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:

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

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

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

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

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, 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.)