are women, we don\'t have any other choice here,
we have to decide whether we want to say, well, I assume there may be
some risk to men even though I don\'t know whether there\'s risk or not.
In other words, go beyond the data as they exist because the trial
wasn\'t designed with this in mind. So I have a problem in trying to
vote on this with this question in mind. The study was not really set up
or the data do not lend themselves now for me to have clarification as
having good rationale for a vote to include in the at risk population
because it doesn\'t look as if men are at risk in this population.

CHAIRMAN BRASS: Let me just read the first study objective from the
trial. Specifically to estimate the association between PPA and
hemorrhagic stroke among men and women, men and women, not separately,
age 18 to 29 and estimate the association by type of PPA exposure in
that general population. So that was the rationale, I though, and, while
I was concerned because men were not a prospective sub-group, women
were, that I thought that addressing the study hypotheses and our
conclusion might be helpful. Doctor Delap.

DOCTOR DELAP: Yes. I think I can understand where Doctor Gilman is
coming from. I think there\'s kind of a logical problem here. I mean it
would be hard to say if you\'re going to ask the question for the whole
population, if you feel that there may be a problem in women, how could
you say that there\'s not a problem for the whole population because
women are part of that. So I think Doctor Gilman is trying to say, well,
we\'ve said what we thought about the women and maybe we should just
find out separately what we think about the men and then we can kind of
add it up.

CHAIRMAN BRASS: I\'m happy to do that, but let me again express my
concern that men were not a prospective cohort, that there are reasons
to think that if one designed it prospectively for men, one would have
designed it differently and that the event rate differences, etcetera,
compound that interpretation. But I\'m happy to do it that way instead
of the total cohort if people are more comfortable doing that.

Doctor Johnson.

DOCTOR JOHNSON: Well, I guess I sort of would follow your suggestions
because these are the aims of the study. Total population, which
obviously includes women, and women. I would be uncomfortable voting on
men because it wasn\'t a pre-specified aim and it wasn\'t designed for
that.

CHAIRMAN BRASS: Should we vote on what we\'re going to vote on?

DOCTOR D\'AGOSTINO: I was going to say, again, if the discussion we had
at the beginning of this, that one interpretation, if we say yes, is
that the female data is the thing that\'s driving it and so we\'re not
actually necessarily giving an interpretation but just what the data
says.

CHAIRMAN BRASS: Yes. Have we convinced you, Doctor Gilman?

DOCTOR GILMAN: No. It\'s worse than that, Jim. The problem is that if,
thinking of my own vote, if I vote that it is associated with risk for
the whole population, in my mind, I would be voting on that side of
things because the women overwhelm the men but it doesn\'t mean anything
about the men. Yet implicit in this vote is that men are equally at
risk, and I don\'t know if that\'s true or not. That\'s the problem with
this vote. I don\'t know how to vote, quite frankly.

CHAIRMAN BRASS: Okay. I am happy to do a gender, I\'m happy to do it by
men by that category, and then we can see if it\'s worth doing a third
round. Why don\'t we do it that way. Doctor Neill.

DOCTOR NEILL: I\'m right with Doctor Johnson on this one. The study
wasn\'t designed to answer the question in men. I asked myself the same
kinds of questions, and I guess I have no qualms about answering the
question as regards to the entire study population because that\'s what
the study was designed to answer and, while it\'s open to many
interpretations, many of which I\'ve gone through in my head \-- let\'s
see \-- men don\'t take appetite suppressants, women do, women are the
subject of the marketing efforts of these medicines for appetite
suppressants. I mean the list goes on and on and on and, while there may
not be a risk for men on the drug store shelf, it\'s not like you\'re
going to say men don\'t take this. It ain\'t going to happen.

And so I would strongly urge that we not consider voting for men as a
subset since I think we would be implying that we\'ve got data to inform
that answer when we don\'t.

CHAIRMAN BRASS: Here I\'m going to take the chicken way out and we\'re
going to do both by male and the total cohort and, because there\'s an
inconclusive option, everybody will be able to express whether or not
they\'re comfortable voting that way, and it\'ll be really simple. So
let\'s do it by men. We\'ll do the men sub-group first. Men between the
age of 18 and 49 using the product as an appetite suppressant. All those
who feel in that population PPA has been shown to be safe, please raise
your hand.

All those who feel that it\'s been shown to be associated with risk,
please raise your hand.

All those who feel the data are inconclusive in that population, please
raise your hand.

DOCTOR TITUS: Fourteen inconclusive.

DOCTOR D\'AGOSTINO: Can I abstain?

CHAIRMAN BRASS: Let the record show that Doctor D\'Agostino is
embarrassed to be associated with this vote.

Okay. Men using decongestant. Safe, please raise your hand.

Associated with risk, please raise your hand.

Inconclusive, please raise your hand.

DOCTOR TITUS: I missed somebody\'s vote. I\'m sorry. I don\'t get the
right count. Okay. Fourteen are inconclusive for men on decongestant.

CHAIRMAN BRASS: Okay. Men 18 to 49 with first time exposure to a PPA
product, safe, please raise your hand.

Associated with risk, please raise your hand.

Inconclusive, please raise your hand.

DOCTOR TITUS: Fourteen are inconclusive for men 18 to 49 for the first
time use.

CHAIRMAN BRASS: Now without gender specificity, the population between
the age 18 to 49 using the product for appetite suppressant. All those
who feel HSP has demonstrated safety in that population, please raise
your hand.

Those who feel that there is an association in that population, please
raise your hand.

All those who feel that it\'s inconclusive, please raise your hand.

DOCTOR TITUS: Okay. In the all population 18 to 49 for appetite
suppression, there is zero for it being safe, 13 for there is an
association, and one inconclusive.

CHAIRMAN BRASS: Next is the general population 18 to 49 using the
product as a decongestant, regardless of timing of exposure. Male and
female 18 to 49. All those who feel HSP demonstrates safety in that,
please raise your hand.

All those who feel an association of risk has been demonstrated by HSP
in that population, please raise your hand.

All those who feel that it is inconclusive in that population, please
raise your hand.

DOCTOR TITUS: The all population for decongestants, we have zero think
it\'s safe, five think there is an association and nine it\'s
inconclusive.

CHAIRMAN BRASS: Next and hopefully finally for this group of votes, 18
to 49, all population with first time exposure to a PPA-containing
product. All those who feel HSP establishes safety in that population,
please raise your hand.

All those who feel there\'s an association associated with risk in that
population, please raise your hand.

All those who feel that it is inconclusive, please raise your hand.

DOCTOR TITUS: In the 18 to 49 all population first time exposure, zero
thought it was safe, 13 through there was an association, and one
thought it was inconclusive.

CHAIRMAN BRASS: Thank you very much. Under A, there\'s one issue we have
not dealt with and that\'s specifically the question of dose. I\'d be
interested now in some discussion of, again based on the HSP data,
whether or not dose is felt to be a factor in any risk in these
populations. Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: Can I just ask, do you have a summary of what we
heard and I\'m going to say what I thought it was, that there was some
analysis but it wasn\'t significant but sort of directional. Is that
what we basically have before us?

CHAIRMAN BRASS: Doctor Gilman.

DOCTOR GILMAN: I believe it was suggestive but not statistically
significant.

CHAIRMAN BRASS: Would any of the presenters disagree with that
assessment of the dose data from HSP? That was certainly my impression
and that again, it was a secondary analysis. The recall about dose seems
to me to be even more problematic in that it was harder to verify. There
were strict rules for verifying yes/no, but to verify a dose of exposure
would seem to be to introduce an additional variable into that kind of
analysis which would be more problematic.

Doctor Sachs.

DOCTOR SACHS: The only comment I have is kind of a clinical correlation
in trying to think about maybe the pathophysiology of this, and it might
be a mistake to assume clear linear dose response relationship because
there might be a threshold effect, especially if the hypothesis is that
there\'s some kind of pre-existing dimple or blister in the blood vessel
that busts after using one of these agents.

CHAIRMAN BRASS: Other comments about dose? Would you like a dose vote?
Yes?

DOCTOR DELAP: When we get down to question D, you\'ll see we have some
discussion of dose there and I think it would be fine to skip a vote
here. We\'ve heard what I think the consensus is and we can get a little
further elaboration in question D.

CHAIRMAN BRASS: Thank you. I love being spared a vote. Okay. The next
question is B and, again, focusing on the HSP data, does it provide
information on which populations may be at greater or lesser risk? Now,
we\'ve defined nine different populations already based on gender and
exposure type and implicit in the vote was that women represented a
group of relative risk compared to men and, without doing a statistical
analysis on our votes, there was a suggestion that appetite suppressants
represented a use population. Are there other population identifications
that were gleaned from the presentation which any member of the
committee feels is important to highlight?

It appears not to be the case and, again, I think this goes back to the
limitations on the sub-group analyses and what stratifications were done
did not suggest to me any grouping of the risk by any of the strata so
that it did not appear to be unique to underlying hypertension or
etcetera but, again, that is clearly based on very small numbers but, in
trying to even detect a signal, I don\'t think there was much basis for
reacting to that data. Skip a vote? No vote? Okay.

Now we shift gears and now we will begin‑- Doctor Cantilena.

DOCTOR CANTILENA: I hate to say this, especially to you, but is it
possible to just get a five minute break? I have to answer a page, and
this is real important. I don\'t want to miss it.

CHAIRMAN BRASS: Okay. We will now take the Cantilena break for 10
minutes. Actually, we can take a 15 minute break. 3:15 please. 3:15.

(Off the record for a 15 minute break at 3:04 p.m.)

CHAIRMAN BRASS: The committee will now continue its discussion and in
what follows we will expand upon our earlier discussion in the
presentations to look more globally about the use of PPA in the OTC
market based not only on the HSP and our comments earlier about the HSP,
but the other information that has been compiled and summarized for us,
both from spontaneous reporting base and previous published studies.

So the first specific question we\'ll be discussing is whether or not
there\'s a body of data collected over the years that \-- I\'m sorry \--
there is a body of data collected over the years that has suggested a
possible association between PPA use and hemorrhagic stroke. Taking all
currently available information into account, do the data support the
conclusion that, 1) there is no association between PPA use and
hemorrhagic stroke, there is an association between PPA use and
hemorrhagic stroke, the association still remains uncertain because of
insufficient information.

Who would like to make some initial comment about that postulate?

DOCTOR GILMAN: I think we have heard data suggesting fairly strongly
that there is an association between PPA use and hemorrhagic stroke.

CHAIRMAN BRASS: Again, just to flesh out that, would you comment on what
of the available evidence you find most compelling in that conclusion?

DOCTOR GILMAN: It was the comparison of PPA versus all other similar
agents that was really striking to me. Fourteen percent with CVA for PPA
versus 0.8 percent all other drugs.

CHAIRMAN BRASS: So you\'re referring to the spontaneous reporting data
and what percentage of all PPA adverse events were cerebrovascular
versus the overall database and the enrichment of that in the PPA?

DOCTOR GILMAN: Yes.

CHAIRMAN BRASS: Yes, Doctor Sachs.

DOCTOR SACHS: In a supporting statement, the other thing, even back in
the adverse reporting from 1977 to 1991, the PPA diet reports of CVA
association was 26 percent which was greater than the 20 percent reports
of OCPs. That\'s really compelling.

CHAIRMAN BRASS: Doctor Kittner.

DOCTOR KITTNER: The other thing about these reports was that they were
pretty specific to hemorrhagic stroke and if this was just a background
rate or a coincidence of two independent things, you would expect them
to be similarly associated with ischemic stroke, and they really
weren\'t. I think some of the other points about the case reports have
already been mentioned, that is that there was a relationship to first
dose and often within the first six hours which is consistent with the
pharmacologic effect on blood pressure and the diminished effect with
repeated doses.

Another point in the case report and which we also see in the case
control study seems to me an association with excess use of a PPA.

One final point that I observed in reviewing the case report literature
was that the cases of intracerebral hemorrhage were not really entirely
typical. There were reports showing bilateral hemorrhage, two cases of
bilateral hemorrhage at that time, and 11 cases showing angiographic
features of vasculopathy, at least, or angiographic features that would
be consistent with vasculitis and I thought that\'s relevant in view of
the fact that PPA has close structural and pharmacologic similarities to
amphetamine where drug-induced vasculopathy with intracerebral
hemorrhage has been well-documented. So I think it speaks a little bit
to the potential biological plausibility.

CHAIRMAN BRASS: I noted that in some of your earlier writings and,
frankly, I got a little confused because how could there simultaneously
be an acute first dose six hour effect and then the development of a
vasculopathy? Those seem to be exclusive.

DOCTOR KITTNER: Notice I didn\'t say vasculitis, which is an
inflammatory condition of the blood vessels. I mean many things can
cause angiographic changes in the blood vessels, eclampsia and so on, so
that the pathological underpinnings of those angiographic changes are
not necessarily inflammatory.

CHAIRMAN BRASS: Doctor D\'Agostino.

DOCTOR D\'AGOSTINO: I want to make sure I understand this question. This
question is saying the data that was accumulated over the years, in
addition to the study we just looked at, the hemorrhagic stroke project.

CHAIRMAN BRASS: That is correct.

DOCTOR D\'AGOSTINO: Right. And so that being the case, the idea of
gathering a fair amount of data on spontaneous reports and other sources
and then actually putting the study together, that in a very real way
confirmed what was being shown with a lot of the spontaneous data and
other collected data I think is a very compelling scenario.

CHAIRMAN BRASS: Doctor Johnson.

DOCTOR JOHNSON: Yes. I agree that it\'s sort of the consistency of the
data, the case reports led to this study and the results really sort of
fell out the way that it might have been anticipated. But also, as
Doctor Sachs mentioned, some of the data about other drugs, comparisons
with other drugs, both in the spontaneous reporting system and also
within the HSP Study where there didn\'t seem to be associations with
other drugs, those things all together really just sort of strengthen
the evidence in my mind.

CHAIRMAN BRASS: Other comments about that. Would somebody, because the
issue has been raised multiple times, comment on whether or not the
nature and limitations of the spontaneous reporting base database
influence your confidence in those other data sets as we address this
question? Doctor Cantilena, would you comment on that, please?

DOCTOR CANTILENA: I think you\'re still trying to punish me for the
break. I would say that I think this is an example of where you see
something that might be a signal in the spontaneous system, and then you
go ahead with the HSP Study which I view for the subsets that we\'ve
already discussed as confirmatory of signal. But I guess I get
uncomfortable when people want to hold up the spontaneous reporting
system or MedWatch, as it\'s now known, as strong evidence for there not
being a problem. I just think it\'s not as sensitive as some of us have
heard, but I think it certainly was used appropriately, in my opinion,
in this setting where we spotted something, we thought it was a signal
and then we went ahead with the HSP Study.

CHAIRMAN BRASS: The other issue related to this that I\'d be interested
in some comments on, particularly from our neurology consultants, is the
issue of biologic plausibility, that again, when one is trying to build
the pieces together, it has been suggested by some that there is and by
others that there\'s no biologic plausibility for an association between
phenylpropanolamine and hemorrhagic stroke. Would one of our
neurologists comment on that, please.

DOCTOR GILMAN: May I comment on the previous question?

CHAIRMAN BRASS: Most certainly.

DOCTOR GILMAN: The reported data on association of hemorrhagic stroke
with PPA use is not only just suggestive. I think it must be vastly
under-reported for many reasons. The principal reason is because it\'s
not that easy to report for second. In today\'s hospitals, there is
enormous pressure to see patients. Getting a full history of all drug
exposures is difficult, time-consuming, and one has to keep in mind that
PPA may not necessarily be the drug on a clinician\'s mind when one sees
a young person with hemorrhagic stroke. There are many other issues. Is
the patient going to herniate? Do I need to watch this patient, put the
patient in ICU, etcetera, etcetera? Do we call the neurosurgeon? Is this
a berry aneurism that may need treatment? There are many, many other
issues. So I think the fact that there are so many reports is very
strong suggestive evidence.

CHAIRMAN BRASS: What about the issue of biologic plausibility?

DOCTOR GILMAN: Well, I commented on this a bit earlier. What we have in
common is a hemorrhagic diathesis affecting the brain, the blood vessels
of the brain. Those vessels, some of them, are outside of brain
substance itself. That is, in the Circle of Wil or some of the arteries
that are on the surface of the brain which account for the subarachnoid
hemorrhage component of this. Others are within the substance of the
brain and that includes arteriovenous malformations. In other words,
three somewhat different kinds of pathologies are implicated.

So the biological plausibility that comes to my mind is that there is
some factor related to clotting of blood or to hemorrhaging of blood,
perhaps something related to blood pressure levels or some other
phenomenon. But yes, it is entirely biologically plausible because I can
think of a common mechanism accounting for all of these three different
kinds of hemorrhagic stroke pathologies.

CHAIRMAN BRASS: Any other comments or observations? Doctor Hoffman.

DOCTOR HOFFMAN: Can I just comment as a person who directs a
hypertension clinic. I find some of this a bit difficult to grasp. There
was a comment made that perhaps there was no dose response relationship
because only a tiny amount of PPA would be necessary to rupture an
aneurism. In the blood pressure studies that I\'m familiar with, the
typical responses in blood pressure to PPA were very small. In some
studies have been negative. We should all remember that in the
day-to-day affairs our blood pressure may fluctuate 50, 70 or 100
millimeters of mercury. So I find it a bit difficult to grasp how one
could be so confident that potentially very small or nonexistent changes
in blood pressure due to PPA would ultimately lead to a stroke.

And I\'d like to comment on the issue of hemorrhage. I think it\'s well
known from the work of Walter Cannon in the 1930s that part of the
stress report mediated by catacholamines is actually to have subtle
effects to make the blood easier to clot. These are from the days when
we confronted sabre-tooth tigers. I\'m ont aware of any evidence that
catacholamines would promote hemorrhage.

CHAIRMAN BRASS: I think one of the issues that confounds both sides of
the statement are that we\'re clearly dealing with a very rare event and
that we\'re not dealing with a predictable blood pressure response. And
then I think it was in the FDA presentation that we do not have a large
enough database to identify whether or not there\'s a subset that
response to PPA exposure differentially with respect to either blood
pressure or even selective cerebral hemodynamic effects. And so I think
that is clearly why it doesn\'t happen to everybody who takes PPA.

The question though remains whether or not there may be mechanisms which
apply to a rare individual who\'s susceptible, either because of their
CNS anatomy, an underlying risk factor, or a differential population
response to the exposure.

DOCTOR HOFFMAN: I think that\'s certainly true, and you can\'t exclude
that. But it is interesting, as far as I know, in many people who study
autonomic nervous system, sympathetic function, basal constriction and
so forth, not particularly with PPA. As far as I know, these types of
individuals have really not been described, at least as far as I\'m
aware.

CHAIRMAN BRASS: Doctor Cantilena.

DOCTOR CANTILENA: I guess I would just follow with at comment that while
we\'re in essence trying to extrapolate the results of extremely closely
controlled, clinical setting in terms of the hypertensive response from
the product, I think that this again is sort of an actual use, all
comers, and when someone pops their diet pill and goes home or is on the
way home and someone cuts them off on the highway or their two year old
pitches a fit on the kitchen floor, which happened to me this morning,
it\'s sort of the issue of how does it actually fit in?

So I think that if even a small increase in the average in the clinical
study, in that average there are clearly outliers and then if you have
that individual in an actual use out of the hospital or out of the Phase
One unit setting, you can certainly see that it\'s possible that you can
have an exaggerated response.

DOCTOR HOFFMAN: I don\'t want to be argumentative, but pharmacologically
that\'s not an obvious conclusion because in some animal studies which
have been more extensively done than in humans, PPA is a partial
agonist. So in the setting of low autonomic function, partial agonist
may tend to raise blood pressure but in the setting that you described
of stress and high activation to sympathetic function, one could predict
that the hypertensive response would be blunted. I mean that\'s the
logic behind partial agonists for beta receptor antagonists. They may
even raise heart rate at rest but blunt rapid heart rate that occurs
with exercise.

So I just comment that I don\'t think it\'s a foregone conclusion that
that\'s what would happen.

DOCTOR CANTILENA: Certainly I understand your comment, but I think when
a lot of the data sort of points at the first dose and perhaps those
effects happen after tolerance, I also think the whole issue of
drug/drug interactions, which are not controlled for in an actual use
study, is significant. So I\'m not as familiar with the data as you are,
but I would hazard a guess that there could be settings in the actual
use which that\'s not the case, and that\'s the whole point of my
comment.

DOCTOR HOFFMAN: Yes, thank you. Can I just make one comment. The issue
of tolerance to PPA has been referred to very extensively. I was just
curious to what data people were referring to when they use that to
explain plausibility of a first dose effect.

DOCTOR BLACKBURN: I\'m George Blackburn from the Harvard Medical School,
and I did do a first dose study, large study of 881 healthy individuals
published in *JAMA*, and we did find that the independent factor of PPA
was less than four millimeters, even though, as you point out, 10
percent of the population had a large response but it was equally
distributed for all this fright that you talked about. It was during the
placebo, the 25 milligram given three times and the sustained release
and other determinants were base-line blood pressure in these
individuals and individuals who were higher BMI.

So it does support that, you know, there is some defense that there\'s a
large indigenous autonomic sympathetic tone at the time you take the
first dose and so there is an even distribution and we had, using Yates
analysis, we could find that the age, the gender, the BMI were the major
contributors to this area and then followed by the baseline blood
pressure and only less than four millimeters could be independently
attributed to PPA.

CHAIRMAN BRASS: Thank you.

Are there other comments about question C before we put it to a vote?
Doctor Gilman.

DOCTOR GILMAN: I just wanted to comment that what we\'re talking about
now is the reason for going into Phase IV clinical trials because after
one has completed a Phase III double blind placebo controlled trial to
see the effects of a drug at a particular population against placebo,
one wants to know what this drug is like in the real world when given to
people who are taking polypharmacy at times including people who may
have untoward reactions to a drug and there may be one person in the
100. In this situation, it may be just those people who have a berry
aneurism or just those people who are quote \"ready to have their
stroke\" in various other ways.

CHAIRMAN BRASS: Other comments. If not, we will now vote on Question C
which I will read again. There is a body of data collected over the
years that has suggested a possible association between PPA use and
hemorrhagic stroke. Taking all currently available information into
account, do the data support the conclusion that \-- so you can vote for
either 1) that there\'s no association, 2) there is an association, or
3) that the association still remains uncertain. All those who feel that
there is not an association, please raise your hand.

All those who feel that there is an association, please raise your hand.

All those who feel that the association still remains uncertain, please
raise your hand.

DOCTOR TITUS: There were zero votes for no relationship, there were 13
yes associations and one uncertain.

CHAIRMAN BRASS: We now move on to Question D. Considering your answer to
Question C, can PPA be considered to be generally recognized as safe for
use as a decongestant, an appetite suppressant? When answering this
question, please address whether dose is an important consideration.
Maybe I\'ll start the discussion this time myself because the issue of
dose is, I think, an interesting one. While we concluded that we could
draw no dose conclusion from HSP, that in the same way we lumped the
data when we look at the spontaneous reporting base and the HSP, one
might be concerned that in fact there is a dose relationship that does
exist though clearly the data do not provide sufficient evidence to make
that conclusively.

The other point I\'d like to make is actually taken off one of Doctor
Ganley\'s slides actually, is that no drug is absolutely safe and that
we have a number of drugs that are available over the counter that we
know are associated with rare adverse events, some of them very serious.
We know that there are even more drugs available which, when taken other
than as directed by the label, particularly in excessive doses, may be
associated with serious adverse events so that the definition of
generally recognized as safe I think isn\'t just out of a vacuum but
it\'s against a background of risk and, while the question isolates that
from the efficacy concern with the degree of efficacy that may exist,
ultimately I think the decision is going to have to be made on a risk to
benefit ratio.

So while our discussion will focus on risk, I think it\'s important to
recognize that we\'re not talking about absolutely safe but trying to
provide some context for whatever safety concerns we have, both with
respect to what\'s been generally acceptable as safe in the past as well
as any issues that are unique to this product.

Doctor Johnson.

DOCTOR JOHNSON: I guess for me the issue of risk/benefit is what really
sort of makes this whole question easy. The way I view this \-- and
I\'ll do decongestant and then appetite suppressant \-- is that what
does the consumer lose if this product is taken off the market? There
are a lot of other decongestants. I understand that the members of CHPA
are going to lose money, but that\'s not really our concern. They are
marginally effective drugs, I think, for problems that aren\'t
life-threatening, and so there really are no huge long-term outcome
benefits such that really I think any degree of risk becomes much less
tolerable.

And so in both the situations, I guess I view this risk, even though
it\'s rare, as being one that is not upset by benefits because I view
the benefits of this product as fairly marginal.

CHAIRMAN BRASS: Doctor Gilman.

DOCTOR GILMAN: I agree with what Doctor Johnson said, but just
specifically to address the issue of appetite suppression. Doctor
Schteingart showed us what an effective drug PPA seems to be over the
short-term. I asked him during the break \-- I don\'t know if he\'s
still here. Yes, he is. \-- what is the long-term outcome with those
patients, and his response was, well, 95 percent of people who take
medications for weight loss wind up with the same weight back again
within some years. There has, however, been no study \-- I believe I\'m
quoting him correctly \-- there\'s been no study on the efficacy of PPA
over many years. Say five years, six years, 10 years.

So I agree with what Doctor Johnson said. The benefits are marginal and
short-lived with respect to weight loss and, for decongestants, I agree
there are other products that are equally good.

CHAIRMAN BRASS: If you\'d like to comment, please come to a microphone.

DOCTOR WALSON: Yes. I\'m Doctor Phil Walson from the University of
Cincinnati, and I\'m a paid consultant for CHPA. Well, I\'m tempted to
say a lot of things including the fact that it\'s difficult to comment
on something when I personally think you\'re mixing up causation with
association. 1) you\'re making assumptions from a study that clearly
wasn\'t powered or designed to answer certain questions. For example, in
the population I represent, you wouldn\'t even bother to include them.
That is, children. And they all go to those hospitals where you were
collecting data.

I\'m also a medical toxicologist and I\'m appalled that you could even
talk about collecting data on cocaine use without something we can
measure months past exposure reliably.

CHAIRMAN BRASS: If you could focus on the question.

DOCTOR WALSON: I\'ll focus on the question. But it does all come down to
risk and benefit, and you made the comment. One is that not everyone
responds to any decongestant, one, and I want to go back. There were two
points on Doctor Ganley\'s slide and one is that there are benefits to
consumer accessibility to short-term medications that offer symptom
relief. I don\'t want to get off on weight control because I think it
would be better to stick to decongestants. And these products, I am
worried that when you do remove them you are forgetting a risk and that
is what are your consumers going to turn to? And we\'re already seeing
them turn in both cases, you\'re going to see them turn to products that
are neither regulated, quality controlled nor studied at all. At least
this product does have data showing it\'s efficacious for short-term
use. That is true for both, and you\'re going to turn patients to
ephedra compounds. You\'re going to turn them to other things.

So I think that to say there\'s no benefit, I think you have to weigh
risk and benefit. That\'s what you\'re doing \--

DOCTOR JOHNSON: I didn\'t say there was no benefit. I said I believe the
benefit was marginal and that, particularly for cough and cold, there
were other acceptable products on the market.

DOCTOR WALSON: Yes, there are other choices, but one of the things that
I think consumers would tell you is that \-- and I don\'t have the
plausible explanation \-- that some consumers prefer one product to the
other. I\'m not sure that the other products on the market are either
more effective or safer. So I think that, at least in terms of patients
that were not included in the study, which this study speaks nothing to.
I mean the reason they didn\'t do children is because their own data,
including the FDA data, would show that any adverse event in childhood
is so rare that they would never have been able to power any study to
find it so that I am concerned about the population that I represent,
that at least you need to make sure that you don\'t deny our pediatric
population access to something that wasn\'t even studied.

CHAIRMAN BRASS: Doctor Schteingart, you wanted to make a very brief
comment, please.

DOCTOR SCHTEINGART: Yes. I\'d like to make the comment that it\'s been
well agreed that obesity is a chronic, serious medical condition. It\'s
not a benign condition and that treatment actually has major improvement
in the co-morbidity associated with obesity. There is no effective
long-term treatment of obesity. There is usually a combination of the
things I mentioned before: diet, exercise, behavior therapy, and
medication. I use medication as an aid in helping the patients actually
stay on their diets, even for moderately shorter periods of time. We
don\'t have treatment that has been validated for long-term use like
it\'s been for hypertension or diabetes, which are extremely effective
in normalizing whatever the treatment is supposed to normalize.

However, for short periods of time, the administration of appetite
suppressants or any other anti-obesity drugs can help the patient lose
enough weight to improve their co-morbidities and also to help them
behaviorally continue to adhere to a weight reduction program. But it\'s
true, as Doctor Gilman has indicated, there is no validated long-term
use for PPA because that\'s not the way it\'s been approved by the FDA.
Not, for example, the way that cybutramine or orlistat have been
approved for indefinite use.

CHAIRMAN BRASS: Part of the consideration, in my mind, for generally
recognized as safe, as I indicated earlier, relates to the use as per
the label. And to the degree that information could be placed on a label
which would mitigate the risk, that I think becomes an important
consideration.

Now, having posed that, I\'m concerned that whether there is or not on
the basis of two things. First of all, we have failed to identify any
clear sub-groups that we identified them, other than women, but that we
could steer use away from and 2) this has, to my eye, provided a very
interesting actual use study on how consumers use products and this
label clearly says \"Consult your physician if you have high blood
pressure\" and we ended up with a cohort that was quite rich in
hypertensives. And so the degree to which if a label warning, even if
one could conceive of an effective one, the degree to which it actually
would be effective in steering away at risk populations would remain a
concern in my mind.

Yes, Ms. Cohen.

MS. COHEN: I was referring to the FDA report on page eight and nine and
talking about 75 milligrams and what happened as a result of that, and I
am concerned because I did look at the label and the label, I will
repeat myself and forgive me, for 12 years old and older and adults,
twice a day they can take 75 milligrams twice a day. That\'s 150
milligrams and, if we\'re worried about consumers over-dosing, this
really boggles my mind.

In terms of I would like to respond to the pediatrician. Advertising,
advertising, advertising. So when you talk about what consumers buy,
it\'s the one that\'s advertised the most or on the shelf or where they
place it on the shelf. So I don\'t know how much \-- goes on in a
pharmacy when you go to buy a cough medicine. I bought one yesterday
and, believe me, I read the label. But I\'ve had some experience reading
this information. So I think this report, I am satisfied with the
statistics and what\'s been done and I\'m satisfied that as a result of
75 milligrams there\'s a good chance for hemorrhagic stroke and really,
150 milligrams just boggles my mind.

CHAIRMAN BRASS: Other comments from the panel with respect to Question
D?

DOCTOR SACHS: As a pediatrician, I actually have a different
interpretation of some of the information that you presented. I think
there are very good studies in children that show these medicines are
safe and effective or efficacious to begin with and that if you look at
placebo controlled studies and also studies that look at duration of
cold symptoms, the colds last 10 days if you take something, they last
10 days if you don\'t take something. The placebo effect is very great.
I know in our population when we talk about over-the-counter remedies
for cold and cough, we actively discourage them.

One other reason which was not really emphasized today was the risk of
arrhythmias, especially in children who receive some of these things. So
now having read all the background data and all the HSP Study data, I
mean even though the incidence of stroke in a young person is rare, I
would be greatly concerned about adolescents who might choose to use
these as either cough and cold remedies or appetite suppressants,
particularly in the populations that might be on OCPs. I mean you start
having to label and label and label. That becomes superfluous.

DOCTOR WALSON: Let me respond. A lot of things. One is that, briefly,
it\'s for short symptomatic control and it\'s relative to \-- I\'m sure
you also counsel against use of antibiotics but the fact is if a child
goes to a physician, the odds are overwhelming they will get an
antibiotic for a viral infection. That has been shown. If the child can
stay home, to not visit your office, they will decrease it. So there is
in fact a benefit and that\'s been shown in terms of symptomatic relief,
even though I also don\'t use them when someone gets to the hospital. So
I think that\'s important.

The second thing. I think that there\'s an assumption in your comment
about dose that\'s really not shown out and that is the risk goes down
with age, not up, despite the fact that the doses may not go down very
much, and that\'s because children in fact are resistant. I also ran a
pediatric hypertension lab. They tolerate blood pressure changes
different.

And then one final comment. I\'m a little concerned with this call of
first time use because I\'m not sure there are too many children who
make it to 18 without a use of one of these products.

CHAIRMAN BRASS: First time use was not defined as first life time use.

DOCTOR WALSON: Yes, I know.

CHAIRMAN BRASS: Doctor Cantilena.

DOCTOR CANTILENA: Just to comment in terms of Doctor Ganley\'s slide
where he asked us to consider the dose issues. I think, as I commented
before, sort of when you look at the dose that, at least in our study,
seems to cause trouble, it\'s not several-fold over the recommended
dose. So again sort of getting back to the point of margin of safety. I
think the cases that we\'ve seen and the cases that we heard about from
the spontaneous reporting are not massive overdoses. We\'re really
talking about individuals who I frankly don\'t understand who they are.
They\'re obviously females but in terms of how come they get in trouble,
I mean I obviously don\'t have a clear idea of why that is. But I think
the key for me is that they\'re not significantly out of. It\'s really
we\'re talking about one or two extra pills.

Clearly, the other sort of alarming issue is even though the label
seemed to be in the right format, if that was the same label that was in
effect during the study, it doesn\'t seem to be extremely effective and
I think that\'s a significant concern.

CHAIRMAN BRASS: Other comments before we put this question to a vote? If
not, the question on the table is considering your answer to Question C,
can PPA be considered to be generally recognized as safe for use as,
first, a decongestant? The answer will be yes or no. All those who think
that it can be generally recognized as safe for use as a decongestant
voting yes, please raise your hand at this time.

Abstain is an option this time. All those who feel the answer is no,
please raise your hand.

All those abstaining, please raise your hand.

DOCTOR TITUS: We have zero for yes, 12 noes and two abstentions.

CHAIRMAN BRASS: Same question for appetite suppressant. Considered
generally recognized as safe for use as an appetite suppressant. Voting
yes, please raise your hand.

Voting no, please raise your hand.

Abstaining, please raise your hand.

DOCTOR TITUS: For appetite suppressants, there were zero for yes, 13
noes and one abstention.

CHAIRMAN BRASS: Thank you. The next question is a little too open-ended
for me. Who knows what may come up? But anyway, we\'ll ask it. Does the
committee have any additional recommendations? Let\'s try to limit it to
PPA.

Are there issues from the agency that we haven\'t touched on or that
you\'d like to see expansion of the discussion on?

DOCTOR DELAP: No. Thank you very much.

CHAIRMAN BRASS: On that basis, I\'d like to thank all who participated
in the discussion today. The presenters did an excellent job of staying
on time. Thanks to all the committee members, and we are adjourned.

(The meeting was concluded at 3:57 p.m.)