1
					UNITED STATES OF AMERICA
								+ + + + +

FOOD AND DRUG ADMINISTRATION + + + + +
CENTER FOR DRUG EVALUATION AND RESEARCH
+ + + + +
JOINT MEETING OF THE
NONPRESCRIPTION DRUGS ADVISORY COMMITTEE
AND THE
ENDOCRINOLOGIC AND METABOLIC ADVISORY COMMITTEE + + + + +

FRIDAY
JULY 14, 2000
+ + + + +
		The Committees met at 8:00 a.m. in the Versailles II Room of the Bethesda Holiday Inn, 8120
Wisconsin Avenue, Bethesda, Maryland, Dr. Eric P. Brass, Chairman of the Nonprescription Drugs Advisory Committee, presiding.
PRESENT:
		ERIC P. BRASS, M.D., Ph.D., Chairman, 

								NDAC
GEORGE A. BLEWITT, M.D., Non-Voting Industry Liaison
LUTHER T. CLARK, M.D., Guest Expert JAIME A. DAVIDSON, M.D., Consumer 
Representative, EMDAC
JANET ELASHOFF, Ph.D., Consultant MARIE C. GELATO, M.D., Ph.D., EMDAC 
				Member
EDWIN E. GILLIAM, Ph.D., NDAC Member 
DEBORAH GRADY, M.D., M.P.H., EMDAC Member JULIE A. JOHNSON, Pharm.D., NDAC Member

			2
PRESENT:
	EDWARD P. KRENZELOK, Pharm.D., NDAC 
		Member
	BARBARA P. LUKERT, M.D., EMDAC Member 

MARK E. MOLITCH, M.D., EMDAC Member 
RICHARD A. NEILL, M.D., NDAC Member JANET H. SILVERSTEIN, M.D., EMDAC Member 
WILLIAM V. TAMBORLANE, M.D., EMDAC Member 
SANDRA TITUS, Ph.D., NDAC Executive 
		Secretary
DONALD L. UDEN, Pharm.D., NDAC Member HENRY W. WILLIAMS, JR., M.D., NDAC Member
FDA REPRESENTATIVES:
	ROBERT J. DELAP, M.D.

CHARLES GANLEY, M.D. JOHN JENKINS, M.D. 
LINDA M. KATZ, M.D., M.P.H. KAREN LECHTER, J.D., Ph.D. DAVID ORLOFF, M.D.
	MARY H. PARKS, M.D.

DAIVA SHETTY, M.D.
SPONSOR REPRESENTATIVES:
RENE BELDER, M.D.
MICHAEL BOTORFF, M.D. W. VIRGIL BROWN, M.D. J. JAIME CARO, M.D.C.M. 
JEROME D. COHEN, M.D., FACC, FACP CAROLA P. FRIEDMAN, M.D., FACC CHARLES HENNEKENS, M.D.

	GARY KOCH, Ph.D.
MARK B. KRESTON PATRICIA A. KRIGER MARK PFEFFER, M.D. 
C. MICHAEL WHITE, Pharm.D.

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		I-N-D-E-X
Welcome and Introduction. . . . . . . . . . . . . .4
Conflict of Interest Statement. . . . . . . . . . .7
Introduction
	Dr. Orloff. . .	. . . . . . . . . . . . . . .9
Sponsor's Presentation
Bristol-Meyers Squibb	. . . . . . . . . . . . . . 17
FDA Presentation. . .	. . . . . . . . . . . . . . 80
Questions and Answers	. . . . . . . . . . . . . .118
FDA Questions . . . .	. . . . . . . . . . . . . .218
Discussion. . . . . .	. . . . . . . . . . . . . .227

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	1		    P-R-O-C-E-E-D-I-N-G-S
	2		                             (8:03 a.m.)
	3		CHAIRMAN BRASS:  Welcome to the second day
	4	of the Joint Meeting of the Nonprescription Drug
	5	Advisory Committee and Endocrinologic and Metabolic
	6	Advisory Committee.
	7		I¦m Eric Brass, Chair of the
	8	Nonprescription Drug Advisory Committee from the
	9	Department of Medicine at Harbor-UCLA Medical Center. 
10	I think we will begin this morning by just doing a
11	quick circle of the room and letting everybody
12	introduce themselves.
13		DR. JENKINS:  I¦m John Jenkins.  I¦m the
14	Director of the Office of Drug Evaluation II at FDA.
15		DR. ORLOFF:  I¦m David Orloff.  I¦m the
16	Deputy Director of the Division ofMetabolic and
17	Endocrine Drug Products at FDA.
18		DR. GANLEY:  I¦m Charlie Ganley, Director
19	of Division of Over-The-Counter Drugs.
20		DR. KATZ:  I¦m Linda Katz, Deputy Director
21	for OTC.
22		DR. WILLIAMS:  Yes, I¦m Henry Williams,
23	Howard University, Department of Community Health and
24	Family Practice, then with the Nonprescription
25	Formulary Committee.

				5
	1		DR. GELATO:  I¦m Marie Gelato.  I¦m a
	2	professor of Medicine at the State University of New
	3	York at Stonybrook and in the Division of
	4	Endocrinology and I¦m a member of the Endocrinologic
	5	and Metabolic Drug Committee.
	6		DR. KRENZELOK:  Good morning.  I¦m Ed
	7	Krenzelok.  I¦m Director of the Pittsburgh Poison
	8	Center and a professor of Pharmacy and Pediatrics at
	9	the University of Pittsburgh and a member of NDAC.
10		DR. DAVIDSON:  Good morning.  Jaime

11	Davidson, a clinical and associate professor of
12	Medicine, University of Texas Southwestern Medical
13	School and I see patients.
14		DR. ELASHOFF:  Janet Elashoff. 
15	Biostatics, Cedar Sinai and UCLA, Consultant to the
16	Committees.
17		DR. NEILL:  Richard Neill.  I¦m an

18	assistant professor in the Department of Family
19	Practice and Community Medicine at the University of
20	Pennsylvania and a member of NDAC.
21		DR. TITUS:  I¦m Sandy Titus.  I¦m with the
22	FDA¦s Advisory Committee Staff and I¦m the Executive
23	Secretary for NDAC.
24		DR. JOHNSON:  I¦m Julie Johnson from
25	University of Florida, Departments of Pharmacy

				6
	1	Practice and Division of Cardiology and I¦m a member
	2	of NDAC.
	3		DR. SILVERSTEIN:  I¦m Janet Silverstein,
	4	a professor in Pediatric Endocrinology at the

	5	University of Florida, also a member of EMDAC.
	6		DR. TAMBORLANE:  I¦m Bill Tamborlane,
	7	professor of Pediatrics at Yale School of Medicine and
	8	I¦m a member of the Endocrine Committee.
	9		DR. LUKERT:  Barbara Lukert, professor of
10	Medicine at the University of Kansas School of
11	Medicine Division of Endocrinology, and I¦m with the
12	Endocrinologic and Metabolic Section.
13		DR. GILLIAM:  I¦m Eddie Gilliam.  I¦m a
14	Family Nurse Practitioner from Tucson, Arizona.
15		DR. MOLITCH:  Mark Molitch, professor of
16	Medicine in the Endocrinology Section at Northwestern
17	University Medical School in Chicago.  I¦m with the

18	Endocrinology and Metabolic Drugs Advisory Committee.
19		DR. UDEN:  I¦m Don Uden from the
20	University of Minnesota College of Pharmacy and a
21	member of NDAC.
22		DR. BLEWITT:  George Blewitt, Industry
23	Representative to NDAC.
24		DR. CLARK:  I¦m Luther Clark, Chief of
25	Cardiology at SUNY Downstate at Brooklyn, Consultant.

			7
	1	            CHAIRMAN BRASS:  We did pretty good on the
	2	microphones.  One was left on and I will again just

	3	remind the committee members to please always speak
	4	loudly and clearly into the microphone so your remarks
	5	can be shared by all.  Next may I ask Dr. Titus to
	6	read the conflict of interest statement.
	7	            DR. TITUS:  This is for the July 14th Endo
	8	and Metabolic Drugs Advisory Committee and the
	9	Nonprescription Drugs Advisory Committee.  The
10	following announcement addresses the issue of conflict
11	of interest with regard to this meeting and is made a
12	part of the record to preclude even the appearance of
13	such at this meeting.
14	            Based on the submitted agenda for the
15	meeting and all financial interest reported by the
16	committee participants, it has been determined that

17	all interest in firms regulated by Cedar present no
18	potential for an appearance of a conflict of interest
19	at this meeting with the following exceptions.  In
20	accordance with 18 USC 208(b)(3) full waivers have
21	been granted to Dr. Eric Brass, Dr. Barbara Lukert,
22	Dr. Jules Hirsch, Dr. Robert Kreisberg and Dr. Mark
23	Molitch.
24	            A copy of the waiver statements may be
25	obtained by submitting a written request to the

			8
	1	agency¦s Freedom of Information Office, Room 12A30 of
	2	the Parklawn Building.  We would also like to note
	3	that Dr. Jaime Davidson has interest in Bristol-Meyers
	4	Squibb, Warner Lambert and Parke-Davis which are
	5	unrelated to Pravachol or its competing products.  In
	6	addition, we¦d like to note that Dr. Barbara Lukert
	7	has an interest in Merck, the manufacturer of Mevacor
	8	and Zocor, competing products to Pravachol, which is
	9	unrelated to the firm¦s competing products.

10	            Further, Dr. William Tamborlane¦s
11	employer, the Yale University School of Medicine, has
12	interest in Pfizer and in Parke-Davis, a subsidiary of
13	Pfizer, the manufacturer of the competing product to
14	Pravachol, which are unrelated to the firm¦s competing
15	product.  
16	            Although these interests do not constitute
17	a financial interest in the particular matter within
18	the meaning of 18 USC 208, they could create the
19	appearance of a conflict.  However, it has been
20	determined, none withstanding these interests, that it
21	is in the agency¦s best interest to have Dr. Davidson,
22	Dr. Lukert and Dr. Tamborlane participate in the
23	committee¦s discussions concerning Pravachol. 
24	Further, we would like to note for the record that Dr.
25	George Blewitt is the non-voting industry

			9
	1	representative and is on the committee to represent
	2	industry¦s interest.
	3	            As such, he has not been screened for any

	4	conflict of interest.  With respect to FDA¦s invited
	5	guest, Dr. Luther Clark, has reported interest which
	6	we believe should be made public to allow the
	7	participants to objectively evaluate his comments. 
	8	Dr. Clark would like to disclose that he is an
	9	investigator for research, has served as an
10	educational consultant and received speaker¦s fees
11	from Bristol-Meyers Squibb, Merck and Parke-Davis.  In
12	the event that the discussions involve any other
13	products or firms not already on the agenda for which
14	an FDA participant has a financial interest, the
15	participants are aware of the need to exclude
16	themselves from such involvement and their exclusion
17	will be noted for the record.  With respect to all
18	other participants we ask in the interest of fairness
19	that they address any current or previous financial
20	involvement with any firm whose products they may wish
21	to comment upon.
22	            CHAIRMAN BRASS:  Thank you.  I would now
23	ask Dr. Orloff to provide us an introduction to this
24	morning¦s session.
25	            DR. ORLOFF:  Good morning.  In the

			10
	1	interest of time I will make my remarks brief this
	2	morning.  I think everyone at the table heard the

	3	introduction yesterday.  And so I¦m just going to
	4	touch on a few points this morning.  Let me begin by
	5	thanking again the members of the FDA staff, the
	6	review staff, for their hard work and review of the
	7	NDA and for, in preparation for this meeting.  Again,
	8	I¦ll be touching on the high points, I hope.  We have
	9	a regulatory standard that guides us in the decisions
10	regarding over-the-counter marketing of drugs.
11	            I won¦t read it for you, and let me say
12	again, let me say first of all that these slides can
13	be made available to members of the advisory
14	committee, I believe by early this afternoon, if need
15	be, thanks.  Critical in this language that guides us
16	are issues, and I don¦t have a pointer, of methods of
17	use and collateral measures necessary to use, which
18	really makes our judgments in OTC switches, or the

19	marketing of OTC drugs different and sometimes more
20	complex than those for prescription drugs.
21	            Traditional over-the-counter drugs which
22	need to be used without the physician and need to be
23	safe and effective in such use are therefore often are
24	usually for low-risk symptomatic conditions where

25	self-diagnosis is the rule for short term use as

			11
	1	monotherapy or the worsening or persistence of
	2	symptoms leave the patient to seek more definitive
	3	care.
	4	            What we¦re talking about today is
	5	something completely different than that.  This is
	6	dyslipidemia with atherosclerotic cardiovascular
	7	disease risk, which is an asymptomatic disease which
	8	has added to it from the standpoint of complexity in
	9	mediating an effective therapy by the patient him or
10	herself, the issues that diagnosis and follow-up
11	require blood tests and interpretation.  The treatment
12	is reduce the risk of life-threatening or life-
13	altering outcomes and where optimum benefit requires
14	long-term compliance, not just short-term compliance
15	but long-term compliance with drugs, diet and
16	lifestyle.
17	            And where, in many instances, titration,

18	combination therapy, treatment of co-morbidity is an
19	important aspect of follow-up.  And finally, where the
20	role of the physician, at least as currently, as care
21	is currently undertaken in vigilance for and in
22	anticipation of clinical coronary disease or
23	cardiovascular disease, is an all-important aspect of
24	effecting optimum benefit in the long run.  So what

25	about methods of use and collateral measures of use

			12
	1	that I referred to before?
	2	            Clearly, when we contrast Rx cholesterol
	3	lowering with the hypothetical OTC cholesterol
	4	lowering, this issue of methods of use and collateral

	5	measures necessary to use is something that we have to
	6	look very carefully at.  As I said yesterday, when we
	7	approve a drug for prescription use, we make a
	8	reasoned database judgment that it will be safe and
	9	effective if used according to the labeling.  At that
10	point, to a large extent, the role of the FDA stops.
11	            We rely, from that point on, on the
12	learned intermediary, the physician or other
13	healthcare professional, to mediate the safe and
14	effective use in collaboration with the patient.  The
15	FDA doesn¦t regulate the practice of medicine and, for
16	better or worse, we cannot insert ourselves into the
17	doctor¦s office.  There are limitations to this system
18	for the treatment of hypercholesterolemia that I won¦t
19	go through today.  We spoke about them yesterday.
20	            By contrast, when we approve a drug for
21	OTC use, again a databased, reasoned judgment that if
22	used according to the label, it will be safe and
23	effective.  But in this instance neither we nor the
24	patient can rely on the physician, learned
25	intermediary, healthcare professional, what have you. 

			13
	1	And so we, as regulators in making the decision, have
	2	really an additional burden and there¦s an additional
	3	standard of evidence that may be required and is
	4	unique in contrast to the Rx situation, whereby we
	5	have to examine issues of method of use.
	6	            Now, so what is the evidence that we would
	7	need, or that we do need, to feel, to have assurance
	8	that the drug will be safe and effective when used by
	9	the patient without the learned intermediary.  Well,
10	obviously we need to know about the intrinsic
11	characteristics of the drug that in the simplest
12	fashions speak to its basic safety or elemental safety
13	and efficacy.
14	            But we clearly need more than that.  We
15	need information on manner of use, because the
16	overall, the summation of risk and benefit that now

17	addresses the overall impact of this treatment, is
18	going to be a function of the extent to which there is
19	appropriate targeting or capture of patients who are
20	likely to benefit, appropriate exclusion of those who
21	are unlikely to benefit, or otherwise suitable for
22	more definitive therapy because in those instances
23	there may be risk that begins to outweigh benefit, and
24	there has to be some achievement of the ancillary
25	aspects of treatment or we at least need to ascertain

			14
	1	what those are.
	2	            As I said before in the case of
	3	hypercholesterolemia, that¦s diet and lifestyle,
	4	treatment of co-morbid conditions and follow-up.  And

	5	we have to have some evidence that people can use it,
	6	dosing properly, the proper intervals, and can be
	7	aware of any potential drug interactions, for example. 
	8	I talked to you yesterday about the background in this
	9	area.  I don¦t need to go through it again.  We¦re

10	here for the third time in five years to discuss this
11	issue.
12	            There have been changes in the interim,
13	notably a changing landscape and a vast clinical
14	experience with statins and with pravastatin.  Here¦s
15	my take on the sponsors essential rationale for over-
16	the-counter marketing of pravastatin 10 mg., and I¦m
17	sure you¦ll hear this again.  Cardiovascular disease
18	is the leading cause of death in the United States.
19	            There¦s a well-known continuous and grade
20	of relationship between total cholesterol or LDL
21	cholesterol levels and heart disease risk and
22	furthermore, an abundance of trial data support the
23	benefits of cholesterol lowering across the spectrum
24	of levels of cholesterol and levels of risk.  There¦s
25	a perceived therapeutic gap with under-treatment

			15
	1	across the spectrum of risk.  There¦s a changing
	2	landscape that we¦ve talked about before.  There¦s the
	3	vast experience and, therefore, unrestricted access
	4	according to the sponsor for a motivated low-risk
	5	population to pravastatin 10 mg. is warranted.
	6	            What is the target population that we¦re
	7	talking about today?  Men greater than 35, women
	8	greater than 45, without coronary disease or diabetes,
	9	low-risk, told by the physician to lower their
10	cholesterol but not put on prescription therapy, and
11	with total cholesterols between 200-240 and LDL
12	cholesterols of greater than 130.  Let me remind the
13	committee again, the proposed over-the-counter
14	population-- this is a new indication for pravastatin,
15	first of all.
16	            The proposed over-the-counter population

17	is not currently targeted for drug therapy.  The heart
18	disease risk, I believe in this population, is
19	something below one percent per year.  I can¦t put my
20	finger on it.  We need to address the issue at its
21	most basic of whether this indication, a new
22	indication is supported by data that speak to
23	definitive clinical benefit of the treatment.
24	            And if there are such data and the
25	indication is justified, is over-the-counter access to

			16
	1	prava 10 mg. a safe and effective way to address the
	2	unmet medical need in this at-risk population?  We
	3	have to look at the data presented to us in this
	4	package in order to answer these questions.  You¦ll

	5	hear presentations as before, but obviously different
	6	studies, different designs, on efficacy, from control
	7	trials and consumer-use trials that address lipid
	8	altering, clinical impact of pravastatin.
	9	            You¦ll hear about safety from the control
10	trial database, from spontaneous reports, from drug
11	metabolism studies or inferred from drug metabolism
12	studies and from consumer-use studies.  And you¦ll
13	hear about label comprehension and consumer behavior
14	specifically with regard to the involvement of the
15	physician, a critical aspect of this treatment
16	paradigm, and appropriate self-selection and
17	¦exclusion, clearly something very important in our

18	assessment of whether this can be a safe and effective
19	OTC treatment.
20	            Again, questions.  You¦ll be asked at the
21	end of the day, in effect, regardless of whether we¦re
22	talking about an OTC drug or an Rx drug, is therapy
23	with pravastatin 10 mg. across the broad target
24	population warranted based upon evidence of clinical
25	benefit, safety and considering the balance of risk

			17
	1	and benefit?  Question two, with regard to the OTC
	2	appropriateness or applicability, if this treatment is
	3	justified in the target population, do we have
	4	evidence that benefit can be reaped with an acceptable
	5	level of risk across the population in an over-the-
	6	counter setting?
	7	            This speaks to issues about manner of use,
	8	method of use, and collateral measures that determine
	9	the sum total of risk and benefit.  And finally, is

10	there evidence supported sufficient to support¦ or
11	presented, excuse me, sufficient to support the
12	expectation of the safe and effective use of
13	pravastatin 10 mg. across the broad target over-the-
14	counter population directed by the consumer without a
15	learned intermediary healthcare professional to assist
16	in safe and effective use?
17	            Thank you.  That concludes my remarks.

18	            CHAIRMAN BRASS:  Thank you.  I will now
19	turn the floor over to Mark Kreston for the sponsor¦s
20	presentation.
21	            MR. KRESTON:  Thank you, Dr. Brass.  To
22	members of the Nonprescription Drugs Advisory
23	Committee and members of the Endocrinologic and
24	Metabolic Drugs Advisory Committee, representatives
25	from the Food and Drug Administration, ladies and

			18
	1	gentlemen, good morning.
	2	            My name is Mark Kreston and I am President
	3	of Worldwide Consumer Medicines for Bristol-Meyers
	4	Squibb Company.  My colleagues and I come before you
	5	today with a unique proposition.  We¦re here to
	6	request OTC status for Pravachol 10 mg. which will
	7	fill a therapeutic gap and will have a positive impact
	8	on cardiovascular health.  While we know you
	9	entertained an application yesterday for a different
10	cholesterol-lowering proposal, we ask that the
11	committee evaluate the unique characteristics of this
12	specific molecule.
13	            But not only is our molecule different, so
14	too is our entire approach, as you¦ll see from our
15	consumer-use trials, the level of physician
16	involvement, and our planned post-marketing studies. 

17	Indeed, the concerns raised by this panel yesterday
18	will be addressed in our presentation today.  I¦d like
19	to examine the specific OTC proposition.
20	            Our intended dose is Pravachol 10 mg. once
21	daily in conjunction with diet and exercise to lower
22	cholesterol.  For those who have total cholesterol
23	levels between 200-240 mg. per deciliter with LDL over
24	130 mg. per deciliter.  The specific defined
25	populations are men greater than 35 years of age and

			19
	1	women older than 45 years of age.  Consumers who were
	2	told by their physician that they need to lower their
	3	cholesterol levels but who are not on prescription
	4	therapy.
	5	            These consumers are not at desired levels
	6	of cholesterol despite diet modification and exercise. 
	7	They do not have risk factors such as coronary heart
	8	disease or diabetes, and importantly, are likely to
	9	reach their end-set goal with this therapy.  And
10	finally, it is critically important to this
11	proposition to maintain physician involvement.
12	            So here¦s the flow of the presentation for
13	today.  The background and rationale for OTC Pravachol
14	will be presented by Dr. Jerome Cohen.  Dr. Rene
15	Belder will discuss the extensive and well-established
16	safety profile of Pravachol.  Dr. Carola Friedman will
17	present the OTC clinical program, and Ms. Patricia

18	Kriger will review the post-launch education and
19	marketing programs, which will ensure appropriate use
20	and compliance.
21	            Lastly, Dr. Friedman will provide a
22	summary and will be pleased to take any questions that
23	you may have.  Now we would like to ask the committee
24	members to hold questions until the end and we¦ll

25	leave plenty of time to have that dialogue.  We¦ve

			20
	1	also included for your convenience, in the bottom
	2	right-hand corner, slide numbers for ease of
	3	reference.  Lastly, I would like to acknowledge our

	4	panel of distinguished consultants who have worked
	5	with us to develop this program and they are available
	6	to address questions within their field of expertise. 
	7	Bristol-Meyers Squibb has conducted more than a decade
	8	of research on this molecule, making Pravachol the
	9	most widely studied drug of its kind in the world. 

10	This unique molecule is very well characterized as a
11	result of this research and our proposal to market
12	Pravachol 10 mg. OTC is a logical outcome of this
13	comprehensive body of research.

14	            Thank you for allowing us the opportunity
15	to have this critically important dialogue today.  And
16	with that I would like to introduce our first speaker,
17	which is Dr. Jerome Cohen.  Thank you.
18	            DR. COHEN:  Thank you very much, Mark. 

19	Good morning, ladies and gentlemen, Mr. Chairman,
20	members of the Joint Committee, members of the FDA
21	staff.
22	            My name is Jerry Cohen.  I¦m a
23	cardiologist on the full-time faculty at St. Louis
24	University.  My training and background has been in
25	cardiology, but my interest professionally and

			21
	1	research has been in preventive cardiology,
	2	specifically.  And I¦m pleased to be here today
	3	because I¦ve thought about this problem of OTC lipid-
	4	lowering therapy for more than five years now and I
	5	want to share with you some of the background and
	6	rationale for the proposed switch to OTC therapy or as
	7	an additional remedy to the problem that I¦m going to
	8	present to you.
	9	            Dr. Orloff gave some of the background and

10	rationale and I think he did a very good job.  He also
11	emphasized several points that he wants the committee
12	to consider with regard to this proposal and I want to
13	put the rationale and background in the context¦ I
14	want to put the context in appropriately with respect
15	to the background and rationale as he addressed it. 
16	And so let us begin at the beginning and I know at the
17	risk of some boredom I¦m going to show you a slide
18	that you¦ve seen before.
19	            It¦s a slide that we refer to in brevity
20	as the MRFIT slide, and I show you this with some
21	pride because I am still a member of the MRFIT
22	Executive Committee and we continue to get in data in
23	terms of the National Death Index.  And this data is
24	very powerful data when we consider some of the issues
25	that confront us with respect to OTC therapy.  And so

			22
	1	let us examine the data more carefully than I think
	2	we¦ve done in the past.
	3	            What we have is a cohort of 361,662 men,
	4	and I¦ll get to the women¦s story a bit later, and in

	5	this cohort, it¦s so robust.  We have more than 20,000
	6	African Americans.  In addition we have a huge Latino
	7	base.  It¦s the largest such study of some of these
	8	minorities ever conducted and still being done today. 
	9	And the data are so robust that what I¦m going to tell
10	you for the entire group applies as well to some of
11	the subgroups.  And what you can see is this graded
12	risk between cholesterol levels, and we looked at
13	total cholesterol in this screening process, and
14	coronary mortality rate.  And we know in large groups
15	of people, total cholesterol is really a surrogate for
16	LDL cholesterol.
17	            And what you can see in the left panel is
18	that the higher the cholesterol, the higher the risk. 
19	And the lower the cholesterol, the lower the risk. 
20	And this is something that is well known to you.  But
21	you need to consider it in light of the question
22	before you this morning.  And when you look at the
23	right-hand graph, you will see the relative risk,
24	fixing the relative risk at one for a level of 200 mg.
25	per deciliter, which is ¦normal¦, and I¦ll come back

			23
	1	to that normal in a minute.
	2	            You can see that as the level goes up to
	3	250 mg. and then to 300 mg., the risk doubles and
	4	doubles again.  And we recognize that.  And I¦m happy

	5	to say in medicine, over my professional lifetime, we
	6	have seen the definition of normal come down.  Where
	7	was it when I began?  300 mg. per deciliter.  280,
	8	250, 240, and now what do we call ¦normal¦?  200.  But
	9	I would submit to you is that really normal?  When you
10	look up here, what we want to look at, is that
11	associated with the lowest rate?  And not how we refer
12	to as ideal, and we should strive for an optimal
13	cholesterol level.
14	            That¦s really what we should say, because
15	what does a normal American who has a normal
16	cholesterol die from?  He or she dies, most likely,
17	from coronary heart disease with that so-called normal
18	cholesterol.  And so we have learned from this MRFIT
19	data, a huge amount in terms of population base, and
20	let me tell you that epidemiological data, when
21	conducted in a large scale study properly designed,
22	has never led us astray with regard to the clinical
23	trials that have subsequently followed.
24	            And you¦ll see some of that evidence in

25	just a few moments.  Now another important point to

			24
	1	make apropos to what was said earlier is an
	2	asymptomatic condition.  Let me show you the next
	3	slide.  This is the MRFIT data representing the
	4	distribution of total cholesterol.  The mean is, I¦ll

	5	tell you, is about 206 mg. per deciliter.  If you¦ll
	6	look at the proportion of coronary events that come
	7	from this target group of 200-240, it represents a
	8	substantial proportion of patients who are in that
	9	range.
10	            How do they present?  Well they present in
11	one of three ways.  They present with an acute MI
12	which we can treat very well in hospital today.  They
13	present with angina which we can recognize.  Or, and
14	this is the key, they present asymptomatically as the
15	first time sudden death.  A first event sudden death. 
16	My friends, no symptoms whatsoever.  Thirty percent.
17	            Thirty percent of people who manifest the
18	disease for the first time have a first event sudden
19	death.  How do you get to that guy if he hasn¦t been
20	seen within the medical care system earlier?  Well in
21	fact I think, as you¦ll see, one of the ways we can
22	get to somebody in this range is through the
23	proposition of having available OTC Pravachol.  And so
24	what our target population is here, is this group
25	between 200-240, which represents a substantial risk.

			25
	1	            We don¦t like to use the word low-risk,
	2	because they aren¦t at low-risk.  They are at high-

	3	risk.  They just so happen to be a relatively lower-
	4	risk than the upper end of the distribution here.  And
	5	that¦s an important notion for you to understand as
	6	well.
	7	            If you really want to be at low-risk, have
	8	your total cholesterol around 150 mg. per deciliter. 
	9	Now, reference was made yesterday to HDL.  Now I think
10	it¦s important to consider where we are with HDL.  The
11	current guidelines, and we have with us this morning
12	one of my colleagues who was a member of the
13	guideline¦s writing committee, in fact established LDL
14	as the target molecule.  It is the molecule at which
15	we aim our therapy and we base our therapeutic
16	considerations.
17	            And in fact HDL is taken into
18	consideration only for risk stratification.  And it¦s
19	used in a dichotomous way.  When it¦s over 60 it¦s
20	counted as a so-called negative risk factor.  When
21	it¦s less than 35 it¦s a risk factor that¦s added to. 
22	But it¦s not used as a means of determining whether or
23	not we should treat somebody because total cholesterol
24	is an independent risk factor as is HDL, and I¦ll come
25	back to that point a little later, because I think the

			26
	1	panel had some questions relative to HDL.  Now I want
	2	to go into more of the rational that was touched on a
	3	little bit by Dr. Orloff.
	4	            First we have national policies already in
	5	place and we must consider that.  The national
	6	guidelines were developed and the current ones were
	7	written in 1992 and published 1993.  They are now
	8	seven to eight years old.  They were written at a time
	9	before we had evidence of the statins.  They were

10	written at a time when in fact the principal therapy
11	was said to be, and I stated today, bioacid resin
12	binders.
13	            That¦s the treatment if you go by the
14	current guidelines today.  Because it was pre-
15	experience with the megatrials.  How it defines
16	optimal levels, and again I don¦t necessary-- these
17	are desirable levels that actually is determining its
18	use, it¦s less than 200 and less than 130, and that¦s
19	where we would like to get the population to.  In

20	accordance with that, Healthy People 2010 who recently
21	said that¦s really a wonderful idea.  We¦ve got to
22	move the population down there for reasons of primary
23	prevention and having to do that.  You establish a
24	goal of 199 mg. per deciliter.  We would like to have
25	that as the mean.

			27
	1	            As I mentioned, the current mean is 206. 
	2	That¦s 7 mg. per deciliter.  It may not sound like a

	3	lot to you, but it¦s a big number when you apply it
	4	across the population.  It represents a three and a

	5	half percent reduction.  And what we have available to
	6	us today, in terms of the wisdom of our thinking and
	7	decision making, is the opportunity to create an
	8	option where we have available a tool to help move the
	9	population in that direction.
10	            What is appalling to all of us interested
11	in primary prevention is in fact what exists today. 
12	And all of us who practice know in fact that the
13	cholesterol is significantly undertreated and a
14	therapeutic gap to which Dr. Orloff referred remains
15	today.  What is that gap?  Well, we have people with
16	a defined goal of less than 200.  It says so in the
17	guidelines.
18	            They should be at less than 200, but yet
19	their cholesterol¦s are between 200 and 240 and they
20	go to the doctor and what does the doctor say?  He
21	says your cholesterol is 220.  That¦s a little above
22	average, not to worry, not too high.  300¦s high,
23	280¦s high, 250¦s high.  And so that¦s why it¦s often
24	called the most dangerous cholesterol in America. 

25	Why?  Because it¦s not treated.  It¦s not treated,

			28
	1	it¦s ignored.  If his cholesterol was 280 or 300, doc
	2	said we gotta get you on a drug.  We¦ve gotta lower
	3	that cholesterol.  And that¦s the population for which

	4	we have real concern.  That¦s where the action is with
	5	regard to coronary heart disease.  Now in addition to
	6	that we have, as Dr. Orloff again said, a changing
	7	environment.  Things are changing.  What¦s changing? 
	8	The American people.  And I think the manifestation of
	9	that is here in this room and the coverage that this
10	whole issue at the public forum two weeks ago. 
11	Attitudes have changed.  Americans are interested in
12	self-care.
13	            And they¦re voting with their dollars, 400
14	million dollars are spent annually on supplements used
15	extensively to lower cholesterol and in fact there is
16	very little data for most of what¦s bought with regard
17	to the two things that we are most interested in,
18	safety and efficacy.  And that¦s what we need to
19	consider in light of this changing environment.  Do we
20	have a tool available with proven safety and proven
21	efficacy that we can give to the American people with
22	knowledge of safety and knowledge that we are going to
23	do benefit and with regard to cholesterol reduction. 
24	And that¦s the questions that I think you¦ll be
25	addressing.  Prescription medications are often seen

			29
	1	by this group as a last resort.
	2	            I¦m not sick, I¦m not ill, I don¦t need to
	3	go the doctor and get a prescription.  And this is the
	4	group that might be interested in taking such a
	5	product where available.  And compliance doesn¦t
	6	matter.  You say what¦s long-term compliance?  I heard
	7	that yesterday.  100 percent?  No.  50 percent? 
	8	Maybe.  40 percent, whatever it is, it¦s a positive
	9	number for people who are not currently being treated. 
10	That¦s the idea to bring people into the system, to
11	get their cholesterols lowered first with safety,
12	which I¦ll come back to, and that¦s the idea that we
13	need to consider here this morning.  There is this
14	gap.  We can narrow that gap by an OTC approach and we
15	have data that you¦ll see that will promote
16	interaction with a healthcare provider.  It doesn¦t

17	drive people away, it brings them into the system, and
18	you¦ll see that a bit later.
19	            And it increases access particularly to
20	minority groups and others who may under-utilize
21	medical services and there I think we have an
22	opportunity to really reach out in ways that haven¦t
23	been done before because the number one cause of death
24	in these minority population groups is in fact

25	coronary heart disease.  This isn¦t the answer,

			30
	1	members of the committee and ladies and gentlemen. 
	2	This isn¦t the answer.  There isn¦t the answer to the
	3	question.
	4	            It is one of the answers to a very large
	5	problem and I believe it is a significant answer.  And
	6	the data support cholesterol lowering across a broad
	7	spectrum is huge, and you remember the database, the
	8	five megatrials including three that used pravastatin,
	9	and the primary prevention study, the West of
10	Scotland, the CARE and LIPID studies, were secondary
11	prevention trials, all of them showing highly
12	significant reductions in event rates.  Different
13	population base to be sure, but when we pull the data
14	and in particular looking at safety which we¦ll talk
15	about in a little bit, it gives us confidence about
16	that particular issue.  And so if you look at the

17	megatrials together in terms of randomized clinical
18	trials, we have the spectrum that is pretty broad now,
19	with respect to our knowledge of randomized clinical
20	trials.
21	            No, we do not have a clinical trial, nor
22	does anyone else, with respect to looking at the
23	target population per se.  You won¦t get that.  But

24	what you will get is the preponderance of evidence if
25	you step back from the data and look at everything. 

			31
	1	Look at the clinical trials, look at the
	2	epidemiological data, look at the animal studies, and
	3	you will see, ladies and gentlemen, that the
	4	preponderance of evidence clearly tells us that the
	5	target population will benefit from cholesterol
	6	lowering.
	7	            Don¦t look at a single trial.  Don¦t look
	8	at two trials or five trials, look at everything we
	9	have.  And I would submit to you that there¦s very

10	little that we do in medical practice today, for which
11	we have more proof of efficacy than lowering
12	cholesterol.  Let us go on from these trials and
13	address the HDL issue that came up yesterday.  Is HDL
14	an independent risk factor?  Absolutely.  Does it
15	predict or diminish the benefit of lipid-lowering? 
16	No.
17	            And that¦s the important point here. 
18	Looking at West of Scotland and looking at baseline
19	HDL levels divided by quintiles, you will see that
20	there¦s no evidence of attenuation of the benefit of
21	LDL reduction with Pravachol by HDL at baseline. 
22	Those who have the highest levels clearly show benefit
23	and the benefit at least is great if not greater
24	relatively than those who have the lowest levels of
25	HDL.

			32
	1	            Clearly the absolute risk is lower in
	2	those who have HDL, but that isn¦t the point.  The
	3	point is that these people benefit regardless of their

	4	HDL levels.  And the same can be said when we analyze
	5	the secondary prevention studies.  If you look at the
	6	CARE and LIPID studies taken together and draw the
	7	line looking at HDL again at baseline and looking at
	8	outcomes, you can see at the event rate the benefit
	9	that¦s seen with pravastatin is across all HDL levels. 
10	There¦s no evidence of interaction and there¦s no
11	evidence that these lines become parallel.  Those with
12	high HDL¦s benefit, those with low HDL¦s benefit.  Let
13	me turn, then, for the indications for Pravachol
14	itself.  It¦s a great story in terms of our ability to
15	lower lipids.  When I began many years ago, a couple
16	of¦ we never dreamed we¦d be able to do what we can do
17	today.
18	            Cholesterol lowering was approved in 1991
19	and the sequence we¦ve seen over the last 10 years,
20	amazing, amazing trials that I showed you that allows
21	them to have approval by the FDA for Pravachol, for
22	primary prevention of coronary events based on the
23	West of Scotland, for secondary prevention based on

24	CARE and LIPID, of total mortality by appropriately
25	reduction in coronary mortality, by reinfarction and

			33
	1	stroke in those who¦ve had a myocardial infarction,
	2	and importantly, slowing the rate of progression of
	3	atherosclerosis.  And why do I say that¦s important? 
	4	Because no one here that I¦ve heard in the last two

	5	days mentioned the word atherosclerosis.  And that¦s
	6	what I am particularly interested in is the disease
	7	process.
	8	            The distinction sometimes between primary
	9	and secondary prevention is blurry and with increased
10	technology is becoming more blurred.  We can diagnose
11	subclinical disease now.  Does that person have
12	secondary disease or primary disease?  And so we can
13	slow the rate of progression by use of pravastat.  And
14	when we¦ve considered this at-risk population, this
15	200-240 target population, by all means some of them,
16	some who may be destined to die tomorrow, have
17	underlying disease that we can slow the progression
18	of.
19	            And what we¦re asking for, in this current
20	application, in the proposal before you for the year
21	2000, is in fact an indication for cholesterol
22	lowering, specifically 10 mg. pravastatin cholesterol
23	lowering.  Now, let me conclude with this part of the
24	presentation about what we learned in medical school,
25	¦primum non nocere¦.  When I began thinking about

			34
	1	this, I thought in order to have a product out there
	2	with regard to reducing risk of disease and
	3	particularly an asymptomatic disease, what do we need

	4	to have?  And I kept coming back to this, ¦primum non
	5	nocere¦.  We first must do no harm.  And that¦s where
	6	the standard needs to be highest.  And I agree with
	7	when we say we need a higher standard, not in terms of
	8	clinical trials.  We¦ll never have all the i's dotted
	9	and the t¦s crossed there.  The higher standards must
10	come from safety.  We must protect our population out
11	there.  And we¦re all in agreement with that.  That
12	came through loud and clear at the public forum.  Now
13	let us look at what we have with Pravachol.  As was
14	mentioned, it is the drug that has the largest
15	clinical base experience.  More than 100,000 patient
16	years in randomized placebo controlled studies. 
17	That¦s a huge database that you¦ll see.  There is
18	based on those a lack of significant drug interactions
19	which differentiates it from other statins,
20	importantly so.  There is no evidence of
21	musculoskeletal events and the rates are similar to
22	what was seen in placebo.  The same with hepatobiliary
23	profile, the same in terms of overdose, potential. 

24	And trials using 100¦ 160 mg. have been done without
25	evidence of harm.  Finally in terms of pregnancy,

			35
	1	there¦s no evidence of reproductive risk if taken
	2	inadvertently during pregnancy.  What we have is a
	3	safe compound, as safe as a compound can be.  As Janet
	4	Woodcock said, there¦s no such thing as a perfectly
	5	safe drug and I would agree.  But this is about as
	6	safe as we can get in terms of an over-the-counter
	7	product.  Particularly when we counter-balance it with
	8	the 400 million dollars that¦s being spent for it, in
	9	terms of safety and efficacy.  OTC Pravachol provides
10	a well-characterized, safe option for individual

11	choice and so what we see is a reduction of LDL
12	cholesterol at average of about 18 percent.  This we
13	know will be associated with a significant reduction
14	in risk estimates as we know it from all of the data. 
15	We know that consumers are interested in
16	nonprescription options.  We have a way that we can
17	close or narrow this therapeutic gap.  This option of
18	allowing OTC Pravachol will go a long way at reducing
19	the burden of cardiovascular disease.  So in summary,
20	then, we have a compound that is very, very safe, that
21	is effective in terms of LDL reduction, and no matter
22	how you look at this particular ratio, it comes out
23	very favorable when you in fact start with a low
24	safety base.  We can talk about the numerator benefit
25	later on if you wish, but in fact you have to come up

			36
	1	with a very favorable benefit risk ratio.  And with
	2	that I¦ll conclude my remarks and it gives me pleasure

	3	to introduce our next speaker, Dr. Rene Belder, who in
	4	fact will emphasize and talk about the safety profile. 
	5	Rene?
	6	            DR. BELDER:  Thank you Dr. Cohen.  Good
	7	morning ladies and gentlemen.  My name is Rene Belder. 
	8	I¦m the Executive Director with the cardiovascular
	9	clinical research at Bristol-Meyers Squibb.  I¦ve been
10	with the company for about 12 years, and all those
11	years I¦ve been working with pravastatin.  It¦s now

12	for my pleasure to introduce to you some of the safety
13	data that has been mentioned earlier.  As mentioned
14	before there¦s an extensive profile safety experience
15	with pravastatin.  It has been used in over 200
16	clinical trials.  We started studying it in 1986.  It
17	was a well-established safety and efficacy profile. 
18	It doses up to 160 mg. per day which is four times the
19	highest prescription dose and 16 times the proposed
20	OTC dose.  We¦ve had more than 100,000 patient years
21	of exposure and placebo controlled morbidity and
22	mortality trials of which 50,000 patient years were on
23	pravastatin.  Our long-term safety data is in excess
24	of five years and more than 5,000 patients have been
25	exposed to pravastatin for more than five years in

			37
	1	these trials.  In addition we have an extensive post-
	2	marketing experience.  Pravastatin is available in 68
	3	countries for periods up to ten years.  And we
	4	estimate that there¦s more than 22 million patient
	5	years of exposure.  Certain safety considerations are
	6	important for the OTC availability of statins.  And
	7	these are drug interactions, the safety with respect
	8	to the musculoskeletal and hepatobiliary system, the
	9	risk of overdose and of course, the inadvertent use
10	during pregnancy.  I will discuss in the next few
11	slides each of these topics with you.  I will
12	demonstrate to you that pravastatin 10 mg. is an
13	appropriate choice for the OTC market.  Let¦s start
14	with the drug interactions.  Pravachol has no
15	clinically relevant pharmaco-kinetic drug
16	interactions.  It¦s unique among the statins because
17	it¦s not significantly metabolized by cytochrome P450. 
18	In addition there were no significant interactions in

19	the standard PK studies, for instance, with digoxin,
20	warfarin, and cimetidine.  And of course of interest
21	it is to know cimetidine, as you know, is available
22	for the over-the-counter use.  However, inhibitors of
23	P glycoprotein may cause small increases of
24	pravastatin levels and I¦ll show it to you a little
25	bit more about that in the next slide.  Based on this

			38
	1	profile we propose for the OTC label that there¦s no
	2	warning for drug interactions.  There¦s a lack of drug

	3	interactions with pravastatin and this slide shows you
	4	what it means relative to the other statins.  As you
	5	can see compared to the other statins, there¦s no
	6	significant increase in pravastatin levels when
	7	combined with some of the common 3A4 inhibitors, for
	8	instance, verapamil, itraconazole, erythromycin,
	9	grapefruit juice, and also diltiazem.  As said before,
10	inhibitors of P glycoprotein transfer system may
11	increase levels of pravastatin.  For instance,
12	erythromycin and clarithromycin have shown about a
13	two-fold increase in pravastatin levels and you show
14	that here, that¦s shown here.  That means that for a
15	10 mg. proposed OTC dose, the exposure would be
16	similar to a 20 mg. dose, which is still below the
17	highest prescription dose available.  Furthermore with
18	cyclosporine we have seen about four to five-fold

19	increase in personal levels.  We do not think that
20	these increases are clinically relevant and I would
21	like to refer to you the extensive literature that¦s
22	available about the use of pravastatin in transplant
23	patients.  Doses of 20 and 40 mg. have been used and
24	have been shown to be safe and effective in these
25	patients.  In conclusion, pravastatin¦ In conclusion,

			39
	1	there¦s a lack of drug interactions with pravastatin
	2	and we do not think that a warning on the label is

	3	necessary.  Let¦s move on to safety considerations
	4	with respect to the musculoskeletal system.  I would

	5	like to in particular discuss with you rhabdomyolysis. 
	6	This has been discussed yesterday and rhabdomyolysis
	7	is a serious condition.  It¦s defined with a clinical
	8	diagnosis of rhabdomyolysis combined with a CK level
	9	in excess of 10,000 units.  As you know there are
10	multiple risk factors known for rhabdomyolysis and in
11	patients who present with rhabdomyolysis, often

12	multiple of these risk factors are present.  That
13	makes the attribution of a case of rhabdomyolysis to
14	a specific factor often very difficult.  In addition,
15	the background rate is unknown.  However, rare cases
16	have been associated with pravastatin--, with statin
17	use in general.  I will show you the cases which have
18	been associated with pravastatin, but before I do that
19	I would like to mention that due to the lack of direct
20	drug interactions with pravastatin and due to its
21	hydrophilic nature and its active transport into
22	hepatocytes and virtually no uptake by nonhepatic
23	cells, we would not expect that rhabdomyolysis is a

24	particular concern with pravastatin use.  And these
25	are the data that we have.  There are no cases of

			40
	1	confirmed rhabdomyolysis in our clinical trial
	2	experience.  In the CARE study, one investigator
	3	reported one case of rhabdomyolysis, however, the peak
	4	CK level was less than two times the upper limit of
	5	normal.  Serious musculoskeletal events in our
	6	clinical trial database were similar to placebo with
	7	an incidence of .2 percent in each treatment group. 
	8	Our post-marketing surveillance database will attempt
	9	a 40 mg. dose use show there are very rare cases of

10	rhabdomyolysis, .3 cases per 100,000 years of patient
11	experience.  And as a total of 74 cases that we
12	counted, 57 cases met a definition, in 17 cases there
13	was a CK level that was unknown, however, were
14	conservatively incorporated.  Most cases, 47, had
15	confirming factors.  In 15 cases there was an
16	association also with a fibrate.  In two cases it was
17	clofibrate, in two cases gemfibrozil, in 11 cases was
18	bezafibrate, a compound that is not available at the
19	U.S. market.  FDA review showed a preponderance of
20	cases at the 10 mg. dose and also a preponderance of
21	cases at the Japanese population, posing the question
22	whether or not there would be a dose relationship or
23	perhaps a specific vulnerability of the Japanese
24	population to rhabdomyolysis.  Since most of the sales
25	of pravastatin occurs in Japan, where the 10 mg. dose

			41
	1	is used most likely, we did another analysis whereby
	2	we normalized the cases of rhabdomyolysis and divided

	3	it by the number of tablets distributed.  And you see
	4	that on these two panels here.  On the left-hand panel
	5	distribution by dose, on the right-hand panel
	6	distribution by country.  And as you can see when we
	7	look at the dose distribution, there¦s no apparent
	8	dose relationship with respect to the risk of
	9	rhabdomyolysis.
10	            I would like to point out that at a 40 mg.
11	dose there were only four cases reported and therefore
12	their confidence intervals around this estimate. 
13	Similarly when we look at the distribution by country,
14	there¦s a very similar rate reported in the United
15	States, Japan and France, which is about 85 percent of
16	total pravastatin sales.  And again, there¦s no
17	evidence of a specific vulnerability of the Japanese
18	population.  In summary, the cases of rhabdomyolysis
19	reported with pravastatin are very rare, there are
20	many confounding risk factors, the background
21	incidence is unknown, there¦s no apparent relationship
22	by dose or country, and there¦s no increased risk to
23	be expected due to the lack of drug interactions.  The
24	proposed OTC label nevertheless will contain the

25	appropriate warnings.  In summary, there¦s a wide

			42
	1	safety margin for pravastatin and we do not expect
	2	rhabdomyolysis to be of a particular concern.  Let¦s

	3	now look at the unique safety profile with pravastatin
	4	in the hepatobiliary system.  This slide gives you an
	5	historical overview of the LFT requirements of the
	6	liver function testing requirements with pravastatin
	7	over the years.  We started in 1991 with a class
	8	labeling, and here you see the frequency of liver
	9	function testing that was required.  Over the years we
10	gained experience with pravastatin and in ¦96 on the
11	basis of the results of the West of Scotland study, we
12	had a requirement for liver function testing approved
13	by the FDA, but only a baseline and a testing or any
14	time when the dose is elevated.
15	            At this moment based on the polled
16	analysis of the three prevention studies, we believe
17	that the data supports elimination of all liver
18	function testing.  And I will show you some of the
19	results of this analysis.  In the interest of time, I
20	will only show you the results on ALT.  We have
21	similar results for AST.  This shows you the incidents
22	of post-baseline market formalities more than three
23	times the upper limit of normal in the pravastatin and
24	the placebo group.  As you can see there were more
25	than 9,000 patients in the pravastatin group compared

			43
	1	to more than 9,000 patients in the placebo group and
	2	this was based on more than 250,000 liver function
	3	assays, and there¦s no difference between the placebo
	4	and the pravastatin group in the incidents of marked
	5	abnormalities.  The question was asked yesterday, what
	6	if a patient has a baseline abnormality to begin with? 
	7	And we had 317 patients in the pravastatin group who
	8	had an abnormal level before they start¦ got into the
	9	study.  And there was between one and three times the
10	upper limit of normal.  In the placebo group we had

11	262 patients and again, as you can see, there is no
12	difference in the risk for subsequent abnormalities
13	between the placebo and pravastatin group.  We
14	therefore conclude that there is no necessity for
15	liver function testing with the use of pravastatin. 
16	In summary, a clinical trial database does not have
17	any signal of drug or dose related hepatotoxicity.  A
18	post-marketing surveillance shows that there are only
19	very rare cases of liver failure, less than one per
20	one million years of exposure.  Most of these cases
21	were confounded by predisposing conditions and

22	multiple concomitant medications.  As I said before we
23	do not think that liver function testing is necessary
24	during the use of pravastatin.  Finally, the safety

25	considerations with respect to the risk of overdose

			44
	1	and the risk of inadvertent use during pregnancy.  As
	2	said before, in a clinical trial, pravastatin has been
	3	shown to be well-tolerated and safe in a trial in 48

	4	patients of six weeks duration, is four times high as
	5	prescription dose and, of course, 16 times the
	6	proposed OTC dose.  In our post-marketing surveillance
	7	database we had 14 cases of overdose.  One resulted in
	8	death, it was attempted suicide, and 13 cases
	9	recovered without sequelae.  However, the proposed OTC
10	label of course will contain warnings with respect to
11	overdose and use in children, or at least a warning
12	that it should be kept out of reach of children. 
13	Finally, pregnancy.  Of course, we do not advocate
14	that pravastatin is being used by pregnant women. 
15	However, I will show you the data that is relevant to
16	the risk when used inadvertently by a pregnant woman. 
17	Pravastatin was not teratogenic at doses with a 20

18	fault or a 240 fault greater exposure than humans,
19	based on the surface calculation and 40 mg. dose. 
20	There was no evidence of impaired organogenesis and
21	the offspring had normal birthweight.  Our post-
22	marketing surveillance database has 43 cases of
23	pregnancy reported.  Of 29 cases, the outcome was
24	known, and there was no evidence of teratogenicity. 
25	So our pre-clinical data and the experience with

			45
	1	exposure during pregnancy do not demonstrate it an
	2	increased risk for congenital malformations.  The
	3	proposed OTC label will of course contain a warning to

	4	seek medical attention in case there is a pregnancy. 
	5	In conclusion, these are the issues that we discussed
	6	and Dr. Cohen had mentioned them before as well,
	7	there¦s a lack of significant drug interactions,
	8	serious musculoskeletal events were similar to placebo
	9	in our controlled clinical trials, cases of
10	rhabdomyolysis are very rarely reported in post-
11	marketing surveillance, the hepatobiliary safety
12	profile is similar to placebo and supports elimination
13	of liver function testing, and there¦s a wide margin
14	of safety demonstrated and thus minimizing the risk of
15	overdose, and there¦s no evidence of reproductive risk
16	if taken inadvertently by pregnant women.  We
17	therefore think that pravastatin 10 mg. is safe for
18	the use in the OTC setting.  Thank you for your
19	attention.  I would like now to hand over to Dr.
20	Carola Friedman.
21	            DR. FRIEDMAN:  Thank you.  Good morning. 
22	I¦m Dr. Carola Friedman.  I¦m an Executive Medical
23	Director at Bristol-Meyers Squibb and I¦m very pleased
24	to be here today to present to you the OTC development
25	program that we put forward to support OTC status for

			46
	1	Pravachol 10 mg.  I¦d like to remind you again who is
	2	the OTC population.  These are men who are 35 years or
	3	greater and women who are over 45 years.  They have
	4	been told by their physician to lower cholesterol, and
	5	they are not at a desirable level, despite having
	6	pursued diet and exercise, and yet they are not taking
	7	prescription therapy.  That puts them in cholesterol
	8	ranges of total cholesterol of 200-240 and an LDL
	9	cholesterol of greater than 130 mg. per deciliter. 

10	This is a primary prevention population.  These people
11	do not have established vascular disease or diabetes. 
12	And these people, as you will see, are very likely to
13	reach their NCEP goal with a moderate reduction in LDL
14	cholesterol that will be achieved with 10 mg. of
15	Pravachol.  Now the points that we thought about as we
16	developed the program are points that have been
17	discussed before in these last couple of days as well
18	as points that we talked about with these committees
19	in our previous meetings as we thought about OTC
20	lipid-lowering therapy, and we discussed with FDA the
21	kinds of issues that we needed to consider.  And
22	they¦re listed here.  First, will the product be used
23	by the appropriate people?  Will the OTC defined
24	population in fact be the ones to go to this product? 
25	A very important consideration of OTC therapy is that

			47
	1	it will benefit and not destruct.  And that means that
	2	the physician needs to be maintained--, physician

	3	involvement needs to be maintained, both initially
	4	when thinking about using the product and over time as
	5	cardiovascular risk factors will evolve and change. 
	6	Will compliance in the OTC environment provide a
	7	similar profile of biologic activity that is LDL
	8	reduction?  And importantly will use in a less
	9	supervised environment result in the similar profile
10	of safety that you¦ve just heard about?  The program
11	that we put together to address this is listed here. 
12	First, a label comprehension and then two consumer-use
13	trials, PREDICT and OPTIONS.  The objectives of this
14	program are listed here.  First we wanted to develop
15	a label that consumers could understand and then test
16	it with a special attention to illiteracy.  In the
17	label comprehension trial, as well as all of the
18	consumer-use trials, we use the REALM test to assess
19	literacy in everyone who entered.  In the consumer-use
20	trial, we wanted to really allow everyone to come in
21	so it would be as much as possible if the product were
22	available for purchase in a store in an OTC
23	environment.  And that would include people for whom
24	this was inappropriate to see if they would make the
25	right decisions.  And then we wanted to assess their

			48
	1	behavior in these environments that were as natural as
	2	possible and allow them the myriad of behavior options
	3	that do occur in the real world with a minimal
	4	intrusion of the study architecture.  We wanted the

	5	data to be generalizable and that meant to include
	6	enough numbers of populations that we could do
	7	meaningful subanalyses, and we wanted it to be
	8	reliable.  And importantly we recognized and we heard
	9	from this committee the last time that one trial

10	cannot answer every question.  So we devised, we
11	designed two trials with very different study designs
12	to see if the results would be concordant.  In
13	PREDICT, we created OTC and prescription environments
14	to assess comparability, so that the prescription
15	group would act as, if you will, as a control group. 
16	In OPTIONS, we captured a real-world setting.  Now in
17	the interest of time, I¦m just going to spend a couple
18	of slides on the results of label comprehension.  This
19	study involved 612 people, 27 percent of whom read
20	below ninth grade level.  This was a mall-intercept
21	study.  There was in no way prior knowledge of or
22	interest in cholesterol required.  People were shown
23	the package and then asked a series of questions. 
24	Importantly as you can see here, people understood the
25	key messages, whether they read below ninth grade or

			49
	1	above ninth grade.  Importantly they understood that
	2	they should see the doctor and get their level
	3	checked, they shouldn¦t use if they¦ve had heart
	4	disease or diabetes, and if they had the adverse
	5	symptoms of muscle pain, they should see the doctor
	6	and stop the medication.  Now there has been a
	7	question raised in the FDA review as to whether the
	8	rel--, as to the relevance of the label comprehension
	9	test, given the fact that the label tested was not

10	exactly the same as the label that was submitted. 
11	This slide summarizes the differences in the label

12	tested versus the label that has been submitted to the
13	application that you have.  As you can see here, the
14	changes primarily reflect the evolution and
15	requirements of Drug Facts format.  We have attempted
16	to incorporate all of the key messages.  We have kept
17	the readability level at the same level.  The label

18	tested read at a seven and a half grade reading label
19	and the Drug Facts format label is at about an eighth
20	grade reading label, so that the number of the ¦see
21	your doctor¦ messages are the same, and we have added
22	additional information based on our learnings.  First
23	we have included the LDL greater than 130 mg. per
24	deciliter and we have tried to highlight the
25	importance of the total cholesterol level, 200-240 by

			50
	1	a graphic.  The other changes that we have made is the
	2	age for women has been changed to greater than 45

	3	years and the erythromycin warning was eliminated
	4	based on the pharmacokinetic data.  I¦m going to spend
	5	the rest of my time now talking about the consumer-use
	6	studies that we conducted, first starting with
	7	PREDICT.  The objective of this study was to allow
	8	very diverse populations to participate, to randomize
	9	everyone as they came in to two kinds of environments,
10	not two kinds of therapies but two kinds of
11	environments.  First, an OTC and then prescription,

12	before we knew anything about them, and allow them to
13	do the behavior that would exist in those
14	environments.  The prescription environment served as
15	a control group.  Once they came in they were left
16	alone to behave as they would in the real world for
17	six months.  What we assessed here was whether they
18	would consult a physician if they purchased the
19	product in the OTC environment.  And the secondary
20	objectives were comparative between OTC and
21	prescription to see if utilization of the healthcare
22	system would remain similar and whether the reduction
23	in LDL cholesterol and safety profile would also be
24	similar.  Turning now to how we recruited these

25	people, we again wanted to try to capture a broad

			51
	1	spectrum of the population.  The study was conducted
	2	and advertised in 20 geographically diverse areas.  We

	3	were very careful to characterize the demographics of
	4	the radio and print media to make sure that that
	5	mirrored the demographics of the community and we did
	6	augment advertising by placement on Hispanic and
	7	gospel stations and minority magazines.  The key
	8	communication messages of the advertising, whether
	9	this is a nonprescription medicine for people to lower
10	their cholesterol.  For people who are generally

11	healthy and had total cholesterols between 200 and
12	240.  Importantly the ad had no mention of age or
13	other medical conditions and was really quite general. 
14	This is how people came into the study.  Reflecting
15	interest in our prescription therapies, over 11,000
16	people responded to the ad by calling a call center

17	within six months.  Now we were very careful at the
18	call center not to do any screening so that the call
19	center operators had a script that allowed them only
20	to give directions to the site and the hours of
21	operation to the site to the callers, except for
22	screening out women of child-bearing potential.  The
23	study did exclude women of child-bearing potential
24	because it was started prior to the submission of the
25	pregnancy data that you heard to the FDA.  This

			52
	1	exclusion counted for about five percent of the calls. 
	2	There were 3,888 people who decided to visit the
	3	retail sites, 80 percent of whom responded to the ad,
	4	20 percent by a walk-through.  Importantly, of the
	5	people who decided to come, the vast majority, 3,872,
	6	almost everyone, was ultimately randomized to one of
	7	the two environments.  I¦m going to spend a few
	8	minutes talking about the retail sites because this is
	9	so different from a clinical trial.  This is actually
10	one of the retail sites where people went, and we

11	really wanted to try to make this accessible to
12	everyone, so we placed it in neighborhoods that had
13	access to public transportation, minority populations,
14	populations of low literacy.  And again this is where
15	people were randomized, before we knew anything about
16	their medical conditions or their cholesterol levels. 
17	Now we also wanted to make this as much as being in a
18	store as possible so there were no medical personnel. 
19	As you can see it was dissociated from the clinics. 
20	There was no screening performed, and there were
21	minimal exclusion criteria.  Anyone could purchase the
22	product if they were above the age of consent, if they
23	had not been in a research study in the last 30 days,
24	or if they weren¦t women of child-bearing potential. 
25	At this point, OTC participants could purchase the

			53
	1	product in a prototypical package that we would expect
	2	to be available in the real world.  And once they did

	3	and left the site, there was no contact made with them
	4	for six months.  If they wanted to come back to the
	5	site to re-purchase, they could, but no contact was
	6	made to anyone.  I¦m going to spend a couple of
	7	minutes talking about how people flowed through this
	8	study because it is so different from a usual clinical
	9	trial.  And I think that¦s very important as we
10	consider the analyses of the different patient
11	populations.  As you see here this is the OTC and the
12	prescription group, and this is how it would flow if
13	it were a real or usual clinical trial that we¦re used
14	to in evaluating drug applications.  First, people are
15	randomized to the environment, and you can see the
16	numbers flow down here.  And then if they want to,
17	they would consult the physician.  Then the physician
18	would make a decision of whether their therapy was
19	appropriate.  And then the subject would make a
20	decision of whether they wanted to take it, and this
21	would be the qualified and treated group.  And that¦s
22	of course if everything went according to the
23	protocol.  But we know in the real world that that
24	doesn¦t happen.  What are the options that the
25	prescription had?  Well, really they had to come in

			54
	1	and they had to see the doctor if they wanted to get
	2	a prescription and really their only option, or the

	3	only thing that they could do, is decide whether or
	4	not to fill that prescription, and we see that about
	5	50 people decided not to.  But really, they had to
	6	make this decision and then they came into this
	7	qualified and treated group.  On the other hand, the

	8	OTC purchasers had many other options.  Once they were
	9	randomized, they could go and purchase, they could
10	decide to consult first and then purchase, they could
11	find out if it was right for them and then purchase,
12	they could find out it was not right for them, the
13	physician could recommend that this was not a good
14	idea, but they could still purchase.  So they could
15	really purchase at all these different places.  They
16	had so many other things they could do.  And then of
17	course, once they purchased, they could decide whether
18	or not they wanted to take it.  So these different
19	activities help us characterize or place people in the
20	appropriate analyses.  To characterize the people who
21	are interested in this kind of a OTC proposition, we
22	really wanted to look at everybody before there were
23	any of these biases either by the subjects themselves
24	or by the physician as they came in.  So this is the
25	randomized population which we used to characterize

			55
	1	the people who are interested.  The primary objective
	2	of the study was to see whether OTC purchasers in fact
	3	consulted the doctor.  In terms of tolerability, in

	4	order to compare the OTC and prescription group, we
	5	used the qualified and treated population because this
	6	is really where the two groups had converged and where
	7	they had the equal choices and options.  And of
	8	course, for safety, we looked at everyone who took any
	9	medication at all.  I¦m going to show you now the

10	results of the characteristics of the people who were
11	interested in OTC therapies, really who is coming in
12	to purchase an OTC product.  It¦s a middle-aged
13	population, few people below the age of 35 or greater
14	than 75.  Again, because we excluded women of child-
15	bearing potential in this study, there were a
16	preponderance of men.  Eight percent of this 3,872
17	people were black, five percent were Hispanic, eight
18	percent read below ninth grade literacy.  In terms of
19	their healthcare status, this was a population with
20	access to healthcare who are still seeking
21	nonprescription options.  85 percent of them had a
22	doctor.  83 percent saw that doctor annually, a
23	quarter specifically for cholesterol.  A quarter knew
24	that they had high cholesterol for more than five
25	years.  There are no impediments to taking

			56
	1	prescription therapy.  Three-quarters of the
	2	population had prescription coverage.  And
	3	interestingly, this is actually the characteristics of

	4	the U.S. population, where about 85 percent of people
	5	do have a doctor, see the doctor annually, and about
	6	three-quarters of the population do have prescription
	7	coverage.  This was a motivated group of people. 
	8	Using the MEDFICTS tool, which is a validated tool
	9	proposed by the NCEP, 80 percent were already
10	following an American Heart Association diet.  But
11	twice as many people were using nonprescription

12	therapies to lower their cholesterol compared to
13	prescription therapies.  18 percent taking
14	nonprescription therapies to lower their cholesterol
15	versus nine percent who are taking prescription
16	therapies.  Here¦s what people would do if they
17	decided to see the doctor.  The physician saw both OTC
18	and prescription patients so that there would be no
19	bias in the clinic visits or recommendations.  The
20	visits were intended to mimic a typical practice where
21	people would have a lipid evaluation and then a
22	therapy recommendation according to study guidelines. 
23	If the therapy was appropriate for people, the doctor
24	would recommend that they come back in eight weeks,

25	but again it was up to the participant to make an

			57
	1	appointment to come back.  At six months we contacted
	2	everybody, whether they purchased, whether they saw

	3	the doctor, we really wanted to see what happened to
	4	everybody at the completion of the study and we did a
	5	cholesterol questionnaire, a lipid profile and a
	6	dietary assessment.  And in order to have an
	7	assessment of longer-term compliance over the course
	8	of an entire year, we invited people who were on
	9	therapy for six months to continue into a six month
10	extension.  I¦m going to talk now about the behavior
11	of the OTC consumer.  1,924 people were randomized to

12	the OTC environment.  Of those, 720 ultimately decided
13	to purchase.  I think it¦s important to spend a couple
14	of minutes looking at why people decided not to
15	purchase.  47 percent wanted to consult the doctor. 
16	18 percent recognized from the label that it wasn¦t
17	right for them.  15 percent cited cost, because as you
18	know in this study people were required to pay for
19	medication out of pocket.  Now what are the
20	characteristics of people interested in purchasing the
21	therapy?  This was a primary prevention population
22	free of heart disease and diabetes.  These people knew
23	that a healthy total cholesterol was below 200 mg. per
24	deciliter, 80 percent.  91 percent had been told they
25	had high cholesterol and they were right.  87 percent

			58
	1	had total cholesterols greater than 200 and three-
	2	quarters had LDL cholesterols above their desirable
	3	levels.  This slide depicts the behavior of what

	4	people did when they purchased the product.  The
	5	primary objective of the study was to see the
	6	percentage of people who would see the doctor within
	7	two months of taking the product.  And you can see
	8	here that 77 percent of people fulfilled that primary
	9	objective.  An additional 8 percent of people didn¦t
10	consult the doctor but at the end of the six months
11	returned their medication unused indicating that they
12	never took it and just didn¦t follow on with the
13	proposition.  An additional five percent of people

14	consulted but outside our predefined two month window,
15	leaving 90 percent of people behaving appropriately
16	and 10 percent who took and never consulted.  Now what
17	is the profile of that population?  Here we look at
18	the people who took without consulting, there were 72
19	of them.  Interestingly 88 percent of them had
20	discussed their cholesterol with a doctor in the last
21	six months.  This was still a primary prevention
22	population.  And importantly there was no evidence of
23	increased risk here.  Only two people reported adverse
24	events, one of myalgia and one patient underwent
25	prostate surgery.  90 percent of these people did not

			59
	1	go on to repurchase.  I¦m going to turn now to the
	2	secondary objectives where we look at the OTC
	3	environment versus the prescription environment and
	4	look at comparability.  Here we look at the people for

	5	whom the doctor said this is a good idea, take it and
	6	come and see me again in eight weeks.  We can see for
	7	the OTC group in yellow, prescription in blue, follow-
	8	up after that initial consultation was comparable and
	9	very good in both, indicating that because the product
10	is OTC doesn¦t necessarily mean lack of involvement in
11	the healthcare system.  Now another aspect we really
12	wanted to look at carefully was whether OTC
13	availability would distract people from their
14	prescription therapy.  Would this be adding people
15	into the system or actually taking people perhaps down
16	from a therapy that was already benefiting them?  And
17	how we assessed this was by looking at the people who
18	were randomized to the OTC environment¦ remember
19	everyone who came in was randomized, whether or not it
20	was appropriate for them, there was no screening done. 
21	And when we looked at all the people who were
22	randomized, there were 183 people who were already
23	taking prescription therapy when they answered the ad,
24	and when we looked at them at the end of six months,

25	only two percent had actually shifted down to the OTC

			60
	1	therapy option.  Now there¦s been some discussion
	2	about whether OTC availability would lead people to

	3	abandon lifestyle modification and that was an issue
	4	that has been brought up in the past and one that we
	5	wanted to look at very carefully.  As I mentioned we
	6	used the MEDFICTS tool to assess AHA diet status and
	7	as I mentioned coming into the study about 80 percent
	8	of people were already following an American Heart
	9	Association diet.  When we looked at what they did at
10	six months, the vast majority had not changed.  About
11	ten percent had actually improved, and a small number
12	had worsened.  But interestingly, more people in the
13	prescription group had worsened compared to OTC,

14	indicating that the OTC availability was not something
15	that would lead people to fall off their diet any more
16	than prescription.  Now can there be other benefits to
17	an OTC program?  I think we can perhaps see some of
18	them here.  At entry when people came into the study
19	and saw the doctor, by NCEP criteria, there were 321
20	people who needed a higher dose prescription therapy
21	because they were at high risk.  And in this study the
22	doctor said you¦re really not appropriate for this
23	therapy.  You need a prescription.  You should go talk
24	about it with your personal doctor.  When we contacted
25	these people at the end of six months, 46 percent in

			61
	1	fact had gone on to see their personal physician, and
	2	now 29 percent had started taking prescription
	3	therapy, whereas of course none of them was started,
	4	had been that six months ago.  In addition, new
	5	medical conditions were diagnosed in the work-up of
	6	high cholesterol, including hypertension, diabetes and
	7	thyroid disease.  Importantly and of course not
	8	surprisingly given the very good safety profile that
	9	we¦ve heard about this drug, the safety profile in the
10	OTC environment was excellent.  There were no doubts

11	or serious adverse events related to Pravachol, and
12	the overall incidents of adverse events was similar to
13	the prescription experience.  The most common reason
14	people discontinued was for myalgia or headache,
15	occurring in one percent of both the OTC and
16	prescription group.  Now there has been some

17	discussion in the FDA briefing book about the
18	tolerability and compliance in OTC and prescription
19	environments, and I want to address that on the next
20	slide.  When we look here at the reasons for

21	discontinuation of medication, and again going back to
22	what is the appropriate population to look at?  We
23	think that¦s a qualified and treated population, the
24	people who the doctor said this was right, and then

25	went on to take medication.  That¦s really where the

			62
	1	OTC and prescription group had that equal right, equal
	2	choice, and where we can compare apples to apples. 
	3	When we look at the reasons for discontinuing
	4	medication, there¦s no difference statistically

	5	between OTC and prescription overall, for adverse
	6	events, or for any of the other reasons that people
	7	gave.  Now of course the benefit of allowing Pravachol
	8	10 mg. OTC is the LDL reduction that it can afford. 
	9	And we used as our benchmark the LDL reduction that
10	has been seen in the placebo-controlled dose response
11	trials that initially supported the NDA.  What we can
12	see here is a summary of those results with about an
13	18 percent reduction in LDL cholesterol.  That was
14	highly statistically significant compared to placebo,
15	and this was the benchmark that we gave ourselves to
16	see if we could achieve in the OTC environment.  What
17	did we see and predict?  In the OTC subjects we saw a
18	meeting of that benchmark at eight weeks and
19	sustaining for six months.  And importantly in this
20	lower-risk population, this reduction brought 83
21	percent of the OTC subjects to their NCEP goal.  Now
22	I want to spend a couple of minutes talking about the
23	longer-term compliance because this issue was
24	discussed quite a bit yesterday.  This data is based
25	on the extension protocol which was filed to our four-

			63
	1	month safety update.  What we see here is a summary of
	2	the OTC and prescription group who qualified for
	3	therapy at the beginning of the study.  At one year

	4	about 50 percent of both groups equal were on drug. 
	5	Importantly, when we look at the LDL reduction
	6	achieved in this population, it was very significant. 
	7	This was a really compliant group of people.  We
	8	looked at them eight weeks, six months, one year, 22
	9	percent reduction in LDL cholesterol achieved and

10	maintained.  Then we also wanted to see if people
11	remained involved in the healthcare system over this
12	longer period of time.  It¦s important to remember
13	that in this study people did not have the prompts
14	that would occur in the real OTC world.  There was
15	none of the advertising or education programs, or any
16	of the media that would accompany a real OTC
17	situation.  People could choose to enroll in a
18	Pravachol Partners program, but that was really the
19	extent of the reinforcement messages.  So what did
20	people do at the end of a year?  As you can see, the
21	vast majority of people who started on, who came in,
22	completed therapy and consulted the doctor at a year,
23	there¦s a small number who discontinued before that
24	year, but consulted the doctor prior to
25	discontinuation.  There were some people who

			64
	1	discontinued on their own, but actually came back and
	2	saw the doctor at their annual visit, leaving only
	3	about eight or seven percent who neither consulted the
	4	doctor at a year or prior to stopping the therapy on

	5	their own.  So what do we think PREDICT can tell us
	6	about behavior in an OTC environment?  We can see that
	7	of the 1,924 people who were exposed to OTC Pravachol,
	8	about 25 percent decided to buy and take the drug.  83
	9	percent of those people talked to a doctor and
10	adjusted their behavior accordingly.  For people in
11	whom the doctor thought OTC Pravachol 10 was
12	appropriate, 52 percent were still on drug at 48 weeks
13	and they achieved meaningful LDL reduction comparable
14	to an Rx group.  I¦m going to turn now to the second
15	consumer-use study that we did, OPTIONS.  And this was
16	a study that we wanted to create real-world
17	environments.  We conducted this in 20 communities in
18	six states and allowed people to purchase Pravachol 10
19	in their own pharmacies and observe their behavior for
20	three months.  Now of course when we did this we had
21	to be able to verify that what they said they did,
22	they in fact did.  So to do that we chose OTC pop--,
23	we chose HMO populations so that we would have access
24	to the patient charts, the doctor could verify that
25	data in this real-world setting.  What we wanted to do

			65
	1	was assess whether people saw the doctor within two
	2	months of using the product, and again because the

	3	doctor had access to the charts and we could see if
	4	people would self-select appropriately whether or not
	5	they saw the doctor.  And we had a pre-specified
	6	definition of self-selection in the protocol that was
	7	really to be sure that people weren¦t distracted, that
	8	the high-risk people were not using the therapy.  So
	9	that the definition of appropriate self-selection were
10	people who had no heart disease, diabetes, liver
11	disease or pregnancy, were not currently taking
12	prescription lipid-lowering therapies.  We obviously
13	also wanted to assess safety.  Here¦s how the study
14	was conducted.  We again placed the sites that would
15	be accessible to diverse population and we sent
16	advertising like this to a non-targeted big sample of
17	the HMO.  As you can see this was one of the
18	pharmacies that used.  We had floor stands and posters
19	to attract walk-through.  The advertising was very
20	commercial-looking as much as possible in a clinical
21	trial, and again, participants could  purchase and
22	once they did there was no contact made with them for
23	three months.  We wanted very minimal exclusion
24	criteria, so that people again had to be above the age
25	of consent and could not have participated in a

			66
	1	research study within 30 days.  They needed to have
	2	been an HMO member for six months so we would have

	3	some relevant data in the chart and we did exclude
	4	women who were pregnant or breastfeeding.  Here is the
	5	results of the characteristics of people responding to
	6	the ad.  161,000 people received this mass mailer.  AS
	7	would be expected with a mass mailer, very few people
	8	were interested, about one or two percent ultimately
	9	came to the pharmacies, 2,202.  And when they saw the
10	package and the floor stand, 782 people were
11	interested enough to enroll in the study.  This was
12	about equally divided between walk-through and the
13	mailer.  Looking at the demographics of the people
14	responding to the advertisement, again, mean age of
15	about 51, few people below the age of 35 or above the
16	age of 75, about equal of men and women, 21 percent of
17	the people were black, five percent Hispanic, 12
18	percent read below ninth grade level.  Here is their
19	healthcare status and cholesterol option.  Not
20	unexpectedly in an HMO population, 96 percent saw the
21	doctor yearly.  Nearly a third of the people had seen
22	their doctor specifically for cholesterol.  70 percent
23	had seen the doctor for cholesterol in the last--, or
24	had discussed cholesterol with the doctor in the last
25	six months.  And just like PREDICT about a quarter of

			67
	1	these people knew they had high cholesterol for at
	2	least five years.  But also similar to PREDICT despite
	3	having access to prescription coverage, fewer people

	4	taking prescription therapy, 16 percent, compared to
	5	26 percent paying money out of pocket for
	6	nonprescription therapies.  Now if a person decided to
	7	go to the doctor in the study, they had to make an
	8	appointment with the doctor as they would in the real
	9	world and they saw their own primary care physician. 
10	There were no research physicians in the study.  And
11	this HMO setting, like I said, allowed the physicians
12	to verify the risk factor profile that the participant
13	reported as well as of course whether a person did
14	what they said they did and consulted.  And here¦s the
15	results of the consumer behavior.  Of the 782 people
16	who enrolled, 404 decided to purchase.  The reasons

17	for non-purchase again were very similar to what we
18	saw in PREDICT.  47 percent wanted to talk to the
19	doctor first, 20 percent recognized warnings on the
20	label indicating that the product wasn¦t right for
21	them.  Of those who purchased, again most people--,

22	this was a primary prevention population, and of the
23	people who had lab values in the chart, 89 percent had
24	total cholesterols greater than 200, 79 percent had an
25	LDL cholesterol greater than 130 mg. per deciliter. 

			68
	1	Here¦s the behaviors of the purchase population.  Here
	2	again our primary objective was consultation within

	3	two months.  44 percent of the people achieved that
	4	objective.  Another five percent consulted, but

	5	outside of our predefined two month window.  12
	6	percent purchased the medication but didn¦t take it
	7	within this three month period either because they
	8	weren¦t interested or hadn¦t yet had time to make the
	9	appointment with their physician.  And again because
10	in this study we could assess appropriate self-
11	selection by looking at the charts behind the scenes,
12	we could see that an additional 32 percent, although
13	they didn¦t consult, did appropriately self-select by
14	these predefined definitions of not being at high-
15	risk, leaving only seven percent of people who didn¦t
16	consult and did not appropriately self-select.  Well,
17	let¦s look at the profile of these people who didn¦t
18	consult.  There were 157 of them and as I mentioned,
19	82 percent self-selected appropriately and that they
20	were not at high-risk.  Three-quarters of these people
21	had discussed the doctor in the last six months and 90
22	percent of them had a total cholesterol greater than
23	200.  Importantly the incidents of adverse events in
24	this group was similar to those who did consult.  In
25	OPTIONS a safety profile was maintained, and I think

			69
	1	the safety in the OTC environment was also
	2	demonstrated.  Again we could see of the people who
	3	came into the study who were already taking
	4	prescription therapy, 11 percent shifted to the OTC
	5	option.  So how can we summarize the consumer program
	6	that we put forward to address whether Pravachol 10
	7	mg. can be used appropriately in an OTC setting? 
	8	First, comprehension of the label was evaluated with
	9	special attention to the low-literacy population.  The
10	identification of the OTC consumer and evaluation of
11	that behavior was assessed at large in varied
12	populations by very different study designs that
13	allowed real world behavior.  And of course we do
14	recognize that no matter how natural we try to make
15	these studies, nothing can truly mimic the real world
16	completely, and we are committed to monitoring a real

17	world environment after launch and that program will
18	be discussed by Ms. Kriger in the subsequent
19	presentation.  I think we can also conclude that the
20	characteristics of people who are interested in
21	purchasing OTCs are remarkably consistent across the
22	studies.  Over 90 percent have been told they have
23	high cholesterol and about 90 percent in fact have
24	cholesterol levels above desirable levels.  Three-
25	quarters have LDL above desirable levels.  And

			70
	1	importantly this is a group of people who are
	2	interested in taking nonprescription therapies.  The

	3	people who purchased OTC Pravachol, about a quarter
	4	were taking nonprescription therapies, two to three
	5	times as many who were taking prescription therapies
	6	to lower their cholesterol.  And yet this a doctor-
	7	involved population.  The vast majority see their
	8	doctor at least annually.  From the data that I have
	9	shown you I think we can conclude that Pravachol 10

10	mg. can be used appropriately in the OTC environment. 
11	Consumers can understand the label communication.  The
12	physician does remain involved both initially and over
13	time.  The safety profile, and by a profile of
14	biologic activity, has been demonstrated to be
15	maintained.  OTC availability does not significantly
16	shift people down from prescription therapy.  And in
17	fact we think that OTC availability can serve as a

18	gateway for increased utilization of appropriate
19	therapy by many people.  Thank you for your attention. 
20	I would now like to turn the presentation over to Ms.
21	Kriger who will discuss with you the education and
22	marketing programs that we would want to put forward
23	with a launch of this product.
24	            MS. KRIGER:  Thank you Dr. Friedman, and

25	good morning.  I am Patricia Kriger, Senior Director

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	1	of Rx-to-OTC Marketing at Bristol-Meyers Squibb.  I am
	2	very pleased to be with you this morning to review the
	3	education and marketing program that would accompany

	4	the OTC launch of Pravachol 10, as well as the post-
	5	marketing surveillance program we have planned.  As
	6	outlined earlier, our data demonstrates that consumers
	7	could safely use and would derive benefit from
	8	Pravachol 10 even in the absence of physician
	9	involvement.  However, we strongly believe that the
10	benefit would be maximized by keeping the physician
11	involved.  Therefore, we have developed a
12	comprehensive, educational campaign that emphasizes
13	the importance of keeping the doctor in the loop.  The
14	key goals of our plan are first to deliver a
15	responsible education and marketing program that will
16	complement, and not supplant, current efforts to

17	reduce cardiovascular risk in the United States. 
18	Second, to provide all the tools that consumers and
19	healthcare providers will need to ensure appropriate
20	use in an OTC setting.  We feel confident that the
21	program as proposed will allow us to translate the
22	very positive results we saw in the consumer-use
23	trials into a real world setting.  In fact, we will
24	have many more opportunities available to us to

25	communicate and reinforce key messages in an OTC

			72
	1	environment than we had in the consumer-use trials. 
	2	In an OTC setting we will surround consumers with

	3	multiple messages, including cholesterol awareness
	4	initiatives, healthcare provider programs, retailer
	5	programs, as well as consumer advertising.  To
	6	maximize their effectiveness, these programs must be
	7	designed with the consumer in mind.  So who is the

	8	likely OTC user and what is likely to motivate him or
	9	her?  The profile of the likely OTC use that has
10	emerged from our extensive consumer research is
11	remarkably consistent.  Those most interested in OTC
12	options are concerned about cholesterol, proactive and
13	prevention oriented, are already using diet and
14	exercise to help control cholesterol, and they are
15	doctor involved.  In fact, more than 80 percent have
16	discussed their cholesterol with their doctor in the
17	past year.  And importantly for both epidemiologic as
18	well as attitudinal reasons they are not ready for Rx
19	medicines.  There has been discussion about whether
20	the therapeutic gap can best be addressed by simply
21	lowering the Rx treatment guidelines to include those
22	with cholesterol in the 200-240 range.  It is evident
23	from how consumers perceive Rx and OTC medicines that
24	this is not the total answer.  As we look at how

25	cholesterol concerned consumers view Rx versus OTC

			73
	1	options, this becomes even clearer.  As demonstrated
	2	here, the vast majority of consumers regard Rx as only
	3	for people with severely elevated cholesterol and

	4	something to be avoided for as long as possible. 
	5	Specifically, 78 percent of consumers agree Rx
	6	medicines are for people with severe cholesterol
	7	problems, while only six percent agree this is true
	8	for OTC medicines.  Consistent with this, 58 percent
	9	agree that Rx medicines are something they would avoid
10	for as long as possible, while only 13 percent think
11	this applies to OTC options.  Conversely, OTC is seen
12	as the preferred option if cholesterol is only mildly
13	elevated and is viewed as something to prevent versus
14	treat disease.  As a result, OTCs can complement
15	currently available options by providing a more
16	accessible and less intimidating way into therapy for
17	many low-risk individuals.  With this in mind, let¦s
18	move to the education and marketing program itself,
19	starting with the key objectives.  First, to raise
20	cholesterol awareness and foster a productive dialogue
21	between consumers and healthcare professionals.  This
22	will help close the therapeutic gap highlighted
23	earlier by providing greater access and providing a

24	more acceptable treatment option for many consumers. 
25	The second objective is to ensure that consumers can

			74
	1	appropriately self-select, and third, to encourage
	2	responsible, ongoing use.  Let¦s turn now to the
	3	program elements designed to encourage awareness and

	4	dialogue.  First is consumer advertising, which will
	5	serve to increase awareness broadly and generate
	6	physician contacts.  In addition we¦ll reach consumers
	7	broadly through community outreach and work-site
	8	programs to increase awareness of cardiovascular risk
	9	and to encourage cholesterol awareness, intervention
10	and screening.  In this way, we hope to broaden access
11	to minority and underserved populations who may be
12	less likely to engage in the traditional medical
13	system.  To further facilitate the dialogue between
14	consumers and healthcare providers, we¦ll also provide
15	tear-off pads at the retail shelf with questions
16	consumers should discuss with their doctor.  Pravachol
17	10 labeling will also play a key role in encouraging
18	interaction between consumers and healthcare
19	providers.  Prominently displayed on the end flaps of
20	the carton is the message that consumers should see
21	their doctor.  This message reinforces to the consumer
22	the importance of knowing their cholesterol profile as
23	well as other risks for cardiovascular disease. 
24	Inside the carton right on each blister card is a
25	message that serves as a daily reminder that consumers

			75
	1	should keep the doctor involved in their ongoing
	2	management of disease.  In order to facilitate a
	3	productive two-way dialogue, we plan a comprehensive

	4	education program directed to healthcare providers. 
	5	We¦ll focus on those healthcare professionals who are
	6	most likely to interface with OTC users-- primary care
	7	physicians, nurses, physicians assistants, as well as
	8	pharmacists.  Our objective is to broaden education
	9	about cardiovascular risk, behavior modification and
10	how OTC options fit into the spectrum of cholesterol
11	management.  The tools we¦ll employ include a
12	professionally staffed 800 number, new product
13	bulletins, continuing education programs and materials
14	to provide to the patients.  For the second objective,
15	appropriate self-selection, the labeling will again
16	play a critical role.  As outlined earlier, consumers
17	clearly understand the label and higher-risk
18	individuals understand this product is not for them. 
19	In addition our program will include a toll-free 800
20	number and interactive web site.  The 800 number will
21	provide answers to frequently asked questions as well
22	as access to live operators.  Consumers will be able
23	to request Spanish language package inserts as well as
24	bilingual audiocassettes.  When people contact the 800
25	number, they will be reminded to contact their

			76
	1	physician if they have not already done so.  Through
	2	the web site, consumers can access up-to-date health

	3	information, risk assessment tools, get tips on diet
	4	and exercise, and can easily link to other related
	5	healthcare sites.  Let¦s move now to the third
	6	objective, encouraging responsible use.  This begins
	7	when consumers first purchase the product.  The
	8	starter kit will provide a month¦s supply of product
	9	in a calendar pack format to establish the routine of
10	daily use.  It will also include free enrollment in
11	Pravachol Partners, a user-friendly package insert and
12	educational brochure, as well as incentives for future
13	purchase and cholesterol testing.  We will also work
14	with cholesterol testing companies and retailers to
15	make cholesterol testing more accessible and
16	affordable.  This will be an integral part of our
17	program since we know how important positive
18	reinforcement is to ongoing compliance.  Pravachol
19	Partners is one of the key elements of the compliance
20	program.  The cornerstone of the program is a series
21	of postcards and newsletters with messages tailored to
22	coincide with key points in the adoption curve.  This
23	type of program has been shown to be very effective in
24	improving compliance and should be particularly
25	effective in this information hungry OTC audience. 

			77
	1	These education and marketing programs reflect
	2	extensive learning from our consumer-use trials and we
	3	feel confident that they will address the specific
	4	needs of consumers and healthcare providers.  At the
	5	same time we also recognize that no consumer-use
	6	trial, no matter how well designed, can answer all
	7	questions or anticipate all possible outcomes.  As a
	8	result, we are committed to rigorous post-marketing
	9	surveillance, including conducting a Phase IV study. 
10	This will allow us to characterize the range of real

11	world behavior and modify our education and marketing
12	program if warranted.  The three areas we¦ll be most
13	interested in evaluating will be safety in an OTC
14	setting, how OTC availability will impact cholesterol
15	awareness and action amongst the general U.S.
16	population, and the specific behaviors of OTC statin
17	users.  The primary mechanisms for evaluation include
18	monitoring of adverse events, which will of course be
19	reported periodically to the agency, 800 number
20	contacts from consumers and healthcare providers, and
21	most important, a Phase IV study.  The design I will
22	share with you represents a proposal only.  Clearly,
23	the final protocol would be discussed and finalized
24	with the agency before implementation.  As planned,

25	the Phase IV study will be conducted in three waves-- 

			78
	1	one baseline reading prior to distribution and two
	2	post-launch waves, six and twelve months following the
	3	start of advertising.  Each phase would include a

	4	naturally projectible sample of 10,000 adults and
	5	1,000 OTC statin users.  We would also augment to
	6	include a readable sample of important demographic
	7	subgroups.  The key objective of the study would be
	8	the characterization of cholesterol-related beliefs
	9	and behaviors, including awareness, cholesterol
10	testing, OTC utilization and physician interaction. 
11	The study would be sufficiently powered to allow us to
12	identify the scope and nature of any unanticipated
13	behavior so that we could modify our program as
14	warranted.  In closing, I would like to reiterate our
15	commitment to continuous improvement of our education
16	and marketing program based on learning from post-
17	marketing surveillance to support cholesterol
18	education efforts amongst consumers and healthcare
19	providers and to amplify important labeling messages,
20	to encouraging ongoing dialogue between consumers and
21	healthcare providers and to encourage appropriate
22	behavior and compliance.  I thank you for your time
23	and would like now to turn the podium back to Dr.
24	Friedman for a few closing remarks.
25	            DR. FRIEDMAN:  Thank you very much. 

			79
	1	Before I entertain any questions that you may have,
	2	I¦d just like to conclude with these thoughts.  First,
	3	heart disease is a very important issue in this
	4	country.  Since we began this meeting this morning,
	5	100 people have died of coronary heart disease in this
	6	country.  We also know that people are very interested
	7	in pursuing self-care options.  I think you¦ve seen
	8	demonstrated that Pravachol 10 mg. has an appropriate
	9	profile of both safety and efficacy for OTC use.  We
10	therefore conclude that OTC Pravachol 10 mg. is an
11	appropriate option for the lower-risk individuals who
12	are choosing to lower their cholesterol.  It will
13	bring more people on to appropriate therapy and it
14	will provide an additional approach to treat a major
15	modifiable risk factor for heart disease and be a part
16	of the solution to help close the therapeutic gap. 

17	Thanks very much.  I¦d be happy to entertain any
18	questions that you may have.
19	            CHAIRMAN BRASS:  We¦re not going to do the
20	questions until after the FDA presentation today.
21	            DR. FRIEDMAN:  Okay.
22	            CHAIRMAN BRASS:  Before we take a short
23	break, I just want to remind the committee members

24	that we will have a number of important votes this
25	afternoon and if anybody has flight arrangements, I

				80
	1	hope they don¦t interfere with that.  Those of you who
	2	will need to leave early, I would appreciate knowing
	3	about it during this break so we can plan accordingly. 
	4	At this point we¦ll take a break until 10:05.  Thank
	5	you.
	6		(Whereupon, the foregoing matter went off
	7		the record at 9:53 a.m. and went back on
	8		the record at 10:08 a.m.)
	9		CHAIRMAN BRASS:  We will continue the

10	morning session with the FDA presentations and I¦ll
11	turn the microphone over the Dr. Parks to begin that
12	presentation.
13		DR. PARKS:  Thank you Dr. Brass.  Good
14	morning.  Today you¦ll be hearing several
15	presentations given by reviewers at the FDA on
16	Bristol-Meyers Squibb application for the Rx-to-OTC
17	switch of pravastatin 10 mg.  I¦m Mary Parks.  I¦m a
18	medical officer in the Division of Metabolic and
19	Endocrine Drug Products.  I will first be presenting
20	the clinical efficacy and safety review of this
21	application.  Following me will be Dr. Daiva Shetty
22	from the Division of Over-the-Counter Drug Products
23	and she will be discussing the actual use trials.  And
24	finally Dr. Karen Lechter from the Division of Drug

25	Marketing, Advertising and Communications will be

			81
	1	discussing the label comprehension studies.  Dr.
	2	Brass, members of Joint Advisory Committee, I would

	3	like to present to you today the clinical review of
	4	Bristol-Meyers Squibb application for the
	5	nonprescription availability of pravastatin 10 mg.  My
	6	presentation will be focused on the following.  First
	7	I will discuss the sponsor¦s rationale for
	8	nonprescription pravastatin and who in the population
	9	should be using this product.  I will then present the
10	studies reviewed in this division and the results of
11	these studies followed by the safety of pravastatin
12	and finally, I will conclude the presentation by
13	highlighting the relevant findings in this review with
14	respect to the potential risk relationship of
15	nonprescription pravastatin.  The sponsor¦s rationale
16	for nonprescription pravastatin is, first, the
17	relationship between total cholesterol levels and the
18	risk of dying from heart disease.  You¦ve certainly

19	seen this slide now a couple of times, so I just want
20	to emphasize that this relationship is continuous and
21	great at one with the risk increasing considerably in
22	those individuals whose total cholesterol levels are
23	greater than 240.  The second point in the sponsor¦s
24	rationale for nonprescription pravastatin is based on
25	clinical trials in which drug therapy used to lower

			82
	1	cholesterol level has been able to demonstrate
	2	reduction in cardiovascular events, and this has been

	3	observed in both the primary and secondary prevention
	4	population and across a broad range of cholesterol
	5	levels.  Now despite these findings, these points, the
	6	sponsor contends that there remains a substantial
	7	number of individuals in the population who are
	8	inadequately treated to the NCEP goals.  These goals
	9	you¦re all familiar with.  At this point, I just want
10	to highlight that it¦s based on the presence or
11	absence of a cardiovascular disease and in the absence
12	of cardiovascular disease, it¦s dependent on the risk
13	factor present and that would determine the LDL
14	cholesterol treatment goal for each of the subgroups. 
15	Interestingly, despite the inadequate treatment of
16	dyslipidemia in the population, the sponsor states
17	that there are consumers who are greatly interested in
18	improving their cholesterol levels by buying dietary--
19	, diet foods and dietary supplements.  And their
20	proposal is to, by making pravastatin available as a
21	nonprescription drug, this would provide many
22	individuals in the population an additional means for
23	lowering cholesterol level.  And who are the people
24	that they are targeting?  The sponsor¦s definition for
25	the OTC target population include those who have been

			83
	1	told by their physician to lower their cholesterol
	2	level, but have not been placed on drug therapy.  The

	3	total cholesterol level should be between 200-240 and
	4	the LDL cholesterol is greater than 130.  Those who

	5	should not use nonprescription pravastatin include
	6	those who have established heart disease or diabetes,
	7	are currently on prescription lipid-lowering therapy,
	8	or children or pregnant women.  Several studies were
	9	submitted to support the nonprescription proposal and
10	these were reviewed in this division.  The 10 and 40
11	mg. placebo-controlled studies were actually studies
12	that had been previously submitted to the agency,
13	reviewed by the agency and the original NDA.  Two new
14	studies were conducted in the OTC clinical development
15	program.  The first is PREDICT, the Pravachol
16	Experience in a Documented Consumer-Use Trial.  This
17	was a 24-week open label trial in which after
18	consumers reviewed a product label they were
19	randomized to receive pravastatin either as a
20	prescription drug or as a nonprescription drug, and
21	response, lipid response to treatment was evaluated in
22	this trial.  The second actual-use study was OPTIONS,
23	and it stands for OTC Pravachol in an Observed
24	Naturalistic Setting.  This was a 12-week open label
25	uncontrolled study in which nonprescription

			84
	1	pravastatin was made available to enrollees in an HMO
	2	setting.  Response to cholesterol lowering--, to
	3	pravastatin treatment was not evaluated with respect
	4	to LDL cholesterol reduction in this trial.  The

	5	issues addressed in this review included whether
	6	pravastatin would significantly lower LDL cholesterol
	7	in the OTC population, what is the role of the
	8	healthcare professional in the management of this
	9	condition, and what is the concerns of here as to drug
10	treatment for this chronic asymptomatic condition,

11	whether or not treatment with pravastatin in this
12	population will confer clinical benefit, and then
13	finally safety, safety in the clinical trial setting
14	and safety in the post-marketing setting.  LDL
15	cholesterol reduction was evaluated first and three
16	placebo-controlled studies, again these studies were
17	previously submitted to the agency and the original
18	NDA and they were about eight to twelve weeks in

19	duration.  There was diet reinforcement throughout the
20	treatment duration, and although it was not in the OTC
21	target population, these studies did demonstrate that
22	pravastatin 10 mg. taken daily reduces LDL cholesterol
23	by about 18 to 22 percent compared to placebo.  In the
24	over-the-counter population, at least in a clinical
25	trial setting, the LDL cholesterol reduction was

			85
	1	evaluated in PREDICT, but it wasn¦t evaluated in the
	2	PREDICT cohort, it was evaluated in a subgroup of the

	3	PREDICT population, and that subgroup was called the
	4	qualified and treated subgroup.  And how an individual
	5	came to be part of this subgroup is through this
	6	algorithm.  After being randomized to either OTC or
	7	Rx, the individual or the consumer at his or her own
	8	will, could see the study physician and at this point
	9	a baseline physical exam would be performed, lipid

10	profile would be obtained, and also assessments of
11	cardiovascular risk factor.  And based on those

12	findings, a set of protocol and post-treatment
13	guidelines would be applied in order to determine if
14	the individual was qualified for treatment.  In the Rx
15	population it would be the initiation of treatment,
16	and in the OTC population, as Dr. Friedman had
17	mentioned earlier this morning, it really would either
18	be continuation treatment if they already started

19	treatment, or initiation treatment if they had not
20	started treatment.  The end result or the bottom line
21	here is that LDL cholesterol reduction was summarized
22	in the subgroup of which was only 15 percent of the
23	OTC population and about 19 percent of the Rx
24	population because of careful selection by the study
25	physician after applying this set of treatment

			86
	1	guidelines.  Now these treatment guidelines were meant
	2	to assist the study physician in uniformly deciding

	3	who should be initiated on therapy.  And after being
	4	initiated on therapy, who should have their dose
	5	titrated to either a 20 or 40 mg. dose in order to
	6	achieve a particular goal.  The determination of
	7	qualification for treatment in this trial was based on
	8	the individual¦s baseline risk factors for heart
	9	disease and also their baseline LDL cholesterol.  I

10	wanted to point out that these guidelines are unique
11	to the PREDICT protocol.  They¦re not part of the

12	proposed product label, because in the proposed
13	product label there isn¦t mention for the consumer to
14	treat themselves to a particular goal.  So in some
15	ways this treatment approach in PREDICT is not
16	representative of what we might see in the
17	nonprescription use of this product.  Regardless, LDL
18	cholesterol was summarized in this population, or this
19	subgroup, of which 18 percent required their dose
20	titrated to the 20 or 40 mg. dose in order to achieve
21	their NCEP goals.  And as you heard earlier again this
22	morning, there was about a 17 to 18 percent reduction
23	in LDL cholesterol, and this was observed in both the
24	OTC and Rx patients of this subgroup.  From these
25	findings, the sponsor concludes that the response, the

			87
	1	lipid response to treatment in the adherent individual
	2	will be the same in the prescription setting as in the
	3	nonprescription setting.  And really this is not
	4	surprising.  We really don¦t expect the LDL-lowering

	5	efficacy of pravastatin 10 mg. to be any different in
	6	an individual who takes that drug as obtained from his
	7	or her physician as a prescription drug, compared to
	8	that same individual who takes that same drug bought
	9	over the counter.  But what we don¦t know from these
10	results is really what the lipid response is to
11	treatment in the OTC population.  And the reason why
12	is because we wouldn¦t expect the OTC population who
13	takes any amount of drug to be comprised only of this
14	qualified and treated subgroup.  And we don¦t expect
15	that because PREDICT didn¦t show it.  PREDICT allowed,
16	in the OTC population of PREDICT, allowed consumers to
17	purchase up to two months of drug without having to
18	see a study physician.  So it really gave us an
19	opportunity to observe who would actually buy and use
20	this product without the physician.  And as a result
21	there were 499 people who purchased the medication and
22	used the medication, and about ten percent of them did
23	not consult a physician.  The remainder who consulted
24	a physician, some of them-- the treatment guidelines
25	I had mentioned earlier were at that point applied,

			88
	1	and some of them were disqualified from treatment
	2	because they did not meet eligibility for treatment
	3	based on those treatment guidelines.  And of those who

	4	were qualified, some of them may not have returned for
	5	follow-up.  So the end result here is that LDL
	6	cholesterol reduction as summarized in this subgroup
	7	here was only representing about half of the OTC-
	8	treated population.  And that¦s what I mean by we
	9	really don¦t know what the LDL response is in the
10	actual OTC population.  We don¦t know how the rest of
11	the population, the 49.3 percent who took amount of
12	drug and excluded from this analysis, how they did. 
13	In contrast in the Rx population, because the
14	individual had to see the study physician in order to
15	get medication as a prescription, it¦s not surprising
16	to find that 355 of those who took any amount of drug,
17	almost 100 percent of them were considered qualified
18	and actually considered in the LDL cholesterol
19	analysis.  So we have a fairly good estimate of lipid
20	response in the Rx treated population.  There are some
21	other points I want to make from this slide here.  The
22	conclusion that the OTC population achieved their NCEP
23	goal in 83 percent of them again was limited only to
24	those qualified and treated population.  So indeed we
25	don¦t know if the other half achieved their NCEP goals

			89
	1	because they were not looked at.  And then, finally,
	2	I¦m not really certain how representative this
	3	subgroup is of the sponsor¦s targeted population and

	4	I¦m not certain how representative it is because the
	5	mean total cholesterol--, or the median, excuse me,
	6	the median total cholesterol level in the subgroup was
	7	245, and that exceeds the total cholesterol range of
	8	the targeted population on their product label.  The
	9	other issue that was addressed in this review was that
10	of the role of the healthcare professional.  Certainly
11	this is important in entertaining a nonprescription

12	product because, at least for a chronic asymptomatic
13	condition.  And to get a better appreciation for the
14	role of the physician or the healthcare professional,
15	let¦s look first at the reasons why people were
16	discontinued from their study medication.  As I¦ve

17	mentioned there were 499 individuals in the OTC group
18	who took any amount of drug, the treated population,
19	of which more than half discontinued medication. 
20	About 25 percent of these individuals were
21	discontinued because of a study physician telling them
22	to discontinue their medication.  In contrast in the
23	Rx group, the patients who took any amount of drug,
24	only about a fifth of them discontinued.  The primary
25	reason was protocol violation, but interestingly, only

			90
	1	three were told to discontinue the medication by a
	2	study physician.  So clearly there¦s quite a contrast

	3	here with respect to a physician telling an individual
	4	to stop their medication, so in order to appreciate

	5	the role of the healthcare physician, let¦s examine
	6	these numbers a little bit more closely.  And that¦s
	7	what summarized here in this slide.  If you look in
	8	the OTC group, of the 123 who were told to stop their
	9	medication by the study physician, half of them were
10	told to stop because of this reason:  normal
11	cholesterol, therefore really not warranting drug
12	therapy.  About 25 percent were told to stop their
13	medication because their cholesterol or risk factor
14	was too high and perhaps warranting more aggressive
15	therapy.  And then there were some who were told to
16	discontinue because it was not appropriate or because
17	they were already on lipid-lowering drug. 
18	Unfortunately for our three patients here in the Rx
19	group we don¦t have a specific reason for why the

20	physician told them to stop their medication; however,
21	I think it¦s really quite evident from this slide that
22	for individuals who received drug in a prescription
23	setting, they have a lower likelihood of being
24	inappropriately initiated on therapy as opposed to
25	those in the OTC group where they have an opportunity

			91
	1	to self-select and use the medication without the
	2	healthcare professional involvement in the very
	3	beginning.  So this does raise a question that the
	4	role of the healthcare professional, at least in this
	5	study, is not only important in the management of
	6	dyslipidemia with respect to treatment of an
	7	individual to goal or consideration of dose titration,
	8	but it seems apparent that the healthcare
	9	professionals should be involved in the very early

10	stages, in the decision-making process, and assisting
11	the individual in terms of whether or not drug therapy
12	should or should not be initiated.  Because certainly
13	from PREDICT, in the OTC population, those who self-
14	selected to use were at risk of over-treatment because
15	they had normal cholesterol levels, under-treatment
16	because they had baseline cholesterol levels that were
17	too high, or perhaps high-risk factors, or
18	inappropriate treatment.  The next issue to address is
19	adherence to therapy and, as I mentioned yesterday,
20	adherence to therapy is important because this
21	condition, dyslipidemia, is a chronic asymptomatic
22	condition and so to its management requires long-term
23	adherence to any form of treatment including that of
24	nonprescription pravastatin.  In the PREDICT study

25	which was 24 weeks long, the study drug

			92
	1	discontinuation rate was 58.3 percent, and as I
	2	mentioned earlier, the primary reason, 25 percent of
	3	them was due to the physician recommending them to
	4	stop the medication.  In OPTIONS, the other actual use
	5	study, if you recall this was an open labeled,
	6	uncontrolled study, in which nonprescription
	7	pravastatin was made available to enrollees in an HMO
	8	setting.  It was a 12 week study and 51.4 percent were
	9	told to discontinue their med--, I¦m sorry, not told
10	to discontinue their medication.  51.4 percent
11	actually discontinued their medication and the main

12	reason that they discontinued their medication was
13	because of non-compliance.  As a matter of fact, 41
14	percent of these discontinued medication because of
15	reports of non-compliance.  Now if you¦ll look
16	individually at the reasons listed as non-compliance,
17	it included things such as, too busy, inconvenient
18	hours, not interested, so it really was quite a lot of
19	reasons as being listed as non-compliance.  But
20	certainly this suggests that adherence to therapy for
21	treatment of this chronic condition does not appear
22	ideal  With respect to clinical cardiovascular
23	benefit, the question that we¦re asking here is
24	whether or not treatment with pravastatin 10 mg. in
25	this targeted population will result in a reduction of

			93
	1	cardiovascular mortality and morbidity, and certainly
	2	you¦ve already heard from Dr. Cohen that it hasn¦t
	3	been demonstrated in not only this drug, but other
	4	medications, not demonstrated in this target
	5	population, not for this product at this dose, and
	6	certainly not in an actual use or actual
	7	nonprescription setting.  So in the absence of
	8	clinical benefit we have to ask what are the risks of
	9	drug treatment and the risk was evaluated in the

10	safety review, and first we looked at the safety in
11	the clinical trial setting.  At the 10 mg. dose, we
12	did not notice, we do not note any cases of
13	rhabdomyolysis, myoglobinuria or liver toxicity.  The

14	incidents of myalgia was low and is similar to that in
15	the placebo group.  Similarly, the incidents of liver
16	enzyme elevation was the same between pravastatin and
17	placebo.  Interestingly the discontinuation of
18	medication due to reported adverse events was slightly
19	higher in the OTC group versus that in the Rx group in
20	PREDICT, but we don¦t really know the reasons for this
21	and it may speak to the poor adherence to drug therapy
22	as observed in the actual use studies.  The safety of
23	pravastatin at the 40 mg. dose was evaluated in three
24	large placebo-controlled trials previously submitted
25	to the agency and these trials were about five years

			94
	1	in duration.  And the consecutive elevations in liver
	2	enzyme to more than three times upper limit of normal
	3	was less than one percent for pravastatin and it
	4	wasn¦t significantly different to that of placebo. 
	5	There were no cases of liver failure, and although
	6	there was one case of reported rhabdo, on closer
	7	examination, as mentioned earlier this morning by the
	8	sponsor, this didn¦t really meet the definition of
	9	clinical rhabdomyolysis because of the CK elevations. 
10	However, we acknowledge that there are limitations to

11	safety assessment in the clinical trial setting, and
12	these limitations are related primarily to the
13	exclusion of high-risk individuals, exclusion of
14	patients on interacting medications, exclusion of
15	patients with co-morbid medical conditions, and
16	certainly in a clinical trial setting, there are
17	scheduled visits and close safety monitoring such that
18	at the earliest sign of trouble, an individual is
19	asked to discontinue the medication or to stop or to
20	interrupt medication.  So sometimes safety assessments
21	in the clinical trials are not predictive of what we
22	would expect in the real world use of a product.  So
23	to get a better grasp on the safety of a product in

24	the real world we often looked at the post-marketing
25	spontaneous reports and in collaboration with the

			95
	1	office of post-marketing drug risk assessment, we
	2	looked at the following safety concerns for
	3	pravastatin, primarily liver failure and
	4	rhabdomyolysis.  For liver failure we looked at the
	5	following case definition.  We looked at cases of
	6	liver failure stated by the reporter or if the
	7	individual received a liver transplant and the
	8	reporting time period was that for marketing until
	9	recently this year, about nine years.  There were 13
10	cases of liver failure reported meeting this case
11	definition, eight of them domestic, five foreign, and
12	our safety evaluators looked at these carefully to
13	pull out the confounding cases.  There were only ten
14	unconfounded cases and if we use the domestic
15	unconfounded cases, we get a reporting rate which when
16	we compare then to the background rate of idiopathic

17	liver failure and we found that there was no increase
18	over the background rate of idiopathic liver failure. 
19	So although there have been pravastatin-associated
20	cases of liver failure, it¦s exceedingly rare, and
21	often it¦s certainly not increase of the background
22	rate, and often is complicated by certain medical
23	conditions and medication views, which makes it
24	difficult to assign any degree of any causality to
25	drug.  The other safety concern was that of

			96
	1	rhabdomyolysis and, again, this is not unique to
	2	pravastatin, as seen in all the statins.  The case
	3	definition here used is that of a clinical diagnosis
	4	of rhabdo with a CPK elevation of greater than 10,000. 
	5	The reporting time period here again was marketing
	6	until recently this year, and of note, the background
	7	rate is not known for this adverse event.  And given
	8	this case definition we found 35 cases which were
	9	broken down here into the foreign and U.S. reports. 

10	And I don¦t want to give the committee the impression
11	here that we are making the conclusion that there is
12	a dose relation or relation to country; this is just
13	merely reporting it, or describing it.  It¦s
14	interesting we do see some cases in the 10 mg. dose,
15	but these are more in the foreign cases, and I do
16	believe that that¦s probably has something to do with
17	the use of that particular dose more in the country. 
18	We don¦t have access as the sponsor has to the usage
19	data in the foreign countries.  Most of this was in
20	Japan and, actually, you probably saw that this
21	morning already.  We do have access to usage or, not
22	usage, but prescriptions written in the United States
23	and from IMS HEALTH, we see that indeed the 10 mg.

24	dose is the least prescribed dose across the dosage
25	formulation for pravastatin.  Again I want to

			97
	1	emphasize that the number here is number of
	2	prescriptions written, not number of individuals using

	3	it, so we cannot calculate incidence rates for adverse
	4	events obtained from spontaneous reports.  So in
	5	conclusion for rhabdomyolysis, the true incidence rate
	6	is not known, but the risk exists.  I think this risk
	7	is small, but surprisingly we even see it at the 10
	8	mg. dose, although more in the foreign cases.  There
	9	might be a potential increase in risk if it¦s

10	concomitantly used with certain medications.  The
11	fibrates and cyclosporine is another concern.  As

12	mentioned earlier, it may be through the inhibition of
13	P glycoprotein, and certain co-morbid medical
14	conditions may increase this risk.  So in conclusion
15	for safety review, there are very rare but serious
16	safety concerns that relate to pravastatin and
17	primarily that of the muscle toxicity.  So again in an
18	over-the-counter setting, the safety concern for a
19	drug is dependent again on the consumer¦s
20	comprehension of the label, the consumer¦s ability to
21	follow the label instructions so that there would be
22	no self-titration and no use by high-risk individuals. 
23	In conclusion, in evaluating the prescription to
24	nonprescription switch of pravastatin 10 mg., we ask

25	the question what is the balance of benefit versus

			98
	1	risk of nonprescription pravastatin and I¦d like to
	2	address that question by summarizing the findings or

	3	the issues addressed in this review with respect to
	4	the benefit side of the equation, we talk about LDL
	5	cholesterol reduction and as we saw in the placebo-
	6	controlled trials in the original submissions, that
	7	pravastatin does lower LDL cholesterol.  However, as
	8	observed in both OPTIONS and PREDICT, it seems like
	9	the poor adherence to drug treatment may reduce the
10	effectiveness of this lipid-lowering in the

11	population.  Again clinical cardiovascular benefit has
12	not been established for this drug in this population
13	and certainly the healthcare professional involvement
14	here appears to reduce the inappropriate self-
15	selection as observed in PREDICT.  That might actually
16	fall into the risk side of the equation, also.  And

17	then finally on the risk side of the equation for
18	safety, there are very rare but serious adverse events
19	which may be compounded by an unmonitored,
20	unsupervised use in a nonprescription setting.  So
21	with that, that concludes my presentation.  I would
22	now like to introduce Dr. Shetty.  Thank you very much
23	for your attention.
24	            DR. SHETTY:  Good morning.  My name is Daiva
25	Shetty and I am a medical officer in the Division of

			99
	1	Over-the-Counter Drug Products.  I am going to present
	2	some highlights of the data submitted by the sponsor
	3	about consumer actual use and behavior.  There are
	4	several actual use issues for Pravachol
	5	nonprescription use.  And first of all, are consumers
	6	able to self-diagnose hypercholesterolemia?  Do they
	7	know their own cholesterol values, and do they
	8	understand serum cholesterol values?  Are consumers
	9	able to self-select appropriately?  Can they identify

10	their risk factors for coronary heart disease?  And do
11	they understand how many of those risk factors they
12	should or they should not have prior to their drug
13	therapy?  Are consumers able to self-treat
14	hypercholesterolemia?  Do they know when to start, and
15	are they able to follow label directions for dosing
16	and duration of use?  Are they able to understand the
17	treatment goal and what is the goal to lower
18	cholesterol or to reduce the risk factors for coronary
19	heart disease?  In the interest of time, I¦m not going
20	to talk about the design of the studies, so you can
21	skip through those slides that you have copies.  The
22	actual use trials were submitted to the NDA, PREDICT
23	and OPTIONS.  First study, PREDICT, stands for the
24	Pravachol Experience Documented in a Consumer Trial. 
25	And I would like to make few comments about the label

			100
	1	used in this study.  It stated that this product is
	2	indicated for those whose total cholesterol is between
	3	200 and 240, and LDL cholesterol above 130 mg. per
	4	deciliter.  There was no HDL cholesterol value on the
	5	label.  No specific age requirements listed on the
	6	label either.  Only do-not-use section that those who
	7	are less than eighteen years of age should not use
	8	this product.  The primary objective of this study was
	9	to determine the proportion of the OTC randomized

10	subjects who have purchased OTC Pravachol, consult a
11	physician within two months of using medication. 

12	11,065 subjects called the call center.  3,888 were
13	screened at the screening site.  Of those, 3,872 were
14	enrolled into the study and randomized into two
15	groups, OTC and Rx.  Those two groups were similar in
16	terms of demographics and the number of subjects
17	enrolled.  I would like to make a comment about the
18	call center.  The call center served as a screening
19	site for premenopausal and childbearing potential
20	women, and if the subject who called was a woman of
21	childbearing potential, she was not given directions

22	to go to the enrollment site.  119 subjects were found
23	to be ineligible to participate, and half of them, or
24	61, were women of childbearing age.  This two percent
25	comes from the enrolled population only of 3,872 and

			101
	1	is greatly underestimated.  And the reason it was
	2	underestimated, because these women were not given the

	3	opportunity to be enrolled.  Of 11,065 who called the
	4	call center, we don¦t know how many were women of
	5	childbearing age.  Of 1,924 subjects randomized to
	6	over-the-counter group, 720 purchased the drug.  553
	7	consulted a physician within two months.  And 499 of
	8	those ended up taking Pravachol.  The last column
	9	represents a proportion of the subjects who did not
10	qualify for the treatment.  A total of 266 subjects,
11	or 37 percent of those who purchased, did not qualify
12	for the treatment as it says by the study physician
13	based on the person¦s risk factors or the lipid
14	profile.  Of this 266 also comes from those who
15	consulted a physician, so almost half of those who
16	consulted a physician did not qualify for the

17	treatment.  I would like to remind you what
18	qualification for the treatment was based on.  It was
19	different from the label use.  The guidelines for
20	treatment included only risk factors and LDL
21	cholesterol value.  It also had a goal specified for
22	the treatment.  This goal, less than 130 or less than
23	100 of 60 mg. per deciliter of LDL cholesterol was not
24	listed on the label.  And now then you¦re looking at
25	the baseline lipid profile of qualified and treated

			102
	1	population as assessed by study physician.  Mean LDL
	2	cholesterol value of 162 corresponds with total
	3	cholesterol of mean or median 245, showing that more
	4	than 50 percent of population who were assessed as

	5	qualified did not meet the label requirements for
	6	total cholesterol between 200 and 240.  Looking at the
	7	behavior of the treated population in over-the-counter
	8	group, data show that 58 percent withdrew from the
	9	study.  And most common reason for the draw was
10	withdrawal by a physician.  This 123 subjects
11	withdrawn by the physician represents one-quarter of
12	total treated population in the over-the-counter
13	group, showing poor self-selection for the treatment. 
14	Discontinuation rate due to adverse events in over-
15	the-counter group, even though not statistically
16	significant was a little bit higher in over-the-
17	counter group, eight percent versus five percent in Rx
18	group.  53 subjects in the OTC treated group required
19	titration to a higher dose, and this titration was
20	done at assessment three which was eight weeks after
21	the first visit to the doctor.  Compliance in the
22	PREDICT study even though it was not strictly
23	monitored was assessed by a pill count and self-report
24	and defined as 80 to 120 percent, and was not ideal in
25	both groups.  54 percent in over-the-counter, and 65

			103
	1	percent in Rx group.  Mean duration of the treatment
	2	was significantly short in over-the-counter group, 109
	3	days versus 152 days in Rx group.  I talked about
	4	consumer behavior, self-selection and compliance.  Now

	5	I would like to touch on one other issue for Pravachol
	6	availability as nonprescription drug.  Are consumers
	7	able to self-diagnose hypercholesterolemia?  Subjects
	8	involved in PREDICT and OPTIONS study did not have to
	9	know their own cholesterol values.  They had to go to
10	the doctor, their own other physician, other study

11	physician, to get their lipid profile tested.  Now
12	though the sponsor, a part of consumer behavior,
13	attempted to test consumer cholesterol awareness and
14	knowledge about cholesterol.  And even though 96
15	percent enrolled in this study stated that they were
16	very concerned about their health and their

17	cholesterol, 74 percent answered that total
18	cholesterol less than 200 represents a healthy level. 
19	The knowledge in certain demographic subpopulations
20	and lower literacy was lower, but overall 74 percent
21	said that less than 200 is a healthy level.  However,
22	knowledge about LDL cholesterol was significantly
23	lower.  Only 12 percent stated that LDL cholesterol

24	less than 130 represents a healthy level.  80 percent
25	had no idea what LDL cholesterol values should be. 

			104
	1	And knowledge about HDL cholesterol was not tested in
	2	this study at all.  And all of these values required
	3	for self-diagnosis and the treatment of
	4	hypercholesterolemia according to the current
	5	guidelines.  Now I would like to talk about second
	6	actual use trials submitted to this NDA, which was
	7	called OPTIONS.  The population targeted and enrolled
	8	in this study was not really representative of overall
	9	U.S. over-the-counter population.  The study was

10	restricted to certain geographical areas.  Only six
11	states participated in this study, and all of the

12	participants had healthcare insurance and prescription
13	drug coverage, and this may not be necessary the case
14	in the real over-the-counter setting.  The label used
15	in these studies also were some comments.  Criteria
16	for the treatment on the label:  you had a total
17	cholesterol between 200 and 240, no LDL cholesterol
18	was listed on this label, and a specific age, more
19	than 35 for men and more than 55 years for women were
20	stated on the label.  Now the primary objective of the
21	study was similar as in PREDICT to determine the
22	proportion of subjects who have purchased Pravachol
23	contact their own healthcare provider within two
24	months of using medication.  Out of 161,322 subjects
25	targeted only by the mailer, 2,207 came to the

			105
	1	screening or the enrollment site, and 782 were
	2	enrolled into the study.  Out of 782 who were
	3	enrolled, 404 purchased the Pravachol, 321 ended up

	4	taking it, and only 178 consulted a physician, their
	5	own healthcare provider within two months.  This 178
	6	subjects represents only 44 percent of total purchase
	7	population, meeting the primary objective of the
	8	study.  Looking at the behavior of the treated
	9	population, you can see that only 49 percent continued
10	on treatment for more than 56 days.  And 51 percent
11	withdrew from the study.  The most common reason for
12	withdrawal was noncompliance.  Withdrawal by a
13	physician was done in 20 cases in this study.  This
14	slide points out certain self-selection errors
15	observed in this study.  24 percent of purchase
16	population were not recommended Pravachol by their own
17	healthcare provider, based on the risk factors or the
18	cholesterol level.  Now as you remember the label
19	stated that this product is indicated for those whose
20	total cholesterol was within 200 and 240.  Median
21	total cholesterol of purchase population at baseline
22	was 235.  Again, showing that almost 50 percent of
23	those who purchased Pravachol did not meet the label
24	requirements.  As you may also recall, age for women
25	stated on the label was 55 years or older.  Now

			106
	1	looking at the demographics of purchase population,
	2	data show that 60 percent of women who purchased the

	3	drug were less than 55 years of age.  And this self-
	4	selection error is very important for two reasons. 
	5	First of all, these women less than 55 years old may

	6	not be at risk for coronary heart disease and will be
	7	taking the drug unnecessary.  On the other hand, they
	8	may be of childbearing potential and therefore may be
	9	a safety risk for taking Pravachol during possible

10	pregnancy.  As I finish up my talk I would like to
11	make few comments about the proposed label.  It is
12	unclear what population is being targeted for
13	Pravachol nonprescription use.  Proposed label
14	initially submitted to this NDA stated that this

15	product is indicated for those cholesterol values what
16	I mentioned before.  There was no age requirement for
17	buying this product on the initial label.  This label
18	was modified and new label has been submitted by the
19	sponsor just a few weeks before this advisory
20	committee meeting.  And it stated the same cholesterol
21	values, however the age and the targeted population
22	now is different.  For men more than 35 years and for
23	women more than 45 years of age.  In conclusion based
24	on the information I have given to you, the actual use
25	trials showed low consumer understanding of specific

			107
	1	serum cholesterol values, especially LDL cholesterol
	2	value.  It showed substantial number of self-selection
	3	errors, a high withdrawal rate and poor adherence to

	4	the therapy.  Behavior of childbearing-age women was
	5	not addressed in these two trials and consumer
	6	understanding was not assessed about the goal, length
	7	of the therapy and titration to a higher dose. 
	8	Targeted OTC population under current proposed label
	9	has not bee studied and therefore it¦s not clear how
10	the data from the two actual use trials could support
11	this new OTC target population.  And on this note I
12	would like to finish my talk and invite the next
13	speaker, Dr. Karen Lechter.  Thank you for your
14	attention.
15	            DR. LECHTER:  I¦m Karen Lechter with the
16	Division of Drug Marketing, Advertising and
17	Communications, and I¦m going to be discussing the

18	label comprehension study for Pravachol 10.  The label
19	in this study is different in the format from the one
20	that was submitted with the NDA and its content varies
21	somewhat from the NDA label.  And in your agenda
22	packets this morning, we have attached a copy of the
23	study label and the NDA label for your reference,
24	right behind the questions for the committee.  I will
25	be discussing the Pravachol study characteristics and

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	1	results, the potential for misuse, the tested label
	2	versus the NDA label, and conclusions.  The Pravachol

	3	study had six open-ended and sixteen multiple choice
	4	questions for the label materials.  Two questions were
	5	asked without the label present and there were no
	6	questions about the materials that would be inside the
	7	carton.  For three questions, knowledge was assumed
	8	that should have been tested, making it easier to
	9	answer correctly.  These were questions asking what
10	should be done before use and after one year, and a
11	question stating that people with some medical
12	conditions should not use the product, asking who they
13	were.  These questions assumed that people knew they
14	needed to do something before use and after one year,
15	and that persons with certain medical conditions
16	should not use the product.  We don¦t know if the
17	participants knew this information before the
18	questions were asked.  Results for the two open-ended
19	questions were confounded because they were combined. 
20	What diseases preclude use, and what other diseases
21	are mentioned on the label?  The results should have
22	been separated because some diseases mentioned on the
23	label do not preclude use.  Fortunately there were
24	other questions asked in a different way about the
25	three main medical conditions precluding use that give

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	1	us another opportunity to assess knowledge in this
	2	area.  Due to the nature of the questions asked in
	3	this study, we do not know if consumers can apply the
	4	information to a variety of use situations.  There

	5	were no questions involving the application of the
	6	information to hypothetical situations.  If such
	7	scenario questions had been asked, biased questions
	8	could have been avoided and we could have been more
	9	comfortable about accepting the results for some of
10	the questions.  There were no questions about whether
11	participants could use the product themselves, which
12	would have been cross-checked against their medical
13	history to determine if they answered correctly.  The
14	design of label comprehension study should begin with
15	a set of communication objectives.  I discussed these
16	yesterday and I won¦t go into them again today.  The

17	sponsor said that the primary objective for this study
18	was whether consumers understand they should see a
19	doctor before using Pravachol 10.  The secondary
20	objectives begin with the product purpose:  to lower
21	cholesterol if it is between 200 and 240 after diet
22	and exercise.  There were no questions about diet and
23	exercise.  The secondary objectives also asked about
24	those who should not use the product as listed in the
25	second bullet here.  The secondary objectives included

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	1	who should use the product including non-pregnant
	2	females age 55 or above, males age 35 or above, and
	3	people with total cholesterol of 200 to 240.  The
	4	objectives included understanding the need for follow-
	5	up and that muscle pain should be reported to the
	6	doctor.  The tested label requires application of
	7	several sections of the label at once:  the use
	8	section giving total cholesterol and the ages for men
	9	and women, the warning section, and the ¦ask the

10	doctor before use¦ section.  The questions in this
11	study did not test if consumers could apply all these
12	requirements simultaneously or even a combination of
13	some of these requirements.  The ¦ask the doctor
14	before use¦ section says:  Ask the doctor if you
15	smoke, have high blood pressure, or a family history
16	of heart disease, or if total cholesterol is more than
17	240 and HDL is very low.  It does not define very low
18	HDL.  There were no communication objectives or
19	questions about this section.  These are the
20	characteristics of the participants.  I think you¦ve
21	seen them already.  163 of the 612 participants were
22	low-literacy.  There were no differences in responses
23	from the low-literacy group compared to the non-low-
24	literate group based on t-tests at p < .05, with no

25	adjustments for multiple comparisons.  Despite the

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	1	shortcomings of some of the questions, we can conclude
	2	that certain concepts were well-understood.  They

	3	include the following:  the purpose for using the
	4	product, understood by 90-95 percent; 97 percent were
	5	able to list one of the three diseases precluding use;
	6	however, only 71 percent could name all three.  In
	7	three multiple choice questions, they were asked to
	8	identify the three diseases that preclude use, and
	9	they did so at a rate of 88 to 90 percent.  However,
10	each of these three questions had either one other
11	choice or none of the above choice, making them fairly
12	simple questions.  They understood at fairly high
13	rates that they should not use the product if they are
14	pregnant or drink three or more alcoholic beverages on
15	most days.  Additional concepts that were well-
16	understood were that it was not for people with normal
17	cholesterol, pregnant women or those with hepatitis,
18	and they should see a doctor if they have unusual

19	muscle pain or tenderness after use.  Concepts that
20	were not as well understood were the ages for men and
21	women.  The results were 77 to 80 percent.  They
22	moderately understood the fact that they must see a
23	doctor after eight weeks; however, this question was
24	multiple choice and two of the choices mentioned that
25	something had to be done in eight weeks, perhaps

			112
	1	suggesting to participants that they do something at
	2	that time, which they may not have realized until they
	3	saw that question.  Due to the wording of the
	4	questions, it is not clear that consumers understand
	5	that according to the label they must see a doctor
	6	before use, and to see a doctor for a cholesterol
	7	check after taking the product for one year.  These
	8	questions suggested that there was something that
	9	needed to be done at certain points in time.  One
10	question about seeing the doctor before use was
11	answered by 82 percent of participants.  This question
12	was asked without the label present.  The other
13	questions about seeing the doctor before use were
14	asked with the label in view and resulted in higher
15	scores.  Based on the results, the tested label needed
16	improvement in these areas, to clarify that persons

17	taking erythromycin should not take the product.  65
18	percent got this one correct.  In the NDA label, this
19	warning was eliminated.  It was deemed to be
20	unnecessary.  The label needed to be strengthened in
21	the warning not to use Pravachol 10 if you are taking
22	prescription cholesterol-lowering medicines.  73
23	percent understood this message.  The NDA label says
24	to ask a doctor or pharmacist if you take other

25	cholesterol medicines.  The label needed to be

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	1	strengthened in the message about cholesterol levels
	2	for which the product is appropriate.  76 percent were
	3	correct, but 17 percent said that it was appropriate

	4	for total cholesterol of 250 to 300.  And the label
	5	should have been strengthened in the information about
	6	the ages of men and women to use the product.  77
	7	percent were correct for men and 80 percent for women. 
	8	The proposed NDA label does not have age limitations
	9	other than not to use it under age 18.  But the later-
10	submitted label says that the product is for men over
11	35 and women over 45.  There were some important
12	concepts that were not tested.  There were no
13	questions asking participants if they could use the
14	product.  We generally like to see these questions to
15	determine if consumers can apply the label information
16	to their own circumstances.  If this question had been
17	asked, the responses would have been checked against

18	the medical information that the patients provided to
19	determine if they responded correctly.  However this
20	question about self-use was not asked.  There were no
21	questions asked about applying multiple criteria for
22	use or non-use at once.  We don¦t know if consumers
23	will understand they need to meet certain cholesterol
24	levels, perhaps certain LDL levels, maybe age by sex
25	requirements, and must not have a broad list of

			114
	1	conditions in order to be able to use the product
	2	appropriately.  There were no questions asking these
	3	special circumstances on the label under which a

	4	doctor should be consulted before use, only the
	5	general advice to see a doctor before use was tested. 
	6	Yet the label said to consult a doctor before use if
	7	you have the factors listed in the first bullet here. 
	8	There were no questions to test understanding of
	9	treatment failure, success, or long-term benefits of
10	use.  There were no questions about the need for diet
11	and exercise.  We also do not know if consumers
12	understand what a healthy cholesterol is from this
13	study.  The label tells them to continue taking
14	Pravachol 10 if they have reached a healthy
15	cholesterol level.  It tells them they may need a
16	prescription dose of Pravachol if they have not
17	reached a healthy cholesterol level.  No questions
18	were asked about their understanding of healthy

19	cholesterol.  17 percent said Pravachol 10 was
20	appropriate for cholesterol of 250 to 300.  This
21	misunderstanding may be the basis for inappropriate
22	use.  In addition, we don¦t know whether consumers
23	understand they must apply a combination of
24	characteristics to use the product, based on total
25	cholesterol, sex, age, and perhaps LDL.  It is

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	1	possible that some will assume if they qualify under
	2	one characteristic, for example, total cholesterol,
	3	that they can use the product.  There were substantial
	4	differences between the tested label and the label
	5	submitted with the NDA, and the subsequent label that
	6	we have not evaluated.  These were differences in
	7	content and format, making them sufficiently different
	8	that the results of this label comprehension study may
	9	not apply to the NDA or later labels.  I will point

10	out the most significant differences between those two
11	labels and, again, you may want to refer to the copies
12	of those labels in your agenda packet.  The tested
13	label says at the top, ¦Before you start see your
14	doctor to check cholesterol labels and discuss risk
15	factors for heart disease.¦  The NDA label has nothing
16	at the top about seeing a doctor.  The tested label

17	has a pictogram of a doctor and a patient on the side
18	of the use section with the statement, ¦See your

19	doctor before use.¦  The NDA label does not have a
20	pictogram or a separate statement to see the doctor
21	before use.  The tested label says it is for
22	cholesterol of 200 to 240.  The NDA label says it is
23	for cholesterol of 200 to 240 plus LDL greater than
24	130.  The tested label was for men age 35 and over,
25	women age 55 and over.  The NDA label had no age

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	1	limitations in the use section, but did say, ¦Do not
	2	use if you are under age eighteen.¦  And the recently
	3	submitted label said that it is for men age 35 and

	4	above, women age 45 and above.  The LDL requirement
	5	that was not tested would be especially important to
	6	test to see if consumers could apply it simultaneously
	7	with the total cholesterol and other requirements for
	8	use and non-use.  The tested label said, ¦Do not take
	9	the product with erythromycin.¦  The NDA label has
10	nothing about erythromycin.  The tested label had a
11	¦do not use¦ section with six bullets.  The NDA label
12	has a ¦do not use¦ section with three bullets.  The
13	tested label had one ¦ask the doctor before use¦
14	section.  Some of the do not use information from that
15	label was moved in the NDA label to four sections
16	about asking a doctor, pharmacist or a healthcare
17	professional before use.  It is significant that the
18	appearance of the NDA label and the label submitted
19	subsequently are quite different from the tested one. 
20	Formatting often has substantial effects on
21	comprehension.  The tested label was not in the Drug
22	Facts format that we currently require for all NDA OTC
23	products.  It had four pictograms and a double column
24	in the use section.  The NDA label and subsequent
25	label are in the Drug Facts format, and the NDA label

			117
	1	had two pictograms with no double columns.  These
	2	format changes coupled with the content changes I
	3	described may affect comprehension.  In conclusion,
	4	because the label was substantially modified in
	5	content and format after this label comprehension
	6	study, we do not know how well the new label would be
	7	understood by consumers.  Participants appear to
	8	understand some important aspects of the label;
	9	however, some issues were moderately or poorly

10	understood or the results were unclear.  Further
11	critical information was not tested.  For the tested
12	label significant numbers may not understand the age
13	by sex requirements, when to see a doctor based on
14	time, contraindicated medications, and the total
15	cholesterol required for use.  We have inadequate
16	information whether consumers would understand the
17	simultaneous requirements for use, whether they can
18	apply the information to a variety of common
19	situations, or if they can self-select appropriately
20	to use the product.  In summary, we cannot conclude
21	from this study that consumers can understand the
22	label sufficiently to use the product safely and
23	effectively in an OTC setting.

24	            CHAIRMAN BRASS:  Thank you.  At this time
25	we¦ll open the format to questions to either sponsor

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	1	or the FDA from committee members.  Dr. Blewitt.
	2	            DR. BLEWITT:  I have a question of Dr.
	3	Lechter and that regards to Drug Facts format.  It¦s

	4	my understanding that the whole industry is moving to
	5	the Drug Facts format because it has been determined
	6	that this is a format that is better understandable
	7	and better conveys the content of the label to the
	8	consumer.  So it¦s my understanding that there¦s an
	9	assumption that the Drug Facts labeling is better than
10	whatever existed before.  Secondly, then, I would ask
11	if there is an industry-wide move to, now that the

12	industry is moving as a whole towards the Drug Facts
13	format label, that if the industry is now testing all
14	of these labels because they¦re in the new format.
15	            DR. LECHTER:  I don¦t know what the
16	industry is doing.  We did some testing before the

17	regulation was finalized and did find that the Drug
18	Facts format was an improvement over the other formats
19	we had tested.  I don¦t know what testing is currently
20	being done by industry.
21	            DR. BLEWITT:  Well, it just leads to my
22	question of should it really be necessary to test the
23	revised label that¦s in the Drug Facts format when in
24	fact this is a perceived improvement over what has
25	existed before, and if there are no substitute changes

			119
	1	in the content of the label?
	2	            DR. LECHTER:  Theoretically, if we¦re just
	3	taking the same content and moving it into the Drug

	4	Facts format, there should be no reason to retest. 
	5	However, in this case there were substantial content
	6	changes.  There was removal of some very prominent
	7	warnings to see a doctor before use, there was an
	8	addition of the LDL requirement, there was movement of
	9	materials to sections about--, from the ¦see your
10	doctor¦ section into the ¦see your doctor, your
11	pharmacist, your healthcare professional¦, and so that
12	not only was the format changed, there were content
13	changes as well that we think may affect
14	comprehension.
15	            CHAIRMAN BRASS:  Dr. Krenzelok.
16	            DR. BLEWITT:  I¦m sorry.  If I could just
17	follow.  My question is whether--, I know the
18	erythromycin was removed, but whether there has been
19	removal or just whether it has just simply been moved. 
20	The ¦see your doctor¦ which was on the original label
21	was now not appropriate because, it would not be
22	appropriate in the Drug Facts label.  So in fact
23	you¦re moving that to ask a doctor before--, you¦re
24	moving it down into the label, but¦s it the same
25	question.

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	1	            DR. LECHTER:  I think the strength of the
	2	warning in the new label is greatly reduced from that

	3	of the tested label and the strength of the warning to
	4	see a doctor before use, and therefore may not come
	5	across to readers as clearly as the advice to see a
	6	doctor had been on the tested label.
	7	            CHAIRMAN BRASS:  Please identify yourself.
	8	            DR. FRIEDMAN:  Dr. Friedman.  Dr. Lechter,
	9	that¦s correct.  We did take the see your doctor

10	warning from the top of the Drug Facts label because
11	it is precluded by that regulation of having it there. 
12	We would be willing, we agree with you that it is very
13	important to have it there and we would be very
14	willing to work out some way that we could have it
15	there.  The other mentions about healthcare
16	professionals such as pharmacists are also mandated by
17	Drug Facts.  We do not in any way want to dilute that
18	message and would be very happy to work within the
19	confines of those requirements to make that as strong
20	as possible.  But I think the number of messages to
21	see your doctor are the same, and as I think Dr.
22	Blewitt eluded to, things have been moved to conform
23	with the requirements and certainly our intent is to
24	have that message as strong as it can be¦
25	            DR. LECHTER:  Right.

				121
	1		DR. FRIEDMAN:  --as it can be within the
	2	regulations.
	3		DR. LECHTER:  They¦ve been moved but they

	4	haven¦t been tested, so we don¦t know how well they
	5	come across.
	6		CHAIRMAN BRASS:  Dr. Krenzelok?
	7		DR. KRENZELOK:  Thank you.  Safety is a
	8	very important aspect that we¦re asked to consider in
	9	reviewing these applications.  I noted that the

10	sponsor had approximately, I think it was sixteen
11	reports of overdose, and I think it¦s well established
12	that this is a fairly safe drug in overdose,
13	certainly.  But did either the agency or the sponsor
14	acquire information from the American Association of
15	Poison Control Centers and examine that data?
16		DR. FRIEDMAN:  Yes we did.  I can show you
17	the slide if you like, but basically--, you¦d like to
18	see the slide?  I think there are about 1600 reports,
19	there are no deaths.  There is one case reported of
20	rhabdomyolysis in a man who had diabetic ketoacidosis,
21	and there are three hepatic events which are listed
22	only as increased transaminase levels.  This is sort
23	of the-, you know the highlights from the reports.
24		DR. KRENZELOK:  The AAPCC data breaks it
25	down by no effect, mild, moderate, major, fatality and

				122
	1	so on.  Did you break it down just in tabular form at
	2	all just by those particular categories?
	3		DR. FRIEDMAN:  No, we didn¦t.  I guess the
	4	overall look at that data was that there were no
	5	different conclusions from our database as well as the
	6	FDA FOI database, so we really just summarized it this
	7	way.
	8		CHAIRMAN BRASS:  Dr. Davidson.
	9		DR. DAVIDSON:  Three questions, quick
10	questions.  Do we test, does the agency test the label
11	in Spanish?  Have you seen a review of the Spanish
12	label to be sure that it¦s proper Spanish?
13		DR. LECHTER:  I¦m not aware of any--,
14	first of all, the agency does not do the testing.  The
15	sponsors do the testing.
16		DR. DAVIDSON:  The review.
17		DR. LECHTER:  I have not seen any
18	submissions that show testing of the label in Spanish.
19		DR. DAVIDSON:  Okay, thank you.  The
20	second question for Dr. Parks.  60 patients with
21	normal cholesterol, you know, were not allowed in this
22	study, but do we really know what the normal lipids
23	for those 60 patients were?  Because, you know, if
24	it¦s physicians making the decisions, it may be lipids
25	that should be treated.

					123
	1		DR. PARKS:  The reason listed as normal
	2	cholesterol was obtained directly off of forms where
	3	the physician checks it off, so we don¦t have a
	4	corresponding--, or I didn¦t see a corresponding level
	5	with that reason normal cholesterol.  With regards to
	6	cholesterol in that population, the data I reviewed
	7	were of the entire 285 in that qualified and treated
	8	subgroup in the OTC group.  I did not look at the
	9	individual 60 in the normal population.
10		DR. DAVIDSON:  Okay.
11		DR. FRIEDMAN:  Could I clarify that?  We
12	actually did look at that 60.
13		DR. DAVIDSON:  Okay.
14		DR. FRIEDMAN:  And about 50 percent of
15	those people had LDL cholesterols above 130 mg. per
16	deciliter and about half of them had levels below.
17		DR. DAVIDSON:  Fifty percent?

18		DR. FRIEDMAN:  Yes, about that.
19		DR. DAVIDSON:  Over 130?
20		DR. FRIEDMAN:  Yes.
21		DR. DAVIDSON:  Thank you.  And then, for
22	Dr. Shetty, you have 200 patients, close, that did not
23	qualify for the study.  Could you tell us why they did
24	not qualify?
25		DR. SHETTY:  I don¦t have all the exact

				124
	1	numbers, but based on the risk factors and the lipid
	2	profile that was based on those specific guidelines
	3	used in the PREDICT study.  Either LDL was too high or
	4	too low, or the risk factors were more than two.
	5		DR. DAVIDSON:  Thank you.
	6		DR. SILVERSTEIN:  My question¦s for Dr.
	7	Friedman.  I don¦t know how to do this.  
	8		(Laughter)
	9		DR. SILVERSTEIN:  I¦m moving this.  Okay.
10	As you said appropriately you had, in the PREDICT
11	study, a very motivated population and in the absent

12	study you had a population that had ready access to
13	healthcare.  How many of those--, I somehow missed it
14	in going through the two books--, how many of those
15	people who enrolled in this study knew their total
16	cholesterol and HDL cholesterol levels before
17	enrolling?
18		DR. FRIEDMAN:  In terms of the enrolled
19	population, about high 70¦s knew their total
20	cholesterol before enrolling.  Again, there was no
21	education, they didn¦t have their levels at the
22	enrolled site.  They only had their levels in PREDICT
23	if they saw the doctor.  So of the enrolled
24	population, about 75 percent of people knew their
25	total cholesterol.  Of the people who actually

			125
	1	purchased the product, it rolls to about 80 percent or
	2	so.  In terms of LDL cholesterol knowledge, that was
	3	really much less and I think that does show that
	4	knowledge of LDL cholesterol is really, you know, we
	5	haven¦t gotten that message out to the public.  I
	6	think that we hope that as we put that on the label,
	7	people will start to inquire, and the purpose there is
	8	really that they need to see their doctor or talk to
	9	their doctor about their full lipid profile.
10	            DR. SILVERSTEIN:  Could I ask a second
11	question?  And that was my concern, too, about
12	appropriateness of patient selection.  The second
13	question has to do with the fact that this is a
14	chronic disease and not static, and to really somehow
15	get the message across to the patients that because of
16	that their dose may change over time.  And do you
17	have, as part of your education program?
18	            DR. FRIEDMAN:  Yes.  Certainly the patient
19	educational booklet that is enclosed in the starter
20	kit talks specifically about that.  We thought it was
21	important to talk about all cardiovascular risk
22	factors and how they should all be modified and as
23	well, I think it¦s important that we saw in the
24	PREDICT study without the prompts that these people do

25	go back and see their doctor annually or talk to their

			126
	1	doctor after they stop medication.  So, and some of
	2	them as was mentioned got titrated up appropriately
	3	as, you know, their profile may have changed over the
	4	course of time.
	5	            CHAIRMAN BRASS:  Dr. Molitch.
	6	            DR. MOLITCH:  I¦d certainly like to
	7	applaud the sponsor for all the educational materials
	8	that they¦re planning for the patients in this over-
	9	the-counter portion of treatment.  I would hope that

10	those materials are also provided to all the patients
11	who are getting the same medication by prescription,
12	whether this is approved for over-the-counter or not,
13	because it certainly would be beneficial for those
14	patients.  I have a couple of philosophical questions
15	that perhaps the sponsor could answer.  I agree that
16	lowering cholesterol perhaps in this patient
17	population is important.  And how about--, what would
18	be the difference in doing the approach that you¦re
19	taking here versus perhaps trying to educate
20	physicians in treating these patients and prescribing
21	the drug at these lowered cholesterol levels?  So

22	that¦s one question.  And then the second, and this is
23	partially borne out by the survey that was reported by
24	you, that perhaps the over-the-counter designation of
25	this drug in fact denigrates hypercholesterolemia in

			127
	1	patients¦ eyes as a serious problem.  Because you can
	2	get this drug over-the-counter, it¦s not such an
	3	important problem, and so that they may not take it as
	4	seriously.  Perhaps you can address those two
	5	questions.
	6	            DR. FRIEDMAN:  I think certainly as a
	7	company, Bristol-Meyers Squibb is absolutely committed
	8	to ongoing education in the medical and lay community. 
	9	As you know we put forward huge efforts, as does the

10	rest of the industry, government in academia.  I think
11	really one of the reasons we are here today is that it
12	appears that that may not be the only complete
13	approach, or perhaps another approach, an additional
14	approach, may enhance those efforts.  And what we¦re
15	looking for here is an approach to a lower-risk
16	population.  You know right now the current efforts
17	are really focused on secondary prevention people. 
18	Very, very few people in primary prevention are being
19	targeted either by the major organizations or
20	industry, and you know, I think that here¦s a group of
21	people that we can add to the people that are
22	currently being targeted and add to being treated
23	appropriately.  It is a lower-risk population.  It¦s
24	not a population without risk.  But as Dr. Cohen
25	showed earlier, there is vast, vast under-treatment of

			128
	1	this population.  Certainly less than ten percent of
	2	them are being treated now.
	3	            DR. MOLITCH:  But why couldn¦t that be
	4	addressed by educating physicians to treat them?
	5	            DR. FRIEDMAN:  Well, perhaps I can call on
	6	some of my colleagues here who have been involved in
	7	development of the guidelines.  Certainly those
	8	programs have been well under way.  The results of the
	9	megastatin trials have been known now for, you know,

10	almost a decade.  And, you know, we still seem to have
11	this problem.  There certainly is huge efforts going
12	on to educating physicians.  And maybe I could ask Dr.
13	Brown from, as a perspective who did work on the
14	guidelines to address that.
15	            DR. BROWN:  Yes.  In 1986 we met in this
16	very room to begin the NCEP, and I am one of the old
17	guys who actually worked on that original panel that
18	created part of this problem.  We, in 1986, the first
19	Pravachol studies were just getting underway.  The
20	report that we wrote came out in 1987, the year that
21	Lovostatin was released on the market.  That was eight
22	years before we had the first clinical trial that
23	showed prevention of vascular disease with a statin,
24	that was 1994.  So what we were working with here are
25	principles that have become dogma that would horrify

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	1	me because that was certainly not our intention to
	2	create dogma that we call the NCEP.  My feeling is
	3	that it¦s time for us to reexamine the thought that

	4	was made, the principles that were laid down 14 years
	5	ago.  And it¦s time for us to do something new because
	6	what we did made tremendous progress but we¦re
	7	reaching a plateau in its impact.  If we had everyone
	8	in America follow the NCEP guidelines with regard to
	9	those above 240, we would still have in this country
10	the number one cause of death as cardiovascular
11	disease.  It would still outrank cancer as a cause of
12	death.  These people would just move into this 240
13	down to 200 group where we would still have a very
14	high incidence of coronary events.  So this is a very
15	serious problem.  It is not low cholesterol that we¦re
16	dealing with here.  And I would say, I think David
17	Orloff said this very well about the agency¦s approach
18	to over-the-counter drugs, if I might digress a
19	moment.  And that is that there is a tradition that
20	the agency has adopted which has served them well in
21	dealing with over-the-counter drugs, but I would
22	submit to you that tradition, when dealing with a
23	recalcitrant problem that just won¦t go away, maybe

24	it¦s time to do something that¦s nontraditional, to
25	think about a new approach to this problem.  And I

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	1	think the learned intermediary that we depend upon
	2	greatly to support that tradition should not only be
	3	viewed to be the doctor.  There are many other learned

	4	intermediaries that the doctor needs to deal with this
	5	problem.  We need people who are educational
	6	specialists.  We need other people who can get
	7	involved in this problem if the over-the-counter
	8	measures were taken.  They would be incorporated into
	9	this.  It would be a natural way to bring in a whole
10	series of other individuals to help us as physicians
11	deal with the problem that continues, and will
12	continue to be during my lifetime and your lifetime,
13	the number one cause of death in America.  And so my
14	plea to you is to think outside the box a little bit
15	and help us doctors deal with this problem.  I think
16	the approach that this company has taken is absolutely
17	on target.  It is not to remove cholesterol treatment
18	from the doctor¦s domain, but it¦s to help the
19	physician deal with the problem that he is having, or
20	she is having, a tremendous struggle with and is not
21	doing very well with.
22	            DR. MOLITCH:  I¦m sorry.  Neither speaker
23	has addressed the question that I asked because I
24	agree that perhaps we want to lower those guidelines
25	for therapy.  I¦m not disagreeing with that at all. 

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	1	I¦m just asking for the approach to that lowered
	2	guideline, whether that should be through the
	3	physician being educated to have a lower guideline for

	4	recommending therapy versus this coming up through the
	5	patient who is doing this with, perhaps, a little less
	6	guidance in this sort of borderline situation.
	7	            DR. BROWN:  I thought I was answering the
	8	question.  Let me clarify why I thought I was
	9	answering it.  The guidelines are written for us to
10	use the tools that we currently have appropriately. 
11	And what we¦re asking for here is a new tool so that
12	new guidelines can be written.  The physician if
13	followed the guidelines would not address this issue. 
14	I don¦t care how well educated they are.  We¦ve made
15	tremendous efforts over the years.  I must have 10,000
16	cholesterol talks over the last 15 years trying to

17	educate physicians.  The issue, I think now, is to
18	again, think outside the box and get the physician

19	some help here, you know.  And that will help educate
20	those doctors who are somewhat less educable.  And so
21	we need to do something new.  No, just more speeches
22	to doctors is not going to answer the question.
23	            DR. FRIEDMAN:  Yes.  I also I think want
24	to answer this from the data that we have from PREDICT
25	and OPTIONS.  You know, we¦re not talking just about

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	1	getting people to treat to lower levels.  Even if you
	2	look, and I think the information was in the briefing

	3	book we provided to you, if you look at the people who
	4	came into the PREDICT and OPTIONS trials who had

	5	access to healthcare, who saw their doctors every
	6	year, very few of them were actually at their NCEP,
	7	the current NCEP goals.  If you look at the people
	8	with heart disease, it¦s about 10 or 15 percent, and
	9	in the other populations it¦s not much better.  So I
10	think if you, you know, I think that¦s actually
11	exactly the point here that, you know, here is almost
12	the best that we can do and, you know, this was very
13	consistent in both studies in a population that maybe
14	is, you know, even a little bit better than overall. 
15	So I don¦t think it¦s a question of bringing the
16	guidelines down.  Even with the current guidelines,
17	the under-treatment is enormous and we¦ve documented
18	that in our studies.
19	      I think the other question you raised about the
20	denigration of cholesterol lowering to sort of a
21	frivolous undertaking, you know, I think everyone

22	knows they need to lower their cholesterol and sort of
23	a question of how they¦re going to do it.  I think

24	that we saw that the people here are really committed
25	to lowering cholesterol.  I think they do take it

			133
	1	seriously for those of you who heard the results of
	2	the National Consumer League study and independent
	3	study when they asked people if they would just start

	4	an OTC statin, what they¦d do, and the vast majority,
	5	again confirming our data, said that they would speak
	6	to their doctor.  I think these people do take it
	7	seriously.  It¦s a very disease prevention-minded
	8	population.  If you look, for instance, you know, what
	9	these people are doing.  The postmenopausal women who
10	came into this program, 50 percent of them were taking
11	hormone replacement therapy, much higher than the
12	average.  Look at the incidents of smoking in this
13	population, ten percent compared to 20 percent on
14	average.  These people want to do something.  And, you
15	know, I think there is some kind of failing here that
16	maybe this kind of program can address.
17	            CHAIRMAN BRASS:  I just want to follow-up
18	on Dr. Molitch¦s point because it really sets up a
19	central dilemma.  I have a lot of specific points, but
20	I can¦t get over this really central dilemma in my
21	mind.  In both of your studies which have some really
22	outstanding features, incidentally, which I hope we
23	have a chance to talk about later, the primary outcome
24	was go see your doctor.  And I have this circular
25	paradox in your mind where we¦re all acknowledging the

			134
	1	central role of the learned intermediary, whether it¦s
	2	a pharmacist, physician or whatever, in this process,

	3	and yet at the same time considering an OTC NDA.  And
	4	not at all am I the only one.  But I¦m having a lot of
	5	trouble getting past this.  We say the doctor is
	6	critical, so let¦s make it available without the
	7	doctor.  I can¦t resolve that paradox.
	8	            DR. FRIEDMAN:  I think we certainly say
	9	that the doctor is very important.  And I guess the
10	question really is, you¦re right, is OTC diametrically
11	opposed to doctor involvement?  And I think we see
12	from our studies that it isn¦t.  Here are people who
13	do see doctors.  Twice as many of them are taking OTCs
14	to lower their cholesterol as taking prescription
15	therapies.  And you know, we also do have OTC
16	recommendations that we do have in our practice.  You
17	know, we recommend certainly diet, we recommend
18	dietary adjuncts to lower cholesterol.  And there are
19	other OTC therapies, certainly aspirin, for secondary
20	prevention, is one of the great successes.  So you
21	know, I think that perhaps the thought that an OTC
22	approach is antithetical to a doctor approach may be
23	not borne out by the data.
24	            CHAIRMAN BRASS:  Dr. Grady.
25	            DR. GRADY:  I¦d also like to compliment

			135
	1	the sponsor on the PREDICT study and I think that the
	2	results of it are really kind of crucial, at least to

	3	me, to understand whether this is a good OTC product. 
	4	But the interpretation of the PREDICT results by the

	5	agency and by the sponsor seems like they¦re quite
	6	different.  So I have some questions that I¦m hoping
	7	that the two of you together could answer.  And it
	8	seems to me that one important one was that the
	9	randomized groups were the 1,900 patients who were
10	randomized either to OTC or to prescription.  But I
11	guess as I¦m understanding it you were not able to

12	measure cholesterol at the end of the study period in
13	this whole, in the whole 3,800, is that correct?
14	            DR. FRIEDMAN:  That¦s correct.  You know,
15	I think the importance here, the difference between
16	PREDICT and a randomized control trial, is that what
17	we call randomize was randomizing to environments. 
18	And then it was really, I guess it was almost when

19	they saw the doctor that that¦s when we could screen
20	because, you know, there¦s no screening when you go
21	and buy an OTC product.  And that¦s really where the
22	standardization, if you will, for certain parameters
23	occurred.  In looking at cholesterol reduction or
24	whatever in one environment or another, that¦s I guess
25	where we¦ve done the usual screening criteria that is

				136
	1	done in a usual controlled trial.  The doctor has sort
	2	of done that and leveled the playing field for those
	3	evaluations.
	4		DR. GRADY:  But the 2,400 who saw a
	5	physician were not, that group was really not followed
	6	up at the end either, right?  Is that correct in terms
	7	of measuring cholesterol?
	8		DR. FRIEDMAN:  No, not all for measuring
	9	cholesterol, because again, it was a real world
10	situation.  For those that we could, we did measure

11	cholesterol.  But I think what we wanted to do, the
12	objective was to see whether cholesterol reduction in
13	one environment, the current prescription one versus
14	the cholesterol reduction in an OTC environment, for
15	people for whom ultimately it was appropriate would be
16	the same.  Because certainly in the OTC environment
17	people could stop taking it, you know, over a period
18	of time, a year.  You know, no one had to go back, and
19	in fact they didn¦t get their medication at the
20	doctor¦s office.  They had to go specifically back to
21	the retail site.
22		DR. GRADY:  So the only group whose 
23	cholesterol were measured were the ones who were
24	qualified and treated in both groups?
25		DR. FRIEDMAN:  The cholesterols were 

			137
	1	measured initially in everyone who consulted.
	2	            DR. GRADY:  At the end, though.
	3	            DR. FRIEDMAN:  At the end, you know, again

	4	we had--, I think that the follow-up was not adequate
	5	enough to answer that.  I think what you¦re looking at
	6	is a--, in those groups of everyone who came in--, I
	7	mean I think that the importance is that everyone who
	8	came into the OTC group, or the prescription group,
	9	not all those people, they had lots of places to go. 
10	They were randomized to the environment.  It¦s really
11	as if you were randomized to, you know, go to a
12	supermarket to buy your drug versus being randomized
13	to go to a pharmacy.  But it doesn¦t mean that the
14	drug is right for you.  You just came in, you were
15	interested in the ad, and then a lot of things could
16	happen.
17	            DR. GRADY:  I understand that, but it just
18	makes it not a randomized comparison and I know it¦s
19	difficult to do.  I think there is more, a better
20	randomized comparison of who actually did see a doctor
21	and got consulted.
22	            DR. FRIEDMAN:  Perhaps just from that
23	perspective and the issue--, because I know this is a
24	big issue in a consumer trial, the issue of

25	randomization and when to make appropriate

			138
	1	comparisons, and perhaps I could ask Dr. Cook to
	2	comment on that from a statistical point of view.
	3	            DR. COOK:  Yes, my name¦s Gary Cook.  I¦m
	4	a statistical consultant to Bristol-Meyers.  The
	5	randomization basically created two groups at the time
	6	of randomization, but each of those groups was going
	7	to go down a different path.  If a patient was in the
	8	Rx group, then they had to make the decision to
	9	actually see a physician for a prescription and then
10	to decide if they then qualified and got a
11	prescription, whether they would follow through with

12	that.  It does turn out that, my understanding is that
13	there were 405 patients who qualified and consulted
14	with the physician and there were 50 of them who
15	basically didn¦t fill the prescription.  So not
16	necessarily all of the patients who qualified and were
17	thought to need a prescription on the Rx side actually
18	filled a prescription and followed through.  350 of

19	them did.  Now on the OTC side, we had something like
20	499 patients who were treated, but not all of those
21	patients saw the doctor.  We basically had 90 percent
22	of the patients ultimately saw a doctor, but it was a
23	somewhat smaller percentage who saw the doctor

24	initially.  Now when they saw the doctor several
25	things could happen, and most of those were good

			139
	1	things.  They could be told they had a normal
	2	cholesterol which they didn¦t know before ever seeing
	3	the doctor or even coming in contact with the OTC
	4	option.  So these were patients who in some sense were

	5	out of the system, but because they chose to purchase
	6	the OTC product and then go see the doctor, they found
	7	out they had a normal cholesterol and they were fine,
	8	and there were about 60 such patients who did that. 
	9	That¦s a correct decision.  That¦s actually a success
10	for the OTC product.  And then there were another 30
11	some patients who, when they saw the doctor on the OTC
12	side, they were actually found to have much higher
13	cholesterol than would be appropriate for OTC, and so
14	they got put on a prescription for that particular
15	product.  And that¦s a correct decision for them as
16	well.  The right thing happened to them because they
17	purchased the OTC product and then were ultimately
18	given a prescription for what was actually the right
19	thing.  Some of them were told that they already had
20	a prescription, and that was the correct thing in that
21	they didn¦t need the OTC product.  So there were about
22	120 some patients who when they actually saw the
23	physician they found that it was inappropriate for
24	them to use the OTC product, but they didn¦t know that
25	until they actually saw the physician.  But because

			140
	1	this is a physician-assisted use of an OTC product,
	2	they eventually did find out the right thing.  Now the
	3	groups do not become actually comparable until the
	4	doctor has seen them on both sides and now you
	5	basically have patients who have both qualified and
	6	treated.  And at that point you can see what happens
	7	to their cholesterol.  Now the real question here is
	8	not necessarily whether or not you have a formal
	9	randomized comparison at the level at which you have

10	qualified and then treated, because at that particular
11	point you have groups that in some sense have gone
12	through somewhat different pathways to get where they
13	are.  And so you can¦t necessarily on the basis of
14	randomization alone as in a classical clinical trial
15	compare the reduction in cholesterol of those groups
16	with one another.  The only question that you can
17	really directly ask is, ¦Is the reduction that these
18	individuals had consistent with what you might expect
19	them to have on the basis of what was seen in previous
20	randomized trials and is that reduction greater than
21	what the reduction might have been had those patients
22	been hypothetically randomly assigned to placebo?¦ 
23	Now my understanding from placebo-controlled trials is
24	that when patients are randomly assigned to placebo,
25	they either have very little change or cholesterol

			141
	1	slightly increases, or at most it decreases by two or
	2	three percent.  Now in these patients, there was a
	3	decrease of approximately 18 percent, which is

	4	consistent with what would be expected from the
	5	randomized clinical trials.  So each of the two groups
	6	performed as expected, and each of the two groups
	7	performed better than what a hypothetical placebo
	8	would, and in that sense each of the two groups showed
	9	comparable efficacy.  It¦s a different line of
10	reasoning than what a classical randomized trial would
11	do, but for this particular type of care, one doesn¦t
12	really need a classical clinical trial to show that
13	Pravachol at a dose of 10 mg. reduces cholesterol. 
14	That¦s already been established.  All that was needed
15	was to see that in each of these two arms that
16	qualified for treatment and that used treatment, that
17	the reductions that you got were consistent with what
18	you¦d expect.  But it¦s not a classical randomized
19	trial.  It was never intended to be that.
20	            DR. PARKS:  I just want to add that I do
21	agree with you that I think that there are some really
22	nice unique features about PREDICT and one of them is
23	that the eligibility criteria, the list of exclusion
24	criteria were not very extensive, and so when the
25	study was opened up to the public here, or the

			142
	1	consumer, there was a lot of capture of a lot of
	2	people and we were able to see who was going to use
	3	this product without a physician.  I think what
	4	becomes complicated is when they actually went in to
	5	see the physician at, in the OTC group it would be the
	6	second visit.  And at that point those treatment
	7	guidelines were applied, the intervention started by
	8	the physician in that setting there.  And then when
	9	they limited the lipid response evaluation to just

10	that group of the qualified and treated, that¦s an
11	enriched population in the OTC group.  As I mentioned,
12	there are about half of them in the OTC group that
13	took the medication and we don¦t know anything about
14	them.  You really want to know in the real world use
15	of this product, of the people who are not going to
16	meet this protocol-defined qualified and treated
17	subgroup, how are they going to actually do and the
18	agency doesn¦t really know because those data were not
19	available.
20	            DR. FRIEDMAN:  I think just for
21	clarification, we do know of the people who took the
22	product, who purchased and took the product, we know
23	about all of them except for 72 who didn¦t consult a
24	doctor, so we don¦t know their lipid levels.  We know
25	they¦re self-reported risk factor profile and what

			143
	1	they had done in the past.  And I think, you know, as
	2	you look sort of in a broad picture of first of all

	3	that these people did see a doctor, so that¦s good,
	4	and then if you also look as to why the doctor said
	5	this wasn¦t appropriate, for the vast majority would

	6	have gotten benefit, either their levels were high and
	7	they weren¦t doing anything about it anyway, so then
	8	it¦s philosophical.  Is it better to get a 20 percent
	9	reduction in LDL cholesterol when it would have been
10	best to get a 30 percent, but now they¦re not getting
11	anything.  For the vast majority of them, they needed
12	some cholesterol reduction.  And I, sort of in my
13	mind, is the big picture.  That¦s sort of the
14	question.
15	            CHAIRMAN BRASS:  Dr. DeLap.
16	            DR. DELAP:  Yes.  There is one other
17	aspect of this study that I¦d just like to note.  I
18	think it was a very nice study in many respects and it
19	answered a lot of interesting questions, but of course
20	you can never totally mimic the OTC experience in a
21	study.  One of the things we¦ve been talking about is
22	how many people came back to see the doctor and how
23	much good advice they got.  Well, as I understand, the
24	design of the study was such that if you wanted to
25	continue on the product, you didn¦t have to come back

			144
	1	and see the doctor.  So what we¦re not really
	2	capturing here is, without that incentive that you had
	3	to come back and see the doctor depending on the
	4	product, if you could just go to Wal-Mart and buy it,
	5	would they still have come back?
	6	            DR. FRIEDMAN:  Well, we did capture it
	7	indirectly.  People were--, you¦re right.  There was
	8	an IRB recommendation that we do not let people go on
	9	and use the product for more than two months if they
10	had not seen the doctor.  So if you look at the
11	people, the 72 people that we classified as not seeing

12	the doctor, there is a 72--, 62 rather, never did see
13	the doctor.  Ten people attempted to go on and
14	purchase more medication without seeing the doctor. 
15	We classified them as never seeing the doctor because
16	they--, so we know that of this cohort who purchased
17	medication, 720, that there were only 10 who decided
18	to go on and try to repurchase, keep going with this,
19	without seeing the doctor after two months.  So we
20	actually do have that information.  We can¦t say
21	anything more about them because we intervened.  We
22	said that they had to see the doctor.  But we actually
23	classified them as not seeing the doctor.  So I think
24	we do have some information from the study.
25	            CHAIRMAN BRASS:  Dr. Lukert.

			145
	1	            DR. LUKERT:  Did patients have to pay out
	2	of their own pocket to see either their own doctor or
	3	the study doctor?
	4	            DR. FRIEDMAN:  People paid out of pocket
	5	to purchase medication.  They were ultimately
	6	reimbursed at the end of the study, but they didn¦t
	7	know that during the study.  The study physician
	8	visits were free.  Many people did see their own
	9	doctor which, you know, was part of, and they did that

10	as part of their normal care.  So if they had coverage
11	they got it, if they didn¦t, you know, they did as
12	they normally would in their lives.  But the specific
13	study physician visits were free of charge.  And I
14	think we¦ve talked about this before, we struck a
15	balance of making people pay for medication in a
16	study, but we did let people see the study doctor for
17	free.  I think it¦s important, though, that for many
18	people this was an inconvenience because they already
19	had their own doctor.  So they actually made a
20	specific visit to a study doctor.  Maybe this is even
21	showing how motivated people are to see a doctor
22	because 80 percent of these people already have a
23	doctor that they¦re used to seeing, but they actually
24	made, you know, went out of their way to see the study
25	doctor.

				146
	1		DR. SHETTY:  I would like to point out
	2	that the OTC group had the access for the medication

	3	only for two months.  Their supply was given only for
	4	two months and they had to go to the doctor in case

	5	they wanted to continue in treatment, so that forced
	6	them to go to the doctor within two months.
	7		CHAIRMAN BRASS:  Dr. Lukert, now when you
	8	say you¦re going to change the subject, it will be
	9	about cholesterol?  Okay.
10		(Laughter)
11		DR. GRADY:  Could we stick with PREDICT? 
12	I¦m sorry I set off that whole thing.  I just had a
13	couple of very specific numbers questions about
14	PREDICT.  Could we do those first?  Is that all right? 
15	Well, here¦s the other puzzling thing to me and that
16	is, this issue of the 499 who were treated in the

17	over-the-counter group.  So these were the ones who
18	were qualified and actually got treated.  The FDA

19	staff stated that 266 of those were really unqualified
20	for treatment and Dr. Davidson, I think, asked why
21	they were unqualified.  Now, that was unqualified
22	based on the actual guidelines of PREDICT?  Or is that
23	unqualified based on some physician¦s recommendation?
24		DR. PARKS:  I just want to clarify that of
25	the 499 who were treated, not all of them were

					147
	1	qualified.  These are just individuals¦
	2		DR. GRADY:  Well, those are the numbers

	3	I¦m trying to get.  How many were qualified and how
	4	many were unqualified, and why?
	5		DR. PARKS:  Okay.  Of the 499 who took any
	6	amount of medication, 315 were qualified for
	7	treatment.  And of those 315, 285 were actually
	8	treated.  Now with respect to qualification, it was
	9	based upon that set of treatment guidelines I told

10	you, and it was based on whether or not they had a
11	baseline, if there was no evidence of diabetes or
12	cardiovascular risk factor or established heart

13	disease, or two or more risk factors, then they had to
14	have a particular LDL to actually get started on the
15	treatment.  So if we look at¦
16		DR. GRADY:  Okay, but they were
17	unqualified based on the sort of outline of the OTC
18	program.
19		DR. PARKS:  Based on the treatment
20	guideline, exactly.
21		DR. GRADY:  Okay, but 90 percent of those
22	who were qualified did get treated?
23		DR. PARKS:  Yes.  285, about 285 of the
24	qualified got treated. 
25		DR. GRADY:  Okay.  Thank you.  And

				148
	1	finally, you said that a quarter of persons who took
	2	the OTC medication were subsequently recommended by a

	3	physician to stop.  Is that the same group that we¦re
	4	talking about, who were the unqualified group?
	5		DR. PARKS:  It was a quarter out of the
	6	499.  So yes, they would be part of the unqualified
	7	group.
	8		DR. GRADY:  Okay.  That¦s not an
	9	additional group that subsequently recommended to
10	stop.
11		DR. PARKS:  No, it¦s part of that--, yes
12	it¦s part of that 499.
13		DR. GRADY:  Okay, thanks.
14		DR. COOK:  Gary Cook here.  But the reason
15	they were recommended to stop was because for many of
16	them when they saw the physician, they learned that
17	they had normal cholesterol.  So that was the right
18	thing.  Or they learned that they actually should be
19	on an Rx dose, which also was the right thing.  And if
20	they had not actually participated in the OTC
21	environment, they would not have learned either of
22	those is the right thing.
23		DR. LUKERT:  I want to go back to the

24	basic question about if we¦re trying to solve an
25	educational problem with an option that indirectly

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	1	will bring about education.  It seems to me that what
	2	we said that the major problem is that a lot of people
	3	who are seeing doctors regularly with cholesterol
	4	levels within the range that we¦re trying to address

	5	with the OTC are not being treated because the current
	6	guidelines don¦t indicate treatment for those levels
	7	of cholesterol.  And it seems to me that the major
	8	problem is that we have to rewrite the guidelines,
	9	educate physicians and educate the public to be

10	advocates for this position.  But we¦re trying to
11	avoid that issue.  We¦re not trying to avoid it, we
12	think that issue¦s going to be difficult to solve so

13	we plan to solve it by offering yet another option for
14	the person with an over-the-counter preparation that
15	may or may not be effective.  We¦ve already said that
16	the people have difficulty identifying who should be
17	eligible, even when they¦re given very specific
18	guidelines.  The consumer has difficulty with that. 
19	And we¦re going to have people who are going to be
20	taking a drug in a sub-optimal way.  They¦re not going
21	to be titrated to the target.  So it¦s just going to
22	be another choice out there among all the other
23	supplements and choices that they have that may
24	actually delay them from getting effective treatment. 
25	And I don¦t think we¦re solving the problem of getting

			150
	1	yet another possibly ineffective option instead of
	2	addressing with massive attempts to educate both the
	3	public and the physicians.
	4	            DR. FRIEDMAN:  Can I just clarify?  I
	5	think we¦re talking about two different issues here. 
	6	One is that--, one there¦s expanded access to a lower
	7	risk population.  But the other is the issue that even
	8	within the current guidelines, people are not being
	9	treated according to those guidelines.  Yeah, so, but

10	this is not--, and just bringing the guidelines down,
11	though, are not going to answer that.
12	            DR. LUKERT:  No, I think it has to be, you
13	know, the guidelines certainly have to be something
14	that you can defend so that the physician isn¦t
15	getting confused by, you know, the guidelines are
16	telling us one thing, and then by some other people
17	being told something else.  So we have to be
18	consistent.  And then certainly we have to make
19	patients advocates for themselves and doctors, we have
20	to keep pounding away at this problem making doctors
21	address the problem.
22	            CHAIRMAN BRASS:  Dr. Uden.
23	            DR. UDEN:  I have a couple of questions,
24	and some of these are open-ended and some of them are

25	close-ended, trying to follow good types of questions. 

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	1	Did the sponsor consult with the FDA prior to the
	2	design of PREDICT and OPTIONS?
	3	            DR. FRIEDMAN:  The design of PREDICT and
	4	OPTIONS was the result of previous meetings that we¦ve
	5	had with these committees for considering lipid-
	6	lowering therapy.  When we developed the OTC Pravachol
	7	program, the FDA had a policy in place that they were
	8	not discussing protocol designs about this issue
	9	because of the guidance to industry.
10	            DR. UDEN:  My second question actually

11	refers to the new proposed label submitted with the
12	NDA.  I didn¦t hear any rationale presented why the
13	age restrictions were eliminated and now it¦s only
14	over 18, it¦s only restricted under 18 years of age.
15	            DR. FRIEDMAN:  The proposed label--, you
16	know, I think our intent and certainly the people that
17	you see who are interested in this are generally
18	middle-aged population.  We saw very few people under
19	the age of 35 and very few older people who were
20	interested.  And that was always our intent, how to
21	capture that ideally, we have been working on. 
22	Actually the label that we have submitted is for men
23	above the age of 35 and for women above the age of 45,
24	yes.  And I¦m not sure if that¦s actually the label

25	that you have in front of you.  If not, we¦d be happy

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	1	to give you the proposed label that has been submitted
	2	recently.
	3	            DR. UDEN:  Okay, given that label, then I

	4	want to ask a question of Dr. Shetty.  In the OPTIONS
	5	trial, you stated that 59.8 percent of women less than
	6	55 years selected the drug.  How many of those women
	7	were less than 45 years who selected the drug?
	8	            DR. FRIEDMAN:  I can show you that if I
	9	can¦
10	            DR. SHETTY:  Less than 35 and above 35.
11	            DR. FRIEDMAN:  This is the age
12	distribution in OPTIONS, and you can see that of
13	course most people, this is PREDICT and OPTIONS.  So
14	most people did fall above the age of 55.  And then
15	you know, the majority of people were then between 45
16	and 55.  And if I could just follow-up actually, you
17	know, not only with age, one thing to point out that
18	the mean age of menopause in United States women is 51
19	and a half.  And then the next slide, actually, goes
20	on to their cardiovascular risk and how many of these
21	women below the age of 55 had total cholesterol levels
22	greater than 200.  Of the purchasers you can see that
23	over 90 percent in PREDICT and OPTIONS of the women

24	below the age of 55 who purchased drug in fact had
25	total cholesterols greater than 200.

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	1	            DR. UDEN:  Thank you.
	2	            CHAIRMAN BRASS:  Dr. Tamborlane.
	3	            DR. TAMBORLANE:  I was waiting for
	4	somebody to raise the HDL question, but I guess I have
	5	to do it.  I suppose I direct this to Dr. Cohen. 
	6	Specifically if you want to show slide 2-9 from your
	7	presentation.  I think the question that has come up
	8	is what is, you know, how can we extrapolate from
	9	using cholesterol and cholesterol changes as a
10	surrogate marker for ultimate clinical benefit?  And

11	I don¦t think we¦ve actually yet had that question
12	resolved.  My reading of this slide, which looks at
13	the effect of placebo versus Pravachol, stratified by
14	entry HDL, is that these data was for all total
15	cholesterol and LDL values.  So the question is what
16	are these efficacy outcomes if you only look at the
17	target population of entry total cholesterol of 200 to
18	240 and then LDL over 130?  This related and second

19	question is how did the lipid-lowering, what was the
20	reduction in LDL and total cholesterol in these
21	studies?  I¦m only a pediatric endocrinologist and I
22	don¦t follow this literature.  This was a optimized
23	titrated dose.  What kind of outcomes did you get? 
24	What was the actual lipid-lowering effects?
25	            DR. BELDER:  To start with the last point

			154
	1	in all the prevention studies that we did we only used
	2	40 mg., so we never titrated.  Another issue is that
	3	Pravachol lowers cholesterol very uniformly,

	4	independent of what the baseline levels is of
	5	triglycerides, HDL or total cholesterol.  So the
	6	reduction is very uniform, around to 30 percent.
	7	            DR. TAMBORLANE:  Excuse me.  I just want
	8	to highlight that.  So it was 30 percent in these--,
	9	about 30 percent in this study versus 18 in the 10
10	mg.?
11	            DR. BELDER:  That¦s correct.
12	            DR. TAMBORLANE:  So it was significantly
13	less.
14	            DR. BELDER:  Now your first question was
15	the influence of the level of HDL on the relative risk
16	reduction in our studies, and then for the target
17	population.  Unfortunately, in the West of Scotland
18	study, we did not have to target population.  However,
19	in the CARE and the LIPID studies, you know that the
20	CARE study was a study that was performed in patients
21	with normal cholesterol levels.  We did have to target
22	populations; however, it was a secondary prevention
23	study.  If we looked, and we did an analysis according
24	to the baseline cholesterol levels and we took the

25	patients who had a baseline cholesterol level of 180

				155
	1	to 240, and we did another analysis that did the same
	2	thing, but then from 200 to 240, and we looked at the

	3	baseline of HDL because it continues variable and we
	4	did not see that there was any influence of the
	5	baseline HDL level on the relative risk reduction and
	6	clinical events.
	7		CHAIRMAN BRASS:  Do you have that on for
	8	us to see?
	9		DR. BELDER:  Unfortunately I don¦t have a
10	slide because we did-- yesterday, we did the analysis.
11		(Laughter)
12		CHAIRMAN BRASS:  Because I agree with his
13	point and I--, this is really a poor surrogate. 
14	Because the issue is raised by the AFCAPS sub-
15	analysis, which showed no risk reduction with another
16	statin, and so the point you¦re making now is very
17	important.
18		DR. BELDER:  And I would also like to

19	emphasize that the CARE study had patients with
20	relatively normal HDL levels, so it was unlike the
21	AFCAPS study that was selected for patients with low
22	HDL levels.  So we did that for both LIPIDS and for
23	CARE, and we did not find that the level of HDL at
24	baseline influenced the relative risk reduction. 

25	Another point that I would like to make is that we

			156
	1	also looked at the change of HDL during the study, and
	2	very¦
	3	            DR. TAMBORLANE:  Before you move on to

	4	that, statistics are great.  Relative risk is one
	5	thing, but absolute rates are also important.  I think
	6	you can have a relative risk of twofold, at a rate of
	7	one to two, versus seven to 14 percent, so I think
	8	that you really need to look at this in a hard way to
	9	really convince the committee that there¦s a clinical
10	benefit because you¦re trying to use the surrogate. 
11	So relativity may not be the important issue.
12	            DR. BELDER:  I can address that issue.  Of
13	course the CARE and the LIPIDS study had relatively
14	high-risk patients included because they were all
15	secondary prevention.  However, the data that has been
16	shown consistently is that independent of the baseline
17	risk of the patients, the relative risk reduction
18	across all studies was similar.  They were all

19	approximately 30 percent relative risk reduction
20	independent of the baseline risk of the patient.  And
21	so in the AFCAPS/TexCAPS study there was the lowest
22	risk population that has been studied that the
23	relative risk reduction was the same.  The absolute
24	risk reduction of course is much smaller, but the

25	relative risk reduction is the same.  And the other

			157
	1	point that I wanted to make is that we also looked at
	2	the change in HDL levels during the study.  And we
	3	found that if a patient¦s HDL level changed, went up

	4	during the study, that did not influence the relative
	5	risk reduction that the patient received on the basis
	6	of his LDL reduction.  So the LDL reduction would
	7	predict--, I should say it differently.  That if a
	8	patient do, let¦s say for instance, exercise would
	9	raise his HDL level, he would still have the same
10	magnitude of benefits, due to his LDL-C lowering.  So
11	you can add those two benefits more or less together.
12	            CHAIRMAN BRASS:  I just want to emphasize
13	his point about absolute risk, because relative risk
14	may be constant but as you go to a lower risk
15	population, the absolute risk falls, or the absolute
16	benefit falls.  But if there¦s a risk of exposure,
17	that risk will not fall.  So the risk to benefit
18	equation will fall.  And I¦m not saying this is an

19	issue, but I¦m just re-emphasizing why the absolute
20	risk in this population is important.
21	            DR. FRIEDMAN:  I guess also, though, I do
22	want to remind the committee that we¦re not asking for
23	an indication for event reduction.  And I guess the

24	question is, is cholesterol lowering an appropriate
25	end point?  It certainly is for prescription

			158
	1	cholesterol lowering therapies.  And I think we
	2	brought this up, you know, really because there had
	3	been a lot of discussion yesterday about the issue of
	4	HDL and it was really--, I hope we didn¦t confuse more

	5	than clarify.  But I think we do want to be very clear
	6	that the indication that we are looking for here is to
	7	lower cholesterol.
	8	            DR. TAMBORLANE:  I guess I¦m confused
	9	because I assumed that that would be an indication
10	based on data for clinical outcome resulting in
11	lowering cholesterol.
12	            DR. FRIEDMAN:  Yeah, though again, as a
13	reminder, for prescription approval for a cholesterol
14	lowering drug, there is no requirement for event
15	reduction or clinical outcome.  There are only LDL
16	markers.
17	            CHAIRMAN BRASS:  So I think to summarize,
18	I think that a label that says LDL reduction may be an
19	approvable label are part of our assessment is what
20	the extrapolation of the risk to benefit of that
21	surrogate will be, and that will be part of our
22	deliberations and discussions.  Dr. Johnson?
23	            DR. JOHNSON:  I want to come back to the
24	age issue and clearly, I think there were three
25	variations on the label which has, I think, importance

			159
	1	in terms of label comprehension and selection.  But I
	2	have a more fundamental question about why you picked

	3	35 and 45 when I think the people that are interested
	4	aren¦t necessarily the people we want to target.  We
	5	want to target the people who are interested and at
	6	some risk.  And a man at 35 and a woman at 45 is
	7	probably a good 20 years from their first event, so
	8	we¦re going to ask those people, or try to convince
	9	those people that they should take this drug for 20

10	years before they¦re really even at risk for an event. 
11	So I guess I¦m curious why 35 and 45 and not 45 and

12	55, which are the defined risk factor cut points in
13	the NCEP guidelines?
14	            DR. FRIEDMAN:  Yeah, I think the
15	determination of ages are a very important one and
16	certainly one that deserves a lot of discussion now
17	and as we move forward with this.  I think we picked
18	this--, first of all the 45, 55 are risk factors

19	because the feeling is at that age one is already
20	starting to have, by that age, a burden of
21	atherosclerosis.  And we see this as a prevention kind
22	of issue by the age of 35 and 45, respectively, men
23	and women are now starting to have, significant

24	numbers of people are coming in to the higher
25	cholesterol levels that will benefit from this.  And

			160
	1	I guess we see this as a prevention option for people
	2	who are already--, and I think the other thing that¦s

	3	important is these people are already taking steps to
	4	lower their cholesterol.  So that, you know, we saw
	5	that.  Twenty-five percent of them are already
	6	pursuing nonprescription therapies to lower their
	7	cholesterol.  We see this as a meaningful option for
	8	those people who are interested in doing that.  And
	9	maybe Dr. Cohen has a couple of perspectives on the
10	risk benefit because I think also, to your point, the
11	safety issue is absolutely of paramount importance. 
12	We recommend to everybody that they follow a diet and
13	probably will recommend to many people that they take
14	dietary adjuncts to lower their cholesterol.  So I

15	think the question is in risk and benefit, what is the
16	risk of which is really the safety profile of the drug
17	to what is the ultimate benefit for that given period
18	of time.
19	            DR. COHEN:  Thank you for that question. 
20	It¦s a good question and it¦s one that I think we¦ve
21	given considerable thought to.  And as a clinician and
22	a cardiologist, you come back to the disease process
23	we¦re trying to prevent.  And the number one cause of
24	death in men over the age of 35 is coronary heart
25	disease.  The number one cause of death in women over

			161
	1	the age of 45 is coronary heart disease.  That¦s what
	2	we¦re trying to prevent.  And as I mentioned in my
	3	preamble, in fact, about 35 percent are sudden first-

	4	event deaths.  You don¦t have a chance to see them,
	5	and this is the kind of patient we¦re trying to get
	6	at.  And who is that patient?  It¦s not a guy with a
	7	cholesterol of 300.  It¦s a guy who may smoke, who¦s
	8	got a blood pressure of 142 and the doctor says,
	9	that¦s not so bad.  And he¦s got a cholesterol of 235. 
10	That¦s the high-risk man.  And he doesn¦t realize it

11	because he¦s looking at individual numbers, and none
12	of the numbers knocks your socks off, except when he
13	dies everybody says this was a high-risk guy.  Let¦s
14	pay attention to the risk factors.  Let¦s focus on the
15	high-risk people, men age over 35, women 45 and over.
16	            CHAIRMAN BRASS:  But you¦d agree that

17	dropping the age to 35 would represent an additional
18	extrapolation of the surrogate variable in terms of
19	risk event rates, et cetera?

20	            DR. COHEN:  Yes, I would agree with that. 
21	And at some point I hope to be able to show you a
22	slide that kind of puts it into a perspective overall. 
23	I¦m not going to do that now, but I hope that we can

24	get back to this issue of this question.  It¦s a very
25	important one, obviously, thank you.

			162
	1	            DR. ORLOFF:  Dr. Brass, may I make a point
	2	of clarification, stepping back right here.
	3	            (Laughter)
	4	            DR. ORLOFF:  We need to get straight on
	5	this for the purposes of our discussion.  The
	6	indications for use of any drug are a reflection of an
	7	expectation of benefit.  And LDL-lowering indication
	8	is an implied indication to reduce the risk of
	9	cardiovascular disease of the occurrence of some

10	atherosclerotic disease event.  In those instances
11	where we grant indications for the use of these drugs
12	based solely on the LDL-lowering data, that is because
13	the judgment is that under the conditions of use
14	recommended in the labeling, the benefit to that
15	population of patients will outweigh the risk.  That¦s
16	the problem that we need to get to today.
17	            DR. COHEN:  Mr. Chairman, may I address
18	that problem?  David, we¦ve talked about this and
19	you¦ve hit the nail right on the head in terms of this
20	issue and I think it¦s one that we need to look at in
21	terms of the totality of the data.  And when you look
22	at the totality of the data we have a clear evidence
23	of efficacy in terms of the 18 percent reduction.  Now
24	let us look at a level playing field.  There was a
25	situation not long ago where an Rx switch was made to

			163
	1	OTC, and it was nicotine replacement therapy.  Nobody
	2	ever said show me the data for preventing lung cancer. 
	3	Nobody said show me you can forestall COPD down the

	4	road.  What did you want?  You wanted intermediate
	5	variable reduction that we know in the long run will
	6	translate into benefit.  And that¦s what we¦re after
	7	here.  We know from all of the science, the animal
	8	studies, the epidemiologic data, and the clinical
	9	trial data that exists, that an 18 percent LDL
10	reduction will translate into a huge--  That¦s why the
11	goal of 2010, the newest goal is 199 for everybody. 
12	Where are the data to support that?  That¦s the U.S.
13	government.  That¦s all of us in this room
14	collectively thinking about how we¦re going to prevent
15	our number one epidemic in the United States of
16	coronary disease.  The answer is not defibrillators

17	for preventing first-event sudden death in airports
18	and in ballparks.  That¦s not the answer to this

19	disease process.  The answer is dealing with the basic
20	disease of atherosclerosis and we have it in front of
21	us today, ladies and gentlemen.
22	            CHAIRMAN BRASS:  Dr. Gilliam.
23	            DR. GILLIAM:  Two questions.  One, in your
24	safety data you had 43 women who had taken this
25	medication while they were pregnant.  Do you have any,

				164
	1	how long did they take¦
	2		CHAIRMAN BRASS:  Please be sure you talk
	3	into the mic.
	4		DR. GILLIAM:  How long did they take this

	5	medication, that kind of thing?  And then the second
	6	question was in your use studies, a question about how
	7	many of these people were taking herbal products,
	8	other medications that are, to try and lower their
	9	cholesterol?
10		DR. FRIEDMAN:  To first answer the
11	pregnancy, I can show you the specific breakdown.  The
12	exposure for probably a third of the women or half of
13	the women was well, it was about less than six weeks. 
14	We might have that slide.  Maybe we can look for that. 
15	It was about less, it was six weeks or less, four to
16	six weeks.  There was another, approximately a third

17	or so, or maybe a little less, it was six to 14, 15
18	weeks.  There were a couple of women who took

19	Pravachol throughout the full duration of their
20	pregnancy.  There¦s the slide.  This is all during the
21	first trimester and as Dr. Brown points out this is
22	all during the period of organogenesis. 
23		DR. ELASHOFF:  As I recall you didn¦t know
24	the outcome from a lot of those studies.
25		DR. FRIEDMAN:  We know the outcome in 29

			165
	1	of these pregnancies and of those in which we know the
	2	outcome there were no cases of teratogenicity.
	3	            CHAIRMAN BRASS:  Dr. Davidson.
	4	            DR. DAVIDSON:  Well, first I want to

	5	congratulate the sponsor for being inclusive, you
	6	know, for the material you are producing.  And I have
	7	to agree with Dr. Cohen.  It would reduce the LDL 18
	8	percent, it would get a lot accomplished.  The problem
	9	is I don¦t know if your studies and going over-the-
10	counter will address the problem.  Number one, in your
11	studies, 85 percent of the population already have
12	medical attention.  And in 50 percent of the patients
13	that the drug was prescribed, the drug was
14	discontinued by the physician in patients without
15	normal lipids.  And that¦s a problem.  It¦s a problem
16	not for the consumer; it¦s a problem of education that
17	we all need to do.  Then you know, your studies really
18	don¦t solve the problems.  Second, your population at
19	target was not a low-literacy population or the
20	average American.  You know, if you look at the
21	answers, you know, actually your low-literacy did
22	better in the answers than the over ninth grade deal. 
23	Then who did you choose for the studies?  You know,
24	people who already have insurance, that have HMO
25	options.  Either your material that you used was too

			166
	1	good and actually easy to understand, or you know,
	2	your population was really more educated than you
	3	think.  Then those are the first parts of my
	4	questions, if you can answer.  I have a couple of more
	5	after that.
	6	            DR. FRIEDMAN:  I think to your first point
	7	about access to healthcare and that is clearly a very
	8	important issue for every aspect of healthcare.  We
	9	actually see this as potentially an additional venue
10	that could, where we could use other access to
11	healthcare and bring the message out in additional
12	ways that may, in the current prescription
13	environment, not be reaching so many people.  I do
14	want to make it clear that we didn¦t choose anybody. 
15	We advertised and we made sure that the demographics
16	of the media represented the community.  We also
17	augmented the advertisement in minority radio stations
18	and magazines.
19	            And we also specifically placed the sites
20	in minority communities so we could get the reach that
21	we did.  I absolutely agree, and also the messages on
22	the package and then the ad whatever the person
23	bought, are really what we intend to have in the true

24	OTC environment.  We didn¦t have in the study some of
25	the additional tools that we would want to have in an

			167
	1	OTC environment, such as audiocassettes for low-
	2	literacy people, audiocassettes in Spanish, package
	3	inserts and label in Spanish, which we would intend to

	4	have.  But for one, we did not exclude people if they
	5	did not speak English, and we actually had healthcare
	6	professionals at some of the clinics that we chose
	7	that were reflecting the communities.  So I think we
	8	tried as much as possible to do that.  I totally agree
	9	with you that this is a big issue of access, and as
10	Dr. Cohen said there are a lot of Healthy People 2010
11	goals and narrowing that gap is one of them and maybe
12	this can help.
13	            DR. DAVIDSON:  The second part was, you
14	know, even if they have over-the-counter, if the
15	physician will discontinue the therapy, you know, is
16	a big problem.  And those are things you need to
17	address.
18	            DR. FRIEDMAN:  Absolutely.
19	            CHAIRMAN BRASS:  But if I could just
20	interrupt for one second, because I think this
21	concept--  Well, we all agree the healthcare system is
22	doing a non-optimal job.  I think we all agree on
23	that.  But I think this bashing about primary
24	prevention of this population is being overdone.  The
25	PREDICT study was done in 1998.  The amount of

			168
	1	randomized placebo-controlled trials that demonstrated
	2	a positive risk-to-benefit ratio in this low-risk
	3	population in 1998 was simply not available.  And to
	4	say that physicians were acting inappropriately in

	5	1998 based on the information available in 2000, I
	6	just don¦t think is necessarily an accurate reflection
	7	of what physician behavior in primary prevention is
	8	going to be over the next five years.
	9	            So I think we have to be a little bit
10	careful about--, and again, nobody¦s questioning that
11	there is a lot of room for improvement in the
12	healthcare system.  I just think we¦re looking at an
13	absolute worst-case scenario when we look at how
14	primary prevention was being done in that period of
15	time for what was then a low-risk population with
16	limited evidence for indication for treatment.  If you
17	could identify yourself, please.
18	            DR. PFEFFER:  Yes.  Mark Pfeffer.  I¦m a
19	consultant for the sponsor.  And some of the issues
20	you brought up about safety and the issues you¦re
21	bringing up about time are really very important
22	because these are all moving targets.  And I¦m here as
23	a care investigator and when we started, this drug

24	wasn¦t even approved for use to lower cholesterol. 
25	And we all had our preconceived notions.  As a matter

			169
	1	of fact, if you think of the safety profile as it was
	2	rolling out, we had to do slit lamp exams to make sure
	3	that we weren¦t getting corneal opacifications.
	4	            And with dialogue with the agency and with
	5	data that barrier was removed in the midst of the
	6	study.  We had to do very careful surveillance labs
	7	which was brought up that you don¦t do that in real
	8	life, and that had to be done.  And because of that,
	9	and because we¦ve now pooled three studies together,
10	we have a quarter of a million samples that say we

11	can¦t detect the difference between placebo and the
12	act of therapy.
13	            Now this wasn¦t known to the
14	investigators.  The pravastatin pooling project
15	started before the lipid study came out, which just
16	came out a few years ago.  In 1992 the investigators
17	from these studies with sponsor support, develop the
18	pravastatin pooling project.
19	            You¦re seeing numbers here that the world
20	doesn¦t even know yet.  And that was put together to
21	look at efficacy, to look at pre-specified subgroups,
22	and I happen to be the lucky one to say, ¦Let me do
23	the safety analysis.¦  And because of that we now know
24	that there is no difference over placebo that could be
25	detected.  Now you could never be that certain about

			170
	1	safety, and then we have the 22 million patient years. 
	2	So I think now, we¦re in a different place, and we
	3	need a new step to help with the education of both the
	4	consumers and the patients.
	5	            DR. DAVIDSON:  I didn¦t finish.  You know,
	6	still my point is that if this product goes over-the-
	7	counter, you know, if we want to use it properly, you
	8	know, there will need to be a lot of healthcare
	9	education, otherwise it won¦t happen.  When you¦re

10	going to have an 800 number, who is going to mind that
11	800 number and what are the qualifications of those
12	people?  And is the 800 number a bilingual 800 number?
13	            DR. FRIEDMAN:  Could I have the schema of
14	107, please?  This is the schema of the toll-free 800
15	number that would occur during the hours of eight to
16	ten.  Consumers¦ calls would come in and by an
17	automatic triage they would select English or Spanish. 
18	Then they would also get, beyond that, there would be
19	a phone triage to an automated handling which would go
20	to Pravachol Partners enrollment, and then consumer
21	promotion increase.
22	            For most OTC products, that¦s the largest
23	amount of increase that¦s come in.  Then the next
24	would go to a consumer affairs specialist, and again,
25	now they have already selected English or Spanish, and

					171
	1	then they would have a script that could answer
	2	questions about product use that would go through a
	3	script.  If there were medical related questions, they

	4	would be directed to the personal physician or to the
	5	healthcare professional.
	6		DR. DAVIDSON:  Why only eight to ten?
	7		DR. FRIEDMAN:  We have another, if I could
	8	have the next slide, please.
	9		DR. DAVIDSON:  No, no.  Let¦s finish.
10		DR. FRIEDMAN:  It¦s 8:00 a.m. to 10:00
11	p.m.
12		DR. DAVIDSON:  Right, I know.  Eastern or
13	Standard time?  Which leaves a lot of people out of
14	the loop.
15		DR. FRIEDMAN:  Sure.  Well, that¦s
16	something we¦d be happy to extend.  We do also have an
17	off-hours 800 number.
18		DR. DAVIDSON:  Okay.  Could you go back to
19	that slide?
20		DR. FRIEDMAN:  Sure.
21		DR. DAVIDSON:  You know, who is your
22	consumers affairs specialist?  What is the
23	qualification for that person?
24		DR. FRIEDMAN:  That person is someone who
25	has been trained in the use, to answer questions per

					172
	1	the labeling and the fact book.  That person is not
	2	intended to take the place of that person¦s physician
	3	and it¦s really just to be able to using the
	4	information, being able to provide that information to
	5	that consumer that¦s already in a fact book that
	6	actually the consumer would more or less for him or
	7	herself, but might need some clarification.
	8		DR. DAVIDSON:  Yeah, I really still don¦t
	9	get my question out.  What is the background of that
10	person?
11		DR. FRIEDMAN:  That person would probably
12	have a college education and then have specific
13	training from a healthcare professional.
14		DR. DAVIDSON:  Thank you.
15		CHAIRMAN BRASS:  Dr. Neill.
16		DR. NEILL:  Why did you ask for approval
17	for the 10 mg. dose as opposed to 20 or 40?
18		DR. FRIEDMAN:  Why are we asking now for
19	approval?  Why are we asking for approval for 10
20	versus other doses?
21		DR. NEILL:  Yes.
22		DR. FRIEDMAN:  I think for several
23	reasons.  First, Rx-to-OTC switches have historically

24	been at lower doses.  And I think, very importantly,
25	the choice of the lower dose actually has come, has

				173
	1	evolved from discussions from these committees and
	2	with FDA where there was a real concern and interest
	3	in differentiating the lower-risk person who could

	4	take this OTC from the higher-risk individual who
	5	really needed much more intensive intervention with a
	6	physician.  And we think that we accomplish this by
	7	this dose.
	8		We, in fact, the last time we were before
	9	this committee, we had a much broader reach in our
10	program, and in fact it was a great concern of the FDA
11	and the committee that perhaps that would be confusing
12	and distract people from the healthcare system.  So
13	our intent here is to have a lower dose for a lower-
14	risk population, who most of whom will achieve a
15	meaningful benefit or get to their goal on this dose.
16		DR. NEILL:  Why did you choose this lower-
17	risk population for that low dose for your indication?
18		DR. FRIEDMAN:  Again, it was because of
19	discussions that we¦ve had with the FDA and this
20	committee.  The concern that the higher risk
21	population really needs to be under intense medical
22	supervision, and that this could potentially be a
23	distraction.  That was a concern voiced at our last
24	meeting.  We heard it and this is how we¦ve responded.
25		DR. NEILL:  And last question for FDA. 

			174
	1	Given the move of cholesterol monitoring outside the
	2	physician¦s office, I could imagine a time when this

	3	medication is available over-the-counter and that even
	4	higher-risk patients given access to cholesterol
	5	testing could appropriately manage themselves with an
	6	OTC medicine and with OTC testing.  My question to you
	7	is, that¦s a real shift.
	8	            Yesterday you discussed the extent to
	9	which patients currently titrate other OTC medicines
10	for symptom-related conditions.  And I sat trying to
11	imagine or come up with any medication that is already
12	OTC that has a symptom of a condition that I felt was
13	as serious, or the consequences of which were
14	potentially as serious, or the safety profile given
15	incorrect use of this OT medicine might be as serious
16	as coronary heart disease.  I couldn¦t come up with
17	any.  Can you?
18	            CHAIRMAN BRASS:  You can answer it very
19	briefly, but really I think that¦s more for our
20	general discussion this afternoon and let¦s focus. 
21	But if you want to go ahead and make a brief comment.
22	            DR. DELAP:  I think that you¦ve hit a very
23	important nail on the head, there, and that¦s partly
24	why we¦ve spent two days out of our lives with this

25	meeting.

			175
	1	            DR. GANLEY:  The example would be insulin. 
	2	Insulin¦s essentially an OTC drug and people self-
	3	monitor, and that¦s why I bring up the issue.  If it¦s
	4	under-treated in the higher-risk populations, then why
	5	aren¦t we focusing on those populations, also?  If
	6	there¦s going to be self-monitoring, which seems to be
	7	a requirement for the treatment of cholesterol, I
	8	think we should try to maximize benefit and
	9	individualize therapy and not look at it just on a
10	population basis.
11	            CHAIRMAN BRASS:  Dr. Jenkins.
12	            DR. JENKINS:  I have a question for the
13	sponsor, but first I want to go back to what Dr.
14	Orloff was trying to clarify about the indication.
15	Because you can¦t separate an indication for
16	cholesterol lowering from an expectation of
17	cardiovascular risk reduction and cardiovascular
18	benefit, because you can¦t interpret the benefit of a

19	cholesterol reduction unless you can interpret that in
20	the context of what you think that benefit translates
21	into for a cardiovascular benefit.  And that¦s what
22	you¦d have to take into your risk benefit equation,
23	which is what stands behind the agency¦s decision to
24	approve a drug or not.  So you can¦t just say that

25	this is an indication just for LDL lowering.  That

			176
	1	doesn¦t make any sense.  LDL in and of itself doesn¦t
	2	mean anything until you translate it into what does

	3	that mean for reduction in cardiovascular risk.  So
	4	you have to apply that process to this, what we
	5	consider to be a new indication, for the treatment of
	6	people 200 to 240, LDL greater than 130.  You have to
	7	translate the LDL reduction into some benefit whether
	8	you do it through extrapolation or data for a
	9	cardiovascular benefit, and then you have to calculate
10	in your mind or someway whether that benefit outweighs
11	the risk.
12	            That¦s just a clarification of the
13	indication.  The question I wanted to ask goes back to
14	the question we started with with Dr. Uden a few
15	moments ago, and that¦s about the age criteria for the
16	labeling.  And I have to say I still haven¦t heard a
17	very clear answer on how you arrived at the criteria. 
18	As I looked at the information that Dr. Lechter shared
19	with us, the label you tested in the label
20	comprehension study said men over 35 and women over
21	55.  The label that was then submitted to the NDA only
22	mentioned if you were under 18 you shouldn¦t take the
23	drug.  The label you¦re now proposing is over 35 for
24	men, over 45 for women, which as we heard from
25	yesterday¦s discussion is somewhat different from the

			177
	1	other company¦s proposal which was, I think, 40 and
	2	over for men and greater than or equal to one year

	3	postmenopausal for female.  Clearly a decision to
	4	treat patients has to be based on a calculation that
	5	the risk benefit ratio for treatment in that
	6	population is favorable.  So I¦d like to understand,
	7	why have you migrated in your program and how did you
	8	arrive that it¦s a favorable risk benefit treatment
	9	option for people as young as 35 if they¦re male, and
10	as young as 45 if they¦re female?  What¦s the
11	scientific rationale?  The only rationale I¦ve really
12	heard so far was, that¦s when people seem to indicate
13	they want to start taking drugs.
14	            DR. FRIEDMAN:  I think first starting with
15	the risk equation, certainly there are, as you get
16	younger especially in women, I think it¦s very
17	important to assess the risks and I think we¦ve been
18	very careful to ascertain that the risk is extremely
19	minimal and no different from men or women.  As you
20	look at the risk of developing coronary disease for a
21	45 year old woman and a 35 year old man, it¦s
22	essentially the same reflecting that ten year
23	difference.  And again, we don¦t have clinical outcome
24	trials on this issue.  But I think what we¦ve been
25	hearing is that people are looking to lower

			178
	1	cholesterol, that lowering cholesterol is a good
	2	thing.  We have approved therapies to lower
	3	cholesterol, dietary adjuncts, that we have accepted

	4	to recommend to people, foods and dietary adjuncts,
	5	because of the feeling of safety.  And you¦re right,
	6	it is a risk benefit assessment.  I don¦t think, I
	7	don¦t want to today say that it has to be 35 or 45. 
	8	You know, I think that it has to be something that is
	9	beneficial of a prolonged dialogue as to what is the
10	best age.  But I think that as we looked at it, given
11	the incredible safety profile of this drug, we saw
12	extremely minimal risk and benefit for people who are
13	looking to do this anyway.
14	            DR. JENKINS:  Can I just follow-up with
15	that?  On the issue of risk of cardiovascular disease
16	in these target populations, can you give me any
17	estimate or any idea about a 35 year old male who has
18	no other risk factors other than his total cholesterol
19	is within the 200 to 240 range and the LDL is greater
20	than 130, do you have any estimates on what¦s the
21	time-to-event frame that we¦re looking at for a
22	cardiovascular event?  What¦s the expectation for--,
23	when will you see an event in a 35 year old male with
24	those as his only risk factors?  On average, I
25	understand that it has to be average data.

			179
	1	            DR. COHEN:  That¦s a good question and I
	2	think that we don¦t have clinical trial data to look

	3	at.  You saw yesterday from the AFCAPS/TexCAPS, which
	4	is the lowest-risk population studied in placebo-
	5	controlled trials, the curves begin to separate after
	6	six months.  And in that population, which isn¦t quite
	7	the same age but it¦s the lower-risk end that we¦re
	8	really discussing here, and age is really a surrogate
	9	for a lower-risk individual if you¦re talking about a
10	lower age person.
11	            But the trials continue to separate over
12	time, and that was pointed out.  So at five years, the
13	benefit continues to digress, to diverge, and all of
14	the analysis that you can do, when you come to
15	randomized clinical trials, minimizes the benefits. 
16	Why is that?  It¦s because all of these trials have
17	intention to treat analysis by design.  And so people
18	who are not taking a drug on treatment are counted as
19	taking the drug.  In addition, we¦re looking at
20	defined event rate over five years in time.  We know
21	with the digression that the benefit is going to be
22	high down road.  I don¦t know when a 35 year old man¦s
23	going to have a heart attack, nor do you.  Or maybe

24	he¦ll get hit by a truck tomorrow.  No one in this
25	room knows that.  All we know is the United States of

			180
	1	America has this huge problem.  I don¦t know if it¦s
	2	John Doe or Jane Smith who¦s going to have that
	3	problem, and so we have to face it from this kind of

	4	issue.  Then you put it in the perspective of primum
	5	non nocere, what¦s the risk?  And if you can assure
	6	yourself that the risk is vanishingly small, I will
	7	show you slides later that might suggest what the
	8	benefit can be.  And I can tell you in this
	9	population, Dr. Jenkins, the risk is above average.
10	            DR. JENKINS:  No, I understand that point. 
11	I don¦t think you answered my question, but I don¦t

12	think you have the data to answer the question.  Let
13	me just point out, though, I don¦t think anyone
14	disagrees with your public health message, that those
15	are important critical goals, but one of the
16	fundamental tenants of drug approval is that the
17	benefit is going to be derived from the patient who
18	takes the drug and that the risk is carried by the

19	patient who takes the drug, so I¦m just trying to put
20	it into perspective.  Not the public health societal
21	benefit of reducing cardiovascular disease, which will
22	be a wonderful societal benefit.  The question I¦m
23	trying to frame is what¦s the benefit to Joe Doe
24	individual¦
25	            CHAIRMAN BRASS:  I¦m going to interrupt

			181
	1	now.
	2	            DR. COHEN:  Could I just answer that
	3	question briefly?  The benefit is a calculated risk

	4	reduction that we could do.  And so if you know his
	5	cholesterol is x and he goes on a lipid-lowering drug,
	6	Pravachol 10, over-the-counter, and its 18 percent
	7	point less than x, then we can estimate from many,
	8	many data that his risk is that much lower in the
	9	order of magnitude of 20 to 30 percent.
10	            DR. JENKINS:  The only point I¦m trying to
11	make is that¦s the risk calculation we should be
12	addressing for approval in a drug, not your public
13	health goals, which are wonderful, but that¦s not the
14	drug approval risk benefit calculation.
15	            CHAIRMAN BRASS:  I¦m going to interrupt
16	now, and we¦re going to take our lunch break at this
17	point.  We will reconvene at 1:30 and continue the
18	general questions prior to getting to the FDA-specific
19	questions.
20	            (Whereupon, the proceedings went off the
21	record at 12:30 p.m. for a lunch break.)
22
23
24
25

				182
	1	          A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	2		                             (1:33 p.m.)

	3		CHAIRMAN BRASS:  Okay.  If we could come
	4	to order, please.  At this point we¦re going to
	5	continue the discussion of the presentations by the
	6	sponsor and the FDA.  The sponsor, based on questions
	7	this morning, has taken advantage of the lunch hour to
	8	complete another pivotal trial with 10,000 patients.
	9		(Laughter)
10		CHAIRMAN BRASS:  But unfortunately the
11	data analysis won¦t be ready for another five minutes.
12		(Laughter)
13		CHAIRMAN BRASS:  So they will be making
14	some additional comments about the risk issue in just
15	a few minutes.  But while they pull that together, I
16	thought we would continue the questioning.  And
17	perhaps I might begin with just a couple of issues. 
18	Could you comment on any pharmacokinetic and safety

19	data you have on patients with renal insufficiency
20	given the right of elimination of this compound?
21		DR. BOTORFF:  Mike Botorff.  I¦m a
22	professor of clinical pharmacy at the University of
23	Cincinnati.  When you compare the pharmacokinetics of
24	the various statins, most of them are very lipid-

25	soluble and you hear repeatedly that pravastatin is

			183
	1	more hydrophilic or water-soluble.  It is eliminated
	2	by several mechanisms, involving the kidney as one,
	3	when an oral dose is given.  Generally, the renal
	4	excretion unchanged is about 20 percent or a little
	5	bit less.  It¦s been studied both in single dose and
	6	in multiple doses in patients with various degrees of
	7	renal insufficiency, including those on dialysis,
	8	resulting in really no change in the pharmacokinetics
	9	at all.  Both those papers have been published.

10	            CHAIRMAN BRASS:  Thank you.  I want to
11	turn a little bit more to understand the target
12	population and its behavior in the OTC setting.  And
13	much of the discussion earlier today was related to
14	the qualified who took drug and that very small
15	cohort.
16	            I¦d like to go back to a slightly larger
17	cohort and make sure I understand something.  In the
18	PREDICT trial, there were 2,400 plus patients who were
19	designated after randomization as appropriate for
20	consultation.  I¦m looking at page 89 of your
21	briefing, and that was called the consult group, post-
22	randomization.
23	            So that, again, on page 89 it¦s 3,800
24	visited, 3,600 were randomized, 2,500 consulted.  And
25	I want to look at the characteristics of that 2,500

				184
	1	patients in contrast to patients who actually
	2	completed.  And before I even start, though, I want to
	3	emphasize that I think the sponsor did a variety of
	4	innovative things in their two actual use studies that
	5	has generated the kind of data we often don¦t see
	6	about actual use populations.  So that many of the
	7	issues that might come up for discussion, in fact
	8	already have, would even have been raised in many of
	9	the conventional trial designs.  So I really do
10	congratulate the more innovative context of some of
11	this trial design.
12		But my understanding is these 2,500
13	patients had to opportunity to review the carton and
14	after reviewing the carton thought that they were in
15	fact appropriate users.  Is that correct?
16		DR. FRIEDMAN:  The 2,500 patients
17	represent both the OTC and prescription environments. 

18	So for the OTC people, they reviewed the carton and a
19	prototypical OTC ad.
20		CHAIRMAN BRASS:  But that¦s prior, is that
21	prior to randomization?
22		DR. FRIEDMAN:  No, after randomization. 
23	So they were randomized to these environments without
24	any knowledge at all.  Okay, they came in and they
25	were randomized to the two environments without

				185
	1	showing them anything.  So that is truly without any
	2	selection bias.  And then after randomization the OTC
	3	participants could see the OTC package and a
	4	prototypical OTC ad that you would see in a magazine. 
	5	The prescription people, the people that were
	6	randomized to prescription, those 1,900 saw a
	7	prototypical DTC ad and did not see anything else.
	8		And then when they left the site, they,
	9	you know, then they left the site.  The OTC people

10	could have purchased at that point, but that was the
11	only information given to the people at the site.
12		CHAIRMAN BRASS:  Okay.  Again, I apologize
13	for the confusion, but try and understand.
14		DR. FRIEDMAN:  Yes.
15		CHAIRMAN BRASS:  On page 89, there is a
16	population of 2,466 identified as the consult
17	population.
18		DR. FRIEDMAN:  That¦s correct.
19		CHAIRMAN BRASS:  On page 91, it¦s
20	indicated that there were 1,900 randomized OTC and
21	1,900 randomized to prescription.
22		DR. FRIEDMAN:  That¦s correct, because
23	about two-thirds of people, after they left the site,
24	decided to consult.  That was up, you know, whatever
25	reason they had.

						186
	1		CHAIRMAN BRASS:  I see.  So there was a
	2	patient-based selection.
	3		DR. FRIEDMAN:  That¦s correct.
	4		CHAIRMAN BRASS:  Once randomization
	5	occurred, not to follow-up.
	6		DR. FRIEDMAN:  Not to consult.  That¦s
	7	right.  That we don¦t know because we did not, we
	8	didn¦t ask them at the end of the six months and we
	9	didn¦t intervene, but for whatever reason they could
10	just say they weren¦t interested, or whatever.  So

11	two-thirds of the entire cohort who were randomized
12	decided to consult.
13		CHAIRMAN BRASS:  Okay.
14		DR. FRIEDMAN:  And that¦s why you get that
15	drop-off.  The information that they had before making
16	the decision to consult was the package for the OTC
17	and an OTC ad, and a DTC ad for the Rx, and that¦s it.
18		CHAIRMAN BRASS:  In the 720 patients who
19	then saw the label and elected to purchase.
20		DR. FRIEDMAN:  Yes.
21		CHAIRMAN BRASS:  Okay.  Do you have what
22	the cholesterol profile is of that 720?
23		DR. FRIEDMAN:  Yes.  This is the total
24	cholesterol and LDL cholesterol.  Is that the
25	information you want?

				187
	1		CHAIRMAN BRASS:  Yes.  Now I¦m interested
	2	in, there¦s a little bit of flopping between the LDL
	3	130 and 160 number, and for primary prevention, in
	4	fact, earlier in your document you indicated that 160
	5	would be the level that would be indicated for
	6	treatment and was your criteria for those who should
	7	enter the trial.  But then, subsequently, very often
	8	you used	130.  Could you just clarify that difference?
	9		DR. FRIEDMAN:  Yes.  The treatment
10	guidelines that we gave to the physicians--  Again, we
11	wanted as uniform treatment guidelines so we could

12	then follow behavior and LDL reduction, you know, in
13	a systematic fashion in this study, which we didn¦t do
14	in OPTIONS, but in a systematic fashion.  So we gave
15	treatment guidelines more or less following the
16	principles of NCEP.  So for the lower-risk primary
17	prevention population, we had treatment guidelines of
18	160 to 190, and for the higher-risk, 130 to I think it
19	was 190.
20		CHAIRMAN BRASS:  Right, so the 130 here is
21	a little misleading in terms of them representing the
22	target treatment population of this study.  Because
23	wasn¦t the intent to treat, and again, I¦m just¦
24		DR. FRIEDMAN:  Well, this is the profile. 
25	I can give you the lipid levels of the people who were

				188
	1	in fact treated, if that would be helpful.
	2		CHAIRMAN BRASS:  Okay.  Well, let me
	3	switch back then.  You subsequently say that 80 some-
	4	odd percent ultimately met targets.
	5		DR. FRIEDMAN:  NCEP goal.  That¦s correct.
	6		CHAIRMAN BRASS:  Was that, were those
	7	goals the 160 number or the 130 number?
	8		DR. FRIEDMAN:  It depended on where we
	9	thought we--  The goals were defined by the NCEP, so
10	if you were a lower-risk primary prevention, it was
11	160.  If you were a higher-risk primary prevention, it
12	was 130.  So that was the guidelines given to the
13	doctor.  The number reached, so that¦s what that 83
14	percent represents.  If you would like to see the
15	number specifically of the percent reaching LDL less
16	than 130, it was about 63 percent.  But again the

17	doctors were not told, you know, to go any higher.
18		CHAIRMAN BRASS:  Okay.  One of the
19	positive aspects of the OPTIONS trial, while it is
20	limited because of the population all being accessible
21	to physicians, one of the advantages is that you have
22	gold standard medical histories by looking at the
23	charts.
24		DR. FRIEDMAN:  Yes.
25		CHAIRMAN BRASS:  And one of the things

				189
	1	that was kind of interesting to me if I understood it
	2	right in OPTIONS was that 26 percent of the patients
	3	who were currently on prescription lipid-lowering
	4	agents selected themselves to take the OTC, and that¦s

	5	page 127 of the, it¦s on 26 and 27.  Does that number
	6	ring a bell?  Is that consistent with?
	7		DR. FRIEDMAN:  I don¦t know if, I know
	8	that at the end of the three month period, when we
	9	looked, there were 99 people who came in on
10	prescription therapy.  And we looked at their behavior
11	at the end of¦
12		CHAIRMAN BRASS:  But at the start 27 of
13	that 99 took Pravachol 10 mg.
14		DR. FRIEDMAN:  Yes, there were some OTC
15	purchasers who took and then went off it and went back
16	on their prescription, that¦s correct.
17		CHAIRMAN BRASS:  Well, what I¦m trying to
18	extrapolate that experience to is the unsupervised OTC
19	use of the compound.  And it seems that theoretically
20	that represents two potential risks.  If 27 percent of
21	all the people currently on hypolipidemic prescription
22	drugs begin in an unsupervised way, whatever our
23	intent is, to begin taking the OTC products, it seems
24	there are two potential risks associated with that.

25		One, if you believe that the risk of

			190
	1	rhabdo is increased by co-administration of statin and
	2	fibrates.  They may be putting themselves at increased

	3	risk.  Or, two, they may be putting themselves at risk
	4	for discontinuation of the more effective therapy. 
	5	And when you start talking about 27 percent of that
	6	cohort beginning to discontinue drug in an
	7	unsupervised setting, who is most likely a higher-risk
	8	population, that again, the risk-to-benefit comes into
	9	question.  Could you comment on those issues?
10	            DR. FRIEDMAN:  Yeah, two comments.  First
11	about the use with other prescription-lowering
12	therapies and a potential, though I don¦t think it has
13	been positively associated, potential for increase
14	safety issues, I think we can go back to the label
15	comprehension study where there is a comprehension of
16	the warning, ¦Do not use if you¦re taking other
17	prescription-lowering medicine¦, and that was well
18	understood.
19	            CHAIRMAN BRASS:  Well, except that¦s not
20	a real use comprehension study.  And whereas those 27
21	percent of the patients on prescription drugs who
22	started, had the carton in front of them, presumably
23	had the opportunity to read that carton, and yet start
24	it.  And I think that kind of actual use data is much
25	more powerful than the multiple choice question on the

			191
	1	comprehension study.
	2	            DR. FRIEDMAN:  Yeah, I, certainly I think
	3	the consumer use studies really give us a lot of
	4	information and I think the other piece of information
	5	that these give us is that, one, if people don¦t
	6	consult, you know, most people don¦t continue on with
	7	the therapy.
	8	            And when we saw that, at the end of the
	9	three month period, these people had an evaluation, in
10	fact it was 11 percent who shifted from prescription

11	to OTC in OPTIONS and in PREDICT, it was two percent
12	who shifted from prescription to OTC.  In OPTIONS you
13	could say that, well, it¦s an HMO population.  They
14	all have healthcare.  In PREDICT, it¦s a much broader
15	population.
16	            So, you know, I think the reality is there
17	may be a little of that.  That¦s probably what will

18	happen.  But I think that these numbers are really
19	quite small and you have two studies to evaluate that. 
20	And so that is the issue of the shift.  Then the issue
21	of the safety, I think perhaps you can think about
22	with the label comprehension.
23	            CHAIRMAN BRASS:  Well, I understand again,
24	the absolute magnitude of the number who shift may be
25	small and it may be anywhere between two and 27

			192
	1	percent, given the confidence intervals on those
	2	numbers.  It¦s something in that range.  My point is
	3	that the absolute risk in that population for
	4	cardiovascular events may be substantially higher

	5	evidenced by the fact that some doctor, even our
	6	limited healthcare system, decided they needed
	7	therapy, and so the absolute increase in risks from a
	8	small percentage of patients discontinuing
	9	prescription therapy versus a large number of low-risk
10	patients accessing therapy, I think, is a legitimate
11	question in the room.
12	            DR. FRIEDMAN:  I agree with you.  I think,
13	though, that what¦s central though to your hypothesis
14	is exactly that a doctor did put them on therapy.  So
15	it is a person, you know, I think what you were
16	concerned is the people who don¦t see the doctor.  But
17	here are people who are in the system, have been
18	seeing their doctor, and you¦re right, some of them
19	may not go back.
20	            But I think our data, what you brought up
21	was, well here are people who have doctors, so what
22	about the people who don¦t?  Well, the people who
23	don¦t probably wouldn¦t have been put on therapy.  So
24	people who have been put on therapy have doctors.

25	            CHAIRMAN BRASS:  And I recognize that

			193
	1	we¦re talking hypotheticals.  So neither of us can
	2	definitively address this.  But one of my concerns,

	3	and I realize PREDICT was biased to shifting in one
	4	direction, but that an interpretation of this is that
	5	patients who have had physician relationships, are on
	6	prescription therapy, may say, may say, I don¦t know,
	7	may say I no longer need to go to my doctor because I
	8	can take the drug over-the-counter and discontinue the
	9	healthcare relationship.  I don¦t know to what degree
10	that will happen.
11	            DR. FRIEDMAN:  The other piece of data,
12	though, to think about is the one year data where,
13	again, people in the OTC environment were just as
14	compliant with going back and getting that annual
15	visit with a doctor compared to the prescription
16	environment.  I agree with you.  It¦s a theoretical
17	risk.  We¦ve tried to evaluate it with these pieces of
18	data.
19	            CHAIRMAN BRASS:  And one last question. 
20	Of the 720 OTC PREDICT patients, what percentage of
21	them had cholesterols over 240?  You showed us over
22	200.  What percentage had over 240?
23	            DR. FRIEDMAN:  Just a moment.  We have a
24	lot of data.  The book is very heavy.  I can show you¦
25	AB109.  Now again in PREDICT, now this is¦that¦s not

					194
	1	it.  In PREDICT, we only know the cholesterol because
	2	those are people who consulted, so we don¦t know the
	3	cholesterol of all the purchase people.
	4		CHAIRMAN BRASS:  I see.
	5		DR. FRIEDMAN:  I can show you the baseline
	6	for both PREDICT and OPTIONS.  The baseline total
	7	cholesterol distribution for the people who purchased. 
	8	But again, for PREDICT, that will only be for the
	9	people who consult.
10		CHAIRMAN BRASS:  Fair enough.
11		DR. FRIEDMAN:  So, yeah, AB103.  And that

12	gives you for PREDICT in yellow and OPTIONS in blue,
13	the total cholesterol distribution.
14		CHAIRMAN BRASS:  So adding up quickly, a
15	little over 40 percent were over 240?  Is that fair?
16		DR. FRIEDMAN:  That¦s right.
17		CHAIRMAN BRASS:  Okay.
18		DR. FRIEDMAN:  Again, though, the
19	important thing also for PREDICT is that these people
20	all consulted a doctor.
21		CHAIRMAN BRASS:  I understand.  I
22	understand.  Are you ready for the risk data or do you
23	want some more time for that?
24		DR. HENNEKENS:  Well, I¦m Charles
25	Hennekens.  I¦m a preventive medicine consultant to

			195
	1	Bristol-Meyers Squibb.  Dr. Friedman asked me to speak
	2	to the issues you raised just before lunch, both the
	3	committee and the FDA with respect to the quotient
	4	points about benefit and risk ratio and with respect
	5	to age as a former clinician and epidemiologist, I
	6	would tend to raise the lower limit from 35 to 40 in
	7	men and 45 to 50 in women simply because this is the
	8	time at which the event rates begin to rise
	9	exponentially.
10	            But even this needs to be viewed in the

11	context that years ago working with Sidney Blumenthal
12	and Mary Jane Jesse we demonstrated that children of
13	men who had an MI by age 50 already exhibited
14	hyperlipidemia in childhood, so certainly in early
15	middle age one could pick up this upset of the
16	population in men in their 30¦s and women in their
17	40¦s.
18	            Now the data from AFCAPS/TexCAPS for this
19	OTC target population indicates five year
20	cardiovascular event rates of about five percent for
21	this target population over five years.  Now as
22	expected, this is slightly lower than the projections
23	one would get from an observational database because
24	of the selection of people into the trials.  But even
25	after adjusting for the expected poor compliance that

			196
	1	one would get in the OTC population, this would
	2	translate conservatively to at least a 20 percent
	3	reduction and the absolute event rate to four percent
	4	among those who were taking Pravachol 10.
	5	            This is because the 18 percent reduction
	6	in LDL-C from Pravachol 10 would be expected from
	7	epidemiologic data and with good compliance in the
	8	trials to really achieve about a 40 percent to about
	9	an absolute risk down to three percent.
10	            CHAIRMAN BRASS:  If I could just
11	interrupt.  In the discussion yesterday and part of

12	that discussion was inferred in the conversation this
13	morning, there was concern that the AFCAPS  population
14	does not represent the OTC target population because
15	of the HDL cutoff.  And that part of the discussion
16	this morning, and I apologize for the degree, it was
17	a continuation of a discussion from yesterday, is

18	trying to define in the OTC target population as
19	defined by sponsor what the risk rates will be and
20	extrapolation of benefit.
21	            DR. HENNEKENS:  Yes.  Well, I think the
22	HDL issue is a red herring here because even in the
23	AFCAPS/TexCAPS study one has to conclude that if you
24	look at the overall database, there is no
25	heterogeneity in the reduction of LDL-C and people

			197
	1	with low, medium and high HDLs.  There is a
	2	significant benefit even among those with high HDLs.

	3	            CHAIRMAN BRASS:  Again I apologize, but
	4	yesterday we saw data that showed the event rate was
	5	different.
	6	            DR. HENNEKENS:  Yeah.  Well, the issue of
	7	yesterday, there were two issues I heard yesterday. 
	8	One was that there was no significant benefit at the
	9	high HDL levels in AFCAPS/TexCAPS.  This was based on
10	a comparison of 21 versus 23 events.  This was a
11	subgroup of a subgroup.  The overall HDL analysis is
12	a data-derived subgroup and it is statistically
13	significant in favor of benefit.
14	            The subgroup of the subgroup, defined

15	inexplicably by the sponsors based on those that would
16	be eligible in their OTC target, left you a subgroup
17	of a subgroup that had 21 versus 23 events.  So I
18	reject the notion that there¦s no benefit in the high
19	HDL.  It is true that there¦s some gradient across HDL
20	levels, but that¦s also true in all populations one
21	looks at.
22	            And I think that that--, it¦s an
23	independent risk factor.  One sees benefits of LDL

24	lowering at the highest levels of HDL in men and in
25	women alike.  So at any rate, I make this a fairly

			198
	1	conservative small absolute risk reduction which, as
	2	you know, is in marred contrast to a secondary
	3	prevention population where during this five year
	4	period you¦d expect reductions--, a 20 percent
	5	reduction would lead you from 20 percent to 20 percent
	6	from 25 percent in the placebo group.  So it¦s a much
	7	bigger benefit in the higher-risk secondary prevention
	8	group.
	9	            But this 20 percent reduction in secondary
10	prevention has a far greater impact in the individual

11	then in primary prevention, but for a safe drug like
12	Prava 10 I think this reduction is important both from
13	a clinical and public health impact.  And indeed
14	estimates could be made that the 20 percent reduction
15	and secondary prevention, even though it has a bigger
16	benefit to the individual might avoid 10,000 events

17	whereas in the population in primary prevention over
18	five years it would avoid about 100,000 events.
19	            Now with regard to the fact that one can
20	demonstrate a benefit of cholesterol-lowering in this
21	population, I did serve on the NCEP coordinating
22	committee as the College of Preventive Medicine
23	representative.  In 1986 the guidelines called ATP I
24	were based on the totality of evidence that included
25	randomized trials of drugs and diet that gave LDL

			199
	1	reductions of 11 percent.
	2	            This translated to benefits on coronary

	3	events, but equivocal findings on total mortality. 
	4	Prava 10, as you know, reduces LDL-C by 18 percent. 
	5	In 1992, ATP II guidelines were changed primarily to
	6	make a more targeted goal of an LDL less than 100 for
	7	secondary prevention.
	8	            Now, these are the current guidelines. 
	9	They don¦t reflect or have anything to do with any of

10	the statin trials that have been completed in the last
11	six or seven years and they show marked reductions on
12	MIs, stroke, vascular death and total death.  And the
13	point I want to make here is that these guidelines are
14	reactive to accumulating data and positions taken.  If
15	the FDA were to approve OTC use of Prava 10, then I
16	would assume that they would be incorporated into
17	future guidelines to react to the data as they
18	accumulate it and become accepted.
19	            With regard to adherence to the current
20	guidelines as the Chairman and others have said,
21	nobody would disagree that they¦re sub-optimal;
22	however, I think it should be stated that with 13
23	years of NCEP, six years of landmark statin trials,
24	widespread advertising in the medical journals,
25	educational programs and perhaps, last but not least,

			200
	1	drug detail people at the doorstep of all the
	2	healthcare providers on a daily basis, Dr. John LaRosa

	3	has published in the American Journal of Cardiology in
	4	the last year or so results from the NHANES data,
	5	which quantitated this to be, in secondary prevention
	6	and people with events, less than 15 percent are
	7	achieving the current guidelines.  In primary
	8	prevention, less than five percent are achieving the
	9	guidelines.
10	            So I think the introduction of Prava 10

11	into the OTC as an OTC option has to be looked at in
12	the context of a current situation that is
13	complementing a big existing need.  Now with respect
14	to the risk side of the equation, I concur completely
15	with Dr. Belder¦s safety analysis, but I think that
16	it¦s important to point out the suggestion that their
17	liver failure associated with Pravachol has to be
18	viewed in the context that this has no, is nothing in
19	excess of the background.  And secondly, that with
20	regard to rhabdomyolysis, the risk is either
21	exceedingly small or nonexistent, so I would think
22	that I would not be able to conclude that there are
23	small but significant risks associated with this drug. 
24	So in principle I would say that I concur that OTC

25	options for a prescription drug require particularly

			201
	1	rigorous evaluation, but I think that as I view the
	2	benefit-to-risk ratio with these conservative
	3	estimates, I believe in this society in the year 2000,
	4	that this particular drug qualifies, so thank you.

	5	            CHAIRMAN BRASS:  Dr. Johnson, you had a
	6	question.
	7	            DR. JOHNSON:  I¦m sort of going back to
	8	some of the questions that were being answered before
	9	this statement.  And that is these people who shifted,
10	did you interview them to try to gain some
11	understanding in terms of why they shifted from Rx to
12	OTC?  I mean especially people who have prescription
13	coverage.  It¦s a little hard for me to understand why
14	they would go from something that is, you know, a co-
15	pay of five to 15 dollars or something like that, to
16	have to pay for something out of pocket.  So I¦m

17	wondering if you gained any insight that might be
18	useful in your advertising to minimize that Rx-to-OTC
19	movement.
20	            DR. FRIEDMAN:  I agree with you.  That
21	would be very helpful.  Unfortunately, we don¦t have
22	that information.  I think that that attitudinal
23	research would be very important and certainly we

24	would want to be sure that the messages for OTC and
25	the messages for prescription were very distinct and

			202
	1	very careful.  But unfortunately I don¦t have that
	2	information for you today.
	3	            DR. JOHNSON:  On sort of a related
	4	question, and this has to do with what I think is the

	5	current label and is on page 70 of the documents that
	6	you provide to us.  One of the statements it says,
	7	¦Ask a doctor or pharmacist before use if you are
	8	already taking prescription medications to lower your
	9	cholesterol¦.  I¦m a little curious about the wording
10	of that and why it doesn¦t say, ¦Do not use if you are
11	taking¦¦, because the way that statement is worded
12	somehow implies that it¦s okay to take this.  And I¦m
13	just not understanding what situation they would ever
14	use this is they were on a prescription cholesterol-
15	lowering drug.
16	            DR. FRIEDMAN:  I think that¦s a good
17	point.  You know, I think that would be something--,
18	that¦s a very good suggestion.
19	            DR. JOHNSON:  Okay.  And my other
20	question, again, sort of related to why it¦s not under
21	the ¦do not use¦ category, is ¦if pregnant or
22	breastfeeding ask a health professional before use¦. 
23	Again this implies that it¦s okay to use in a
24	pregnancy and I think it¦s been described yesterday

25	and today that there¦s really no reason to ever use

			203
	1	this drug during pregnancy.  It may be safe if it¦s
	2	inadvertently used, but there would be no situation
	3	where someone would recommend its use, and this
	4	statement suggests, to me at least, that it may be
	5	acceptable to use during pregnancy.
	6	            DR. FRIEDMAN:  There is certainly no
	7	intent that a pregnant woman would use OTC Pravachol
	8	10.  This is the standard pregnancy warning for an OTC
	9	package.  Certainly we could change that language to

10	make it stronger because the OTC product would never
11	be intended for a pregnant woman to use.

12	            CHAIRMAN BRASS:  Dr. Gilliam.
13	            DR. GILLIAM:  To follow-up on that a
14	little bit, then switching from an Rx drug makes me
15	wonder if they really understood what medications they
16	were taking and what their medications are for and if
17	you had any feel for asking them about their
18	medications and what they were for.
19	            DR. FRIEDMAN:  We did know a little bit
20	because there were some people that we considered
21	trading down from the prescription to the OTC who in
22	fact shifted, they were either on 10 mg. prescription
23	and they took the OTC option, so we do know that.  And
24	some people who were, say, on 20 mg. doubled up on the
25	OTC.  So I think that they did know that they were

					204
	1	taking the medicine.  Why they exhibited this
	2	behavior, I¦m not exactly sure.
	3		CHAIRMAN BRASS:  Dr. Davidson.
	4		DR. DAVIDSON:  Three short questions.  We
	5	ask that question and we haven¦t actually had an
	6	answer.  From those that were actually treated and you
	7	were able to get lipids, you know, how many were able
	8	to reach the goals?
	9		DR. FRIEDMAN:  Just bear with me for a

10	moment.  From what you can see here is, this is in
11	PREDICT.  Everybody who qualified, whether or not they
12	took medication, and then this is the people who
13	qualified and actually took medication.  You can see
14	that 80 percent of people, of everyone who qualified
15	whether or not they took medication reached their NCEP
16	goal.  If they took medication it was, in fact, 88
17	percent.  If you used a more stringent criteria, which
18	was not what the study doctors were instructed to do,
19	it¦s about three-quarters.  I mean two-thirds, I¦m
20	sorry.
21		DR. DAVIDSON:  That¦s combining both
22	studies?
23		DR. FRIEDMAN:  This is PREDICT.
24		DR. DAVIDSON:  Right.  Give me just OTC.
25		DR. FRIEDMAN:  It¦s actually a little

				205
	1	better in OTC, but it¦s certainly not different.  Do
	2	you want to give me a minute to find that slide?
	3		DR. DAVIDSON:  Yes.  And maybe somebody

	4	else can answer my next question.  Because my next
	5	question is something that is important for all of us. 
	6	You interviewed 200 people about OTC preference, you
	7	know.  And they were really, you know, interested in
	8	OTC prescription.  Who were those 200 people?  How do
	9	you choose them?  You know, could you give me a little
10	background on those people?
11		MS. KRIGER:  This was a classic consumer

12	research study conducted amongst a random sample of
13	adults 35 plus who are concerned about cholesterol.
14		DR. DAVIDSON:  Okay.  You don¦t have any
15	demographics?
16		MS. KRIGER:  I don¦t have those with me,
17	but it was just, it was a random adult population 35
18	plus.  I don¦t have those, the demographic breakouts
19	with me.
20		DR. DAVIDSON:  Thank you.  And my final
21	question is, from the patients that, you know, you
22	interview, obviously you had a nice ethnic population,
23	but how many really were treated?  You know, because
24	you only told us how many actually came in for the

25	studies, but how many were really entering the study

			206
	1	we do not know.  And that¦s very important for you and
	2	for us because if you have a nice way to reach them,

	3	but you don¦t have a way to retain them, we have a
	4	problem.
	5	            DR. FRIEDMAN:  And you¦re absolutely right
	6	about that.  I do have the demographics at each of the
	7	levels, and what we do see is sort of at each step,
	8	minority populations tend to fall off.  There is less
	9	interest in purchasing and, once people purchase and
10	take they stay on it.  But there is less of an
11	interest in purchasing the product and I think that
12	that is exactly what is seen in the current healthcare
13	system and something that we need to address in a
14	program like this, and again may be, you know, another
15	way of trying to address this.  I do have the lipid
16	data.
17	            DR. DAVIDSON:  Okay.  Let¦s go to the
18	lipid data and we¦ll come back to that point.
19	            DR. FRIEDMAN:  It¦s a very busy slide. 
20	This is the way we have it.  Let me just try to go
21	over for you.  This is the qualified and treated
22	population in PREDICT, OTC and the prescription
23	confidence intervals between the two.  You look at the
24	overall baseline LDL which is about 160, no different,
25	change in the percent reaching the NCEP goal is here,

			207
	1	and the percent reaching LDL less than 130 is here. 
	2	So there¦s really no difference.  We then broke it up
	3	by people whose CHD some physicians did for people
	4	with CHD and very few people without CHD in moderate

	5	risk, and without CHD in lower risk.  And you can see
	6	basically that the numbers are, the numbers per group.
	7	            CHAIRMAN BRASS:  Again, this is part of
	8	the data that confused me as well.   And I realize
	9	now, if you put that back on?  I realize those are
10	means and not medians, but it suggests in both
11	populations, large numbers had LDL less than 160 and
12	therefore in terms of indication for therapy and in
13	terms of their ability to reach the goal.
14	            DR. FRIEDMAN:  Yeah, now don¦t forget in
15	this group right here, this is the moderate-risk
16	group.  The mean baseline was 155, so their goal was
17	130 and 80 percent reached that goal.  Here, which is
18	the lower-risk group and again, the guidelines, and
19	this one for initiation was 160.  Again, 95 percent
20	reached the NCEP goal.
21	            CHAIRMAN BRASS:  Reached the goal of less
22	than 130?
23	            DR. FRIEDMAN:  No, that¦s not 130.  I have
24	that only for the top here.  I don¦t know why that¦s,
25	I¦m sorry that¦s not on this slide.

					208
	1		CHAIRMAN BRASS:  So for that group that we
	2	say 95 percent reached their NCEP goal, what goal was
	3	that?
	4		DR. FRIEDMAN:  160.
	5		CHAIRMAN BRASS:  Yeah, so most of them
	6	were 160.  Half of them were there when they started.
	7		DR. FRIEDMAN:  No, they were above 160 to
	8	get in.
	9		CHAIRMAN BRASS:  Now, they couldn¦t have
10	been with 166 plus or minus 17.
11		DR. FRIEDMAN:  I¦ll have to look at that.

12		CHAIRMAN BRASS:  Yeah, okay.  I¦m sorry,
13	I interrupted you.
14		DR. DAVIDSON:  That was my point.  You
15	know, and it¦s important data for us to know.
16		DR. FRIEDMAN:  Yeah, It think that the
17	overall impression is that the group was split about

18	half and half moderate and lower-risk and the mean LDL
19	was 165 for the lower-risk, 145 for the moderate-risk
20	and 65 percent of people achieved an LDL of less than
21	130 in this environment.  And again that was not with
22	a physician doing anything to get that lower-risk
23	group down to 130.
24		DR. DAVIDSON:  Going back to my question. 
25	We need to learn why we¦re not successful in

			209
	1	maintaining or getting special populations to these
	2	clinical trials for the treatment.  You know, you

	3	mentioned that one of the reasons was because they
	4	didn¦t want to buy the drug?  Is that the main reason? 
	5	Do you have, did you do any analysis of why you could
	6	retain it, or was it that, you know, your material was
	7	not friendly or designed to those special populations?
	8	            DR. FRIEDMAN:  Again, we recruited into
	9	the study robust samples, as you saw, of minority
10	populations.  We did see that there was less interest
11	about, in some minority populations about ten percent
12	less interest in purchasing the product.
13	            DR. DAVIDSON:  Do you know why there was
14	less interest?
15	            DR. FRIEDMAN:  No we don¦t.  And we know
16	that we placed sites in communities.  We had people

17	from the communities in the sites, but I don¦t have
18	any further information.  I agree with you that that¦s
19	an extremely important issue in all healthcare related
20	aspects and certainly something we would want to work
21	with groups to--  I mean the whole goal of this is to
22	improve access.  And that¦s what we¦d like to do.
23	            DR. DAVIDSON:  Did you field test your

24	material for sensitivity for this population before
25	you embark on the trial?

				210
	1		DR. FRIEDMAN:  No we did not.
	2		DR. DAVIDSON:  Thank you.
	3		CHAIRMAN BRASS:  Dr. Grady.
	4		DR. GRADY:  One of the things we¦re being

	5	asked to do is to try and estimate whether the benefit
	6	outweighs the risk, so to get an idea that benefit,
	7	the absolute risk is important, but also the relative
	8	risk.  So maybe you could help me think about the
	9	relative risk.  In the trials that have already been
10	done using 40 of Pravachol, the lipid LDL reduction
11	was about 30 percent, is that correct?
12		DR. COHEN:  Yes.
13		DR. GRADY:  And the relative risk on the
14	average was about, the relative risk reduction was
15	about 25 percent.  So in the 10 mg. dose, we¦re seeing
16	about, let¦s say an 18 percent reduction in risk of,
17	I mean in LDL cholesterol.  But that¦s also occurring
18	in people whose cholesterols to begin with are at a
19	lower level in whom the relative risk reduction might
20	be smaller.  So when I try to think about the relative
21	risk reduction might be in the population we¦re aiming
22	at, I¦m coming out with a relatively small number
23	like, I don¦t know, ten percent.  Do you think that¦s
24	fair?
25		DR. COHEN:  Mr. Chairman, may I?  I thank

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	1	you for that question.  This is the clinical trial we
	2	did at lunchtime.  And so if you¦ll bear with me I¦m
	3	going to show a slide I haven¦t seen.
	4	            (Laughter)
	5	            DR. COHEN:  These data are from the
	6	Framingham data set, but it¦s looking at the
	7	population group at risk, and that¦s what we wanted to
	8	find.  So we¦re looking at, in this case, men and
	9	women at, the men in two age groups, 40 and 35, the
10	ages of interest, because we know that this is the

11	lower-risk end in terms of absolute risk.  And then
12	we¦re looking at women age 50.  And at the top we¦re
13	looking at those whose LDL is 130, total cholesterol
14	of 240, and the second panel, at the lower panel,
15	we¦re looking at LDL cholesterol of 140, total
16	cholesterol 240.  Same stratification with regard to,
17	thank you, male/female and age.  And you can see what
18	impact the increase in cholesterol has in risk just
19	straight away, 11 versus 13, 10 versus 12, and seven
20	versus nine.  And you can see what the absolute risk
21	here is with respect to the observations from these
22	Framingham data.
23	            DR. GRADY:  What relative risk are you
24	using to get that absolute risk reduction?
25	            DR. COHEN:  This is based, it says it

			212
	1	right here.  Absolute risk reduction for 18 percent
	2	reduction in LDL and total cholesterol.  And that, I
	3	think, is fair because what we¦re talking about is an
	4	OTC user population who uses the drug, who uses it
	5	with compliance, who takes it in accordance with
	6	directions, who is following, whatever percentage that
	7	is.  Maybe it¦s half of those who initially try it,
	8	maybe it¦s somewhat more or less.  But less us say
	9	whatever that number is, put a figure on it.  Then

10	that group will reduce their cholesterol and average
11	LDL by 18 percent and based on the Framingham data we
12	would come back to the risk estimate reduction.  Can¦t
13	show you clinical trial data that would be in order of
14	this magnitude, 2.7, 2.0 and 0.9 percent.  This is ten
15	year risk of a cardiovascular event and I can tell you
16	the endpoints if you wish.  It¦s a composite endpoints
17	of coronary deaths, myocardial infarction, angina, and
18	hospitalization for unstable angina, coronary
19	insufficiency.  So that kind of puts it into a risk
20	respective to allow the committee, I think, to make a
21	judgment about this cost benefit ratio, recognizing
22	what the potential benefits are when you look at it
23	across the population base and considering it relative
24	to the risk in this population.
25	            DR. ELASHOFF:  Excuse me.  I don¦t get any

				213
	1	sense of how you could have gotten risk reduction data
	2	out of the Framingham data.
	3		DR. COHEN:  Ma¦am, this is projected or
	4	estimated risk reduction.
	5		DR. ELASHOFF:  How is it estimated?  How
	6	is it projected?  From what?
	7		DR. COHEN:  It¦s projected at, looking at
	8	rates relative to those whose LDL is at that 18
	9	percent lower level.  This is an epidemiologic
10	approach in the absence of clinical trials.  Now we do
11	have clinical trial data all the way down to
12	AFCAPS/TexCAPS range, and in that range we saw exactly
13	what we predicted from the epidemiologic model.  As
14	you heard yesterday there was a 37 percent reduction
15	in events.
16		CHAIRMAN BRASS:  Let a statistician talk
17	to a statistician.
18		DR. KOCH:  Okay, first, I don¦t know
19	exactly what they did to get these numbers.
20		(Laughter)
21		DR. KOCH:  My understanding of how they
22	might get the numbers is that they access the
23	Framingham database and they used a regression
24	equation for which the inputs would be gender, age,
25	LDL and total cholesterol.  And then they then, in the

			214
	1	control group without Pravachol 10, they used what
	2	that would be projected at directly, and then they
	3	basically hypothetically considered how the patients
	4	who would have an 18 percent reduction of LDL and
	5	total cholesterol would do while still keeping age and
	6	gender fixed but then correspondingly reducing the two
	7	cholesterol measures.  And they excluded diabetics and
	8	heart disease, et cetera.  But they were using
	9	prediction equations from Framingham with and without
10	the anticipated reduction in cholesterol that was

11	demonstrated in the studies.  So it¦s basically a
12	simulation or a projection using the Framingham
13	database and prediction equations that came from
14	Framingham, or at least that¦s my understanding of
15	what was done.
16	            DR. BROWN:  That¦s a successful tactic
17	that they use.  That¦s a successful tactic that has

18	been used to predict the outcome of clinical trials. 
19	So it¦s not an illegitimate effort that they¦ve done
20	here.
21	            DR. ELASHOFF:  I didn¦t say that.  I said
22	that I just didn¦t understand what they had done.
23	            DR. BROWN:  I just noticed your eyebrows
24	going up high.
25	            DR. ELASHOFF:  I mean, in essence,

			215
	1	although it¦s a little more complicated model, you¦ve
	2	taken some standard curve and slipped down the 18
	3	percent on it, but you¦ve put other things into the
	4	model and whether or not there are interactions in
	5	there that we should be worried about or not, or other
	6	factors, I don¦t know.  But in essence you¦ve taken
	7	one of those curves and slipped down that amount. 
	8	Okay.
	9	            CHAIRMAN BRASS:  The only other thing I
10	would add is it¦s important to recognize those are ten
11	year risk rates.
12	            DR. GRADY:  One other question.  It is
13	important that they are ten year risks, but the other
14	question is, are these cardiovascular events, does
15	this include chest pain or is this, what are the
16	events?  Is it angina?
17	            DR. CARO:  Hi, Jaime Caro from Boston. 

18	The running of Framingham risk equations for these
19	kinds of models is now a fairly standard way of
20	calculating the risk reductions, and yes, there are
21	other things in there.  Blood pressure is in there,
22	diabetics status, gender, age and so on.  Interactions
23	are in there.  Is there published equations from the
24	Framingham heart study?  Your question was?
25	            DR. GRADY:  What are the cardiovascular

				216
	1	outcomes?
	2		DR. CARO:  What are the events.  Yes,
	3	there¦s several risk equations that have been
	4	published.  The one that was used for this is the more
	5	comprehensive one that includes stroke, TIA, MI,
	6	coronary insufficiency, death and angina.
	7		DR. GRADY:  Thank you.  It¦s also
	8	interesting if you look at what the relative risk is
	9	there, it¦s about a 25 percent risk reduction in the
10	50 year old females, about 20 percent in the 40 year

11	old males, and only about 12 percent in the younger
12	men.
13		CHAIRMAN BRASS:  Dr. Johnson.
14		DR. JOHNSON:  Are we to conclude from this
15	that you¦re changing your ages from 35 to 45, to 40
16	and 50?
17		(Laughter)
18		DR. FRIEDMAN:  I think that¦s a compelling
19	argument.
20		(Laughter)
21		CHAIRMAN BRASS:  Dr. Krenzelok.
22		DR. KRENZELOK:  Along the lines of age,
23	and certainly a much more mundane observation than
24	what we¦ve been discussing for the last half hour or
25	so, I had an opportunity to really take a look at the

			217
	1	PravaCare program newsletters which I think are very
	2	informative and so on, but depending upon what age is

	3	ultimately the bottom age, it probably would be really
	4	good to have consistency between the indications and
	5	the newsletter, for example.  I was reading one and it
	6	just struck me that, sort of suggestive that young
	7	people should begin to take this.  On the front page
	8	of one of them it said, if you¦re over the age of 20
	9	chances are you need to begin to manage your
10	cholesterol level now.  So maybe it would be a good
11	idea to introduce some consistency and raise that to
12	35 or 40, or somehow incorporate some other issues
13	into it.
14	            DR. FRIEDMAN:  I agree with you.  I think,
15	I¦m sorry, I don¦t remember the exact language in all
16	the newsletters, but certainly the intent of the
17	newsletters is to have people manage cardiovascular
18	risks.  And actually the first step is lifestyle
19	modification.  So I think we need to make it clearer
20	that you should start, or anyone in their family,
21	should start modifying the risk at a young age.  But
22	certainly the time for intervention with drugs would
23	be different.  Very good point.
24	            CHAIRMAN BRASS:  Are there any other
25	general questions before we go on to the FDA

			218
	1	questions?
	2	            DR. UDEN:  Just one general question about
	3	that which you¦ve just talked about.  In your, when
	4	you did the prelude to the PREDICT and the other
	5	study, you said that all of these people-- the comment
	6	was made many times-- had followed diet and exercise
	7	prior to entry.  What data do we have that they
	8	actually followed diet and had exercised and to what
	9	diet and what exercise?
10	            DR. FRIEDMAN:  Yes.  To assess diet, we
11	were very interested in assessing diet very carefully,
12	but yet, as would be done in a clinical setting, to
13	not superimpose a true clinical trial environment.  So
14	we chose the MEDFICTS tool, which is a validated tool,
15	used and proposed by the NCEP¦it¦s in the NCEP ATP II
16	treatment guidelines-- when what it does is it¦s a

17	questionnaire that clinicians should use in their
18	office to categorize people into an AHA STEP I and

19	STEP II, or no AHA diet.  We administered this diet to
20	people, everyone who came in, and at any time they
21	would have a physician contact, and also at the end of
22	six months.  The people, the participants were not
23	aware of their score, so they didn¦t, we didn¦t want

24	to have a training effect of how they would answer it. 
25	And that is how we assessed their dietary adherence

			219
	1	throughout the course of the study.  According to the
	2	MEDFICTS tool, 80 percent of people in this population
	3	were following an AHA STEP I or STEP II diet.  The
	4	majority of them maintained that diet.  It was about

	5	ten percent improved, is what I showed you.  In terms
	6	of exercise and smoking, we also looked at that in the
	7	studies.  But again, we thought diet would be the most
	8	important thing to look at in a validated way.  So we
	9	looked qualitatively at exercise and smoking.  We
10	didn¦t have very detailed exercise questionnaire.  And
11	we, in response to that questionnaire, again, about
12	half the people said that they were exercising as
13	defined as three times a week or more, and again that
14	statement was maintained constant, but that was very
15	soft data.  We did ask about smoking and the smoking,
16	we saw that there were ten percent of people who came
17	into the trial were smokers, which is about half the
18	national rate.  And at the end of the trial it was the
19	same.
20	            CHAIRMAN BRASS:  Dr. Blewitt.  Dr.
21	Jenkins.
22	            DR. JENKINS:  I would just like to go back
23	to the slide you showed of your controlled clinical

24	trial you did during lunch.  There was something Dr.
25	Grady pointed out that I was wondering if you could

				220
	1	clarify for me that I don¦t quite understand either,
	2	and we¦re interpreting a lot of numbers on to
	3	equations quickly.  And that¦s why the relative risk

	4	reduction was 25 percent, 20 percent, and 12 percent
	5	in the three different groups.  Just how does the math
	6	work out that way?
	7		DR. CARO:  It has to do with the
	8	interactions and the equations.  Age interacts very
	9	heavily with gender, with the presence of
10	hypertension, and so on.  And because it interacts, a
11	risk does not change linearly with age, and therefore,
12	nor with cholesterol values.  And so as you run the
13	equations, you have two curves which are not parallel
14	to each other.
15		CHAIRMAN BRASS:  I think that point¦s very
16	important because I think it got confused in some of
17	the earlier implications in that the relative risk
18	reduction is not, to my understanding, constant across
19	the population and at the lower the risk, the lower
20	the relative risk reduction as well as the absolute
21	reduction.  I think it¦s very important.
22		DR. CARO:  Not necessarily.  It depends on
23	what¦s leading to the risk.
24		CHAIRMAN BRASS:  I agree.  I apologize. 
25	I genuinely.

				221
	1		(Laughter)
	2		CHAIRMAN BRASS:  Dr. Neill.
	3		DR. NEILL:  Two questions.  Did you
	4	measure in either of your two consumer-use studies,

	5	especially the OPTIONS where you had access to the
	6	patient chart, the extent to which patients monitored,
	7	evaluated their response to treatment outside the
	8	physician¦s office?  I asked this yesterday, so I felt
	9	compelled to ask it today.  In other words, using a
10	drugstore or another of these prevalent means to
11	measure cholesterol outside of a physician¦s office.
12		DR. FRIEDMAN:  We didn¦t monitor that
13	systematically.  In PREDICT, the only information we
14	had was people who brought in laboratories from their
15	personal physician¦s offices, but we did not monitor
16	the use of outside services.
17		DR. NEILL:  Last question.  Did you
18	monitor in any of the trials the extent to which
19	patients may have taken more than the recommended
20	dose?  And if so, how did you monitor it and what were
21	the results?
22		DR. FRIEDMAN:  No we didn¦t.  People were
23	asked, the only way that we looked at it was to see

24	how many cartons people purchased, which give us an
25	estimate.  There was a comment made earlier from the

			222
	1	FDA reviewer about compliance.  Just as we don¦t in
	2	our regular clinical practices ask people to bring in

	3	their medicines and count their pills, we didn¦t ask
	4	them to do that here.  So a pill count of compliance
	5	seemed to be very unreliable and in fact, when we
	6	looked at compliance and tried to correlate it with
	7	LDL reduction, there was absolutely no correlation. 
	8	So people didn¦t bring in all their unused pills.  So
	9	what we did look at, though, to try to see if people
10	were buying a lot more than they should, is the
11	expected number of cartons that should be purchased. 
12	And there we found that people were buying, for the
13	most part, the expected number of cartons.
14	            DR. NEILL:  What¦s for the least part?
15	            DR. FRIEDMAN:  Well, that¦s a little hard
16	to say and I don¦t have the data completely broken up
17	because, again, there were the people who stopped

18	taking therapy, so you would expect that they would
19	have bought one or two cartons.  We do need, I don¦t
20	have that data to correlate exactly, but I think what
21	I can say is that people were not buying or taking two
22	or three cartons when they should have been taking
23	one.
24	            CHAIRMAN BRASS:  Dr. Katz, would you like
25	to reintroduce the charge?

			223
	1	            DR. GRADY:  Could I ask just one more
	2	question?  And I don¦t, I mean, of the pharmacologist,
	3	I think, in the room.  You know, if the rate of
	4	adverse effects, and the worst one is potentially
	5	rhabdomyolysis, if there were to be interactions, if
	6	there were to be a higher rate of outcomes in an OTC
	7	population, how much might that be?  Are we thinking,
	8	you know, twofold, tenfold, a hundredfold?  Does
	9	anybody have any estimates of, you know, what that
10	might be?
11	            DR. FRIEDMAN:  I¦d like to ask Dr. White
12	who has looked at our cases of rhabdomyolysis very
13	carefully to answer that.
14	            DR. WHITE:  Michael White, University of
15	Connecticut, School of Pharmacy, Hartford Hospital. 
16	I think when you look at drug interactions as a
17	specific subsa as we¦ve already seen, we¦re looking at
18	increases in plasma levels with a 10 mg. dose of
19	twofold, 1.5 to twofold, which would give you the same
20	risk as you had if you were going from a 10 mg. dose
21	up to a 20 mg. dose, which there¦s substantial
22	information to show overall safety.  Now overall if we
23	take the 57 people who had cases of rhabdomyolysis

24	that met the FDA¦s criteria of greater than 10,000,
25	and that conservatively if you take the 17 people in

			224
	1	the study who also had unknown levels, but the doctor
	2	had said that they had rhabdomyolysis, we put them all
	3	in together and what you saw for an overall risk was
	4	0.3 for 100,000 patient years or about, an over
	5	threefold less than what we had heard yesterday.  And
	6	at some point you have to think that you¦re
	7	approaching what the underlying background information
	8	is, especially when you look at confounders.  And we
	9	did go and I looked through personally each one of the
10	individually reported cases, looking at potential
11	confounders, and there were a number of them.  Twenty-

12	four patients that had critical confounders, and I¦m
13	looking at E-4-1.  But anyway, there were a number of
14	cases that had critical confounders that led you to
15	believe that those cases couldn¦t have really have
16	been due to pravastatin based on the time course

17	average of over two years that they were ended up
18	being on pravastatin.  And then the very consistent
19	time course that they had of other factors that they

20	know are much more commonly related to rhabdomyolysis. 
21	And then there were other ones that had important
22	confounders, leaving about one-third of those overall
23	cases without any known confounders.  So I think that
24	when you put all those things in together based on the
25	very low incidents and the fact that idiopathic

			225
	1	poliomycitis that people know can cause rhabdomyolysis
	2	happens from five to a hundred cases per 100,000

	3	patients and that it¦s known that that can cause
	4	rhabdomyolysis.  How close are we getting to the
	5	underlying background information?  And then also

	6	looking at the pharmacologic effects, knowing that
	7	active uptake in the liver, passive uptake into other
	8	cells and that you¦d need very, very high
	9	concentrations to be able to penetrate those cells and
10	potentially have those effects.  Thank you.
11	            CHAIRMAN BRASS:  Dr. Katz.
12	            DR. KATZ:  Good afternoon.  I¦m Linda
13	Katz, Deputy Director from the Division of Over-the-
14	Counter Drug Products.  For those of you who were here
15	yesterday, I will not go through the charge in the
16	same way that I did yesterday, because we spent a good
17	deal of time at this meeting in discussion going over
18	the critical issues.  What I would like to do is to
19	focus you on the next slide to the areas for
20	deliberation, and just to identify a few key issues
21	and points again that we¦d like for you to take into
22	consideration as you answer the questions that are
23	covered under efficacy and safety, OTC considerations,
24	and approvability.  We¦ve heard a lot about who is the
25	target population.  And in going ahead and looking at

			226
	1	the efficacy and safety, it¦s important to see if the
	2	data that we have in this application does support the
	3	efficacy and safety for the targeted population for

	4	the indication, which is a new one.  And I make this
	5	point again, that this is a new indication and this is
	6	not a switch.  We are looking at individuals with
	7	milder elevations of cholesterol levels that what we
	8	currently have approved for Rx.  And therefore, when
	9	we go ahead and we¦ve looked to answer the questions
10	of benefit risk, we need to make sure that we have the
11	data to support the treatment in that particular
12	population.  In addition, when we go through OTC
13	considerations, we need to make sure we understand how
14	consumers will utilize these products.  We need to
15	again make sure that the consumers can understand how
16	to use them and to understand how to monitor their
17	laboratory data, both in terms of efficacy as well as
18	monitoring for any adverse effects.  We also need to
19	look into taking in to consideration what exactly is
20	the goal for the consumer, and has that goal been
21	clearly identified for the consumer?  The paradigm
22	that¦s been identified today is different from that
23	from yesterday, because as we see it set in today¦s
24	studies, that there¦s been more of a physician
25	involvement.  But that¦s something also we need to

			227
	1	take in to consideration, just how the physician
	2	should be involved for the consumer in the OTC market

	3	place.  The additional point that I¦d like to make is
	4	we are talking about a consumer and not a patient.  If
	5	someone goes into a drugstore to buy a product, that
	6	they are out there, and one hopes that they will
	7	follow the labels and can comply with things as
	8	instructed.  But again, individuals are perfectly free
	9	to buy a product and they don¦t necessarily have to go
10	and follow through.  And when you, again, in your
11	deliberations, when we finally get to the last
12	question will be approvability.  And approvability,
13	again, will be based on the benefit risk that has been
14	demonstrated for this particular population.  With
15	that I¦d like to turn over the meeting to Dr. Brass so
16	that you can begin the final portion and the
17	deliberations of the questions.  Thank you.
18	            CHAIRMAN BRASS:  Thank you.  The questions
19	that have been distributed look eerily familiar to
20	those of you who were here yesterday and I¦ll remind,
21	just a couple of general points said to hopefully
22	maintain focus.  The first several questions are not
23	OTC-specific questions, but are in fact general

24	questions.  But that in answering all of these
25	questions, the answers should be rooted in the data

				228
	1	that has been presented in the context of the NDA
	2	today and not an extrapolation to what you think might

	3	be true or might become available.  We will save that
	4	to the end where the final question gives us an
	5	opportunity to add additional information as to what
	6	would swayed you in either direction.  I¦m going to
	7	break question one up the same way I did yesterday and
	8	read it paraphrased as somebody interpreted it
	9	yesterday, to be based on the data submitted in the
10	NDA, has the sponsor adequately demonstrated a
11	clinical benefit defined as lowering of LDL with
12	lovastatin 10 mg. in the target population, but we¦ll
13	change it pravastatin.
14		(Laughter)
15		CHAIRMAN BRASS:  Didn¦t think I caught it,
16	did you?
17		(Laughter)
18		CHAIRMAN BRASS:  So that question is now
19	open for discussion.  Seeing no discussion, oh, I¦m
20	sorry.
21		DR. ELASHOFF:  The question being did they
22	demonstrate that LDL was lowered?
23		CHAIRMAN BRASS:  That¦s correct.
24		DR. GRADY:  Well, actually the way the

25	question¦s stated in the page here, it says the

				229
	1	expectation of a cardiovascular benefit.
	2		CHAIRMAN BRASS:  That¦s why I didn¦t read

	3	that question. That¦s not, we¦re going to do it like
	4	we did yesterday and split it up and first do the LDL
	5	part.  Okay, is that clear?  No, it¦s not, Dr. Grady? 
	6	Based on the data submitted in the NDA, has the
	7	sponsor adequately demonstrated a clinical benefit
	8	defined as lowering of LDL with pravastatin 10 mg. in
	9	the target population?  Okay.  All who agree with that
10	statement, please raise your hand and indicate yes.
11		(Hand vote taken)
12		DR. TITUS:  Thirteen yesses.
13		CHAIRMAN BRASS:  Opposed?  Abstained?
14		DR. UDEN:  Yes.
15		(Laughter)
16		CHAIRMAN BRASS:  Fourteen yes, no noes, no
17	abstentions.  The second part of the first question: 
18	Based on the data submitted in the NDA, has the
19	sponsor adequately demonstrated a clinical benefit
20	defined as outcome-based cardiovascular benefit with
21	pravastatin 10 mg. in the target population?  So now
22	has the benefit been demonstrated with respect to
23	cardiovascular risk?  And that is open to discussion. 
24	Since I want there to be discussion on this point, I
25	will ask Dr. Grady to express her opinion.

			230
	1	            DR. GRADY:  Well, obviously, I think all
	2	of us would be much more comfortable if there were a

	3	trial with real clinical outcomes because what we¦re
	4	doing here is using a surrogate outcome which is

	5	changing LDL cholesterol as a predictor of real
	6	clinical benefit.  And I¦m always leery of surrogate
	7	outcomes.  On the other hand, this is one of the best
	8	surrogate outcomes that we have studied over the past
	9	ten years.  I would say that if we believe that this
10	magnitude of change in LDL is a predictor of real
11	clinical benefits in this low-risk population,
12	whatever their HDL cholesterols happen to be, then we
13	can probably expect that the magnitude of that benefit
14	is something on the order of one in a 100 to one in
15	250 or something like that over a five year period,
16	which again brings up the importance of people
17	sticking with this therapy over a five year period. 
18	Because I don¦t think any clinical benefit can be

19	expected over six months to a year.  You don¦t ever
20	see that even in trials.  So there are a lot of steps
21	I think and that¦s my worry, is there are a lot of
22	steps we have to make assumptions that everything is
23	going to go well.  If everything went well, I think
24	there is the expectation of clinical benefit.

25	            CHAIRMAN BRASS:  And the agency can

			231
	1	correct my reinterpretation but the question
	2	specifically says demonstrated, as I have now phrased
	3	it, as opposed to an expectation of.  And I think
	4	there¦ll be the opportunity to discuss the expectation

	5	when we talk about risk-to-benefit and other potential
	6	interpretations of the LDL, so that I would put a
	7	relatively personally high threshold on that syntax,
	8	demonstrated a clinical benefit.  Including, though,
	9	if you were confident that the surrogate extrapolated
10	to this population, then I think you could consider it
11	having been demonstrated.  Is that fair or am I?
12	            DR. KATZ:  You¦re correct.  What we¦re
13	looking for is demonstrated.
14	            CHAIRMAN BRASS:  Dr. Molitch?
15	            DR. MOLITCH:  It certainly is not directly
16	demonstrated.  It can be extrapolated from other data
17	as probably a very small thing.  I think this
18	discussion about HDL was not a totally meaningless
19	discussion.  I think that when we looked at the
20	absolute risk reductions, in fact, they probably did
21	get smaller with higher HDLs, so that the
22	AFCAPS/TexCAPS data really doesn¦t quite reflect the
23	population that might be using this.  And again, I
24	will editorialize as I did yesterday that if we were
25	actually looking at a cost benefit ratio as opposed to

				232
	1	a risk benefit ratio, then I would love to see some of
	2	those costs expended in patients with higher lipid
	3	levels that weren¦t ever receiving these drugs.
	4		CHAIRMAN BRASS:  Dr. Davidson.
	5		DR. DAVIDSON:  Well, there¦s no evidence
	6	based on what they presented.  And number two, you
	7	know, the intended population that I saw was not
	8	really what I feel is the intended population for
	9	over-the-counter.  Therefore, you know, the answer is
10	to that question, you know, as far as I¦m concerned
11	is, the intended population was not there and we don¦t
12	have evidence-based medicine because they didn¦t
13	measure the outcomes.
14		CHAIRMAN BRASS:  Dr. Elashoff.
15		DR. ELASHOFF:  Yeah, I wanted to emphasize
16	that it¦s not just that it has to be estimated from

17	other data, but that it does have to be extrapolated
18	from other data.  That is, that you¦re going on many
19	cases out beyond the range of the other data, and
20	extrapolation validity is heavily dependent on exact
21	details of the model you¦re fitting.  And whether that
22	fits well everywhere in details as where as sort of
23	reasonably well in the middle.
24		CHAIRMAN BRASS:  Dr. Johnson.
25		DR. JOHNSON:  I have a question for Dr.

			233
	1	Davidson.  And that is, I guess, what you think the
	2	intended population is.  I guess my impression is the

	3	intended population is a well-motivated population and
	4	my suspicion is your concern is the under-served
	5	population wasn¦t well-represented in the study, and
	6	I think the problem there is really one of a lack of
	7	knowledge in that population to make them motivated
	8	and so, I guess I would contend that they probably did
	9	hit the population that¦s likely to use this product. 
10	That may not be from a public health perspective, the
11	optimal, not include all of the population we want,
12	but it probably is the population that will actually
13	use the product.
14	            CHAIRMAN BRASS:  I will just remind that
15	in the context of this question, it¦s not necessarily
16	the OTC population.  It¦s the general.  And the target
17	population referred to is specifically the target

18	population as defined by the sponsor, so it¦s that
19	intended population defined based on the criteria set
20	up by sponsor for age, LDL, total cholesterol, et
21	cetera.
22	            DR. DAVIDSON:  Well, the problem is that,
23	you know, they can define, but it is an over-the-
24	counter product.  You know, and therefore, they made
25	the wrong definition.

			234
	1	            DR. TAMBORLANE:  I also would be
	2	interested in your being a little more specific,
	3	Jaime.  What target population did they miss?
	4	            DR. DAVIDSON:  Well, you know, many of
	5	those patients, you know, were actually seeing
	6	physicians, 85 percent of those were seeing physicians
	7	but were not treated.  Then if I would go to that
	8	population then what I will do is, you know, very
	9	well, you know, I was told that, you know, at the time
10	the study was done, we didn¦t know what to do with

11	cholesterols, you know, at certain point.  Then if
12	that¦s where we¦re going to change, then you know, the
13	target is not the patient.  The target is us, the
14	physicians.
15	            DR. TAMBORLANE:  Okay.  Because it¦s not
16	under-served populations that some of the stuff we
17	heard about the first day, those kind of.
18	            DR. DAVIDSON:  Well, they¦re different

19	things, you know.  I really want to also be sure that
20	we serve everybody, you know.  In the United States,
21	we have more than 80 million or 90 million minorities
22	or ethnic differences, you know, and they¦re at high-
23	risk with this problems.  You know, then if we¦re

24	going to go for an over-the-counter medication, you
25	know, those people also need to be reached.  You know,

				235
	1	and we need to consider because over-the-counter will
	2	be misused or improperly used or maybe not used for

	3	what I feel is the intended population.  Intended is
	4	everybody in the United States that is at risk.
	5		CHAIRMAN BRASS:  I don¦t want to continue
	6	this part of the conversation because it¦s
	7	specifically directed to the OTC issues.  And I want
	8	to save that to the OTC, so if it¦s general about
	9	cardiovascular benefit, Dr. Silverstein.
10		DR. SILVERSTEIN:  I guess I¦m trying to
11	get back to that question, too, because we¦ve
12	digressed a little bit.  And the question is whether
13	or not efficacy in reducing cardiovascular risk with
14	an OTC preparation has been demonstrated?
15		CHAIRMAN BRASS:  No, no.  It does not say
16	OTC.
17		DR. SILVERSTEIN:  Just the 10 mg.

18		CHAIRMAN BRASS:  That is correct.
19		DR. SILVERSTEIN:  Okay.  Okay, I see.
20		CHAIRMAN BRASS:  Any other comments before
21	we vote?  I will read the question again.  Based on
22	the data submitted in the NDA, has the sponsor
23	adequately demonstrated clinical benefit defined as

24	improved cardiovascular, a decrease in cardiovascular
25	events with pravastatin 10 mg. in the target

				236
	1	population?  All who feel the answer to that question
	2	is yes, please raise your hand.  A question about the
	3	question.
	4		DR. JOHNSON:  What does ¦is¦ mean?
	5		(Laughter)
	6		DR. JOHNSON:  Okay.  You said that
	7	demonstrated means demonstrated or it could mean--,
	8	I¦m a little confused.
	9		CHAIRMAN BRASS:  Well, it means
10	demonstrated.  I was simply illustrating that things
11	could be demonstrated in other ways other than a
12	placebo-controlled clinical trial.  And if, in fact,
13	you feel it has been demonstrated in any way, that the
14	answer to this question is yes.  And because I think
15	arguments have been made that in an attempt to
16	demonstrate to you, that the answer to this question

17	is yes in the absence of this trial.  So if you feel
18	that it in fact has been demonstrated to you, then you
19	should vote yes.  If it has not been demonstrated to
20	you, you should vote no.  Okay.  All who feel the
21	answer to that question is yes, please raise your
22	hand.
23		(Hand vote taken)
24		DR. TITUS:  One yes.
25		CHAIRMAN BRASS:  All those who feel the

				237
	1	answer to that question is no, please raise your hand.
	2		(Hand vote taken)
	3		DR. TITUS:  Thirteen noes.
	4		CHAIRMAN BRASS:  All abstentions, please
	5	raise your hand.  And once more we add up to the right
	6	number.  Okay, the second issue again focused on a
	7	general context of the 10 mg. dose is, has the sponsor
	8	presented adequate data to support the safety of
	9	pravastatin 10 mg. in the target population?  And
10	again this question is not yet OTC-specific.  This is
11	just a general safety question.  Are there any
12	comments or discussion?  All who feel that the answer
13	to that question is yes, please raise your hand.
14		(Hand vote taken)
15		DR. TITUS:  Thirteen yes.
16		CHAIRMAN BRASS:  All who feel the answer
17	to that question is no, please raise your hand.
18		(Hand vote taken)
19		DR. TITUS:  Zero no.
20		CHAIRMAN BRASS:  All who are abstaining,
21	please raise your hand.
22		(Hand vote taken)
23		DR. TITUS:  One abstention.
24		CHAIRMAN BRASS:  Question three.  Taking

25	into consideration the balance of risk and benefit,

			238
	1	has the sponsor presented data that are adequate to
	2	support the use of pravastatin 10 mg. in the low-risk

	3	population with total cholesterol 200-240, LDL greater
	4	than 130, regardless of HDL level without CHD or
	5	diabetes?  Yesterday we elected not to discuss this
	6	question, feeling that our answers to one and two
	7	implied an answer and felt the time would be better
	8	spent focusing on those issues specifically in the OTC
	9	context.  Is there any difficulty in that plan for
10	today?
11	            DR. KATZ:  That¦s fine.  When you get down
12	to the last question, obviously, we¦ll have to modify
13	since it refers back to this question.
14	            CHAIRMAN BRASS:  That¦s correct.  Now we
15	focus on the issues related to the efficacy and safety
16	in the OTC context.  Assuming an indication for the
17	use of pravastatin 10 mg. in the proposed target
18	population could be justified based on an expectation
19	of clinical benefit, has the sponsor adequately
20	demonstrated that consumers can achieve such a
21	clinical benefit in an OTC setting?  In responding to
22	this question, please consider the following:  the
23	ability of consumers to self-select, the ability of
24	consumers to evaluate response to treatment, the
25	ability of consumers to adhere to chronic therapy, the

			239
	1	need for the physician or other healthcare
	2	professional in the effective treatment, the capacity
	3	of the proposed label to direct consumers in the

	4	effective use of pravastatin.  And I think I will
	5	begin the discussion of this point by talking about
	6	two issues in specific.  One relative to point C - the
	7	ability of consumers to adhere to chronic therapy with
	8	pravastatin.  There¦s been much discussion about this
	9	and I think all of us are disappointed by the long-

10	term compliance.  However, I¦d like to suggest that
11	that may be a legitimate disappointment, but not a
12	primary consideration in this decision-making.  That

13	in fact a subset of appropriate consumers were able to
14	comply for an extended period of time with a favorable
15	benefit and the risk to the overall exposed population
16	was low enough, we would consider that to be not a bad
17	thing.  And there is precedent for that.  When this
18	committee, or a variation on this committee, discussed
19	the use of nicotine products for smoking cessation, it
20	was in the face of data that said most patients would
21	not complete the therapy with nicotine-containing
22	products for smoking cessation but those that did
23	would derive benefit, and those that didn¦t would not
24	be exposed to unacceptable risk.  So I think that the
25	issue of compliance needs to be done in the context of

			240
	1	the population risk and the patients who do comply,
	2	their benefit.  And so I think that the context in
	3	which we talk about that needs to be focused in that

	4	way.  The second point I would make is the same one I
	5	have made for an extended period of time, including
	6	the previously referred to discussions in the
	7	historical past.  And that is I remain concerned about
	8	the ability of an OTC population to exercise
	9	appropriate decision-making to derive benefit in the
10	absence of a learned intermediary, whether it¦s a
11	physician or otherwise.  The sponsor indicated in
12	their design of these two actual-use trials that with
13	the presence of a learned intermediary one could
14	achieve benefits in the OTC setting that were
15	comparable to that in the prescription setting, but it
16	was artificial in the sense that all these patients to
17	a very high degree, in fact, were utilizing a learned
18	intermediary to achieve that end.  And it related to
19	Dr. Davidson¦s point.  In a general use population,
20	will there be high percentages of patients who attempt
21	to self-medicate in the absence of the learned
22	intermediary with some risk and certainly not optimal
23	benefit?  I personally remain concerned about the
24	impact of OTC availability in the absence of a learned
25	intermediary on degrading patient-physician

			241
	1	interactions for those individuals who do as
	2	illustrated by the dropout rates even in this kind of

	3	setting with populations who are being studied in this
	4	kind of controlled setting.  And finally, the other
	5	point I would derive from the data presented by
	6	sponsor in terms of, and again I have to compliment
	7	the sponsor for doing the study well enough to provide
	8	us this degree of insight, is that the learned
	9	intermediary had to make lots of interventions in
10	order to treat the populations who were randomized to
11	the learned intermediary.  Some of these might be very
12	low-risk issues ¦ a patient with a cholesterol greater
13	than 250 continuing to take the drug ¦ but I think all
14	represent illustration of limitations to the degree
15	that you¦ve defined a target population for this drug
16	and to the degree adherence to that target population
17	is viewed as important.  Two assumptions that I think
18	are worthy of challenge, but to a degree those are
19	assumptions, I think the data indicates that
20	indiscriminate availability will resolve in
21	substantial use outside of the target population.  And
22	I open to other committee members.  Dr. Blewitt.
23	            DR. BLEWITT:  I¦m not sure that I actually
24	saw that in the study.  It seemed to me that they cast
25	a very wide blanket.  They went to numerous sources

			242
	1	and in the process they determined what the population
	2	was that¦s going to take the drug.  So when you go out
	3	to thousands of people, then you find out who in fact
	4	is going to take it.
	5	            CHAIRMAN BRASS:  No, I¦m basing my
	6	comments on those people who were randomized to OTC,
	7	read the label, started taking the drug, and then
	8	subsequently were found not to fit the target
	9	population when profiled.  So I¦m not using the
10	largest denominator.  I¦m looking at the denominator
11	who self-selected to use.  And we saw similar data
12	yesterday as well.
13	            DR. BLEWITT:  I understand.  And I just am
14	not sure that in you trying to convert actual-use
15	studies to real life, and that¦s certainly legitimate. 
16	But I can¦t see that, how that differs, if you will,

17	from OTC--, other than chronic use, from OTC drugs in
18	general.  You are going to have a certain population
19	who are going to take non-steroidals for arthritis. 
20	Or, you know, they¦ll be self-treating osteoarthritis
21	and things like that.  So it¦s going to happen.  And
22	the question is how bad is that going to be if people
23	do that?  And my take on it is that it¦s not going to
24	run you into some terrible problems.  If someone

25	decides not to see their physician but to do it on

			243
	1	their own, if they¦re doing it right, and if they¦re
	2	following up their cholesterol levels on a regular
	3	basis, and checking periodically with their physician,

	4	I don¦t see anything personally wrong with that.  In
	5	fact, I would see that as a potential advantage. 
	6	            CHAIRMAN BRASS:  Yeah, all I would
	7	emphasize is two points.  One is, I think the long-
	8	term use is a nontrivial difference between the
	9	example you cited.  And the context of this question
10	is, again, not an approvability risk-to-benefit ratio,
11	but the question is whether or not it has been
12	demonstrated that the target population utilizes this
13	drug for the purposes indicated in the OTC setting.
14	            DR. BLEWITT:  I understand that and I
15	agree.  But I also have to ask what level of proof do
16	you require?  Is this a leap of faith or does it just
17	take a little step in logic to take you from one point

18	to the next?  And I don¦t see it as a particular leap. 
19	I think there have been enough presentations today
20	from experts to suggest that there is a real
21	population overall to be served.  And I¦ll go back to
22	what I heard Dr. Cohen say earlier because I had said
23	this to myself, it¦s not the people who aren¦t going

24	to take it, whether 20 or 30 percent of the people who
25	are eligible take it, it¦s the 20--, it is the 20 or

				244
	1	30 percent who actually do take it.  It¦s not who
	2	decided not to do it.  It¦s not the people who aren¦t

	3	compliant.  It¦s those that are that would tend to be
	4	served by this, by this OTC availability of this drug.
	5		CHAIRMAN BRASS:  That¦s the point I was
	6	trying to make.  I agree with that.  Dr. Clark.
	7		DR. CLARK:  I think that it¦s pretty clear
	8	that this proposal would move healthcare into a new
	9	arena and I think that what has been demonstrated here
10	is that in order for it to be effective, you do need
11	a learned intermediary.  But I think that should not
12	come as a surprise because it¦s new to both the
13	patients, consumers and providers.  And I think it may
14	have been Dr. Brown who mentioned he¦s given 10,000
15	lectures in 15 years to physicians where it¦s not a
16	new arena.  So I think the expectation that there
17	would need to be ongoing educational programs and
18	other types of supports to make this effective because
19	it is something different should not be taken as a
20	negative but an expectation of moving in this
21	direction.
22		CHAIRMAN BRASS:  Dr. Uden.
23		DR. UDEN:  Which means that we are relying
24	upon the sponsor and good faith on the sponsor that

25	they will continue to move forward and educate the

			245
	1	population that we¦re trying to target, and educate
	2	physicians about this.  And, you know, once the
	3	product is OTC, no matter what they say here, we do
	4	not have any assurances because they don¦t have to do
	5	it to have those educational programs.  That being
	6	said, I do believe that with the educational programs
	7	that they have, or at least have tried to have
	8	presented here, I think they¦ve done a pretty good
	9	job.  In fact, a very good job in presenting data that
10	would led me to believe that, you know, if this was

11	OTC, that some consumers would be able to greatly
12	benefit from it.
13	            CHAIRMAN BRASS:  Dr. Blewitt.
14	            DR. BLEWITT:  As regards compliance, my
15	other musings on this, my musing on this is that if I
16	were a drug company and I were now marketing this drug
17	for long-term use, it would be in the company¦s best
18	interest to want people to comply with this regimen. 
19	The more people that take it long-term, the better off
20	you are, so that is your target.  I sometimes get the
21	perception that, well, they¦re talking about this
22	educational program today, but then what happens when
23	it¦s approved?  You know, is it going to just fall by
24	the wayside?  And I know that these things don¦t just
25	happen and that there¦s every, there is certainly a

			246
	1	push to continue those educational programs.  And that
	2	without them, I think that there is a population that
	3	won¦t be well served.
	4	            CHAIRMAN BRASS:  Dr. Johnson.
	5	            DR. JOHNSON:  I guess my take on it is
	6	that there may be some what would be defined as
	7	inappropriate or not the target population using this
	8	drug.  But when I, based on both the data presented
	9	yesterday and today, it appears that the true high-

10	risk people are not selecting this therapy.  People
11	with ischemic disease, people with diabetes.  So those
12	in whom we would be very concerned about them using
13	this therapy, those people aren¦t selecting and I
14	think that¦s a good thing.  So who does that leave? 
15	That leaves people in the primary prevention category
16	really in three groups:  less than 200, 200 to 240,
17	and over 240.  If the people less than 200 are taking
18	drug, they¦re probably wasting their money, although
19	we don¦t know that.  It may be that a total
20	cholesterol of 150 as the MRFIT data suggests is the
21	optimal LDL, or the optimal total cholesterol.  So
22	they¦re probably not going to derive much benefit, but
23	I also think these are such safe drugs that they¦re
24	probably not at much risk.  The 200 to 240¦s our
25	target, so they¦re okay.  And I guess the way I view

			247
	1	the people over 240 is that certainly it would be
	2	better if they were on 20 or 40 mg. of pravastatin,
	3	but they¦re on nothing.  And if they go from nothing

	4	to 10 mg. of pravastatin, they¦re still gaining more
	5	benefit than from nothing.  So I guess I don¦t see
	6	even in the inappropriate use categories that those
	7	are really bad things in the big picture.
	8	            CHAIRMAN BRASS:  I¦m just going to comment
	9	because I think that the risk population as you

10	characterized it for the OTC use is variable.  I
11	happen to agree that if a patient with a total

12	cholesterol of 260 took this drug ¦inappropriately¦ as
13	opposed to taking nothing, a good would be done, not
14	a horror.  But I am more concerned about the risk
15	populations in two ways.  One, I come back to the 27
16	percent of patients who were on a prescription drug,
17	self-selected themselves to take this OTC product. 

18	And neither the PREDICT or OPTIONS study was very
19	enriched in patients with coronary artery disease or
20	diabetes to allow the de-selection to be assessed
21	adequately, so I come back to this relatively small
22	cohort, but 27 percent of them did in fact select. 
23	And I come back to that if ten percent of patients on
24	optimal therapy with a physician discontinue therapy
25	to switch to the less optimal OTC drug in an

			248
	1	unsupervised situation, that too represents an at-risk
	2	population in terms of the decision-making.  Dr.
	3	Tamborlane.
	4	            DR. TAMBORLANE:  Yes, to follow up, I
	5	mean, a subtle change in the sort of interpretation of
	6	the next, these two questions then the OTC setting
	7	becomes more of a safety issue rather than an efficacy
	8	issue.  Is that, because from your earlier statement,
	9	that is, if you had poor compliance and, you know,

10	somebody took it, then that¦s okay.  You know, that
11	might be okay for clinical efficacy, but a major
12	concern of safety is not the toxicity of the agent but
13	the fact in the OTC setting that a substantial number
14	of patients would not get optimal therapy, namely
15	proper titration by a learned intermediary.
16	            CHAIRMAN BRASS:  I think that¦s right. 
17	The reason I mention in the context of this question
18	which is a benefits question is because this question
19	is structured in a way to include consumer self-
20	selection for the target population.  And as I¦ve
21	indicated previously, the assumption that the target
22	population is the right one or the wrong one is
23	something that can be discussed separately.  But we¦re
24	being asked to assess the ability of consumers to
25	self-select based on that target population

			249
	1	definition.  And what I¦m suggesting is in a variety
	2	of ways, some of which would generate little concern,

	3	some of which to generate more concern, the ability of
	4	consumers to self-select, in my opinion, has not been
	5	demonstrated.  And to a degree that¦s part of the
	6	benefit assessment is why I answered it that way.  Dr.
	7	Gelato.
	8	            DR. GELATO:  Just to sort of get up a
	9	question of are these people who are on prescription
10	drugs going to go off of them.  And I guess I would

11	view those people as being high-risk people, because
12	if they¦ve been put on a medication, they¦re high-
13	risk.  And what that says to me is if they¦re on one
14	drug, they¦re probably on multiple and maybe this
15	isn¦t a fair thing.  But it seems like they would be
16	going back to their physician and I would assume that
17	you would ask them what are you taking?  You know, so
18	there would be some fail-safe there, because I think
19	that¦s a population that¦s going to be directing, you
20	know interacting pretty heavily with their primary
21	care provider, I would imagine, because they probably
22	have more than one problem, because we¦re thinking
23	about diabetics and people who have heart disease and
24	so on.  So I, I don¦t know, maybe I just don¦t feel
25	it¦s the same concern because I think that they¦re

			250
	1	going to be monitored in a different way, but maybe
	2	that¦s not right, so.
	3	            CHAIRMAN BRASS:  Dr. Davidson.
	4	            DR. DAVIDSON:  I want to say, you know, my
	5	concern is we need people to take the medication but
	6	we need these people to take the medication correctly
	7	and we need to reach those people who have the high-
	8	risk, you know, to be treated and treated to target. 
	9	You know, and I think we¦re all saying the same is how
10	to get that?  Is over-the-counter the way to do it,
11	you know?  And that¦s my concern, you know.  I agree. 

12	We need to treat them.  You know, we already answered
13	question one.  The drug is a good drug.  It lowers
14	lipids.  You know, but how do we get to the real
15	people that need it, you know?  And that¦s part of the
16	problem, you know.    
17	            CHAIRMAN BRASS:  Dr. Silverstein.
18	            DR. SILVERSTEIN:  Question about the

19	ability of consumers to evaluate the response to
20	treatment and to monitor cholesterol levels. 
21	Somewhere in these books when I was reviewing it, I
22	noted that the amount of people who had LDL
23	cholesterol follow-up was lower in the OTC group than
24	in the treatment group, which says that they¦re not

25	getting adequate follow-up of their lipid levels.  And

			251
	1	I¦m concerned about that.  I¦m concerned about people
	2	who can buy a drug over-the-counter really adequately
	3	following up.  I really don¦t think that¦s been
	4	demonstrated in this study.  You know, the fact that
	5	they had to go to a doctor to get a refill, basically,
	6	after two months.
	7	            CHAIRMAN BRASS:  I will allow sponsor to
	8	comment on the data but I would just extrapolate more
	9	to your last point, that I think the follow-up rates

10	in the study design employed by sponsor are likely to
11	be much higher than would be in an unlimited access
12	kind of setting.  So that again, the demonstration of
13	the consumer¦s ability to follow-up and interpret has
14	not, in my opinion, been demonstrated even though the
15	follow-up, I think, was actually pretty good.
16	            DR. FRIEDMAN:  Yes.  Just to clarify a

17	couple of points.  First, the follow-up was actually
18	a little better in the OTC versus prescription, 85

19	versus 83 percent.  And I would like to make the point
20	that the OTC participants were unaware that they could
21	not repurchase if they didn¦t have the follow-up. 
22	That was never in the consent and they did not know
23	that they would not be allowed to repurchase if they
24	didn¦t see the doctor.  They only found out about that
25	when they went to that retail site and tried to

			252
	1	repurchase.  And we know that of the 720 people that
	2	did purchase, only 10 of them were denied the
	3	repurchase because they didn¦t see the doctor.
	4	            CHAIRMAN BRASS:  Dr. Grady.
	5	            DR. GRADY:  Yeah, I think that I take a
	6	different view on this.  I mean, I think there is some
	7	danger that people with high-risk won¦t get
	8	appropriate care and follow-up.  On the other hand, we
	9	don¦t do appropriate care and follow-up of people at

10	high-risk right now.  We don¦t control their lipids. 
11	We do a horrible job at it.  And what we¦re really

12	doing is restricting these drugs from those people. 
13	They can¦t get them unless they go to physicians.  The
14	other, I think, problem is that if you start thinking
15	about people at lower-risk, what we¦ve also done for
16	hypercholesterolemia, which is really not a disease. 
17	It may be a risk factor, it may be a mechanism, but

18	it¦s not a disease.  We¦ve medicalized it, and we¦ve
19	labeled it.  And those are some of the real downsides
20	to treating healthy people with preventive
21	interventions that have, you know, a low potential
22	benefit.  So I think if you can avoid that by using
23	over-the-counter medications, the balance here
24	actually may be favorable.
25	            CHAIRMAN BRASS:  Do you believe there are

			253
	1	data in the submitted NDA to draw conclusions on
	2	issues you raised?
	3	            DR. GRADY:  I think that the data showed

	4	that the treatment and follow-up, I particularly like
	5	this proposal because they really do emphasize that
	6	patients, that people who have high cholesterol need
	7	to go see their physicians.  And they did in equal
	8	numbers, I think they showed that.  And in fact the
	9	physicians who were treating the patients who were in
10	the medical care group here were instructed to tell
11	them to treat themselves at levels of cholesterol that
12	most physicians in practice may overlook.  So I think,
13	you know, it¦s an artificial setting here, but both
14	for the OTC as well as for the treatment group, and I
15	think they did a pretty good job in demonstrating that
16	the outcomes, in terms of seeing their physicians,
17	changing their lipids and so forth, were pretty good. 
18	And given that this is a difficult study to do, kind
19	of study to do.
20	            CHAIRMAN BRASS:  I understand and again,
21	but to the degree to which the 85 percent of the OTC
22	group seeing their physician is integral to your
23	assessment of the success of the OTC program, you
24	could leave the pills out of the box and have them buy
25	the box with a note in it to say go see your doctor

				254
	1	and tell them to start you on monitoring treatment.
	2		DR. GRADY:  That¦s what they¦re proposing
	3	to do.
	4		DR. UDEN:  If Dr. Neill has a question
	5	related to that, I will hold my question.  Mine is a
	6	proof.
	7		DR. NEILL:  Not a question, but a
	8	statement.  I think that they have demonstrated the
	9	ability to self-monitor, to evaluate their response,

10	and also to adhere to chronic therapy and that their
11	demonstration is that the ability of consumers to do
12	this is poor, and that that is comparable to what
13	happens in the prescription environment.  And I don¦t
14	think that we¦re discussing whether or not it¦s been
15	demonstrated, but rather, can¦t it be done better? 
16	And I think I know the answer to that.  No, and not
17	even doctors in the office do it better.
18		CHAIRMAN BRASS:  Dr. Uden.
19		DR. UDEN:  Just a clarification.  Again,
20	what population are we talking about here?  Each,
21	total cholesterol of 200 to 240, LDL cholesterol of
22	greater than 130, and what age?  Greater than 50 for
23	women and 40 for men?  What¦s our population here
24	again?
25		DR. NEILL:  In the NDA, the target--, and

				255
	1	I¦m not aware that the NDA can, that we¦re being asked
	2	to consider a different age than is in the NDA.  I
	3	understand that the labeling may change and that the
	4	sponsor may want to resubmit for a different age
	5	range, but I¦ve already answered two questions related
	6	to the target population.  Men greater than 35 years
	7	and women greater than 45 years.
	8		DR. JENKINS:  That¦s the sponsor¦s
	9	proposed target populations.  I think that¦s what you
10	should base your answers on.  If you think there¦s a
11	different target population that you would answer
12	differently, you will have the opportunity at the end
13	to suggest things that could be done differently that
14	you might feel more comfortable with.
15		CHAIRMAN BRASS:  Other comments before we
16	vote on this question?  Okay.  So the question is, has

17	sponsor adequately demonstrated consumers can achieve
18	such a clinical benefit in an OTC setting, including
19	consideration of the following subpoints?  All who
20	feel the answer to that question is yes, please raise
21	your hand.
22		(Hand vote taken)
23		DR. TITUS:  Eight yesses.
24		CHAIRMAN BRASS:  All who feel the answer
25	to that question is no, please raise your hand.

			256
	1	            (Hand vote taken)
	2	            DR. TITUS:  Six noes.
	3	            CHAIRMAN BRASS:  Any abstentions?  Next
	4	is, are issues related to safety in the OTC setting. 

	5	Assuming that pravastatin 10 mg. is deemed adequately
	6	safe when used for the proposed indications target
	7	population, has the sponsor presented adequate
	8	evidence that consumers will be able to use
	9	pravastatin 10 mg. safely in an OTC setting?  Consider
10	the following points:  ability of consumer to identify
11	adverse reactions, ability of consumers to monitor
12	hepatic safety, need for and ability of the consumer
13	to identify and avoid interacting drugs, likelihood of
14	the use of pravastatin at higher than recommended
15	doses, the ability of women who are pregnant or likely
16	to become pregnant to avoid use, the need of the
17	physician or the healthcare professional in the safe
18	treatment, the capacity of the proposed label to
19	direct consumers in the safe use.  I would just open
20	the discussion in addition to my relevant comments
21	earlier to say that I do not believe that the liver
22	toxicity issue is one of concern in this population,
23	and I do not think that the issue of interacting drugs
24	is nearly the issue it was for another drug we

25	considered because the issue of, the route of

				257
	1	elimination for this compound, making inadvertent
	2	interactions less likely.  I do remain concerned about
	3	potential pharmacodynamic interactions that may
	4	contribute to the rhabdomyolysis, but admittedly, that
	5	would be a relatively rare instance.  Other comments
	6	or points for discussion?  Dr. Johnson.
	7		DR. JOHNSON:  I think in general there¦s
	8	a lot of safety here and I think there are a couple of
	9	things in the package insert which I¦ve already

10	brought, or in the Drug Facts label which could be
11	done to increase the safety of the use of this
12	product, assuming that sort of at-risk patients use
13	the product, but in general I agree that hepatoxicity
14	is not a problem, drug interactions are not a problem,
15	and rhabdo is probably in reality a very, very small
16	problem.
17		CHAIRMAN BRASS:  Dr. Davidson.
18		DR. DAVIDSON:  I think as far as safety¦s
19	concerned is a very safe drug and actually the sponsor
20	addressed the issues in the label that are required.
21		CHAIRMAN BRASS:  Other comments?  Yes, Dr.
22	Molitch.
23		DR. MOLITCH:  I think one of the concerns
24	that I have is not specifically these aspects, but for
25	the patient who has some great notion that they have

			258
	1	hypercholesterolemia, and will take one tablet a day
	2	of this, and will think that everything is hunky-dory
	3	about that, and in fact their cholesterol is 280,
	4	their LDL is 190, and they then don¦t seek adequate

	5	care for that.  So to me, this has a safety aspect to
	6	it, too.  It¦s not quite the same as what¦s listed
	7	here.
	8	            CHAIRMAN BRASS:  No, I agree, and it is
	9	included there.  The likelihood of use of pravastatin
10	at, I¦m sorry, no it says at higher.  Yeah.  But I
11	agree with the point you¦ve made and it is one that I
12	remain concerned about and as I¦ve indicated, because
13	of the high use of the learned intermediary, I do not
14	think we have the database with this NDA to make that
15	assessment.  Dr. Neill.
16	            DR. NEILL:  All the caveats about the

17	patient education materials and their alterability
18	after marketing aside, this proposed label does
19	include a slightly different set of ¦see your doctor
20	if¦, which includes some big groups that haven¦t been,
21	smokers, for example.  And so I am also more
22	comfortable that the risk of under-treatment in a
23	higher-risk population may be lower.
24	            CHAIRMAN BRASS:  Dr. Tamborlane.
25	            DR. TAMBORLANE:  I want to get back to

			259
	1	this, I think I tried to make this point before, that
	2	if you¦re concerned about that people aren¦t going to

	3	get proper treatment because they¦re not getting, you
	4	know, they have higher levels and stuff.  We really

	5	were talking about that under four, not four, but,
	6	under four rather than this question.  This question
	7	is really restricted to risk of the toxicity of the
	8	drug.  So I just wondered whether everybody considered
	9	that when they voted the last vote.  That the failure
10	to get proper treatment at the higher values, et

11	cetera, was really what we just voted on before.
12	            CHAIRMAN BRASS:  Dr. Molitch.
13	            DR. MOLITCH:  I actually just have one
14	question, perhaps for the FDA, or somebody, I¦m not
15	sure whom.  Do we have data on other drugs that are
16	over-the-counter for what percentage of people who
17	take those drugs actually read the warning labels or

18	the labels that are inserted in these packages?  Is it
19	like somebody who reads the manual before trying to
20	work a computer?  Is it like one percent, or ten
21	percent or 90 percent?  Do we have any understanding
22	of that information?
23	            CHAIRMAN BRASS:  This question has come up
24	a lot before and the general answer is no.  In my 

25	opinion, we do not know that.  And similarly for the

			260
	1	package insert.  Dr. Blewitt.
	2	            DR. BLEWITT:  No, that¦s actually not
	3	true.  There¦s been a lot of work done on that.  CHPA
	4	has given a number of presentations on studies that

	5	they have done with regard to patients¦ ability to
	6	read the label and have shown excellent results.  I
	7	don¦t have the numbers or anything like that, but I¦m
	8	sure if you ever wanted that review-- oh, on cue.
	9	            CHAIRMAN BRASS:  Could we have the back
10	mic on please?  Why don¦t you just come to the table
11	and grab a mic?
12	            DR. SOLLER:  My name¦s Dr. Bill Soller. 
13	I¦m Senior Vice President of Consumer Healthcare
14	Products Association.  There have been a number of
15	studies that have been done over the years that have
16	asked consumers, nationally representative studies,
17	that have asked consumers whether they read the label
18	the first time before using the product.  And
19	uniformly, the percentages are above 95 percent.  One
20	study 99 percent, the Heller Study.  And I only would
21	add to that and what Dr. Blewitt was saying, and that
22	was that there have been many label comprehension
23	studies that have been done on the switches since the
24	Nonprescription Drug Advisory Committee started
25	meeting in ¦92, and there were issues relating to

			261
	1	whether individuals read warnings before using these
	2	products.  And uniformly, that was a very high
	3	priority issue for the committee.  And the label
	4	comprehension studies that were done, plus the actual-

	5	use studies, were sufficient for the committee to vote
	6	in the affirmative for the switch of those products. 
	7	So I think putting that, the practical experience
	8	together along with the Heller Studies and other
	9	things that have been done by this association and
10	other associations around the world that show a very
11	high percentage of individuals read the label before
12	using the product the first time, gives a lot of
13	confidence in these kinds of decisions.
14	            CHAIRMAN BRASS:  Yes.
15	            DR. ELASHOFF:  Apropos of that and the
16	possibility that a number of young women will take it,
17	although you might read it the first time, this is
18	supposed to be taken chronically, you¦re not likely to
19	read it over again the second and the third time, and
20	by the time the person gets pregnant, they may well
21	have forgotten about that sort of thing.  It¦s an
22	ingrained part of their life and may not look at it. 
23	So I¦m concerned about the fact that there really

24	isn¦t any that I would call real information about
25	safety in pregnancy.

			262
	1	            DR. DELAP:  I¦d like to, the reason we¦re
	2	having a little, it¦s hard to answer that question
	3	about the label use and practice in a general sense. 
	4	I think Dr. Soller gave the best possible general
	5	answer to the question.  We tend to focus much more on
	6	the issue at hand in a deliberation like this.  How
	7	well does the current label communicate, and then the
	8	actual-use studies tend to tell us how well it
	9	communicates over time.  And the best studies are the
10	ones that Dr. Brass suggested in the conversation
11	yesterday.  And perhaps we¦ve seen some of that today. 
12	The really wide open kind of study where you just let
13	people use the product and you see who bought it, see
14	how they used it, and you see what happened.  That¦s
15	the best kind of experience.  It¦s not easy to do.
16	            DR. GANLEY:  I just want to add something. 
17	I¦m not sure at the public meeting we had two weeks

18	ago, I can¦t remember if it was National Consumers
19	League that presented data, and it was actually a
20	little less in a survey that they did of what people
21	actually do in terms of reading the labeling.  I think
22	it was greater than 90 percent, and it was even, I
23	think, less for a package insert.  But I think more
24	importantly it¦s not just reading it, but following
25	the directions.  And there is some data on the vaginal

				263
	1	antifungals where it asks people not to use it until
	2	they¦ve at least been diagnosed with this condition

	3	previously by a physician.  Yet I think approximately
	4	40 percent of people who used them had never had it,
	5	or had not sought a physician¦s diagnosis before.  So
	6	it¦s not just reading the label, but understanding it
	7	and following through with it.
	8		CHAIRMAN BRASS:  Other questions or

	9	comments about the safety in the OTC setting?  If not,
10	we¦ll proceed to a vote on that question.  So again
11	the question is, has the sponsor presented adequate
12	evidence that consumers will be able to use
13	pravastatin 10 mg. safely in an OTC setting?  All who
14	feel the answer to that question is yes, please raise
15	your hand.
16		(Hand vote taken)
17		DR. TITUS:  Eleven yesses.
18		CHAIRMAN BRASS:  All who feel the answer
19	to that question is no, please raise your hand.
20		(Hand vote taken)
21		DR. TITUS:  Three noes.
22		CHAIRMAN BRASS:  Any abstentions?  We¦ll
23	move on to the next question, which is approvability. 
24	Assuming that the sponsor has provided sufficient
25	information to support the safety and effectiveness of

				264
	1	pravastatin 10 mg. for the proposed indication and the
	2	target population, has the sponsor--  Start all over

	3	again.  The question now is, has the sponsor provided
	4	sufficient evidence that pravastatin 10 mg. can be
	5	used safely and effectively in an OTC setting?  Open
	6	for discussion.  Dr. Neill.
	7		DR. NEILL:  Should I note the exclusion of
	8	the phrase ¦in the target population¦?
	9		DR. KATZ:  In the target population¦
10	should stay there.
11		CHAIRMAN BRASS:  It¦s implicit, again, in
12	terms of the--, that¦s correct.  It¦s implicit in the
13	OTC setting phrase.  Comments or questions?
14		DR. SILVERSTEIN:  The one thing that
15	hasn¦t been done is the label has been changed so much
16	that we don¦t really know the comprehension of the new
17	label.  I think that would need to be tested before,
18	you know, it could be put on the market.
19		CHAIRMAN BRASS:  Yes.
20		DR. GELATO:  Also, I guess I would like
21	clarification on what we mean by ¦effective now¦.  Do
22	we mean just the lowering of the cholesterol or do we
23	mean that it has an associated benefit in terms of

24	cardiovascular, or are we just looking at it, can
25	lower¦

				265
	1		CHAIRMAN BRASS:  Well, this turns out to
	2	be the, this question we¦re about to vote on turns out
	3	to be the $64,000 question.  And so, that¦s actually
	4	degrading it, I guess, in the current game show.
	5		(Laughter)
	6		CHAIRMAN BRASS:  But, and so, as we did
	7	yesterday, the issue of effectiveness is as you define
	8	it for clinical approvability.  So is there
	9	effectiveness when used in an OTC setting that in your
10	mind using whatever effectiveness, so LDL and, as a

11	surrogate, or anything else you want to use to assess
12	that clinical effectiveness in making the overall
13	risk-to-benefit.  Because this is in fact the risk-to-
14	benefit equation.  So it now is implicitly that you¦re
15	defining what that magnitude about benefit is, what
16	the magnitude of that risk is, and is it favorable in
17	the OTC setting and justify approval?
18		DR. JOHNSON:  I have sort of a procedural
19	question.  If we vote yes on this, is that saying to
20	the FDA, yes, everything is perfect in this package,
21	and it¦s ready to go out the door.  Or can there be
22	yes with qualifications, or how¦s this go?
23		CHAIRMAN BRASS:  Well, I¦ll let you
24	correct me.  But yes means approvability of the NDA as
25	submitted with suggestions for post-approval studies. 

				266
	1	If you feel that there are additional studies that are
	2	not in the NDA that are required to document the
	3	approvability, then the vote should be no, is that
	4	correct?
	5		DR. KATZ:  That¦s correct.
	6		DR. DELAP:  If I could just add on these
	7	questions.  I mean, the votes are important but the
	8	discussion around the votes is at least as important,
	9	so you know, if you do decide to vote yes, but you
10	think that something should be done before it¦s
11	approved you can say that.  Or if you want to vote no
12	and say, but I would vote yes if you had this
13	additional piece of information, you can do that, too. 
14	So we¦re going to look at what people say as well as
15	how they vote.
16		DR. JOHNSON:  Well, in that case, I¦ll say
17	what I wanted to say.

18		(Laughter)
19		DR. JOHNSON:  I mean, as it¦s written, age
20	35 and age 45, I guess my vote is no because I feel
21	that that is too low a risk population to target.  If
22	the age was 40 and 50, that sort of changes my comfort
23	level.  If it¦s 45 and 55, it might change it even
24	more.  I also feel that it¦s not ready just to
25	absolutely sign off on.  I think there does need to be

			267
	1	a lot of work done on the label.  There needs to be
	2	label comprehension studies.  There may be could be a

	3	little bit more done to understand actual-use and sort
	4	of targeting on the people who do do this Rx-to-OTC
	5	switch and what behavior causes that and can that be
	6	prevented through education and those kind of things. 
	7	So I, those are my concerns with the absolute package
	8	as it sits, you know, that we¦re looking at.
	9	            DR. GELATO:  I would just like to say that
10	I absolutely agree with that.  I think given what we
11	have in front of us it would be very difficult for me
12	to just go ahead and say, oh yeah, go ahead with it. 
13	But I think with the caveats that Dr. Johnson has
14	mentioned, because I think that this product comes
15	really close to what you¦d like to see, and I think
16	with just a little bit more.  At least that¦s my
17	feeling.  That you could, you know, put this right
18	over the top.  And I¦d also like to say that I think
19	that before, agreeing with Dr. Neill, that if somebody
20	has a cholesterol of 280 and they decide to take this,
21	I actually think that¦s a good thing.  So, you know,
22	if they¦re high-risk that¦s something else.  But I
23	think that, again, those patients or people may be at
24	some point more likely to interact with a physician

25	because of the fact that they are high-risk.

				268
	1		DR. DELAP:  If I could just imply once
	2	more.  I think, again, I think the construct that Dr.
	3	Brass had is a good one.  I mean, the first part of
	4	the question is based on what you have in front of you

	5	today and then, what else do you need to persuade you? 
	6	I think that¦s a good construct and we are interested
	7	in getting votes, so.
	8		CHAIRMAN BRASS:  Dr. Blewitt.
	9		DR. BLEWITT:  Yeah, it does, of course,
10	permit you to approve this based upon additional work. 
11	So, you know, label comprehension study, the fact that
12	you don¦t have one and you need one isn¦t a deal
13	breaker.  Now you can still say yes, but you know, you
14	should do a few more things.  In other words, just
15	because some more work is needed doesn¦t mean that
16	it¦s a no vote.
17		CHAIRMAN BRASS:  Dr. Grady.
18		DR. GRADY:  Well, it¦s kind of an odd

19	situation, isn¦t it?  I mean, we all voted that
20	there¦s inadequate demonstration of benefit, but I
21	think that in my mind the reason I voted that way was
22	because I think that the, as the NDA¦s framed, the
23	likely benefit is very small in the population
24	targeted.  On the other hand, the risk is very, very
25	small.  On the other hand, I think those two things

			269
	1	come much closer together the lower the targeted
	2	population gets.  So I very much agree with Dr.

	3	Johnson.  I think it¦s a targeted population at
	4	somewhat higher risk.  And they¦re were lots of issues
	5	about the label.  The label was changed too much for
	6	my comfort.  I think there need to be better labeling
	7	studies.  I think that it¦d be nice to repeat a
	8	prevent-style study after, it this is improved.  And
	9	then the final I worry about that we haven¦t brought
10	up today that I tried to bring up yesterday is that I

11	think there need to be efforts to convey risks better. 
12	I think it would be inappropriate, you know, for all,
13	you know, 45 year old men with cholesterols of 239 to
14	rush out and start taking a drug.  But that¦s because
15	people don¦t understand risk and they don¦t understand
16	risk reduction, so I¦d really like the company to take
17	some responsibility for conveying risk and risk
18	reduction in more understandable ways.
19	            CHAIRMAN BRASS:  Dr. Davidson.
20	            DR. DAVIDSON:  Well, it would be nice if
21	a cholesterol of 240 would hurt a little and a 260
22	would hurt more so the patients will take the pills
23	more often.  You know, but it doesn¦t happen.  Then

24	the deal is, you know, my question from yesterday it
25	remains the same.  If we do that and patients will

			270
	1	take a 10 mg. pravastatin, are we going to give them
	2	a sense of security that does not exist, and
	3	therefore, they¦re not going to go for medical care. 

	4	And on the other hand, if we do, you know, maybe those
	5	patients will benefit because they will never go to
	6	medical care.  And for the sponsor, one of the things
	7	that it important is how to reach the populations that
	8	are high-risk.  And you did not prove, at least to me
	9	today, that in your trial you reached those

10	populations that really need to be reached.
11	            CHAIRMAN BRASS:  I just want to follow-up
12	on that.  Because as somebody who has voted no to
13	questions four and five, and as somebody who has been
14	here through, since the very first NDA for a lipid-
15	lowering agent, I just want to make a couple of
16	observations.  First of all, I think we are much

17	further along than we were in 1995.  I think that
18	today we¦re talking about an agent that everybody

19	agrees has efficacy in lowering LDL and that that LDL
20	lowering is a potential benefit.  Additionally I think
21	that we¦re dealing with an agent that there is
22	increasing confidence can be used safely in the OTC
23	environment because of the characteristics of the

24	drug.  And those are two very different things.  My
25	residual concerns are in the absence of data on a

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	1	couple of critical points, some of which you have
	2	eluded to, that I remain concerned that we do not have
	3	adequate data to assess the impact of exposing a

	4	general population, regardless of how the target
	5	population ends up getting refined and redefined, and
	6	I agree there¦s lots of opportunities to improve the
	7	risk-to-benefit ratio by doing so.  But given the lack
	8	of demonstration of patients to self-select into that
	9	target population, that the impact on a truly general
10	population without queues and queues to follow-up, et
11	cetera, other than what¦s on the package, has simply
12	not been demonstrated.
13	            And I remain concerned about the
14	hypothetical non-optimal therapy associated with that
15	and I believe that it is possible to demonstrate that
16	in the general population, the use would be associated
17	with predicted benefit.  I just don¦t think we have

18	seen that data and I think there¦s the opportunity to
19	get that data.  The other point that I would make in
20	terms of the generalized ability of this in terms of
21	the OTC setting is the definition of the benefit and
22	this is what Dr. Grady was eluding to, and I think
23	even some of the constructs we saw in a preliminary
24	fashion this afternoon if defined in a way that would

25	allow an assessment by the agency to critically review

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	1	that and make an endorsement as to whether or not that
	2	is a logical risk benefit assessment in the target
	3	population would go a long way to reassuring us that

	4	that potential benefit will in fact be measurable and
	5	in a way that whatever population ends up getting
	6	exposed to it is justified to whatever risk that will
	7	represent.  Dr. Johnson?
	8	            DR. JOHNSON:  The sponsor might want to
	9	clarify this.  We¦ve, there¦s a lot of focus on the
10	high-risk people who maybe go from Rx-to-OTC, but if
11	a recall correctly, they also had data on people who
12	in a sense got in to the system and remembering 20-
13	something percent, but I don¦t know it¦s 20-something
14	percent of what, so I¦m wondering if that you can give
15	us a little clarification, because there may be a
16	tradeoff.  We may have some percent that actually get
17	into the system and get higher level of care than is
18	available OTC and at the same time we lose some Rx
19	into the OTC and maybe that balance becomes equal.
20	            CHAIRMAN BRASS:  I don¦t disagree with
21	that except that we don¦t have the data.  For example,
22	this population which did include, I acknowledge, a
23	sizable cohort that ended up on therapy one way or

24	another represents a highly motivated population, 85
25	percent of whom have physicians, and there¦s no

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	1	natural history study of that population to see how
	2	many would have ended up on some form of therapy
	3	without the queues provided by the study.  So I¦m not
	4	disagreeing with, I¦m not saying my hypothesis is

	5	right.  All I¦m saying is we do not have the data
	6	presented to us that allows us to make that
	7	assessment.
	8	            DR. FRIEDMAN:  I think when you look at
	9	these people that come in, you know, somewhere between
10	15 and 30 percent of them are at their NCEP goal.  We
11	did have a cohort of 321 people and when they saw the
12	study physician, that felt more appropriate to be on
13	prescription therapy because of being at higher risk,
14	either because of their levels or their risk factor
15	profiles.
16	            When we contacted those people, the 321

17	people at the end of the six months, we found that 46
18	percent of them had gone to see their personal
19	physician, and none of these people of course were on
20	therapy to begin with.  At the end of the day, 29
21	percent of them had gone on to prescription therapy. 
22	So we actually did bring people into the medical
23	system and on to appropriate care.  We didn¦t look at
24	the number of people that got dietary counseling and
25	all that other, the other aspects to it.

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	1	            CHAIRMAN BRASS:  Because we¦re about to
	2	lose people to airplanes, I¦m going to, unless there¦s
	3	an objection, ask for a vote on this question with an
	4	opportunity to continue the discussion on relative
	5	points and suggestions afterwards.  Are you objecting? 
	6	Because he¦s going to leave right now.
	7	            DR. KRENZELOK:  I see that, but I¦m
	8	objecting, even though I know he has to get to a plane
	9	at 3:30.  It seems like the previous conversation
10	we¦ve had really illustrates that we shouldn¦t make

11	this a yes or a no vote.  That the vote should be an
12	oral vote, you can say yes with reservation, with
13	these types of enhancements or improvements, because
14	it seems like it would be inappropriate to vote yes or
15	no on the issues based on our conversation.
16	            CHAIRMAN BRASS:  Well, again, I will let
17	the FDA tell me what they would like to hear, but I
18	disagree.  I think we have been presented with an FDA-
19	-, an NDA and asked for an opinion about that, and as
20	Dr. Delap pointed out, the discussion actually matters
21	more than the vote.  They will do whatever they want
22	anyway.  And that taking into account our discussion,
23	I think, will be much better integrated than taking
24	into account oral vote.
25	            DR. KATZ:  That¦s correct.  Actually we

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	1	would like to get an actual vote, and for those people
	2	who have to leave right after the vote is taken, if
	3	you can give your opinion before you walk out the door
	4	it would be appreciated if you want to have an
	5	additional comment, and then our discussion could
	6	continue.
	7		DR. DELAP:  And we are interested in a
	8	vote based on the information you have on the table
	9	before you and not on other information that you might
10	get.
11		CHAIRMAN BRASS:  Okay, you¦re at risk of
12	losing votes, but go ahead, it¦s your choice.
13		DR. GILLIAM:  I want to make a quick
14	comment is, you can still vote yes even if you have
15	reservations about other studies that need to be done. 
16	I mean it says here if yes, are there any other
17	studies that are needed?
18		CHAIRMAN BRASS:  Post-marketing.  Post-
19	approval studies.  Post-approval studies, not¦
20		DR. KATZ:  Again, what I would like to
21	request is that be, if there are any additional
22	comments from sponsor, to do it after the vote because
23	I would really like to get everybody¦s opinion before

24	would have to leave for their, to catch their planes. 
25	Thank you.

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	1		CHAIRMAN BRASS:  Okay.  I won¦t reread the
	2	question.  All who are in favor of the proposition,
	3	please raise your hand and vote yes.
	4		(Hand vote taken)
	5		DR. TITUS:  Two yesses.
	6		CHAIRMAN BRASS:  All opposed, please raise
	7	your hand and vote no.
	8		(Hand vote taken)
	9		DR. TITUS:  Twelve noes.
10		CHAIRMAN BRASS:  Any abstentions?  Dr.

11	Gilliam, would you like to make any comments before
12	you run to catch your plane?
13		DR. GILLIAM:  Nothing other than what¦s
14	been said earlier.
15		CHAIRMAN BRASS:  Dr. Elashoff, you¦re next
16	on the plane trip list.  Any comments?  Okay.  Now, if
17	you¦d like to make some comments for the discussion or
18	we, okay please.  Why don¦t you go to that, I think
19	this microphone¦s live.
20		DR. UDEN:  Do you want to have sponsor
21	before you have our feedback, Dr. Brass?
22		CHAIRMAN BRASS:  Yes.
23		DR. UDEN:  Okay.
24		CHAIRMAN BRASS:  Now if you¦d like to
25	make, I want to-- You¦ve intimidated him.

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	1		DR. UDEN:  That¦s the first time I ever
	2	intimidated the President of a company.
	3		CHAIRMAN BRASS:  You¦ve also promoted him.
	4		DR. UDEN:  I would have voted yes if in

	5	fact the labeling issues and population issues would
	6	have been taken care of.  So I was voting actually as
	7	the question was on the NDA.
	8		CHAIRMAN BRASS:  Other comments?  Yes, Dr.
	9	Neill.
10		DR. NEILL:  I would encourage you to come
11	back, and I would encourage you to consider other

12	higher doses which might make it easier for you to
13	show a clinically meaningful benefit in a population
14	that may be slightly different, meeting a higher age
15	and perhaps a different total cholesterol and LDL
16	range for which benefit has already been shown in

17	other studies.  This seems to be a very safe drug
18	meeting most of the safety considerations for OTC-
19	ness.  And given that I think the already existing

20	approvals for the Rx drug make me want to consider why
21	it has to stay that way.  And those considerations
22	seem to revolve more around the ability of the
23	consumer to self-select, to monitor the condition pure
24	of the other things that have already come up.  I
25	mean, this otherwise seems to be an approvable thing. 

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	1	I would agree that the label issues need to be very
	2	clear, but I think that¦s implicit in the discussion

	3	about the target population.  I wouldn¦t just change
	4	the target population, I would ask you to consider
	5	making my life easier by considering the dose as well.
	6	            CHAIRMAN BRASS:  Dr. Molitch.
	7	            DR. MOLITCH:  I was certainly for you in
	8	favor of empowering patients and physicians and having
	9	patients come to us with demands for medication when
10	appropriate.  And in fact if the studies, what were to
11	happen with this is this were approved if it went
12	exactly true to form that the patients had to see the
13	physician at two months and couldn¦t get any further
14	drug until they saw their physicians, were checked
15	out, had laboratory testing, I would have no real
16	problem with this.  I¦m concerned about patient, the
17	inappropriate use of inappropriate patients that
18	wouldn¦t be caught with a compulsory two-month look,
19	or some sort of a look that had to be done at two
20	months.
21	            CHAIRMAN BRASS:  Isn¦t that called
22	prescription therapy?  Dr. Tamborlane.
23	            DR. TAMBORLANE:  I think from the NDA
24	point of view, I think I share some of your views.  I
25	thought the study design was really good bringing

				279
	1	people in.  It was very undifferentiated.  But there
	2	are too many queues with whence you are in the study
	3	to see what I would have considered a real use
	4	situation where a lot of people don¦t read the labels
	5	and don¦t go to the doctors.  So I think that that
	6	kind of data would be what I would be looking for in
	7	further studies.
	8		CHAIRMAN BRASS:  Dr. Williams.
	9		DR. WILLIAMS:  My comment is usually the
10	one from last meeting we had and that is about the
11	aged population, those people who can¦t see the label. 
12	Many individuals who are in the aged population are
13	using over-the-counter medications and they bring it
14	in to the doctor¦s office, unbeknownst to the doctor. 
15	And I just wanted to see more data about their usage
16	as well as the safety that¦s in their possible usage
17	of the medication.
18		CHAIRMAN BRASS:  Dr. Krenzelok.
19		DR. KRENZELOK:  Well, I think a lot of
20	people in this room probably have served as an expert
21	witness before and have been in court and they always
22	hold you to a reasonable degree of medical or
23	toxicological or pharmacological reason and so on.

24		CHAIRMAN BRASS:  Are you arguing against
25	less than .05 health?

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	1	            DR. KRENZELOK:  We could look at that too. 
	2	But if you look at 51 percent as being a reasonable of

	3	certainty, I think that they¦ve really presented far
	4	beyond that 51 percent and I don¦t know that we could
	5	hold them to a hundred percent or anybody for that
	6	matter.  So I¦m a little bit disappointed that we¦ve
	7	held them to such a high degree of responsibility and
	8	answerability and that¦s why I voted in favor of it.
	9	            CHAIRMAN BRASS:  Dr. Neill.
10	            DR. NEILL:  We¦re holding them to that
11	high degree of responsibility within the target
12	population that they defined.  And the reason that I
13	think that it¦s appropriate to do that in that target
14	population is because I don¦t believe absent a huge
15	undurable trial that a benefit will be shown given the

16	competing co-morbidities that exist within that group. 
17	Could it?  Yes.  Will LDL¦s be lowered?  Yes.  Will it
18	prevent those 35 year olds from dying in automobile

19	accidents, AIDS, homicides, suicide, all the other
20	things that befall them in some other respect,
21	probably not.  Making the differences of such a small
22	size that the power and the numbers necessary to drive
23	power to see those small differences would be huge. 
24	Which is why I think we¦ve made comments about the

25	target population, the age which are related to

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	1	changes in the label, and also perhaps, in my instance
	2	anyway, changes in the actual cholesterol and LDL
	3	levels.
	4	            CHAIRMAN BRASS:  Dr. Johnson:
	5	            DR. JOHNSON:  I want to make again clear,
	6	my vote was no.  And the reason was not because I
	7	don¦t believe this is approvable, but not that it was
	8	approvable as it stands and again my major concern is
	9	age and I think you should determine the age not 40

10	and 45, not sort of picking things out of the air, but
11	really looking at epidemiologic data or whatever you
12	can as you did this afternoon.  To really sort of well
13	define your target population where you can derive the
14	most benefit.  And, as I made comments earlier, but
15	since now it¦s sort of official after the vote, I
16	think we need label comprehension studies and a few
17	more things to understand actions and behaviors of the
18	consumer population, but I congratulate you on some
19	very nice studies that you did perform.
20	            CHAIRMAN BRASS:  Mr. Kreston.
21	            MR. KRESTON:  Thank you very much, Dr.
22	Brass.  First of all, I want to thank the committee
23	for what I think were extraordinary deliberations

24	today.  It was a, feels to me that there has been
25	tremendous progress made and we¦ve gotten a lot

			282
	1	greater clarity on the issues.  And one thing I¦d like
	2	to request at this point since it feels like there was
	3	a lot of uncertainty relative to continuancy of
	4	approval versus definitive approval to ask for some

	5	direction from this committee right now that if we
	6	were to commit to changing the label and modify it to
	7	be the 40 year old and 50 year old population and also
	8	agree to do additional label comprehension if you
	9	could give us your sense of perspective on the
10	approvability.
11	            CHAIRMAN BRASS:  Well, I think you¦re

12	hearing that from the discussion, but I think any
13	negotiation should be done between you and the agency
14	based on the general discussion.  And we¦ll try to
15	bring out those points rather than trying to, is that
16	fair?
17	            DR. DELAP:  That¦s fair, and I would add
18	that we may choose to ask members of the advisory
19	committee to participate in those discussions as well. 
20	We can legally ask for one or two members to
21	participate without having a full-blown meeting again.
22	            CHAIRMAN BRASS:  Dr. Davidson.
23	            DR. DAVIDSON:  I think one thing that will
24	help greatly is if we can look back and see why the
25	self-selection did not occur well.  You know,

			283
	1	retrospectively, you may learn some things that may be
	2	important for us.  Second, you know, why some of the

	3	special minorities did not stay in the program.  That
	4	will help us, will help you.  You know, but I agree
	5	with everybody else.  We want to congratulate you
	6	because you presented good data, you tried very hard,
	7	you know, and you have a good safe product.  Thank you
	8	very much.
	9	            CHAIRMAN BRASS:  Dr. Silverstein.
10	            DR. SILVERSTEIN:  This is a question that
11	I¦m just curious about the answer to.  Since this was
12	an unusual population, at least compared to the
13	patients I see, you know, most of the people had
14	physicians, most of them saw them annually, the HMO
15	sees them free, so the more you see them the better
16	bargain you get.  In general, are people who buy over-
17	the-counter drugs a more compliant group, a more, are
18	they different from the general population for
19	instance?
20	            DR. GANLEY:  The general population buys
21	over-the-counter drugs.  So I think that probably goes
22	hand-in-hand.  I just want to make a few comments and
23	it deals with some of the discussion we¦ve had already
24	and I totally agree with Dr. Neill.  It would be a lot
25	easier if we could identify a population that was, had

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	1	a little higher cholesterol and a little more risk and
	2	achieved some more benefit by individually titrating

	3	therapy to a higher dose.  But I guess the one thing
	4	goes back some of Dr. Davidson¦s comments, and it
	5	really belonged, it really has to do with the paradigm
	6	that they¦ve created where it brings the physician
	7	into the OTC setting.  Are we to include a statement
	8	in the label, ¦Do not use if you don¦t have
	9	healthcare¦?  Or should the patient have some sense of
10	high long the duration of therapy is prior to
11	purchasing this product, where many of the studies
12	that they¦re pointing to require several years of
13	therapy so these curves starting to separate.  Should
14	that be conveyed to a person also before they initiate
15	this type therapy?  And I think the, the one issue
16	that we got on yesterday was about dose titration and
17	they¦ve included the physician in this paradigm as to
18	help along with that.  But everything we¦ve heard here
19	is the physician¦s aren¦t doing it right.  And if you
20	don¦t educate the physicians that this is an
21	appropriate population, then we¦re wasting our time.
22	            CHAIRMAN BRASS:  I think, again,
23	extrapolating what I heard from the committee over

24	actually the past two days, I think emphasis on the
25	long-term treatment is something the committee would

			285
	1	endorse, as being as explicit as possible as early as
	2	possible.  Is that fair?  Dr. Neill?
	3	            DR. NEILL:  With one admittedly minor
	4	caveat.  I¦m a young doctor and I remember telling
	5	patients that I have put on Propanolol, ¦You¦ll need
	6	to take this blood pressure medicine for the rest of
	7	your life¦, which of course, has been usurped by any
	8	number of other classes of medications, and my
	9	difficulty in requiring or asking about label
10	instructions that say, ¦this is a life-long
11	medication¦, and I¦m talking specifically about those

12	words, cannot be supported by any evidence even given
13	our expectation that the cholesterol will need to be
14	lowered, given our utter inability to tell what¦s
15	going to happen three years down the road.  In fact,
16	the evidence says exactly the opposite.  They¦re going
17	to take it as long, and until, the next best thing
18	comes along.  That¦s what the evidence shows.
19	            CHAIRMAN BRASS:  I think that¦s right.  I
20	think those are all fair comments and I think that the
21	specific syntax could get the point across without
22	violating that construct.  Other comments, questions,
23	issues, random desires?  If not, I will again-- Oh,
24	see I knew I was too slow.
25	            DR. JENKINS:  No, I waited till you had no

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	1	other comments.  I just wanted to thank the committee
	2	as well and also thank both of the sponsors.  Because

	3	I think there has been a tremendous amount of learning
	4	that has occurred in the public hearings we had a

	5	couple of weeks ago and in the discussions we had
	6	yesterday and today, particularly about this issue of
	7	OTC cholesterol lowering.  I think we at the table
	8	from the agency would have learned a lot and will be
	9	taking from your learnings and trying to use them as
10	best we can.
11	            CHAIRMAN BRASS:  And I will add my
12	appreciation to the members of the committee, the
13	sponsor, and the FDA for their very excellent
14	contributions.  And this meeting is now adjourned.
15	            (Whereupon the Joint Meeting of the
16	Nonprescription Drugs Advisory Committee and the
17	Endocrinologic and Metabolic Advisory Committee was
18	concluded at 3:56 p.m.)
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